dihydropyridines and Hypertension

For decades, conflicting results were published regarding the increased risk of Prostate cancer (PCa) among calcium channel blocker (CCB) users.. We aimed to evaluate the association between PCa and CCB exposure and assess moderating factors.. We performed a systematic literature search in PubMed, Embase, and Cochrane databases for observational and randomized studies published until November 2020 with no language limitations, including data on the risk for PCa in CCB users compared with non-CCB users. We applied a random-effects model meta-analysis to pool results. In addition, we investigated potential moderating factors, such as CCB type, study type, participants' age, and duration of exposure, using meta-regression methods.. In our primary analysis, we included 18 studies. A statistically significant 5% increase in the risk for PCa was observed among CCB users (risk ratio [RR] = 1.05; 95% confidence interval [CI]: 1.01-1.10), with no significant association between the duration of exposure to CCBs and the risk for PCa (RR = 1.08; 95% CI: 0.98-1.19 for exposure for < 5years and RR = 1.01; 95% CI: 0.9-1.14 for exposure ≥ 5 years). The association remained statistically significant for the subgroup of dihydropyridines (RR = 1.13; 95% CI: 1.05-1.22). In addition, the association was not influenced by participants' age.. CCBs are an important modality in treating hypertension. The 5% increased risk observed in the current meta-analysis could be influenced by residual confounding factors and should not affect hypertension treatment guidelines until more studies provide additional clinical information.

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Male; Odds Ratio; Prostatic Neoplasms

Kidneys are responsible for many crucial biological processes in the human body, including maintaining the water-electrolyte balance, pH, and blood pressure (BP), along with the elimination of toxins. Despite this, chronic kidney disease (CKD), which affects more and more people, is a disease that develops insidiously without causing any symptoms at first. The main purpose of this article is to summarize the existing literature on lercanidipine, with a particular focus on its nephroprotective properties. Lercanidipine is a third-generation dihydropyridine (DHP) blocker of calcium channels, and as such it possesses unique qualities such as high lipophilicity and high vascular selectivity. Furthermore, it acts by reversibly inhibiting L-type and T-type calcium channels responsible for exerting positive renal effects. It has been shown to reduce tissue inflammation and tubulointerstitial fibrosis, contributing to a decrease in proteinuria. Moreover, it exhibited antioxidative effects and increased expression of molecules responsible for repairing damaged tissues. It also decreased cell proliferation, preventing thickening of the vascular lumen. This article summarizes studies simultaneously comparing the effect of lercanidipine with other antihypertensive drugs. There is still a lack of studies on the medications used in patients with CKD, and an even greater lack of studies on those used in patients with concomitant hypertension. Therefore, further studies on lercanidipine and its potential in hypertensive patients with coexisting CKD are required.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Renal Insufficiency, Chronic

Azelnidipine is one of the newer Calcium Channel Blockers (CCB) approved in China, Japan, and India. Some studies have found that the blood pressure-lowering effect of azelnidipine is more than amlodipine, and others found the effect similar.. This meta-analysis was conducted to evaluate the efficacy of azelnidipine in managing hypertensive patients by lowering Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) as compared to amlodipine.. PubMed/MEDLINE, Google Scholar, PROQUEST, and International Clinical Trial Registry Platform (ICTRP) were searched for published articles to evaluate the clinical efficacy of azelnidipine in the management of hypertension patients. Data were extracted from the selected 11 randomized clinical trials (RCTs). The risk of bias 2 (RoB2) tool was used for the quality assessment of the included studies, and the random-effects model was used to estimate the effect size.. There were no statistically significant differences in the reduction of SBP (Mean Difference, MD: - 1.07; 95% CI: - 4.10, 1.95, p-value: 0.49) and DBP (MD: 0.27; 95% CI: - 2.66, 3.20, p-value: 0.86) between both the drugs. In terms of HR reduction, there was a statistically significant difference (MD: - 3.63; 95% CI: - 5.27, - 2.00, p-value: < 0.0001) between both drugs. Egger's test excluded any publication bias for the included studies (p = 0.21). Meta-regression excluded the effect of the duration of treatment on outcome parameters.. Though no significant difference between azelnidipine and amlodipine was found, in terms of reduction in SBP and DBP, azelnidipine reduced heart rate significantly compared to amlodipine.. CRD42023390361.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca

Topics: Amlodipine; Antihypertensive Agents; Calcium; Calcium Channel Blockers; Dihydropyridines; Fura-2; Heart Failure; Humans; Hypertension; Prospective Studies

Dihydropyridine calcium channel blockers (DHPCCBs) are widely used to treat hypertension and chronic coronary artery disease. One common adverse effect of DHPCCBs is peripheral edema, particularly of the lower limbs. The side effect could lead to dose reduction or discontinuation of the medication. The combination of DHPCCBs and renin-angiotensin system blockers has shown to reduce the risk of DHPCCBs-associated peripheral edema compared with DHPCCBs monotherapy. We performed the current systematic review and network meta-analysis of randomized controlled trials (RCTs) to estimate the rate of peripheral edema with DHPCCBs as a class and with individual DHPCCBs and the ranking of the reduction of peripheral edema. The effects of renin-angiotensin system blockers on DHPCCBs network meta-analysis were created to analyze the ranking of the reduction of peripheral edema. A total of 3312 publications were identified and 71 studies with 56,283 patients were included. Nifedipine ranked highest in inducing peripheral edema (SUCRA 81.8%) and lacidipine (SUCRA 12.8%) ranked the least. All DHPCCBs except lacidipine resulted in higher relative risk (RR) of peripheral edema compared with placebo. Nifedipine plus angiotensin receptor blocker (SUCRA: 92.3%) did not mitigate peripheral edema and amlodipine plus angiotensin-converting enzyme inhibitors (SUCRA: 16%) reduced peripheral edema the most. Nifedipine ranked the highest and lacidipine ranked the lowest amongst DHPCCBs for developing peripheral edema when used for cardiovascular indications. The second or higher generation of DHPCCBs combination with ACEIs or ARBs or diuretics lowered the chance of peripheral edema development compared to single DHPCCB treatment.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Network Meta-Analysis; Nifedipine

Hypertension is commonly a quiet condition, and it expands the risk of heart diseases and stroke. Calcium delivers a substantial role in cardiovascular functions and hence is essential for cardiac automaticity and functioning. Calcium channel antagonists are the choice of drugs for the management of cardiovascular diseases; they precisely stop the introduction of calcium through L-type calcium channels are existing channels in the heart. Cilnidipine belongs to the class 4th generation calcium channel blockers as a foremost therapeutic agent used in the treatment of hypertension and heart diseases. This review article focuses on an inclusive account of crucial analytical methodologies used for the pharmaceutical analysis of cilnidipine in pure forms, biological samples and pharmaceuticals. According to literature reports several analytical techniques such as hyphenated techniques, high-performance thin-layer chromatography, high-performance liquid-chromatography, capillary electrophoresis, voltammetry, UV/Vis-spectrophotometry, and Fourier-transform infrared spectroscopy approaches have been used for determination of cilnidipine alone or in the combined dosage form. We have also discussed the pharmacopeial assay methods, physicochemical properties, and also depict the stacked column chart for year wise publication count for cilnidipine. From literature, concluded that the high-performance liquid-chromatography and UV/Vis-spectrophotometry methods are the most prevailing methods for the analysis of cilnidipine. The data presented in this review may provide a very significant base for further studies on cilnidipine in the area of drug analysis.

Topics: Animals; Calcium Channel Blockers; Chemistry Techniques, Analytical; Dihydropyridines; Drug Monitoring; Humans; Hypertension

Calcium channel blockers (CCBs) are used to manage hypertension which is highly prevalent among people with chronic kidney disease (CKD). The treatment for hypertension is particularly challenging in people undergoing dialysis.. To assess the benefits and harms of calcium channel blockers in patients with chronic kidney disease requiring dialysis.. We searched the Cochrane Kidney and Transplant Register of Studies to 27 April 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. All randomised controlled trials (RCTs) and quasi-RCTs that compared any type of CCB with other CCB, different doses of the same CCB, other antihypertensives, control or placebo were included. The minimum study duration was 12 weeks.. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR), risk difference (RD) or mean difference (MD) with 95% confidence intervals (CI).. This review included 13 studies (24 reports) randomising 1459 participants treated with long-term haemodialysis. Nine studies were included in the meta-analysis (622 participants). No studies were performed in children or in those undergoing peritoneal dialysis. Overall, risk of bias was assessed as unclear to high across most domains. Random sequence generation and allocation concealment were at low risk of bias in eight and one studies, respectively. Two studies reported low risk methods for blinding of participants and investigators, and outcome assessment was blinded in 10 studies. Three studies were at low risk of attrition bias, eight studies were at low risk of selective reporting bias, and five studies were at low risk of other potential sources of bias. Overall, the certainty of the evidence was low to very low for all outcomes. No events were reported for cardiovascular death in any of the comparisons. Other side effects were rarely reported and studies were not designed to measure costs. Five studies (451 randomised adults) compared dihydropyridine CCBs to placebo or no treatment. Dihydropyridine CCBs may decrease predialysis systolic (1 study, 39 participants: MD -27.00 mmHg, 95% CI -43.33 to -10.67; low certainty evidence) and diastolic blood pressure level (2 studies, 76 participants; MD -13.56 mmHg, 95% CI -19.65 to -7.48; I. The benefits of CCBs over other antihypertensives on predialysis blood pressure levels and intradialytic hypotension among people with CKD who required haemodialysis were uncertain. Effects of CCBs on other side effects and cardiovascular death also remain uncertain. Dihydropyridine CCBs may decrease predialysis systolic and diastolic blood pressure level compared to placebo or no treatment. No studies were identified in children or peritoneal dialysis. Available studies have not been designed to measure the effects on costs. The shortcomings of the studies were that they recruited very few participants, had few events, had very short follow-up periods, some outcomes were not reported, and the reporting of outcomes such as changes in blood pressure was not done uniformly across studies. Well-designed RCTs, conducted in both adults and children with CKD requiring both haemodialysis and peritoneal dialysis, evaluating both dihydropyridine and non-dihydropyridine CCBs against other antihypertensives are required. Future research should be focused on outcomes relevant to patients (including death and cardiovascular disease), blood pressure changes, risk of side effects and healthcare costs to assist decision-making in clinical practice.

Topics: Adult; Antihypertensive Agents; Bias; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Hypotension; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Benidipine and amlodipine are two well-known drugs used in hypertensive patients with chronic kidney disease (CKD).. In this systematic review we aimed to compare benidipine and amlodipine in terms of efficacy in the management of hypertensive patients.. We searched PubMed, Cochrane CENTRAL, SCOPUS and Web of Science for relevant clinical trials and excluded observational studies. Quality appraisal was evaluated according to GRADE and we assessed the risk of bias using the Cochrane's risk of bias tool. We included the following outcomes: Systolic blood pressure, diastolic blood pressure, heart rate, estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine ratio. Data were pooled as mean differences (MD) with relative 95% confidence intervals (CI).. Eight studies were eligible for our meta-analysis. We found no significant difference between both drugs regarding systolic (MD = - 0.21 [- 1.48, 1.89], (P = 0.81) and diastolic (MD = 0.01[- 0.51, 0.53], (P = 0.97)) blood pressure measurements. The overall heart rate did not differ as well (MD = - 0.03 [- 1.63, 1.57], (P = 0.97)). We found that benidipine was statistically better than amlodipine in terms of eGFR (MD = 1.07 [0.43, 1.71], (P = 0.001)), and urinary albumin/creatinine ratio (MD = - 43.41 [- 53.53, - 33.29], (P < 0.00001)).. Finally we conclude that benidipine seems to show more positive and promising results in the management of hypertensive patients with chronic kidney disease.

Topics: Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Treatment Outcome; Vasodilator Agents

Dihydropyridine calcium channel blockers are a heterogeneous group of antihypertensive drugs. Long-acting dihydropyridine agent amlodipine is widely used for monotherapy and combination therapy for hypertension in clinical practice, while intermediate-acting dihydropyridine agents have shown inconsistent results in randomized clinical trials (RCTs).. A meta-analysis of 18 RCTs enrolling a total of 80,483 patients with hypertension followed for a mean of 51.4 months was performed. Amlodipine therapy was associated with 25% higher risk of heart failure (relative risk [RR]: 1.25, 95% confidence interval [CI], 1.05-1.49, P = .019) but 17% lower risk of stroke (RR: 0.83, [95% CI, 0.72-0.97], P = .009) without statistically significant effect on acute myocardial infarction (AMI) compared to major alternative antihypertensive therapy (MAAT), including β-blocker, diuretic, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. Intermediate-acting dihydropyridine calcium channel blocker therapy was associated with 25% higher risk of heart failure (RR: 1.25, [95% CI, 1.06-1.47], 0.005, P = .005) and 26% higher risk of AMI (RR: 1.26, [95% CI, 1.05-1.51], 0.019, P = .019) compared to MAAT. Results of the subgroup analysis suggested that the intermediate-acting dihydropyridine calcium channel blocker was associated with higher risk of heart failure (RR: 1.30, [95% CI, 1.08-1.56], P = .005) and AMI (RR: 1.50, [95% CI, 1.01-2.22], P = .043) compared to renin-angiotensin system blockers and a trend toward higher risk of AMI (RR: 1.17, [95% CI, 0.99-1.38], P = .064) compared to conventional therapy, including β-blockers and diuretics. Meta-regression analyses suggested that long-acting dihydropyridine calcium channel blocker is associated with lower risk of AMI ( B: -0.327, [95% CI, -0.530 to -0.123], P = .002) with a trend toward lower risk of stroke ( B: -0.203, [95% CI, -0.410 to 0.003] P = .054).. This study suggests that Amlodipine offers greater protection against major complications of hypertension compared to intermediate-acting dihydropyridine calcium channel blockers.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

Chylous ascites is a rare condition. The most frequent causes are lymphomas, solid malignancies, abdominal trauma and cirrhosis. Isolated case reports describe the relationship between calcium channel blockers (CCB) and chyloperitoneum. Lercanidipine is a third-generation dihydropyridine with low rate of adverse events. We describe a case of lercanidipine-induced chylous ascites.. An 80-year-old white female with hypertension treated with lercanidipine, developed chylous ascites and abdominal pain after the dosage of the CCB was doubled. The initial suspicion was a hidden neoplasm, but after a thorough research, no apparent cause was detected and the symptoms resolved after the drug was suspended.. Calcium channel blockers should be considered as possible causes in cases of chyloperitoneum of unknown aetiology.

Topics: Aged, 80 and over; Antihypertensive Agents; Calcium Channel Blockers; Chylous Ascites; Dihydropyridines; Female; Humans; Hypertension

Although blood pressure control is considered the main mechanism for preventing the progression of chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors and angiotensin receptors blockers have an additional organ-protective role. The effects of calcium channel blockers (CCBs) in renal disease are not so clearly defined. CCBs have pleiotropic effects that might contribute to protection of the kidney, such as attenuating the mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors and suppressing mesangial cell proliferation. Some evidence has accumulated in recent years demonstrating that the new dihydropyridinic CCBs (such as lercanidipine or efonidipine) may affect both postglomerular and preglomerular vessels, resulting in a decreased filtration fraction and nephroprotective effect. Increasing clinical and experimental evidence supports this view and the use of CCBs in CKD hypertensive patients.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Renal Insufficiency, Chronic

This review presents the data of assessing antihypertensive efficacy and tolerability vasoselective high-lipophilic the 3d generations calcium channel blocker lercanidpine. The inhibition of the calcium ions flow through the membranes of smooth muscle cells of blood vessels causes peripheral, cerebral, renal and coronary vasodilation decreasing total peripheral vascular resistance and, consequently, blood pressure (BP) lowering and improve regional circulation. During reception of lercanidipine the level of norepinephrine remains the same even when using high doses of the drug. Negative inotropic effect does not occur therefore, lercanidipine can be used in the treatment of myocardial ischemia. Renal protection properties slow down the development and progression ofchronic renalfailure (CRF). The drug can be successfully used in patients with arterial hypertension, chronic renalfailure, diabetic and non-diabetic nephropathy. Lercanidpine also may be effectively used in the treatment of hypertension with associated clinical conditions: bronchial asthma, chronic obstructive pulmonary disease, bradiarrythmias, atrioventricular blockade 2-3 degree, sinus node dysfunction, peripheral arteries deseases with symptoms of the extremities ischemia, sleep disturbance, depression, dystonia, asthenic and cephalgic syndme in the frame of the cerebrovascular insufficiency manifestations. Therapy with lercanidpine, in addition to lowering blood pressure, can help to nephroprotection, neuroprotection, antianginal effect, the regression of left ventricular hypertrophy, improvement of lipid metabolism and glucose tolerance. With over 30 years experience in the application and modification of the molecular structure, slow the onset of action and superior long-lasting effect reception of letranidipine well-tolerated and provides a high adherence ofpatients to the treatment of hypertension.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Perioperative Care; Vascular Resistance

Renin-angiotensin system inhibitors should be considered as the first-line therapy in the treatment of patients with hypertension and diabetes. However, most of the diabetic subjects with hypertension require at least two drugs to achieve blood pressure targets. The ACCOMPLISH trial suggested that the best combination in the treatment of high-risk hypertensive patients should include a renin-angiotensin system inhibitor and a dihydropyridine. However, not all dihydropyridines block the same receptors. Those dihydropyridines that block T-type calcium channel blockers may provide additional advantages. A number of studies suggest that compared with amlodipine, manidipine have the same antihypertensive efficacy, but with a lesser risk of ankle edema. In addition, manidipine, but not amlodipine, significantly reduces urinary albumin excretion rates.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Nitrobenzenes; Piperazines

Isolated systolic hypertension is the most common hemodynamic form of hypertension in the elderly. With a rapidly aging population, the prevalence of hypertension, particularly isolated systolic hypertension, is expected to increase substantially. This phenomenon of increasing systolic pressure in the elderly is believed to be secondary to pathophysiological changes of aging as well as modifiable risk factors. Isolated systolic hypertension is associated with substantial mortality and morbidity, particularly of cerebrovascular disease. It is a rapidly growing public health concern and its management continues to remain a challenge to practicing physicians. Recent studies like the Systolic Blood Pressure Intervention Trial (SPRINT) and Heart Outcomes Prevention Evaluation (HOPE)-3 have implications for antihypertensive therapy in general and for the management of isolated systolic hypertension in particular. In this article we will review: 1) epidemiology and pathophysiologic mechanisms, 2) impact of isolated systolic hypertension on cardiovascular outcomes, 3) optimal management strategies, and 4) systolic blood pressure goals in the light of SPRINT and HOPE 3 trials.

Topics: Adolescent; Adult; Age Distribution; Aged; Aging; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prevalence; Randomized Controlled Trials as Topic; Risk Factors; Sex Distribution; Sodium Chloride Symporter Inhibitors; Young Adult

This meta-analysis evaluates the efficacy and safety of lercanidipine/enalapril fixed-dose combination in patients with mild to moderate essential hypertension.. Four observational studies on patients with sitting diastolic blood pressure (SDBP) between 95 and 109 mmHg, treated with lercanidipine/enalapril fixed-dose combination, were analyzed. The Random-Effect Model was used to limit heterogeneity across the studies. Weights were applied to determine the influence of each study on the combined results. The efficacy outcome measure was the reduction from baseline to endpoint in systolic and diastolic blood pressure (SBP and DBP, respectively). The incidence of treatment-emergent adverse events (TEAEs) was also investigated.. The total number of patients analyzed for efficacy and safety was 9565. No differences between study groups in demographics characteristics were observed. Mean blood pressure in the pooled population of the four studies was 162/94 mmHg at baseline. Overall, the lercanidipine/enalapril fixed-dose combination reduced SBP by 26 mmHg (95% CI, 23-29), and DBP by 13 mmHg (12-15), p < 0.05 for both. No safety concerns were reported.. This meta-analysis supports the use of the lercanidipine/enalapril fixed-dose combination for the treatment of mild-to-moderate hypertension.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Drug Therapy, Combination; Enalapril; Essential Hypertension; Female; Humans; Hypertension; Male; Middle Aged; Outcome Assessment, Health Care

The dose-effect relationship of fixed-dose combinations of anti-hypertensive drugs has been only poorly explored. This pooled analysis investigates the dose-response relationship of fixed-dose lercanidipine + enalapril in patients with mild-to-moderate hypertension.. This was an individual patient data analysis of four randomized studies (n = 2340).. The primary efficacy variable was the change from baseline in sitting diastolic blood pressure (SDBP). Secondary variables were change from baseline in sitting systolic BP (SSBP), proportion of responder patients, and safety.. All fixed-dose combinations were superior to placebo in the reduction of SDBP. The greatest effect was observed with the market-available combination lercanidipine 20 mg/enalapril 20 mg (-15.3 mmHg vs. baseline; p < 0.05). The reduction in SDBP associated with the other two marketed fixed combinations of lercanidipine/enalapril were -10.7 mmHg for the 10 mg/20 mg combination and -9.8 mmHg for the 10 mg/10 mg combination (p < .05 for both comparisons). Similar findings were reported for SSBP reduction: the greatest effect was observed with lercanidipine 20 mg/enalapril 20 mg (-19.2 mmHg). The reduction in SSBP was -12.5 mmHg for the 10 mg/20 mg combination and -11.1 mmHg for the 10 mg/10 mg combination (p < .05 for all comparisons). The highest responder rate was reported with lercanidipine 20 mg/enalapril 20 mg (75.0%); this figure was 56.1% with the 10 mg/20 mg and 53.0% with the 10/10 mg combination. No safety concerns were reported.. This pooled analysis of four randomized studies shows evidence of a dose-response effect in BP reduction with different fixed combinations of lercanidipine + enalapril. To our knowledge, this is the first analysis investigating the dose-response effect of a specific fixed-dose combination of anti-hypertensive agents. Further studies on this intriguing topic are however necessary.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Hypertension is an important risk factor for premature death as it increases the probability of stroke, myocardial infarction, and heart failure. Antihypertensive drugs can decrease cardiovascular (CV) morbidity and mortality. The majority of hypertensive patients need more than one antihypertensive agent to attain blood pressure (BP) targets. Monotherapy can effectively reduce BP only in 20%-40% of patients. Multiple mechanisms including increased peripheral vascular resistance, increased cardiac work, and hypervolemia are involved in the pathogenesis of hypertension. Targeting multiple pathways may more potently reduce BP. Increasing the dose of a single agent in many cases does not provide the expected BP-lowering effect because the underlying mechanism of the BP increase is either different or already corrected with the lower dose. Moreover, drugs acting on different pathways may have synergistic effects and thus better control hypertension. It is well known that diuretics enhance the actions of renin-angiotensin aldosterone system and activate it as a feedback to the reduced circulated blood volume. The addition of a renin-angiotensin aldosterone system blocker to a diuretic may more effectively reduce BP because the system is upregulated. Reducing the maximal dose of an agent may also reduce possible side effects if they are dose dependent. The increased prevalence of peripheral edema with higher doses of calcium channel blockers (CCBs) is reduced when renin-angiotensin aldosterone system blockers are added to CCBs through vein dilation. The effectiveness of the combination of enalapril with lercanidipine in reducing BP, the safety profile, and the use of the combination of angiotensin-converting enzyme inhibitors with CCBs in clinical trials with excellent CV hard end point outcomes make this combination a promising therapy in the treatment of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Evidence-Based Medicine; Humans; Hypertension; Patient Satisfaction; Treatment Outcome

Azelnidipine is a unique dihydropyridine calcium channel blocker with selectivity for L-type calcium channels that has been launched for the treatment of hypertension. Azelnidipine exhibits long-acting blood pressure-lowering effects without increasing heart rate. High blood pressure is associated with many metabolic disorders, including glucose intolerance and insulin resistance. Antihypertensive medications that interfere with various steps in the renin-angiotensin system improve glucose tolerance and insulin resistance; however, the effects of calcium channel blockers on glucose metabolism and insulin resistance remain controversial. Recent studies have demonstrated that azelnidipine could improve insulin resistance and glucose tolerance by potentially inhibiting sympathetic nerve activity. In addition, azelnidipine exhibits anti-inflammatory and anti-oxidative effects, suggesting that it is a beneficial antihypertensive agent with anti-atherogenic and cardioprotective effects for the treatment of not only hypertensive patients with glucose intolerance, but also those with metabolic disorders.

Topics: Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Glucose Intolerance; Humans; Hypertension; Metabolic Diseases; Renin-Angiotensin System

Arterial hypertension is the most common risk factor in patients with metabolic disorders. In the selection of antihypertensive therapy it is necessary to consider not only the anti-hypertensive and organoprotective effects of drugs and their metabolic effects, which has prognostic value. Calcium antaginists, along. Lercanidipine related to the third generation dihydripyridine calcium antagonist, has been much more selective for the so-called slow calcium channels of vascular smooth muscle cells, which is associated with a good hypertensive, organo and metabolic action. Combination therapy with an ACE inhibitor and a calcium channel blocker is also a justified tactic for the management of patients with high-risk cardiovascular and metabolic disorders. Attention is paid new fixed combinations, including angiotensin converting enzyme inhibitors and calcium antagonists.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Metabolic Diseases; Risk Factors; Treatment Outcome

Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.

Topics: Aldosterone; Cytochrome P-450 CYP11B2; Dihydropyridines; Drug Interactions; Epithelial Sodium Channel Blockers; Eplerenone; Glucocorticoids; Heart Failure; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

The treatment of essential hypertension is based essentially on the prescription of four major classes of antihypertensive drugs, i.e. blockers of the renin--angiotensin system, calcium channel blockers, diuretics and beta-blockers. In recent years, very few new drug therapies of hypertension have become available. Therefore, it is crucial for physicians to optimize their antihypertensive therapies with the drugs available on the market. In each of the classes of antihypertensive drugs, questions have recently been raised: are angiotensin-converting enzyme (ACE) inhibitors superior to angiotensin II receptor blockers (ARB)? Is it possible to reduce the incidence of peripheral oedema with calcium antagonists? Is hydrochlorothiazide really the good diuretic to use in combination therapies? The purpose of this review is to discuss these various questions in the light of the most recent clinical studies and meta-analyses. These latter suggest that ACE inhibitors and ARB are equivalent except for a better tolerability profile of ARB. Third generation calcium channel blockers enable to reduce the incidence of peripheral oedema and chlorthalidone is certainly more effective than hydrochlorothiazide in preventing cardiovascular events in hypertension. At last, studies suggest that drug adherence and long-term persistence under therapy is one of the major issues in the actual management of essential hypertension.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Design; Drug Therapy, Combination; Forecasting; Humans; Hypertension; Practice Guidelines as Topic

Topics: Calcium Channel Blockers; Dihydropyridines; Evidence-Based Medicine; Humans; Hypertension

Consistent BP lowering effect is essential for antihypertensive treatment. The dihydropyridine calcium channel blockers (CCB) are potent antihypertensive drugs, and have been reported to reduce future cardiovascular events. The effects of CCB on ambulatory BP have been reported, and could reduce not only daytime, but also nighttime and morning BP. Furthermore, when classified as circadian BP patterns--dippers, non-dippers, extreme dippers, and risers--, long-acting CCBs act to restore abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients. These effects partly explain the favorable effects of CCB in preventing future cardiovascular events. This review summarizes the studies of long-acting dihydropyridine CCBs for the "24-hour perfect management of BP".

Topics: Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Humans; Hypertension

Calcium channel blockers are a heterogeneous class of drugs, including dihydropyridine and non-dihydropyridine subgroups, commonly used in the treatment of hypertension. A systematic review of the 24-hour time course of the blood pressure-lowering effect has not been published.. To assess how much variation there is in hourly systolic and diastolic blood pressure lowering by dihydropyridine calcium channel blockers over a 24-hour period in people with hypertension aged 18 years or over, with baseline systolic blood pressure of at least 140 mmHg or diastolic blood pressure of at least 90 mmHg, or both.. We performed electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2014), MEDLINE (1946 to February 2014), EMBASE (1974 to February 2014), and ClinicalTrials.gov (to February 2014). We also screened references of published studies and reviews to identify additional trials.. We included all randomized, placebo-controlled trials assessing the hourly effects of dihydropyridine calcium channel blockers by ambulatory blood pressure monitoring in adults with hypertension with a follow-up of at least three weeks.. Two authors independently selected the included trials, evaluated the risk of bias, and analyzed the data.. We included 16 randomized controlled trials of dihydropyridine calcium channel blockers in this systematic review, with 2768 randomized participants. Drugs studied included amlodipine, lercanidipine, mandipine, nifedipine, and felodipine (all administered once daily) and nicardipine (administered twice daily). We analyzed and presented data by hour post dose. The blood pressure-lowering effect was stable over time; there were no clinically important differences in blood pressure-lowering effect of calcium channel blockers between each hour for either systolic blood pressure (estimated mean hourly differences ranged between 9.45 mmHg and 13.2 mmHg) or diastolic blood pressure (estimated mean hourly differences ranged between 5.85 mmHg and 8.5 mmHg). However, there was a moderate risk of bias for this finding. Once-daily dihydropyridine calcium channel blockers appeared to lower blood pressure by a relatively constant amount throughout the 24-hour dosing interval.. Six dihydropyridine calcium channel blockers studied in this review lowered blood pressure by a relatively similar amount each hour over the course of 24 hours. The benefits and harms of this pattern of blood pressure lowering are unknown. Further trials are needed with accurate recording of time of drug intake and with reporting of standard deviation of blood pressure at each hour. We did not attempt to assess adverse effects in this review due to the lack of reporting and the short duration of follow-up.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Randomized Controlled Trials as Topic; Time Factors

The review describes the classification, mechanisms of action, the effects of calcium channel blockers slow and the clinical benefits of dihydropyridine calcium antagonists, the third generation. Presented modern aspects of clinical pharmacology and research results on the efficacy, safety and organoprotective lercanidipine.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Medication Therapy Management; Outcome Assessment, Health Care; Protective Agents; Treatment Outcome

The renoprotective effects of benidipine, a calcium channel blocker (CCB) developed in Japan, are reviewed herein. Benidipine has a sustained antihypertensive effect independent of its blood concentration since it binds to dihydropyridine (DHP) receptors via a "membrane approach" (approach to the cell membrane followed by long retention at the DHP binding site). Benidipine dilates glomerular afferent and efferent arterioles equally through inhibition of Ttype Ca channels. Thus, it may cause a decrease of intraglomerular pressure and is superior to CCBs (capable of inhibiting only L-type Ca channels) in terms of suppression of proteinuria. Additionally, benidipine suppresses worsening of renal function more powerfully than CCBs (suppressing only L-type Ca channels), allowing better prognosis as to renal function. The inhibitory effect of benidipine on T-type calcium channels results in the suppression of aldosterone formation in the adrenal glands and of oxidative stress induced by aldosterone. Thus, the aldosterone-inhibitory and antioxidant activities of benidipine mediated by inhibition of T-type calcium channels would result in renoprotection and suppression of disease progression in hypertensive patients with chronic kidney disease (CKD). If such patients have proteinuria, renin-angiotensin system (RAS) inhibitors are used as first-line drugs, but benidipine, as an L-/T-type CCB, is recommended when they require some concomitant drugs. Moreover, the superiority of RAS inhibitors has not been demonstrated in hypertensive patients with CKD and without proteinuria. Thus, in such patients, benidipine should be considered as a first-line antihypertensive drug.

Topics: Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Dihydropyridines; Humans; Hypertension; Kidney; Kidney Diseases

Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date.. This review will discuss available evidence on the renal effects of two calcium channel blockers: amlodipine and lercanidipine, on the basis of clinical data.. MEDLINE and EMBASE were searched for inclusion of relevant studies. No limitations in time were considered.. Results from preclinical and clinical studies suggest that amlodipine is overall less effective in terms of renal protection when compared with other antihypertensive tested agents. Its beneficial effect in retarding the progression of renal disease is achievable only when combined with a blocker of the renin-angiotensin system. Conversely lercanidipine seems to provide renal protection in a similar way to ACE inhibitors, probably thanks to its mechanism of action which acts directly on the afferent and efferent renal arterioles.. Treatment of hypertension with CCBs should take into consideration the special effects of each single agent at different levels; lercanidipine for example may play a useful role in the management not only of hypertension but also in renal protection of hypertensive patients.

Topics: Amlodipine; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; PubMed

Several classes of antihypertensive agents have been in clinical use, including diuretics, α-blockers, β-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARB), and organic calcium channel blockers (CCBs). All these drugs are being currently used in the treatment of Hypertension & various disease conditions of the heart either alone or in combination. Cilnidipine is a new antihypertensive drug distinguished from other L-type Ca(2+) channel blockers or even other antihypertensives, which will be useful for selection of antihypertensive drugs according to the pathophysiological condition of a patient.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Patient Selection; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome

The review of literature presents the basic principles of treatment of arteril hypertension in patients with chronic kidney disease. The possibilities of combination therapy with dihydropyridine calcium antagonist lercanidipine and third-generation ACE inhibitor enalapril. Presented studies showing nephroprotective properties of each of the drugs included in the fixed combination in patients with nephropathy. Lercanidipine is highly lipophilic and vazoselektivnost proved its clinical efficacy in patients with proteinuria and decreased kidney function. Given in the literature demonstrating the combination of lercanidipine + enalapril. This combination makes it possible to achieve a more pronounced reduction in blood pressure, including elderly patients, patients with diabetes and obesity. The combination of pharmacological effects of lercanidipine and enalapril, creates additional opportunities for organo and reduce the risk of side effects of therapy.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Drug Combinations; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Renal Insufficiency, Chronic; Treatment Outcome

Dihydropyridinic calcium channel blockers are a subclass of antihypertensive drugs with growing significance in the therapeutic armamentarium. Early studies in the 1990s had aroused certain fears with regard to the safety of the first drugs from this class, since they had a fast onset of action and a short half-life, and thus they were associated with reflex adrenergic activation. New molecules with long half-lives and high lipophilia have shown safety and efficacy in the control of blood pressure, as well as in the reduction of several end points related to hypertension. Moreover, these new molecules, which block special subtypes of calcium channel receptors, provide drugs not only with an action profile that goes beyond the antihypertensive effect, but also with a lower rate of side effects. Therefore, in the light of new studies that include calcium channel blockers alone or in combination, these agents will probably be used even more extensively for the management of hypertension in the following years.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypertension; Hypertrophy, Left Ventricular

Dual calcium-channel blocker (CCB) with a dihydropyridine (DHP) and a nondihydropyridine (NDHP) has been proposed for hypertension treatment. However, the safety and efficacy of this approach is not well known.. A MEDLINE/EMBASE/CENTRAL search for randomized clinical trials published on this topic from 1966 to February 2012 was performed. Efficacy outcomes of decrease in systolic (SBP) and diastolic (DBP) blood pressures from baseline, changes in heart rate (HR), and adverse effects were compared between dual CCB therapy vs. DHP or NDHP. SBP, DBP, and HR were expressed as weighted mean deviation (WMD).. A total of 6 studies with 153 patients were included. Dual CCB produced a significantly greater reduction in SBP (21.6±9.2 mmHg) from baseline than DHP (10.3±6.3 mmHg (WMD = 10.9 mmHg, P < 0.0001)) or NDHP (8.9±4.2 mmHg (WMD = 14.1 mmHg, P = 0.002)). Dual CCB therapy reduced DBP from baseline more than either monotherapy (dual CCB = 17.5±10.2 mmHg vs. DHP = 11.6±8.7 mmHg, WMD = 5.5 mmHg, P < 0.001; and NDHP = 10.5±5.6 mmHg, WMD = 5.3 mmHg, P = 0.03). Dual CCB therapy had significantly lower HR compared to DHP (P < 0.001) but was comparable to NDHP (P = 0.12) (Delta change dual CCB = -4.0±3.5 vs. DHP = -2.0±1.5 and NDHP = -6.0±5.0 beats/min). Dual CCB therapy did not increase adverse effects.. Dual CCB therapy lowers blood pressure significantly better than CCB monotherapy, without an increase in adverse events. However, given the lack of long-term outcome data on efficacy and safety, dual CCB therapy should be used with restraint, if at all. Large-scale long-term trials are needed to further evaluate such a strategy.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

The purpose of this study was to evaluate the efficacy and safety of Cilnidipine tablets to treat Chinese patients with mild to moderate essential hypertension, and to examine the ability of Cilnidipine to lower blood pressure without eliciting unfavorable side effects. Medical databases and review articles were screened for randomized controlled trials that reported the effects of and adverse reactions to Cilnidipine and Amlodipine in treating Chinese patients with mild to moderate essential hypertension. The quality of the included studies was critically evaluated. A total of 547 articles were found, from which 11 articles met the inclusion criteria. The heterogeneity test, the efficacy analysis (Q statistic = 4.62, p = 0.91, I(2) = 0%) and safety analysis (Q statistic = 3.73, p = 0.93, I(2) = 0%) showed that Cilnidipine was equally effective and safe compared to Amlodipine. The funnel-plot displayed a symmetrical figure, indicating there was no publication bias, and all articles included described high quality trials. In conclusion, Cilnidipine is a useful agent to treat mild to moderate essential hypertension in China.

Topics: Calcium Channel Blockers; China; Dihydropyridines; Humans; Hypertension; Randomized Controlled Trials as Topic

We discuss the clinical studies on the efficacy and tolerability of lerkanidipine in arterial hypertension.

Topics: Age Factors; Aged; Atherosclerosis; Blood Pressure; Calcium Channel Blockers; Carotid Intima-Media Thickness; Dihydropyridines; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Pharmacovigilance; Randomized Controlled Trials as Topic; Treatment Outcome

This review summarizes data on the effectiveness of lercanidipine. Lercanidipine is dihydropyridine calcium antagonist of the third generation, characterized by high vazoselective, long duration of action and good antihypertensive effect. It may be assigned to elderly patients with isolated hypertension and has several important organoprotective properties. Treatment with lercanidipine promotes nephroprotection, reduction of left ventricular hypertrophy, improvement of elastic properties of blood vessels and reduction of central pressure. Sympathetic activation in the application of lercanidipine is virtually absent, that ensures its good tolerability and high adherence of patients to treatment.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Treatment Outcome

Abstract The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high-quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The efficacy of manidipine and amlodipine was statistically equivalent: effect size for DBP = -0.08 (p = 0.22) and SBP = -0.01 (p = 0.83). The global safety of manidipine was significantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle oedema RR was 0.35 (0.22-0.54). Publication bias was not significant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine.

Topics: Adult; Amlodipine; Ankle; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Edema; Humans; Hypertension; Meta-Analysis as Topic; Nitrobenzenes; Piperazines; Publication Bias; Randomized Controlled Trials as Topic; Treatment Outcome

Dihydropyridine calcium channel blockers (CCBs) are widely prescribed for the management of hypertension in Eastern Asians. In this study, the Asian Pacific Heart Association's Writing Committee reviewed randomized controlled trials that were conducted in the Eastern Asian region and compared a CCB with an antihypertensive drug of another class. These trials studied ambulatory blood pressure, measures of target organ damage and cardiovascular events as outcomes. Eleven trials studied ambulatory blood pressure in hypertensive patients and demonstrated that the 24-h blood pressure reduction with CCBs was greater than with other classes of antihypertensive drugs, with a weighted mean difference of 5 mm Hg systolic and 3 mm Hg diastolic. Twelve trials that studied various measurements of target organ damage in hypertensive patients produced inconsistent results when comparing CCBs and other classes of antihypertensive drugs. Four trials that studied the hard outcomes had limited power, but confirmed the findings of previous placebo-controlled trials in the region and actively controlled trials in Europe and North America; they suggested that CCBs provided superior protection against stroke and that some agents, such as amlodipine, also provided similar protection against myocardial infarction. In conclusion, CCBs should be recommended as a preferred drug for the management of hypertension in the Eastern Asian region to improve blood pressure control and to confront the aggravating epidemic of stroke and coronary heart disease.

Topics: Asia, Eastern; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Randomized Controlled Trials as Topic; Societies, Medical; Treatment Outcome

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

Topics: Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Clinical Trials as Topic; Diabetes Complications; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Irbesartan; Losartan; Nitrobenzenes; Obesity; Olmesartan Medoxomil; Piperazines; Ramipril; Tetrazoles; Valine; Valsartan

Derivatives of 1,4-dihydropyridine belong to group of calcium channel blockers and remain large group of antihypertensive agents. Particular chemical structure and presence of highly reactive binding groups make 1,4-dihydropyridines "privileged structures", which can be modified and change their pharmacological effects. This fact applies to new derivatives as well as metabolites of those drugs. Particularly interesting are outcomes of experiments with metabolites of furnidypine, which tend to cause different pharmacological effect, as well as have different profile of adverse effects from mother drug. Our paper concerns with potential new possibilities of using derivatives of 1,4-dihydropyridines, as well as their metabolites, as agents of more "optimised" effect.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Structure-Activity Relationship

Voltage-dependent calcium channels are divided into L type, T type, and N type. L type calcium channel blockers are widely used for treatment of hypertension and cardiovascular diseases. However, recent experimental and clinical findings suggest that not only L type calcium channel but also T and N type calcium cannels are possibly involved in cardiovascular diseases, through activation of sympathetic nervous system or aldosterone release. Therefore, it is proposed that L type calcium channel blockade combined with T type or N type calcium channel blockade may have additive benefits in preventing cardiovascular and renal diseases. Further future study is needed to clarify class effect and drug effect of each calcium channel blocker.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Calcium Channels; Cardiovascular Diseases; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Kidney Diseases; Meta-Analysis as Topic; Sympathetic Nervous System

Japanese Society of Hypertension Committee published Guidelines for the Management of Hypertension in 2009 (JSH2009). The first choices of antihypertensive drugs are calcium channel blockers, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, diuretics, and beta-adrenergic blockers. Because dihydropyridine calcium channel blockers have the greatest hypotensive efficacy without affecting organ blood flow, they are indicated in the patients with complications and the aged. Positive indications of calcium channel blockers are left ventricular hypertrophy, tachycardia (non-dihydropyridine), angina pectoris, chronic phase of cerebrovascular disease, and elderly patients. Patients with bradycardia are contraindicated by non-dihydropyridine calcium channel blockers.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cerebrovascular Disorders; Coronary Disease; Diabetes Complications; Dihydropyridines; Evidence-Based Medicine; Humans; Hypertension; Kidney Diseases; Practice Guidelines as Topic

Microalbuminuria is an issue of great concern in hypertensive patients owing to its close relation with cardiovascular morbidity and mortality. Treatment should aim to reduce microalbuminuria to the normal range. Drugs that block the renin-angiotensin system have specific antiproteinuric properties, but more than one drug is needed to achieve blood pressure control in most cases. The aim of this study was to compare the effects of adding manidipine to the treatment of patients with essential hypertension and persistent albuminuria, despite full-dose treatment with a renin-angiotensin system blocker on urinary albumin excretion (UAE) after 24 weeks of therapy. Patients with diabetes and renal insufficiency were excluded. At baseline, blood pressure and UAE were 155.1 +/- 12/87.76 +/- 11 mmHg and 293.19 +/- 285 mg/g, respectively. At study end, blood pressure was 137.1 +/- 13.1/77.24 +/- 10.4 mmHg (p < 0.001 vs baseline). UAE was reduced by 45% to 161.52 +/- 163 mg/g (p < 0.001 vs baseline). No correlations were found between systolic blood pressure reduction and UAE reduction (Pearson's R = -0.034; p = not significant) nor between estimated glomerular filtration rate and UAE reduction (Pearson's R = -0.0056; p = not significant). No patient withdrew from the study owing to side effects. In conclusion, treatment with manidipine resulted in a large reduction in UAE rates, and this reduction appeared to be independent of the degree of blood pressure reduction or changes in estimated glomerular filtration rate. Our data supports the added value of manidipine in the treatment of patients with hypertension and microalbuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Renin-Angiotensin System

Hypertension, a significant factor in the development of cerebrovascular disorders, heart disease and renal failure, is a common disorder worldwide. Despite the availability of a wide range of antihypertensive agents, almost two-thirds of hypertensive patients have poorly controlled blood pressure (BP). Numerous clinical trials have shown that most patients require at least two antihypertensive agents to achieve adequate BP control and associated significant reductions in cardiovascular morbidity and mortality. Combination therapy using two drugs with different, complementary mechanisms of action achieves better efficacy and tolerability outcomes than treatment with either component drug alone. When such a combination is administered as a fixed-dose formulation, other benefits, such as improved compliance and potentially lower costs, are also likely. The good efficacy and tolerability of the combination of a calcium channel antagonist and an angiotensin-converting enzyme inhibitor is well established, and this combination is recommended by European Society of Hypertension/European Society of Cardiology guidelines as a first choice in high-risk hypertensive patients, including those with type 2 diabetes mellitus. Lercanidipine/enalapril is a promising example of a fixed-dose combination of these drug classes. In clinical trials in hypertensive patients, including those with type 2 diabetes, lercanidipine/enalapril improved BP to a greater extent than either drug as monotherapy (in patients who were previous non-responders to lercanidipine or enalapril) or the combination of lercanidipine/hydrochlorothiazide, and was equally well tolerated. Further studies are required to evaluate the cardiovascular protective effects of lercanidipine/enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Evidence-Based Medicine; Humans; Hypertension; Renin-Angiotensin System; Treatment Outcome

Recent hypertension guidelines have highlighted the need to achieve blood pressure control in order to effectively reduce cardiovascular and renal morbidity and mortality. However, blood pressure control remains poorly achieved in the general population, particularly in high- or very-high-risk hypertensive patients. In view of the growing need to achieve better blood pressure control and provide adequate cardiovascular and renal protection in hypertensive patients, the implementation of combination therapies--especially fixed-dose combinations--is currently recommended. A greater use of fixed-combination therapies, based on a single daily administration of two drugs, in fact, may favor better compliance and adherence to prescribed antihypertensive medications. Among the possible fixed-dose combinations, the one based on angiotensin-converting enzyme inhibitors and calcium-channel blockers, may be considered an effective, safe and well-tolerated approach and may provide a beneficial impact on cardiovascular risk. This article reviews the potential role of fixed-combination therapy in the treatment of hypertension with a specific focus on an emerging calcium-channel blocker angiotensin-converting enzyme inhibitor fixed-dose combination based on a new-generation dihiidropiridinic calcium-channel blocker (lercanidipine) and the prototype angiotensin-converting enzyme inhibitor (enalapril).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension; Medication Adherence

Hypertension is a leading contributor to the burden of cardiovascular disease. The importance of lowering blood pressure (BP) to reduce the risk of cardiovascular events has been demonstrated in numerous clinical trials. Most patients require combination antihypertensive therapy utilizing agents from complementary drug classes to achieve BP goals. A calcium channel blocker (CCB)/angiotensin receptor blocker (ARB) combination is a rational approach for such an antihypertensive strategy. Benefits of CCB/ARB combination therapy include additive BP-lowering effects and lower incidences of adverse events (AEs). These agents demonstrate benefits associated with their respective drug classes. The ARBs confer stroke protection, renal protection, and tolerability similar to placebo, without dose-related symptomatic and metabolic AEs, while CCBs are beneficial in reducing stroke and treating angina and cardiac ischemia. The efficacy of this combination has been recently investigated in clinical trials wherein amlodipine was combined with olmesartan medoxomil or valsartan. This article discusses the rationale for using CCB/ARB combinations in patients with hypertension.

Topics: Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Humans; Hypertension

Cilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca(2+) channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca(2+) channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca(2+) channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.

Topics: Adrenergic Fibers; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, N-Type; Dihydropyridines; History, 20th Century; History, 21st Century; Humans; Hypertension; Norepinephrine; Reflex; Treatment Outcome

The calcium channel antagonists (CCAs) were originally introduced as vasodilators for the treatment of coronary heart disease, but are now also noted for their clinical efficacy in the management of hypertension. Data from large clinical studies have shown that CCAs are not associated with the undesirable metabolic effects (e.g. worsening of dyslipidemia and reduction of insulin sensitivity) seen with older agents such as thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) that are used to treat hypertension. Indeed, reductions in cardiovascular risk and rates of onset of new cases of diabetes mellitus have been reported in trials in patients with hypertension treated with CCAs. These beneficial effects extend beyond those expected to accompany reductions in BP. Until recently, the biochemical effects underlying these metabolic changes were only poorly understood, but pharmacologic studies have now started to shed more light on these issues. Of particular interest are studies with manidipine, some of which suggest that this agent may be associated with greater improvements in insulin sensitivity and may have better renal protective properties than other CCAs. Confirmation of potential differences among CCAs in terms of the relative magnitude of any beneficial metabolic effects requires further study. Ongoing research is expected to clarify further the action of these agents at the cellular level and to assist with the optimization of antihypertensive therapy, particularly in patients with elevated cardiovascular risk profiles.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Insulin; Insulin Secretion; Kidney Diseases; Lipids; Meta-Analysis as Topic; Metabolic Syndrome; Nitrobenzenes; Piperazines; PPAR gamma; Practice Guidelines as Topic

Achieving optimal blood pressure (BP) control is the most important single issue in the management of hypertension, and in most patients, it is difficult or impossible to achieve target levels with one drug. Blocking two or more regulatory systems provides a more effective and more physiologic reduction in BP, and current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Fixed-dose combination therapy is an efficacious, relatively safe and cost-effective treatment option in most patients with essential hypertension. Of note, the once-daily administration of a fixed-dose enalapril/lercanidipine, by bringing together two distinct and complementary mechanisms of action, reduces BP effectively and has the potential for improved target organ protection relative to either class agent alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension

In all actual clinical guidelines, dihydropyridine calcium channel blockers (CCBs) belong to the recommended first line antihypertensive drugs to treat essential hypertension. Several recent large clinical trials have confirmed their efficacy not only in lowering blood pressure but also in reducing cardiovascular morbidity and mortality in hypertensive patients with a normal or high cardiovascular risk profile. In clinical trials such as ALLHAT, VALUE or ASCOT, an amlodipine-based therapy was at least as effective, when not slightly superior, in lowering blood pressure and sometimes more effective in preventing target organ damages than blood pressure lowering strategies based on the use of diuretics, beta-blockers and blockers of the renin-angiotensin system. One of the main clinical side effects of the first and second generation CCBs including amlodipine is the development of peripheral edema. The incidence of leg edema can be markedly reduced by combining the CCB with a blocker of the renin-angiotensin system. This strategy has now led to the development of several fixed-dose combinations of amlodipine and angiotensin II receptor antagonists. Another alternative to lower the incidence of edema is to use CCBs of the third generation such as lercanidipine. Indeed, although no major clinical trials have been conducted with this compound, clinical studies have shown that lercanidipine and amlodipine have a comparable antihypertensive efficacy but with significantly less peripheral edema in patients receiving lercanidipine. In some countries, lercanidipine is now available in a single-pill association with an ACE inhibitor thereby further improving its efficacy and tolerability profile.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension

Results from clinical studies suggest that the dihydropyridine calcium channel blocker (CCB) lercanidipine may be associated with a lower incidence of peripheral edema than are older dihydro-pyridine CCBs.. The objective of the present study was to conduct a meta-analysis of published data from randomized controlled trials (RCTs) to assess the relative risk (RR) of dihydropyridine CCB-specific adverse events with lercanidipine versus the older dihydro-pyridine CCBs (first generation: amlodipine, felodipine, and nifedipine), and versus the other lipophilic dihy-dropyridine CCBs (second generation: lacidipine and manidipine).. A systematic literature search (all years through August 11, 2008) of MEDLINE, EMBASE, and the Cochrane Library was conducted for English-language reports of single- or double-blind RCTs of > or = 4 weeks' duration that compared the tolerability of lercanidipine with other dihydropyridine CCBs in participants with mild (140-159/90-99 mm Hg) to moderate (160-179/100-109 mm Hg) hypertension.. Eight RCTs (6 used first-generation drugs, and 4 used second-generation drugs) met the criteria for inclusion. Efficacy outcomes for lowering blood pressure did not differ statistically between lercanid-ipine and either generation of medications. Compared with the first generation, lercanidipine was associated with a reduced risk of peripheral edema (52/742 with lercanidipine vs 88/627 with first generation; RR = 0.44 [95% CI, 0.31-0.62]), but not flushing or headache. The frequency of peripheral edema, flushing, and headache did not differ statistically between lercanidi-pine and the second-generation drugs. Study participants were less likely to withdraw from the RCTs because of peripheral edema (RR = 0.24 [95% CI, 0.12-0.47]) or any adverse event (RR = 0.51 [95% CI, 0.33-0.77]) when treated with lercanidipine rather than a drug from the first generation, but not when treated with lercanidipine rather than second-generation drugs.. In this meta-analysis, lercanidipine was associated with a lower risk of peripheral edema and a lower risk of treatment withdrawal because of peripheral edema than were the first-generation, but not the second-generation, dihydropyridine CCBs.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Randomized Controlled Trials as Topic; Treatment Outcome

The dihydropyridine calcium channel blocker lercanidipine and the ACE inhibitor enalapril are frequently used in the treatment of hypertensive patients. In April 2007, a fixed-dose combination of the two drugs was approved in Germany for the treatment of patients not responding to monotherapy. It is expected that the drug will soon be available in the other European Union markets. In this review the present literature is summarized. Two doses will be available with 10 mg lercanidipine each and 10 or 20 mg enalapril. The medication should be taken once daily, optimally =15 minutes before a meal and the consumption of grapefruit juice should be avoided. The fixed-dose combination of the two drugs has a stronger blood pressure-lowering effect than monotherapy with 20 mg enalapril or 10 mg lercanidipine. The combination is well tolerated and few patients stopped the treatment because of side effects. As expected, the most common side effects reported are cough, peripheral edema, flushing, dizziness and vertigo, occurring in 1-5% of patients. This new fixed-dose combination is a useful adjunct to the present treatment and should increase compliance and help reduce hypertension-related costs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Drug Interactions; Enalapril; Humans; Hypertension

The calcium (Ca2+) channel antagonists (CCA) are used successfully in the treatment of hypertension and angina pectoris. Their mode of action is to decrease Ca2+ entry in the vascular smooth muscle cells. Their molecular targets are voltage activated Ca2+ channels (VACC), especially the L-type (VACC-L). This review examines the role of the VACC-L and of the T-type (VACC-T) in vascular physiology and hypertension. The molecular mechanisms at the base of the vascular selectivity of CCA are presented with, in filigree, the concern of trying to understand the effect of recently developed molecules. In particular, we will examine the ideas having recently emerged concerning the mode of action of last generation dihydropyridines (DHPs) stripped of some of the undesirable effects of prototypes AC considered as highly specific of the VACC-L. These properties could result, in particular, from their effects on the VACC-T, which could occur in addition to those classically observed on the VACC-L.

Topics: Animal Experimentation; Animals; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cells, Cultured; Dihydropyridines; Electrophysiology; Humans; Hypertension; Hypertension, Renal; Kidney Glomerulus; Mice; Muscle Cells; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Rats; Vasoconstriction

Although achieving blood pressure (BP) control is critical to improve cardiovascular prognosis in hypertensive patients, many of them fail to achieve BP goals. The majority of hypertensive patients need more than one antihypertensive agent to attain BP targets. Combination therapy is required when monotherapy fails to attain BP objectives and as a first-line treatment in certain situations, such as markedly elevated BP values, when lower targets are required in high or very high cardiovascular risk patients. The advantages of combination therapy are well documented, with an increased antihypertensive efficacy as a result of the simultaneous inhibition of different mechanisms of action and with a lesser incidence of adverse events, because of the possible compensatory responses and the lower doses used. Calcium channel blockers are effective drugs in the treatment of hypertension. The efficacy of lercanidipine has been evaluated in several noncomparative and in comparative studies showing a great efficacy with a good tolerability. On the other hand, the inhibition of the renin-angiotensin system appears to be very beneficial in the treatment of patients with hypertension. Enalapril is an effective and well tolerated angiotensin converting enzyme inhibitor. Although there are several fixed-combination drugs, the combination lercanidipine plus enalapril appears to be one of the most promising therapies in the treatment of hypertension. The aim of this manuscript is to update the published data about the efficacy and safety of this fixed combination.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension; Treatment Outcome

Despite the development of many effective antihypertensive drugs, target blood pressures are reached in only a minority of patients in clinical practice. Poor adherence to drug therapy and the occurrence of side effects are among the main reasons commonly reported by patients and physicians to explain the poor results of actual antihypertensive therapies. The development of new effective antihypertensive agents with an improved tolerability profile might help to partly overcome these problems. Lercanidipine is an effective dihydropyridine calcium channel blocker of the third generation characterized by a long half-life and its lipophylicity. In contrast to first-generation dihydropyridines, lercanidipine does not induce reflex tachycardia and induces peripheral edema with a lower incidence. Recent data suggest that in addition to lowering blood pressure, lercanidipine might have some renal protective properties. In this review we shall discuss the problems of drug adherence in the management of hypertension with a special emphasis on lercanidipine.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Medication Adherence; Proteinuria; Treatment Outcome

The increasing prevalence of hypertension, owing to modern lifestyles and the increasing elderly population, is contributing to the global burden of cardiovascular (CV) disease. Although effective antihypertensive therapies are available, blood pressure (BP) is generally poorly controlled. In addition, the full benefits of antihypertensive therapy can only be realised when target BP is achieved. International guidelines and clinical trial evidence support the use of combination therapy to manage hypertension. In high-risk patients, such as those with coronary artery disease, diabetes and renal dysfunction, BP targets are lower and there is a need for intensive management with combination therapy to control BP and provide additional CV risk reduction benefits. Combinations of antihypertensive agents with different but complementary modes of action improve BP control and may also provide vascular-protective effects. Calcium channel blockers (CCBs) have been shown to be effective in combination with a range of antihypertensive drugs and in different patient populations. As part of a first-line combination strategy, CCBs can provide CV benefits beyond BP control, even in patients at increased CV risk. Benefits include protection against end-organ damage and serious CV events. Indeed, in major intervention trials, these benefits have already been clearly demonstrated. Ongoing studies will provide further data to support the clinical benefits of combination therapy as a first-line treatment approach. Implementation of this approach in clinical practice, together with adherence to global hypertension management guidelines will help ensure patients achieve and sustain BP targets, and reduce the risk of CV events.

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypertension; Practice Guidelines as Topic

Calcium channel blockers (CCBs) share a common mechanism of action. However, the manner in which they exert their pharmacological effects is different between subclasses. Dihydropyridine (DHP) CCBs tend to be more potent vasodilators than non-dihydropyridine (non-DHP) agents, whereas the latter have more marked negative inotropic effects. Both subclasses have a similar capacity to lower BP; however, non-DHPs appear to offer potential advantages in the management of patients with chronic kidney disease and diabetic nephropathy. Representatives of both classes are now available in fixed-dose combinations containing an ACE inhibitor, the benefits of which include effective 24-hour BP control, a reduced incidence of adverse effects, and improved adherence.

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Monitoring; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hypertension; Hypertrophy, Left Ventricular

Calcium antagonists have been shown to be superior over other antihypertensive drugs to prevent stroke. Because this cannot be fully attributed to blood pressure lowering effects, other mechanisms seem to play a role. Previously we found in patients with subarachnoid hemorrhage that nimodipine enhances fibrinolytic activity. The purpose of this systematic review was to investigate the fibrinolytic effect of calcium antagonists in general, especially in patients with hypertension. We systematically studied the entire PUBMED and EMBASE database with the search terms 'calcium antagonist' combined with 'fibrinolysis', '(euglobulin) clot lysis time' (ECLT), 'tissue plasminogen activator' (tPA), or 'plasminogen activator inhibitor' (PAI). Twenty-six prospective studies were identified and 22 manuscripts were included (802 investigated individuals). The results show that calcium antagonists significantly increase fibrinolysis as shown by a reduction of the ECLT standardized mean differences (SMD) -0.58 (95% confidence interval (CI) -1.05 to -0.11)) and an increase of tPA activity (SMD 0.73 (95% CI 0.25 to 1.21)). This increase of fibrinolysis is apparently caused by an increase of the tPA antigen level (SMD 0.16 (95% CI -0.05 to 0.37)) and a decrease of the plasminogen activator inhibitor-1 antigen antigen (SMD -0.36 (95% CI -0.74 to 0.02)). A sensitivity analysis showed that dihydropyridines, but not phenylalkylamines, exert a fibrinolytic effect. This fibrinolytic effect is not only seen in patients with subarachnoid hemorrhage but also in hypertensive patients. In conclusions, calcium antagonists increase fibrinolytic activity. This may add to the beneficial pharmacological effect of calcium antagonists to prevent ischemic events in patients with hypertension and subarachnoid hemorrhage.

Topics: Calcium Channel Blockers; Dihydropyridines; Fibrinolysis; Humans; Hypertension; Ischemia; Subarachnoid Hemorrhage

Lercanidipine, a dihydropyridine calcium channel blocker, and enalapril, an ACE inhibitor, are established antihypertensive agents. A fixed-dose tablet formulation of lercanidipine/enalapril is approved in Germany for the treatment of hypertension in patients not responding to monotherapy. Lercanidipine/enalapril 10mg/10mg once daily significantly reduced sitting diastolic blood pressure and sitting systolic blood pressure, relative to lercanidipine 10mg once daily, in a 12-week, randomised, double-blind trial in patients with mild to moderate hypertension who had previously not responded to 4 weeks' treatment with lercanidipine. In a similarly designed trial, lercanidipine/enalapril 10mg/20mg once daily was significantly more effective than enalapril 20mg once daily in hypertensive patients who had previously not responded to enalapril monotherapy. Fixed-dose lercanidipine/enalapril was generally well tolerated, with a tolerability profile similar to that of either of the individual drugs alone or placebo. Cough was reported in

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension

In patients with hypertension and diabetes, atherothrombosis is a leading cause of morbidity and mortality, and there is now compelling evidence demonstrating that lowering elevated blood pressure (BP) is one of the most beneficial aims of therapy in this high-risk population. Indeed, major international guidelines have set a target BP goal of 130/80 mmHg in high-risk patients and recommend combination treatment with two or more drug classes to help achieve this objective. Manidipine plus delapril is a fixed-dose combination of a third-generation dihydropyridine calcium antagonist and an angiotensin-converting enzyme inhibitor, which is effective in mild-to-moderately hypertensive patients with an inadequate response to monotherapy. It is also effective in the long-term (50 weeks) management of essential hypertension. Comparative studies have demonstrated that manidipine plus delapril is as effective as enalapril plus hydrochlorothiazide (HCTZ) in patients with hypertension that is unresponsive to monotherapy, and as effective as ramipril plus HCTZ, valsartan plus HCTZ, irbesartan plus HCTZ and olmesartan plus HCTZ in patients with essential hypertension and Type 2 diabetes. In addition, manidipine plus delapril exhibited renoprotective effects in normotensive Type 2 diabetic patients, and improved fibrinolytic function (significantly more than irbesartan plus HCTZ) in hypertensive patients with Type 2 diabetes. Manidipine 10 mg plus delapril 30 mg once daily was generally well tolerated, with no unexpected adverse effects and evidence of a low incidence of ankle edema. Thus, manidipine plus delapril is a fixed-dose combination treatment that significantly reduces elevated BP with once-daily administration. It is well tolerated and has ancillary properties, such as nephroprotective activity and improvement of fibrinolytic balance, which may help reduce cardiovascular morbidity and mortality, particularly in high-risk patients, such as those with Type 2 diabetes mellitus.

Topics: Blood Pressure Determination; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Survival Analysis

To review the literature regarding the efficacy, tolerability, and utility of lercanidipine in the treatment of hypertension.. A search of the literature was performed using MEDLINE (1966-September 2006), EMBASE Drugs and Pharmacology (1980-September 2006), and Current Contents/Clinical Medicine (week 24, 2005-week 30, 2006). Package inserts from lercanidipine, nifedipine, felodipine, and amlodipine were also reviewed for comparison of adverse effects.. Articles were limited to clinical trials, abstracts, and review articles published in English.. Lercanidipine is a novel dihydropyridine (DHP) calcium-channel blocker indicated for the treatment of mild-to-moderate hypertension. Although it is not yet available in the US, lercanidipine has been utilized extensively in other countries. In 2 randomized controlled trials of approximately 400 patients with mild-to-moderate hypertension, lercanidipine showed efficacy similar to that of 2 other DHPs, felodipine and slow-release nifedipine, in significantly reducing systolic blood pressure and diastolic blood pressure (DBP) after 4 weeks. In a longer trial (12 mo), lercanidipine 10 mg/day led to normalized blood pressure in 49% of patients after 4 weeks. A postmarketing trial of 9050 patients corroborated the results observed in previous clinical trials, with 64% of patients achieving a DBP of less than 90 mm Hg and 32% attaining blood pressure control (<140/90 mm Hg). In elderly patients, lercanidipine was found comparable with lacidipine and nifedipine, showing similar decreases in DBP when compared with nifedipine (-18.3 vs -17.7 mm Hg, respectively). What distinguishes lercanidipine from other members of the DHP class is its lower incidence of adverse effects, particularly edema. One study showed that fewer patients withdrew secondary to adverse drug reactions in the lercanidipine (0.9%) and nifedipine (3.8%) group compared with the felodipine (4.5%) group. Lercanidipine has also shown efficacy similar to that of other antihypertensives, including atenolol, captopril, and losartan.. Lercanidipine may be an option in the treatment of hypertension, as current literature suggests comparable antihypertensive efficacy and better tolerability. Further randomized, double-blind clinical trials must be conducted in order to clarify its position among other antihypertensive medications.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension

Dihydropyridine calcium channel antagonists have been maligned in recent years because of concerns regarding their cardiovascular and overall safety profile. Specifically, it was widely publicised in the mid-1990s that these agents might increase the risk of myocardial infarction, gastrointestinal bleeding and cancer. Data linking these agents with increased cardiovascular risk were based on nonrandomised studies and implicated short-acting, immediate-release agents. These results were inappropriately extrapolated to longer-acting compounds, extended-release products, and to the non-dihydropyridine class. Fortunately, recent studies have vindicated the class from safety allegations. These studies are reviewed herein. Compared with both diuretics and contemporary agents, amlodipine decreases cardiovascular events to a similar or greater extent without evidence for increased coronary heart disease, gastrointestinal bleeding or cancer. Despite these data, initial concerns have had lasting repercussions, as the use of dihydropyridine calcium channel antagonists appears to lag behind what emerging data would support. Dihydropyridine calcium channel antagonists have several noteworthy attributes that merit consideration in the management of hypertension. The blood pressure response to this class of drugs is less contingent on patient factors such as age and race compared with other antihypertensive agents (e.g. ACE inhibitors). Dihydropyridine calcium channel antagonists may exert effects that protect against stroke that are independent of their blood pressure-lowering mechanism. Unlike diuretics and beta-adrenoceptor anatagonists (beta-blockers), dihydropyridine calcium channel antagonists are lipid neutral and do not disturb glucose homeostasis. Dihydropyridine calcium channel antagonists demonstrate a highly desirable profile when administered as part of combination therapy. Combinations of dihydropyridine calcium channel antagonists and ACE inhibitors or angiotensin receptor antagonists display additive efficacy and an enviable adverse-effect profile. Collectively, the cardiovascular benefit, metabolic neutrality and homogeneous blood pressure response illuminated in recent studies, and reviewed here, represent a reaffirmation of the benefit of long-acting dihydropyridine calcium channel antagonists and should serve to help reinforce the critical importance of these agents in the therapeutic armamentarium against cardiovascular disease.

Topics: Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Meta-Analysis as Topic; Treatment Outcome

High blood pressure (BP) is the major cardiovascular risk factor and the main cause of death around the world. Control of blood pressure reduces the high mortality associated with hypertension and the most recent guidelines recommend reducing arterial BP values below 140/90 mmHg for all hypertensive patients (130/80 in diabetics) as a necessary step to reduce global cardiovascular risk, which is the fundamental objective of the treatment. To achieve these target BP goals frequently requires combination therapy with two or more antihypertensive agents. Although the combination of a diuretic and an angiotensin converting enzyme inhibitor (ACEI) is the most commonly used in the clinical practice, the combination of an ACEI and a calcium channel blocker may have an additive antihypertensive effect, a favorable effect on the metabolic profile, and an increased target organ damage protection. The new oral fixed combination manidipine 10 mg/delapril 30 mg has a greater antihypertensive effect than both components of the combination separately, and in non-responders to monotherapy with manidipine or delapril the average reduction of systolic and diastolic BP is 16/10 mmHg. The combination is well tolerated and the observed adverse effects are of the same nature as those observed in patients treated with the components as monotherapy. However, combination therapy reduces the incidence of ankle edema in patients treated with manidipine.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines

Cognitive deterioration and its sequelae of vascular or Alzheimer's dementia is rapidly increasing all over the world. This is primarily caused by the worldwide increase of the ageing population. Additional causes may be sought in factors such as genetics and a habitually unhealthy life style. The significance of high blood pressure in the process leading to cognitive deterioration is relatively unknown. However, timely detection and treatment of hypertension seems to contribute to the preservation of cognition. Experience has shown that this applies in particular to dihydropyridine calcium antagonists. Medical care tends to make insufficient use of the existing possibilities for treating hypertension.

Topics: Aged; Aging; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cognition; Dementia; Dihydropyridines; Humans; Hypertension

Topics: Albuminuria; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Inflammation; Insulin Resistance; Metabolic Syndrome; Nitrobenzenes; Oxidation-Reduction; Piperazines; Thrombosis

Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.

Topics: Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Channels, T-Type; Clinical Trials as Topic; Diabetic Nephropathies; Dihydropyridines; Drug Evaluation, Preclinical; Endothelial Cells; Heart; Humans; Hypertension; Kidney; Renal Circulation; Vasodilator Agents

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Nitrophenols; Organophosphorus Compounds; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Single-Blind Method

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Japan; Male; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Stroke

Topics: Amlodipine; Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Depression; Dihydropyridines; Evidence-Based Medicine; Heart Rate; Humans; Hypertension; Kidney Diseases; Proteinuria; Sympathetic Nervous System

Lercanidipine is a new highly lipophylic dihydropyrdine derivative of the third generation with equal efficacy but an improved tolerability profile. Comparative therapeutic trials have shown that it is as effective as other dihydropyridines, in particular amlodipine, beta-blockers, and angiotensin-converting enzyme inhibitors. Lercanidipine is well tolerated, with most treatment-emergent events related to vasodilation. Lercanidipine produces less reflex tachycardia and peripheral oedema. Common adverse events included headache and flushing. Because of its efficacy and favorable safety profile, lercanidipine has the potential to improve blood pressure control in a wide range of patients, including those who have not responded to, or who have been unable to tolerate other antihypertensive agents.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Controlled Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Severity of Illness Index; Treatment Outcome

Systemic hypertension is a major global problem contributing to enormous disease burden, premature morbidity and mortality. A substantial majority of hypertensive patients require long-term drug therapy for appropriate blood pressure control. Although there are many classes of antihypertensive drugs for clinical use, calcium channel blockers (CCBs) have a special role in the management of hypertension owing to their well established safety and efficacy among the CCBs; the dihydropyridines (DHPs) are recognized for their predictable efficacy and dependability to achieve the recommended target goals of treatment. The older DHPs, such as nifedipine, felodipine and amlodipine, can cause bothersome side effects, such as ankle edema. The new-generation lipophilic DHP CCBs, such as lercanidipine, offer an advantage of less frequent occurrence of ankle edema. Furthermore, lercanidipine (in contrast to older DHPs) exerts favorable cardiorenal effects. Lercanidipine administered alone or in combination with other antihypertensive drugs represents a useful treatment option for efficient blood pressure control without causing significant adverse effects.

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Edema; Humans; Hypertension; Randomized Controlled Trials as Topic

This present study assessed the antihypertensive efficacy of the fixed combination of manidipine and delapril by ambulatory blood pressure monitoring in patients with hypertension inadequately controlled by monotherapy with either component. After a 2-week placebo period, 55 mild to moderate hypertensive patients were randomized to manidipine 20 mg o.d. or delapril 30 mg b.i.d. for 4 weeks. After this period, 30 patients, aged 30-76 years (18 males and 12 females) whose diastolic blood pressure was not adequately controlled (> or = 90 mmHg) by monotherapy were treated with the fixed combination of manidipine 10 mg plus delapril 30 mg o.d. for 8 weeks. A 24-h ambulatory blood pressure monitoring recording was performed at the end of the placebo washout, of the monotherapy and of the combination therapy. Blood pressure control over the 24 h was quantified by the trough-to-peak ratio and the smoothness index. As compared to placebo, the fixed combination of manidipine and delapril produced a statistically significant (p<0.01) decrease in sitting clinic (18 +/- 9/14 +/- 5 mmHg) and 24-h blood pressure (12 +/- 7/10 +/- 5 mmHg) without affecting heart rate. This reduction was greater than that observed with single components. At the end of the 8-week combination treatment period, the rate of normalilized patients was 73%. Treatment with the fixed combination was associated with a positively high smoothness index (1.2 +/- 0.7/13.8 +/- 0.8) and with a relatively good trough-to-peak ratio (0.46/0.60). The combination of manidipine and delapril produced significant and smooth reductions in blood pressure values, which persisted over the 24-h dosing interval. These results support the use of fixed manidipine-delapril combination in the treatment of mild to moderate hypertensive patients inadequately controlled by monotherapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Random Allocation; Time Factors

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Humans; Hypertension; Stroke

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease. A major question is whether drugs reducing blood pressure have other effects that help prevent the main complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. Experimental studies that focus on this question are reviewed in the present paper.

Topics: Animals; Antioxidants; Atherosclerosis; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Humans; Hypertension; Oxidative Stress

Manidipine is a lipophilic, third-generation, highly vasoselective, dihydropyridine (DHP) calcium channel antagonist, which, when given on a once-daily basis, effectively reduces blood pressure (BP) in patients with mild-to-moderate essential hypertension. Manidipine has a gradual onset and a long duration of action, effectively maintaining reduced BP levels throughout the 24-hour dosing period, and is effective in the long term with no evidence of intolerance. The BP-lowering capacity of manidipine is similar to that of other established DHPs and of angiotensin-converting enzyme inhibitors. Diabetic patients and very elderly patients with mild-to-moderate hypertension also respond favourably to treatment with manidipine. Manidipine has neutral effects on glucose and lipid metabolism and is generally well tolerated. Manidipine thus represents a first-line option for lowering BP in patients with mild-to-moderate hypertension.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Kidney Diseases; Male; Nitrobenzenes; Piperazines; Randomized Controlled Trials as Topic; Syndrome

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Hypertension, Renal; Kidney; Nitrobenzenes; Piperazines; Proteinuria; Randomized Controlled Trials as Topic; Renal Circulation

Lercanidipine is a lipophilic, dihydropyridine calcium antagonist with a long receptor half-life. Its slow onset of action helps to avoid reflex tachycardia associated with other dihydropyridines (DHPs). It produces even and sustained blood pressure lowering with once-daily dosing. It has equivalent antihypertensive efficacy to many other agents and is effective as initial monotherapy or in combination. Efficacy has been demonstrated in elderly as well as younger patients and also in the presence of other risk factors. Lercanidipine is well tolerated with DHP-associated adverse effects occurring early in treatment. The incidence of pedal edema and subsequent withdrawals has been found to be lower with lercanidipine than with amlodipine or nifedipine gastrointestinal transport system. Preclinical and preliminary clinical findings suggest lercanidipine may have beneficial effects on atherosclerosis and left ventricular hypertrophy. The efficacy and tolerability profiles of lercanidipine make it a suitable choice for treating hypertension in a wide range of affected patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Middle Aged; Patient Compliance; Practice Guidelines as Topic; Severity of Illness Index; Treatment Outcome

Topics: Adenylyl Cyclases; Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Humans; Hypertension; Muscle Tonus; Muscle, Smooth, Vascular; Vascular Resistance

Recent trials indicate that treatment with calcium channel blockers (CCBs) reduces cardiovascular morbidity and mortality in hypertensive patients (including those with significant coronary artery disease). Since the fundamental mechanism of action of all CCBs is the same, it might be assumed that the findings of these outcome studies can be generalized to all types of CCB. However, in the light of the well-recognized clinical pharmacological differences between the 'rate-limiting' agents, verapamil and diltiazem, and the dihydropyridine group of CCBs, this must be considered to be a misconception. Less well-recognized, and often ignored, are the significant differences between agents within the dihydropyridine group. These differences translate to distinct differences in the therapeutic profiles and may well translate into differences in outcome during long-term treatment. Thus, the differences in pharmacokinetic, pharmacodynamic and therapeutic profiles make it clear that caution should be exercised in assuming that all dihydropyridine CCBs licensed for once-daily administration are equivalent in terms of their durations of action and overall antihypertensive efficacy.

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Manidipine is a lipophilic, third-generation dihydropyridine calcium channel antagonist with a high degree of selectivity for the vasculature, thereby inducing marked peripheral vasodilation with negligible cardiodepression. In addition, manidipine does not significantly affect norepinephrine levels, suggesting a lack of sympathetic activation. It has a gradual onset of action and a long duration of action enabling once daily administration. Furthermore, manidipine dilates both the efferent and the afferent renal arterioles and appears to have beneficial renal effects unrelated to its antihypertensive effect. Once-daily oral manidipine is an effective and generally well tolerated antihypertensive agent for younger and elderly adult patients with mild-to-moderate hypertension. In particular, in a large double-blind trial, the incidence of ankle oedema was significantly lower in manidipine than in amlodipine recipients. Manidipine is also effective in hypertensive patients with comorbidities, such as type 2 diabetes mellitus and/or renal impairment, and appears to improve insulin sensitivity without affecting metabolic function. Thus, manidipine represents a first-line treatment option for patients with essential mild-to-moderate hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dihydropyridines; Humans; Hypertension; Middle Aged; Nitrobenzenes; Piperazines; Renal Insufficiency

Essential hypertension is a major cause of cardiovascular morbidity and mortality in the Western world, yet it remains poorly controlled. Single drug-antihypertensive therapy is unsuccessful in up to half of all patients with hypertension; although lack of adherence may account for a proportion of this, there is evidence of considerable variation in the response of different hypertensive patients to different drug classes. A number of algorithms have been proposed in the literature, with a view to predicting an individual's response to different antihypertensive agents. However, even using such algorithms, hypertension control remains problematic, and they are frequently difficult to apply in everyday clinical practice. Initiation of treatment with low-dose combination antihypertensive therapy, using a drug which reduces total body sodium and/or volume in combination with a drug which blocks the renin-angiotensin system, provides an effective and easily applicable means to improve hypertension control in the primary care setting.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiac Output; Cardiovascular Diseases; Dihydropyridines; Diuretics; Drug Therapy, Combination; Humans; Hypertension; Middle Aged; Renin-Angiotensin System; Sodium

Although end-stage renal disease (ESRD) currently affects only a small percentage (<0.2%) of the US population, its precursor, the mild and moderate forms of chronic kidney disease (CKD), affects 11% of the population, with significant growth in both ESRD and CKD anticipated in the rapidly aging US population. The primary diagnoses in the majority of ESRD patients are diabetes and hypertension. Results of clinical studies demonstrate that the level of proteinuria and sympathetic activation contribute to the progression of CKD to ESRD. There are sufficient clinical data to demonstrate that the dihydropyridine calcium channel blocker (DHP CCB) class of antihypertensives such as amlodipine and nifedipine, although effective in reducing systemic hypertension, lack activity in reducing proteinuria or attenuating sympathetic activity. Experimental studies and a limited number of clinical studies suggest that non-DHP CCBs, including verapamil and diltiazem, have a mechanism of action that differs from DHP CCBs. Non-DHP CCBs could potentially attenuate sympathetic activity and reduce protein excretion in patients with CKD.

Topics: Black or African American; Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Diltiazem; Humans; Hypertension; Kidney; Kidney Failure, Chronic; United States; Verapamil

In patients with kidney disease, control of hypertension is paramount in helping to slow down the progression of both diabetic and nondiabetic nephropathy. A significant amount of data have been published that suggest blockade of the renin-angiotensin system should be considered as first-line therapy for patients with kidney disease. Meanwhile, some studies have suggested that the use of calcium channel blockers may have deleterious effects on patients with kidney disease. This manuscript reviews the renal outcomes of trials in which calcium channel blockers were included in the management of patients with and without kidney disease. The data suggest that agents that block the renin-angiotensin system are superior to calcium channel blockers in protecting against progressive kidney disease. However, there is no conclusive evidence that calcium channel blockers are injurious to the kidney, and they may be particularly beneficial in post-renal transplant patients.

Topics: Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension; Kidney Diseases; Kidney Transplantation; Malpractice; Renin-Angiotensin System

Lacidipine (Caldine, Lacimen, Lacipil, Midotens, Motens) is a once-daily, orally-administered, lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity, resulting in a lack of reflex tachycardia. It has a long duration of action and a high degree of vascular selectivity. In addition to calcium channel-modulated vasodilation, lacidipine displays antioxidant activity greater than that of other dihydropyridine calcium antagonists. In randomised, well-controlled trials, lacidipine 2-6 mg orally once daily had antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor). Lacidipine was effective in elderly patients (including those with isolated systolic hypertension), African Nigerian patients and patients with concurrent type 2 diabetes mellitus. During long-term treatment for 4 or 5 years in patients with isolated systolic hypertension or essential hypertension, the incidence of cardiovascular events and mortality with lacidipine was similar to that with chlorthalidone or atenolol. The European Lacidipine Study on Atherosclerosis (ELSA), in which 2334 patients with hypertension were randomised to 4 years of therapy with lacidipine 4-6 mg/day or the beta-blocker atenolol 50-100 mg/day, demonstrated significantly lower atherosclerotic progression and plaque formation with lacidipine compared with atenolol in patients completing the full 4 years of the study. Between-group differences in favour of lacidipine for the primary efficacy variable (mean change in carotid artery intima-media thickness) did not reach statistical significance in the intent-to-treat population. The tolerability profile of lacidipine (headache, flushing, pedal oedema, dizziness and palpitations) is similar to that of other dihydropyridine calcium antagonists, but with a lower incidence of peripheral oedema. Data from the ELSA study suggest that the incidence of serious adverse events during long-term lacidipine therapy is similar to that with atenolol.. Lacidipine is an effective, well tolerated, once-daily, oral antihypertensive agent that can be used in a wide variety of patients. As with other members of its class, lacidipine has shown potentially beneficial antiatherosclerotic effects, although definitive data with respect to possible superiority over other drug classes are still required. Therefore, lacidipine is an attractive therapy for the long-term management of essential hypertension.

Topics: Area Under Curve; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Economics, Pharmaceutical; Half-Life; Heart Rate; Humans; Hypertension; Kidney

Lercanidipine (Zanidip) is a vasoselective dihydropyridine calcium channel antagonist that causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug that exhibits a slower onset and longer duration of action than other calcium channel antagonists. Furthermore, lercanidipine may have antiatherogenic activity unrelated to its antihypertensive effect. In two large, nonblind, noncomparative studies involving approximately 16 000 patients with mild-to-moderate hypertension, systolic blood pressure (BP) [SBP] and diastolic BP (DBP) were significantly reduced after 12 weeks' treatment with lercanidipine 10-20 mg/day. Furthermore, in the largest study, 64% of patients were responders (DBP <90 mm Hg) after 12 weeks of treatment and an additional 32% had their BP normalised (BP <140/90 mm Hg). In comparative trials, lercanidipine 10-20 mg/day was as effective as nifedipine slow release (SR) 20-40 mg twice daily, amlodipine 10 mg/day, felodipine 10-20 mg/day, nifedipine gastrointestinal therapeutic system (GITS) 30-60 mg once daily or verapamil SR 240 mg/day at reducing SBP and DBP in patients with mild-to-moderate hypertension after 2-16 weeks of therapy. In addition, 4 weeks of lercanidipine therapy (10 mg/day) was as effective as captopril 25mg twice daily, atenolol 50 mg/day or hydrochlorothiazide 12.5 mg/day. Lercanidipine 5-30 mg/day effectively decreased BP in elderly patients (aged >60 years) with mild-to-moderate hypertension or isolated systolic hypertension to the same extent as amlodipine 5-10 mg/day, nifedipine GITS 30-60 mg/day or lacidipine 2-4 mg/day after 24-26 weeks of therapy. In addition, a limited number of studies suggest that lercanidipine may have antihypertensive efficacy in patients with severe or resistant hypertension, in hypertensive patients with type 2 diabetes mellitus and in postmenopausal women with mild-to-moderate essential hypertension. Lercanidipine is well tolerated, with most treatment-emergent events related to vasodilation. Common adverse events included headache, flushing and peripheral oedema. Importantly, the incidence of vasodilatory oedema was significantly lower in patients receiving lercanidipine than in those receiving some other calcium channel antagonists.. Once-daily lercanidipine is an effective and well tolerated antihypertensive agent in patients with mild-to-moderate hypertension.

Topics: Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Interactions; Humans; Hypertension

Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension. Results from clinical trials showed that, in 95 patients with mild-to-moderate hypertension, long-term treatment with azelnidipine effectively controls blood pressure (BP). The mean reduction from baseline in sitting systolic/diastolic BP after 1 year of treatment was 27.8/16.6 mm Hg. Among 172 patients with uncontrolled hypertension receiving non-calcium channel antagonist antihypertensive agents, the addition of azelnidipine therapy significantly reduced mean BP in a noncomparative, 1-year study (a reduction from 165.7/95.4 mm Hg at baseline to 138.2/79.9 mm Hg at study end). The antihypertensive efficacy of azelnidipine in patients with mild-to-moderate hypertension was shown to be similar to that of amlodipine or nitrendipine in randomised, double-blind studies. Azelnidipine and amlodipine controlled 24-hour BP to a similar extent. Azelnidipine is generally well tolerated; vasodilator adverse events such as as headache and hot facial flushes account for most of the adverse events. Its use is not associated with reflex tachycardia.

Topics: Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Hemodynamics; Humans; Hypertension; Randomized Controlled Trials as Topic

Azelnidipine (Calblock) is a newly developed dihydropyridine-type calcium antagonist for the treatment of hypertension. In hypertensive animals, a single oral administration of azelnidipine caused a slowly developed and long-lasting hypotensive effect with a little reflex tachycardia. The extent of tachycardia was less with azelnidipine than with other agents of the same class. Long-term administrations of azelnidipine produced a stable antihypertensive effect with a slight decrease in heart rate. The hypotensive effect was preceded by an increase in plasma drug concentration and it persisted even after plasma drug concentration declined to very low levels. In the isolated arteries, the calcium blocking action developed gradually after treatment with azelnidipine and survived for a long period of time after the drug was removed from the bathing solution. These data suggest that the high affinity to vascular tissue contributes to the long-lasting hypotensive effects of this agent. The results from clinical studies in hypertensive patients indicated that once daily administration of azelnidipine achieved stable, 24-h control of blood pressure with no change or a slight decrease in heart rate. Clinical studies also showed a low incidence of adverse events such as headache, facial flush, dizziness, and palpitations. These characteristics make azelnidipine a new generation calcium antagonist that can be used for the treatment of hypertension.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Heart Rate; Humans; Hypertension

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Interactions; Humans; Hypertension; Randomized Controlled Trials as Topic

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hyperlipidemias; Hypertension; Memory Disorders; Myocardial Ischemia; Rats

Similarities and dissimilarities of 3 third generation calcium antagonist (amlodipine, lacidipine and lercanidipine) are presented. Lacidipine is characterized by prolonged antihypertensive action despite its plasma half life is just about 14 hours. Duration of lacidipine effect can be explained by accumulation in lipid bilayer of cellular membranes where it interacts with calcium channels. Pharmacodynamics of lacidipine is discussed in detail as well as experience of its use in hypertension including data of ELSA study which has demonstrated ability of lacidipine to inhibit progression of carotid artery atherosclerosis.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Meta-Analysis as Topic; Nifedipine; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Dysfunction, Left

Vatanidipine is a novel dihydropyridine (DHP)-type calcium channel blocker with slow-onset pharmacological actions, which are probably due to both its slow uptake into vascular tissues and resistance in its approach to the calcium channel binding site. Vatanidipine once incorporated into vascular tissues is not easily released, even by repeated washing, thus resulting in a long-lasting action of the agent. A slow-onset and long-lasting hypotensive action was observed in various experimental hypertensive models. Clinical trials using human subjects with essential hypertension indicated that vatanidipine exerts an antihypertensive effect with a slow onset and long duration. In spite of its potent hypotensive effect, the incidence of adverse effects by vatanidipine administration has been reported to be lower than that in cases of nitrendipine. In addition to its vasodilatory effects, vatanidipine efficiently suppressed noradrenaline release from sympathetic nerve endings, thus suggesting this agent exhibits a beneficial effect in the treatment of hypertensive patients, in which the reflex activation of peripheral sympathetic nerves is unfavourable to antihypertensive therapy. In a double-blind study, vatanidipine did not show reflex tachycardia, despite producing a potent and long-lasting hypotensive effect, in contrast to the administration of nitrendipine. In an animal study, vatanidipine exhibited a protective effect against cerebrovascular lesions, through a mechanism independent of its hypotensive effect. In addition, a renoprotective effect was also observed in experimental hypertensive models. In cholesterol-fed rabbits, vatanidipine exerted an anti-atherosclerotic action, which is probably attributable to the inhibitory action of the agent on low-density lipoprotein oxidation. In essential hypertensive patients, the plasma levels of cholesterol and triglyceride decreased after vatanidipine treatment, thus suggesting that this agent may have a therapeutic potential in preventing such vascular diseases as atherosclerosis. Taken together, vatanidipine appears to be a novel and useful antihypertensive agent, which can both prevent target-organ damage and reduce cardiovascular morbidity and mortality.

Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Nitrendipine

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Cardiology; Dihydropyridines; Drug Therapy, Combination; Education, Medical, Continuing; Heart Diseases; Humans; Hypertension; Nitroprusside; Renin; Renin-Angiotensin System; Vasoconstriction

Manidipine is a dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. The resulting reduction in blood pressure (BP) in patients with hypertension is maintained over 24 hours. Manidipine 10 to 40 mg once daily for 4 weeks significantly lowered office BP from baseline and compared with placebo, and significantly reduced 24-hour BP compared with placebo in patients with essential hypertension in a well controlled trial. The decline in BP was maintained over 24 hours (trough to peak BP ratios were >50%) without disturbing the circadian BP pattern. BP reductions with therapeutic dosages of manidipine were maintained for up to 1 year in noncomparative trials. The BP-lowering capacity of manidipine 5 to 20 mg/day appears to be similar to that of other calcium antagonists with which it has been compared in randomised double-blind and nonblind trial. In a well controlled short term trial, manidipine 10 mg daily significantly decreased trough sitting BP compared with placebo in elderly patients with mild to moderate essential hypertension. Decreases in BP were maintained for up to 3 years of treatment. The drug (10 or 20 mglday) also significantly lowered sitting BP from baseline in patients with hypertension and type 2 diabetes mellitus in randomised, long term comparative trials. In general, the observed reduction in BP with manidipine was similar to that observed with amlodipine, enalapril or delapril. The effects of manidipine on urinary albumin excretion (UAE) have not been clearly demonstrated in clinical trials in this patient group. BP was also reduced with manidipine in patients with impaired glucose tolerance. Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Commonly reported events included ankle oedema, headache. palpitation. flushing, dizziness, rash and fatigue. Manidipine appears to have less potential for pedal oedema than amlodipine.. Manidipine has shown antihypertensive efficacy and appears to be well tolerated in adult and elderly patients with mild or moderate essential hypertension. The BP-lowering effects of the drug in patients with hypertension and type 2 diabetes mellitus or impaired glucose tolerance were not associated with any adverse metabolic effects. The effects of manidipine on UAE in this patient group remain unclear. Manidipine provides an additional treatment option for patients for whom dihydropyridine calcium antagonists are appropriate. Manidipine is a dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. The resulting reduction in blood pressure (BP) in patients with hypertension is maintained over 24 hours. Manidipine 10 to 40mg once daily for 4 weeks significantly lowered office BP from baseline and compared with placebo, and significantly reduced 24-hour BP compared with placebo in patients with essential hypertension in a well controlled trial. The decline in BP was maintained over 24 hours (trough to peak BP ratios were >50%) without disturbing the circadian BP pattern. BP reductions with therapeutic dosages of manidipine were maintained for up to 1 year in non-comparative trials. The BP-lowering capacity of manidipine 5 to 20 mg/day appears to be similar to that of other calcium antagonists with which it has been compared in randomised double-blind and nonblind trial. In a well controlled short term trial, manidipine 10 mg daily significantly decreased trough sitting BP compared with placebo in elderly patients with mild to moderate essential hypertension. Decreases in BP were maintained for up to 3 years of treatment. The drug (10 or 20 mg/day) also significantly lowered sitting BP from baseline in patients with hypertension and type 2 diabetes mellitus in randomised, long term comparative trials. In general, the observed reduction in BP with manidipine was similar to that observed with amlodipine, enalapril or delapril. The effects of manidipine on urinary albumin excretion (UAE) have not been clearly demonstrated in clinical trials in this patient group. BP was also reduced with manidipine in patients with impaired glucose tolerance. Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Commonly reported events included ankle oedema, headache. palpitation. flushing, dizziness, rash and fatigue. Manidipine app. Manidipine has shown antihypertensive efficacy and appears to be well tolerated in adult and elderly patients with mild or mo

Topics: Aged; Animals; Antihypertensive Agents; Diabetes Complications; Dihydropyridines; Hemodynamics; Humans; Hypertension; Kidney; Nitrobenzenes; Piperazines

Topics: Amlodipine; Calcium Channel Blockers; Diabetic Angiopathies; Dihydropyridines; Enalapril; Fosinopril; Humans; Hypertension; Randomized Controlled Trials as Topic

Lercanidipine is a vasoselective dihydropyridine calcium antagonist which causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug and as such has a slower onset and longer duration of action than a number of other calcium antagonists. Preclinical evidence suggests that lercanidipine has antiatherogenic potential and it may also protect against end-organ damage. In well controlled clinical studies, once daily administration of lercanidipine 10 or 20mg effectively reduced blood pressure (BP) compared with placebo in patients with mild to moderate hypertension without affecting heart rate. Response rate (percentage of patients with diastolic BP < or =90mm Hg or reduced by > or =10mm Hg from baseline) ranged from 50 to 66% with lercanidipine 10 mg/day and up to 86% with lercanidipine 20 mg/day. The drug had a long duration of action: clinical measurements for diastolic BP yielded a trough/peak ratio of >0.8 for both lercanidipine dosages in 1 study. Comparative trials, either published in full or as abstracts, found lercanidipine 10mg once daily for > or =4 weeks to be at least as effective as atenolol 50mg once daily, candesartan cilexetil 16 mg/day, captopril 25mg twice daily, enalapril 20 mg/day, hydrochlorothiazide 12.5mg once daily, irbesartan 150 mg/day and slow release nifedipine 20mg twice daily in patients with mild to moderate hypertension. In addition, lercanidipine 20 mg/day was as effective as amlodipine 10 mg/day. Lercanidipine is effective in the treatment of elderly patients (aged 60 to 85 years) with mild to moderate essential hypertension and in those with isolated systolic hypertension. In addition, monotherapy with lercanidipine 20 or 40 mg/day has shown efficacy in patients with severe hypertension, and add-on therapy helped control BP in a large proportion of patients with severe hypertension not responding sufficiently to beta-blockers, diuretics or ACE inhibitors. Unpublished data indicate that the drug reduces blood pressure in patients with type 2 (non-insulin-dependent) diabetes mellitus, without adversely affecting glucose homeostasis. Lercanidipine was well tolerated in clinical trials, with most treatment-related adverse events typical of dihydropyridine calcium antagonists, namely headache, flushing, dizziness and ankle oedema.. Lercanidipine is an effective and well tolerated once daily antihypertensive agent in patients with mild to moderate hypertension. In addition, the drug may reduce BP when used as monotherapy in patients with severe hypertension or when used adjunctively in patients with resistant hypertension. Importantly, lercanidipine appears to be at least as effective and well tolerated as other commonly used antihypertensive agents. The drug therefore represents a useful therapeutic option in the management of patients with hypertension and will be particularly useful in patients not responding to, or intolerant of, antihypertensive agents from other drug classes.

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Humans; Hypertension

The emphasis on evidence-based medicine and the use of safe, cost-effective therapeutic strategies demands that management decisions be based upon evidence derived from clinical studies. Whilst prospective double blind clinical trials are regarded as the gold standard, there is no doubt that meta-analysis has proved valuable in defining the benefits of antihypertensive therapy. The antihypertensive efficacy of lacidipine has been assessed in a retrospective meta-analysis of a series of clinical studies in which the drug was compared with placebo and all the major classes of antihypertensive agent. All of the studies entered into the meta-analysis were parallel group double blind trials. Efficacy was based upon the reduction in both systolic and diastolic blood pressure and the effect on heart rate at trough immediately prior to dosing during maintenance therapy. In placebo controlled trials a clear dose response relationship was apparent with blood pressure reductions that were significantly greater than that observed with placebo at doses of 2 mg lacidipine and above. In active control trials, diastolic blood pressure reductions of 10-15 mmHg were observed at the end of the monotreatment phases (> 6-8 weeks) with a final reduction of 15-20 mmHg with the efficacy of lacidipine being equivalent to that of the comparator drug. Comparable results were also achieved for the response rates to therapy which varied between 70 and 85% at the end of the monotreatment phase and 82-98 when combination with other antihypertensive agents was permitted. There was no evidence of cardio-acceleration in any of the trials where significant blood pressure reduction was detected. This retrospective analysis in a large population base confirms the documented antihypertensive efficacy of lacidipine and demonstrates the suitability of the drug as a first line antihypertensive agent.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Databases, Factual; Dihydropyridines; Diuretics; Humans; Hypertension

More than 50% of hypertensive patients are aged above 65 years. Physiopathology of essential hypertension is different in the elderly as compared with the young adult. Furthermore, not only are concomitant diseases statistically more frequent in the elderly, but the aging process in itself produces several specific changes in target organs. Several trials have shown that treatment of hypertension in the elderly, including the 'old elderly', is highly beneficial in terms of reduced morbidity and mortality. The therapy used in all these major intervention trials consisted of diuretics and/or beta-blockers. Recently, the Systolic Hypertension in Europe study and the HOT study extended the list of antihypertensive agents with proven beneficial effects on cardiovascular outcomes to dihydropyridine calcium antagonists. Dihydropyridine calcium antagonists, such as lacidipine, have been advocated as first-choice agents for the treatment of hypertension in the elderly on grounds that: a) they may be more active in lowering blood pressure because of the predominantly low renin status in the elderly hypertensives; b) they may be better tolerated because the side effects related to the activation of the sympathetic system may be less frequent as a consequence of the attenuation of baroreflexes during aging; and c) they may have beneficial effects on a variety of concomitant cardiovascular diseases which are frequently present in the elderly. These assumptions are, however, not always proven in the clinical practice. Only well-designed prospective comparative trials may solve this issue. STOP-2, NICS-EH, HYVET, SCOPE and SHELL are acronyms of ongoing clinical trials specifically designed in the elderly hypertensive. The SHELL study assesses the benefits of lacidipine compared with chlortalidone on the prevention of cardiovascular events. The effects of lacidipine (vs atenolol) on the development and progression of carotid atherosclerosis are also being currently investigated in the ELSA study.

Topics: Aged; Antihypertensive Agents; Dihydropyridines; Humans; Hypertension

Dihydropyridine calcium antagonists have been used for many years in the treatment of angina pectoris and hypertension. According to the common view, their mechanism of action is based on an inhibition of the smooth muscle L-type calcium current, thus decreasing intracellular calcium concentration and inducing smooth muscular relaxation. However, in recent years evidence has accumulated that besides the smooth muscle effects of these agents, their effect on the endothelium must also to be taken into account. It was shown that dihydropyridines can induce the release of nitric oxide (NO) from the vascular endothelium of various vessels and in different species. This was first shown by Günther and colleagues by assaying the methaemoglobin formation in the presence of intact endothelium (in porcine coronary arteries) with and without treatment with nitrendipine. These findings were later confirmed by direct measurement of NO or of nitrite production. In addition, in several preparations, including micro- and macrovasculature, the sensitivity of the vasorelaxing effect of the dihydropyridines to inhibitors of NO-synthase, such as L-N(G)-nitroarginine (LNNA) or L-N-nitro-arginine-methyl-ester (L-NAME), has been shown. With these studies it became evident that the NO-releasing effect was not unique to nitrendipine but was a group phenomenon shared by the dihydropyridines and several nondihydropyridine calcium antagonists. In addition to their action on vascular endothelium, NO release by nifedipine has also been detected in platelets. There are also studies showing long term effects of calcium antagonists involving NO release. Regarding the underlying mechanism of NO release, nitrendipine was shown, not to decrease but to increase intracellular Ca2+ in cultured endothelial cells. This increase was sensitive to both Ca2+-free extracellular superfusion and to gadolinium, a lanthanide known to inhibit shear-stress activated cation channels. This increase in intracellular calcium can activate endothelial NO-synthase, thus inducing the release of NO. These findings on a dual mode of action, i.e. the direct relaxing effect by inhibition of the smooth muscle L-type calcium current and indirect relaxing effect by release of NO from vascular endothelium may help to understand the beneficial antihypertensive effects of the dihydropyridine calcium antagonists and the preferential effect of certain drugs in certain vascular regions (resistance versus conductive vessels). In

Topics: Angina Pectoris; Animals; Calcium; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Nitrendipine; Nitric Oxide; Time Factors

Calcium antagonists are uniquely suitable for managing hypertension by virtue of their efficacy, metabolic neutrality and their ability to countervail counterregulatory adaptive changes, thereby enhancing blood pressure lowering. Recent evidence has accrued underscoring the concept that calcium antagonists are heterogeneous and consist of chemically dissimilar agents. The difference in formulations and pharmacokinetics affect clinical events including the effect on blood pressure, heart rate and the degree with which sympathetic activity is activated. Lacidipine is a new calcium antagonist that is the prototype of the lipophilic dihydropyridines. Of great importance, lacidipine has a slow onset of vasodilator/antihypertensive effect and does not promote an excessive sympathetic drive. These attributes commend its selection as an antihypertensive agent.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

The evaluation of haemodynamic patterns in hypertensive patients by radionuclide techniques and a tomographic gamma camera has revealed differences between older and younger patients. In younger hypertensive patients, the hyperkinetic state is reflected in an increase in heart rate and, consequently, an increased cardiac index and left ventricular ejection fraction (LVEF) in comparison with normotensive controls. Older hypertensive patients, however, show a different haemodynamic pattern, with reduced systolic and diastolic function at rest compared with normotensive elderly people, and marked depression of cardiac reserve during exercise. Elderly hypertensive patients also show strikingly higher hyperresistance and reduced peripheral perfusion in comparison with younger hypertensive patients. These haemodynamic differences need to be taken into account when considering antihypertensive treatment. In a study in elderly hypertensive patients, lacidipine treatment (4 mg/day for 90 days) produced a significant decrease in total peripheral resistance and blood pressure, together with a reduction in left ventricular (LV) afterload and an increase in cardiac output and LVEF (tending towards normal values). The LV peak filling rate was also increased, and evaluation of systolic and diastolic cardiac reserve during exercise showed positive changes in cardiac performance. The haemodynamic changes with lacidipine were similar to those produced by other long-acting dihydropyridines [nifedipine gastrointestinal therapeutic system (GITS) and nitrendipine], but changes occurring with nisoldipine were less significant. The reduction in left ventricular hypertrophy (LVH) is an obvious goal of antihypertensive therapy, and several studies have demonstrated the effectiveness of lacidipine treatment in decreasing LVH in hypertensive patients. In hypertensive patients with associated LV dysfunction, favourable effects on global parameters of LV function similar to those with amlodipine have been noted with lacidipine. Myocardial blood flow was strikingly increased during lacidipine treatment and coronary resistance was significantly decreased, both at baseline and after maximal vasodilatation with dipyridamole. Thus, lacidipine's vasodilatory and anti-ischaemic profile makes it an appropriate choice for the treatment of hypertension.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular System; Dihydropyridines; Humans; Hypertension

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their colleagues. Inferring that those who disagree have an unstated secondary agenda that will bring personal financial rewards or government accolades is inappropriate and counterproductive. Third, the randomized clinical trial, despite all its imperfections, is still the best tool to establish common ground on controversial issues. Finally, what may seem best from the public health perspective may not be in the best interest of the individual patient--a possibility that physicians have to constantly c

Topics: Antihypertensive Agents; Benzimidazoles; Blood Pressure; Calcium Channel Blockers; Case-Control Studies; Clinical Trials as Topic; Dihydropyridines; Diltiazem; Heart Diseases; Humans; Hypertension; Longitudinal Studies; Mibefradil; Nifedipine; Public Health; Randomized Controlled Trials as Topic; Risk Factors; Tetrahydronaphthalenes; Vasodilator Agents; Verapamil

GROUPS OF CALCIUM CHANNEL BLOCKERS: The calcium channel blockers comprise a heterogeneous group of drugs. From both pharmacological and clinical points of view, they can be divided into three groups: the dihydropyridines, the phenylalkylamines and the benzothiazepines. REASONS FOR DIFFERENCES: There are important clinical and functional differences between the three groups. This may be explained by the fact that these families bind at different sites to the calcium channel. In this review, the major differences between the three groups are discussed, with an emphasis on verapamil.

Topics: Antihypertensive Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Sympathetic Nervous System; Verapamil

We evaluated the effects of calcium antagonists on sympathetic activity in hypertensive patients by searching Medline for English language articles published between 1975 and May 1996 using the terms calcium antagonists, sympathetic nervous system and catecholamines.. Data from clinical studies reporting only the effects of calcium antagonists on blood pressure, heart rate and plasma norepinephrine (NE) levels in patients with hypertension were analysed according to class of calcium antagonist (dihydropyridine vs non-dihydropyridine), their duration of action (short-acting (SA) vs long-acting (LA)) and treatment duration.. We identified 63 studies involving 1252 patients. Acutely after single dosing, SA calcium antagonists decreased mean arterial pressure by 13.7 +/- 1.1% and increased heart rate by 13.7 +/- 1.4% and NE levels by 28.6% +/- 2.5%. Change in NE levels correlated with change in heart rate (r = 0.59, P < 0.01) and inversely with change in arterial pressure (r = 0.46, P < 0.05) in patients taking dihydropyridine calcium antagonists acutely. With sustained therapy, both classes of SA calcium antagonists increased NE levels. Whereas NE levels remained slightly elevated and heart rate unchanged with LA dihydropyridine calcium antagonists, both heart rate and NE levels decreased with LA non-dihydropyridine calcium antagonists. SA calcium antagonists stimulate sympathetic activity when given acutely and over the long term, irrespective of their molecular structure. In contrast, sympathetic activation is less pronounced with LA dihydropyridine calcium antagonists and falls with LA non-dihydropyridine calcium antagonists.. The present findings offer a possible pathophysiological explanation for the increase in morbidity and mortablity observed in some studies using SA calcium antagonists.

Topics: Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Delayed-Action Preparations; Dihydropyridines; Heart Rate; Humans; Hypertension; Norepinephrine; Sympathetic Nervous System

This article reviews the pharmacological profile of the dihydropyridine calcium antagonist (CaA) barnidipine [(+)-(3'S,4S)-3-(1'-benzyl-3'-pyrrolidinyl)-methyl-2,6-dimethyl-4-(m-nit rophenyl)-1,4dihydropyridine-3,5-dicarboxylate x HCl]. The characteristics and potential advantages of its pharmacological selectivity are also outlined. Barnidipine is an L-type CaA with high affinity for [3H]nitrendipine binding sites (Ki = 0.21 nmol/l). Its pharmacological profile has been studied in a variety of isolated tissues and animal models, such as isolated coronary arteries (pig, dog, rat), aorta (guinea pig) and in hypertensive rats (spontaneously hypertensive, renal hypertensive, desoxycorticosterone acetate [DOCA]-salt). Barnidipine may be characterized as a highly potent drug with vasoselectivity and, accordingly, a lack of negative inotropic activity. The onset of its action in vivo is slow, and it does not elicit reflex tachycardia. Its long duration of action, due to its lipophilicity, means that satisfactory control of elevated blood pressure can be obtained with once-daily dosing. Another interesting feature of barnidipine is its stereoselectivity. As the barnidipine molecule contains two chiral centres, it can have four possible enantiomers. The active component in the capsules used clinically consists of the S,S form, which is the most potent and longest acting of the four enantiomers.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Dogs; Guinea Pigs; Hypertension; Nifedipine; Rats; Rats, Inbred SHR; Structure-Activity Relationship

Choice of first-line treatment for arterial hypertension: should dihydropiridines be avoided in diabetic patients? The use of dihydropyridines as first-line antihypertensive drugs in Type 2 (non-insulin-dependent) diabetic subjects has recently been challenged by several clinical trials that found increased risk of cardiovascular events (sudden death and myocardial infarction). This report provides a critical appraisal of available data. The main shortcomings of these trials are that clinical events were secondary outcomes in studies designed for other purposes (effects of antihypertensive drugs on blood pressure control or metabolic tolerance); that control groups on placebo or reference treatment were lacking in both trials; and that one trial was stopped at the request of the safety committee. Therefore, estimates of potentially adverse effects are imprecise and may be biased. Until data from large-scale ongoing trials are available, dihydropyridines should continue to be used as second-step antihypertensive drugs in Type 2 patients.

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Contraindications; Diabetic Angiopathies; Dihydropyridines; Humans; Hypertension; Risk Factors

Lipophilic dihydropyridines have many theoretical and practical clinical advantages owing to their long permanence at the cell membrane. They have a greater chance of smoothly and permanently reducing blood pressure over 24 h than other dihydropyridines, a feature that may have positive prognostic implications since 24-h blood pressure is more closely related to the end-organ damage of hypertension. They may avoid the sympathetic activation consequent to an excessive early-dose hypotension, which is responsible for an increase in 24-h blood-pressure variability and reflex tachycardia, two phenomena that may worsen the prognosis of hypertensive patients. A further advantage which has been shown in experimental and clinical settings is the possibility of reducing the extension and progression of atherogenic lesions in blood vessels, which are responsible for cardiovascular complications in hypertension. Some of these features have been shown by the novel lipophilic dihydropyridine lercanidipine. In particular, clinical studies have shown that (i) this drug is effective in homogeneously reducing blood pressure over 24 h, (ii) its antihypertensive effect is similar to that of some common antihypertensive drugs, and (iii) the rate of adverse events experienced with lercanidipine is no greater than that observed with other antihypertensive drugs, with special reference to non-lipophilic calcium antagonists. In particular, studies performed so far have shown that lercanidipine does not exert a dangerous reflex tachycardia.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Tachycardia

Left ventricular hypertrophy (LVH) represents an important intermediate end-point for, for example, the progression to heart failure. The persistence or progression of LVH despite antihypertensive therapy probably reflects the persistence or activation of mechanisms that negatively affect the cardiovascular system and, consequently, long-term outcome.. Long-term treatment with rapid-onset (and usually short-acting) dihydropyridine calcium antagonists is significantly less effective than angiotensin converting enzyme (ACE) inhibition in reducing left ventricular mass (LVM) in hypertensive patients. Both intermittent, and probably only partial, blood pressure control and an increase in sympathetic activity resulting from rapid decreases in blood pressure following dosing with such calcium antagonists may contribute to this relative ineffectiveness. In contrast, more recent studies have demonstrated that the longer acting dihydropyridines can reduce LVM as effectively as ACE inhibitors.. Among the 1,4-dihydropyridines, drugs such as amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) maintain good blood pressure control over the full 24-h dosing period and do not cause dose-related increases in sympathetic activity. In contrast, extended-release felodipine has been shown to provide only intermittent blood pressure control, still leading to sympathetic activation. Notably, during short periods of noncompliance, blood pressure control is maintained with intrinsically long-acting agents such as amlodipine but not with slow-release formulations of short-acting agents such as nifedipine GITS.. It is possible that the rate of onset and duration of action of various dihydropyridines may be pivotal factors in determining their effects on cardiovascular outcomes. Thus, the least beneficial dihydropyridines may be rapid-onset, short-acting agents, such as nifedipine capsules, and the most beneficial may be the slow-onset, long-acting agents such as amlodipine.

Topics: Antihypertensive Agents; Cardiomegaly; Dihydropyridines; Humans; Hypertension; Remission Induction; Treatment Outcome

REQUIREMENTS FOR DRUG REGISTRATION: Current drug registration procedures by the United States Food and Drug Administration (FDA) require at least two placebo-controlled factorial- and/or parallel-study designs. The statistical and graphical analysis of a factorial-design study allows the investigator to identify the optimal dose of the combination but these comparisons require considerable overall patient numbers for statistical power. In contrast, parallel-design studies require about 150 matched patients in each of the four arms.. In an effect to compare combination studies across antihypertensive drug classes, we examined data from studies that formed the basic of past registration applications to the FDA. Our review findings indicated that combined antihypertensive effects were, at best, approximately additive for a number of different combinations. However, this takes no account of the advantages of drug combinations in allowing reduced dosages of each drug with fewer adverse effects than monotherapy.. In the case of calcium antagonists, physicians must differentiate between rapid-onset or short-acting dihydropyridines, which raise the heart rate and plasma noradrenaline, and longer-acting newer calcium antagonists. Recent evidence indicates that the combination of a long-acting calcium antagonist and an angiotensin converting enzyme inhibitor is particularly effective in reducing cardiovascular risk.. Combining drugs with different mechanisms of action seems to be a reasonable and effective way of treating hypertension. It is essential, however, to establish the efficacy and safety of all new drug combinations by performing carefully designed clinical studies that fulfill the stringent FDA requirements.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension

Calcium channel blocker (CCB) is one of the most frequently prescribed cardiovascular drugs. Two main classes of CCBs, dihydropyridines and benzothiazepines, are now clinically available for the treatment of hypertension in Japan. Both drugs inhibit the inward current of calcium ions through the L-type calcium channels. However CCBs have markedly different chemical structures and different effects on cardiovascular system. Therefore, in the present paper, their pharmacokinetic properties and interactions with other drugs are reviewed, and newly developed CCB are also described.

Topics: Benzimidazoles; Calcium Channel Blockers; Dihydropyridines; Drug Interactions; Humans; Hypertension; Mibefradil; Nifedipine; Tetrahydronaphthalenes; Thiazoles

Topics: Calcium Channel Blockers; Case-Control Studies; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Myocardial Ischemia; Nifedipine; Sensitivity and Specificity

The aim was to review the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer- a novel approach which may be of some value while awaiting the outcome of calcium antagonist treatment in prospective, randomised trials of cardiovascular morbidity and mortality.. This paper includes data from clinical trials finished before 1 January 1995. Since 1985, 50 phase III-IV trials have been performed investigating antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment.. In all, 16,590 patients received lacidipine; 13,419 in open studies and 3171 in double blind, comparative trials. Altogether, these patients contributed 5 124 person-years (p.y.). Furthermore, active comparative treatment was given to 1810 patients and placebo to 451.. Both fatal and non-fatal cardiovascular events have been estimated. Efficacy (change in blood pressure and heart rate), adverse event rates, and drop-out rates have been compared for the different treatment regimes. Also the reasons for dropping out of studies have been compared. Adverse effects were also analysed as to their time of occurrence and duration.. Blood pressure was lowered by 2-6 mg lacidipine; in the controlled trials from 166/102 to 144/85 mmHg. Heart rate dropped from 75.6 to 74.1 beats per minute. The estimated event rate for a possible myocardial infarction in all studies was 5.46 per 1000 p.y. The fatal (all causes) event rate was 5.27 per 1000 p.y., and the estimated fatal cardiovascular event rate 2.93 per 1 000 p.y. In one long-term study (48 weeks) comprising 2282 patients (1658 p.y.), the observed fatal (all causes) event rate was 4.2 per 1 000 p.y. The overall incidence in the comparative studies of (one or more) adverse events was: for lacidipine 30.3%, other calcium antagonists 43.8%, diuretics 18.7%, beta-receptor blockers 48.7%, ACE inhibitors 10.4%, and placebo 15.7%. The adverse effects of lacidipine were the expected ones, e.g. headache, flushing, pedal oedema, and palpitations.. When analysing the data on file for lacidipine and some comparatory drugs in almost 19000 hypertensive patients we have found lacidipine to be an effective and well tolerated drug with a reasonable adverse profile typical for a calcium antagonist of the dihydropyridine group. Our study has the obvious limitations of a retrospective analysis of data obtained from a large cohort of patients, most of whom received lacidipine for a relatively short period of time. The present results indicate a lower fatal event rate than previously reported in the actively treated hypertensives in Collins' meta-analyses, comprising ten times more person-years than our analysis. Prospective studies with lacidipine focusing on possible reductions of atherosclerosis as well as incidence of cardiovascular disease are required and are well under way.

Topics: Adult; Aged; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Heart Rate; Humans; Hypertension; Middle Aged

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Diastole; Dihydropyridines; Heart; Humans; Hypertension; Nitrobenzenes; Piperazines; Systole

Short-acting formulations of nifedipine-like 1,4-dihydropyridines cause clearly less regression of left ventricular hypertrophy (LVH) than anticipated from their antihypertensive effect. Moreover, these compounds increase the risk of cardiac death and myocardial reinfarction in patients with coronary artery disease (CAD) not on concomitant beta-blocker therapy. Increased sympathetic activity is one of the non-pressure-related risk factors for LVH and atherosclerosis in hypertensives. In addition, increased sympathetic tone may precipitate clinical events in subclinical or stable CAD. Intermittent increases in sympathetic activity persist during chronic treatment with those 1,4-dihydropyridines that have a poor peak/trough ratio with a rapid fall of BP and deactivation of the arterial baroreflex. On the other hand, these intermittent increases in sympathetic activity do not occur for formulations and compounds with a gradual and sustained antihypertensive effect over the dosing interval. Such long-acting 1,4-dihydropyridines cause regression of LVH as anticipated from their antihypertensive effect, and are similar to angiotensin converting enzyme inhibitors. In contrast to short-acting 1,4-dihydropyridines, long-acting 1,4-dihydropyridines appear not to be detrimental for patients with stable CAD. However, the evidence is still missing for patients with unstable CAD. Neither is there evidence that they will reduce cardiovascular morbidity and mortality in patients with CAD when used for the chronic treatment of hypertension.

Topics: Animals; Blood Pressure Determination; Circadian Rhythm; Dihydropyridines; Humans; Hypertension; Risk Factors; Sympathetic Nervous System

This review describes aspects of the calcium channel blocker controversy as it relates to hypertensive and coronary artery disease patients. Much of the controversy has occurred because of off-label use of short-acting calcium channel blockers that were never approved or recommended for use in patients with hypertension or acute myocardial infarction. A recent analysis of slow-onset, long-acting calcium channel blockers, which lack large peak-to trough fluctuations in drug levels, did not show a signal suggesting an increase in cardiovascular events.

Topics: Cardiovascular System; Dihydropyridines; Humans; Hypertension; Myocardial Infarction

Topics: Antihypertensive Agents; Arteriosclerosis; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension; Hypertrophy, Left Ventricular; Multicenter Studies as Topic

The aim of this study was to review the effect of the calcium antagonists in general and manidipine hydrochloride in particular on the different renal haemodynamic parameters in experimental animals and human beings.. The paper includes data from experimental and human studies performed between 1978 and 1995.. As far as renal blood flow and glomerular filtration rate are concerned in experimental animals and in men, manidipine, a long-lasting dihydropyridine calcium antagonist, demonstrated its action not only on the afferent arteriole, as other dihydropyridines, but also on the efferent one. This action, which avoids producing any increase in intra-glomerular pressure and renal damage, would be similar to that of angiotensin converting enzyme inhibitors. The direct natriuretic effect of manidipine, observed also with other dihydropyridines, has been demonstrated by two studies performed in both spontaneously hypertensive and normotensive rats, indicating a direct renal tubular effect. In 5/6 nephrectomized rats treated with manidipine, blood pressure, proteinuria, serum creatinine and glomerular lesions, observed after histological examination, were significantly reduced with respect to control untreated 5/6 nephrectomized rats. Calcium antagonists have demonstrated a clear beneficial effect on renal vasoconstriction induced by cyclosporine therapy in renal transplant patients and in the prevention of acute renal failure secondary to the administration of radiocontrast agents, amphotoricin B, cisplatin and aminoglycosides.. Calcium antagonists are effective drugs for controlling blood pressure and for inducing renal vasodilatation. Manidipine hydrochloride increases renal blood flow and glomerular filtration rate with vasodilation of afferent as well as efferent arterioles, reducing intraglomerular pressure. According to experimental and human studies on renal haemodynamics, manidipine could be used in diabetic nephropathy, glomerular lesions, microalbuminuria and proteinuria.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation

Topics: Antihypertensive Agents; Cardiovascular Diseases; Dihydropyridines; Humans; Hypertension

GUIDELINES ON DRUG SAFETY: Recent European Union draft guidelines for the safety evaluation of drugs intended for long-term use state that during drug development the safety profile of the new compound should be assessed over a period of time consistent with intended usage. This is in reasonable agreement with guidelines prepared by other regulatory authorities. CLINICAL DRUG DEVELOPMENT: Satisfactory preclinical data on a new compound are used to obtain authorization for human testing from the National Committees on Safety of Medicines. Clinical trials are performed in four phases, ranging from phase I studies performed on healthy volunteers (n = 20-50) to postmarketing (phase IV) studies. The latter are of great importance as they cover large patient populations (n = 2000 to > or = 10,000) and allow detection of rare adverse drug reactions. ADVERSE DRUG REACTIONS: Type B reactions are serious, unpredictable reactions to a drug that necessitate treatment withdrawal. Type A reactions are dose-dependent, and represent the majority of adverse reactions. They are often managed by dose reduction rather than drug withdrawal. ADVERSE REACTIONS TO ANTIHYPERTENSIVE AGENTS: Examples of type B adverse reactions to antihypertensives are the cutaneous and ocular reactions to practolol, and angioneurotic oedema associated with angiotensin converting enzyme inhibitors. Lacidipine, a second-generation calcium antagonist, is an example of a modern antihypertensive agent with a favourable safety profile. The adverse reactions associated with lacidipine are mild to moderate and of the A type, the major ones being those typical of calcium antagonists (headache, flushing and pedal oedema due to vasodilation.

Topics: Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Product Surveillance, Postmarketing

To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints.. In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Topics: Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension.

Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution

In our recent review of calcium antagonists for the treatment of patients with cardiovascular disease we concluded that most patients could be managed with formulations of one of the original calcium antagonists, verapamil, diltiazem or nifedipine. Experience is greatest with these drugs, and none of the newer alternatives appeared more effective or better tolerated. Lacidipine (Motens-Boehringer Ingelheim) is the latest calcium antagonist to be marketed for the treatment of patients with mild to moderate hypertension. It is licensed for once-daily use without the need for a modified-release formulation; in this respect it resembles amlodipine. The manufacturer of lacidipine claims that its gradual onset of action "cushions the fall in blood pressure" and "cushions against side effects".

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

OLD VERSUS NEWER DIHYDROPYRIDINE CALCIUM ANTAGONISTS: First-generation dihydropyridines have a short duration of antihypertensive action, which requires more than one daily dose in order to produce a relatively 'smooth' antihypertensive effect. However, more recent molecules or preparations have been shown to possess a much longer and smoother action. TROUGH:PEAK RATIOS OF NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM (GITS): The Italian Nifedipine GITS Study has shown, by using ambulatory blood pressure monitoring for 24-36 h, that nifedipine GITS, a new slow-release preparation, is capable of producing a marked reduction in both systolic and diastolic blood pressure that extends to 30-36 h after the dose. In this study, nifedipine GITS produced a smooth antihypertensive effect throughout the dose interval of 24 h by whatever method was used to evaluate this effect: (1) hourly blood pressure profiles; (2) trough:peak ratios, corrected or uncorrected by placebo effects (ratios often approached 100%); (3) calculation of individual trough:peak ratios in all treated patients (60% of whom had ratios of > 50%); and (4) calculation of individual trough:peak ratios in 'responders' to nifedipine GITS (approximately 75% of whom had ratios of > 50%). USE OF AMBULATORY BLOOD PRESSURE MONITORING: The large body of data on ambulatory blood pressure monitoring provided by this study has also allowed comparison and analysis of the advantages and disadvantages of the various methods of assessing the smoothness of the antihypertensive action of a drug by ambulatory blood pressure monitoring.

Topics: Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Nifedipine

Topics: Angina Pectoris; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Humans; Hypertension

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diuretics; Humans; Hypertension; Hypertrophy, Left Ventricular

Effects of calcium antagonists on pressor mechanisms: A number of differences have been reported in the variable extent to which calcium antagonists interfere with various pressor mechanisms. In theory, high lipid solubility, membrane-binding characteristics and a prolonged duration of action appear to be requirements for a calcium antagonist to affect mechanisms such as vasodilation, endogenous vasoconstrictor responses, hormone release and natriuretic activity. Reduction in peripheral vascular resistance: A reduction in peripheral vascular resistance is fundamental to the antihypertensive effect not only of calcium antagonists but also of angiotensin converting enzyme inhibitors and alpha 1-adrenoceptor antagonists. However, only the calcium antagonists interfere directly with the pressor responses mediated by both the adrenergic nervous system and the renin-angiotensin system. Mechanism of lacidipine effects: Preliminary results with the new dihydropyridine calcium antagonist lacidipine indicate that it not only has vasodilator activity but that it also interferes with both adrenergic and non-adrenergic endogenous vasoconstrictor mechanisms. This may provide additional potentially beneficial cardiovascular effects, particularly in relation to left ventricular hypertrophy and dysfunction.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Calcium Channel Blockers; Cardiovascular Physiological Phenomena; Cardiovascular System; Dihydropyridines; Humans; Hypertension; Norepinephrine; Vascular Resistance; Vasoconstriction

Importance of L-channels for calcium: Calcium L-channels, the specific target of calcium antagonists, appear to be the receptors for these therapeutic agents. Therefore, the accessibility of these channels/receptors to calcium antagonists is a major determinant of the response to these drugs in cardiovascular disorders, including essential hypertension. As with numerous other drugs, the concentration at the receptor level and its time-course largely determine not only the intensity but also the rate of onset and the duration of the drug's effect. Disadvantages of nifedipine: Within the series of dihydropyridine calcium antagonists, the first compound introduced was nifedipine, a relatively hydrophilic drug. Owing to its hydrophilic character the drug rapidly reaches the receptor, thus explaining the rapid onset of its vasodilator action. Accordingly, reflex tachycardia develops, which is not only triggered by the degree of vasodilation but also by the rapidity of its onset. In addition, nifedipine has a short duration of action, requiring the use of special galenic formulations to allow one dose a day. New dihydropyridine calcium antagonists: In view of the disadvantages of the hydrophilic calcium antagonists, attempts have been made to develop dihydropyridines with a slower onset and a longer duration of action. This may be achieved by drugs which are largely in the ionized state at a physiological pH (e.g. amlodipine) and therefore combine slowly with the receptor and bind firmly to various tissue compartments. Another logical approach is the use of highly lipophilic drugs such as lacidipine. Because of its physicochemical properties, the effect in equilibrium is reached very slowly, after up to 5 h in isolated tissues and after more than 2 h after intravenous administration. Lacidipine appears to slowly enter a lipid compartment surrounding the dihydropyridine binding site, which has to be saturated before an equilibrium effect is reached. In addition, the persistence of the drug in this lipid compartment contributes to its long-lasting vasodilator effect.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Humans; Hypertension; In Vitro Techniques; Models, Biological; Nifedipine

Topics: Aged; Antihypertensive Agents; Dihydropyridines; Drug Administration Schedule; Drug Tolerance; Humans; Hypertension; Safety

Comparison of first- and second-generation calcium antagonists: Despite their diversity of structure, the first-generation calcium antagonists nifedipine, verapamil and diltiazem all have a short elimination half-life and a relatively short duration of action. In contrast, there appears to be wide diversity in these properties among the newer calcium antagonists, which are mostly dihydropyridines. The longer half-life and physicochemical properties of some of the newer agents allow full 24-h blood pressure control. Duration of action of lacidipine: Taken only once a day, lacidipine has proved as potent an antihypertensive agent as slow-release nifedipine administered twice a day. Lacidipine produces a satisfactory fall in blood pressure not only during waking hours but also during sleep at night, as shown by 24-h ambulatory monitoring. Moreover, this blood pressure fall is obtained without any reflex tachycardia or associated side effects. Compared with patients treated with placebo, systolic and mean arterial blood pressure variability (standard deviation) is reduced by lacidipine treatment.. Control of blood pressure using lacidipine once a day meets the criteria proposed by the United States Food and Drugs Administration for antihypertensive drug efficacy and duration of action.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Half-Life; Humans; Hypertension

Characteristics of three different calcium antagonist groups: Most important calcium antagonists used to treat cardiovascular disease belong to one of three main groups, phenylalkylamines, dihydropyridines and benzothiazepines. The best known drug in each group is verapamil, nifedipine and diltiazem, respectively. Dihydropyridines are predominantly vasodilators, with little or no primary cardiac activity; the tachycardia caused by these compounds is a reflex phenomenon. Verapamil and related drugs are also vasodilators, with an additional depressant effect on atrioventricular conduction, heart rate and contractility. Diltiazem's pharmacodynamic profile and side effects may be considered as intermediate between those of the dihydropyridines and verapamil. Characteristics of new calcium antagonists: Several new calcium antagonists have been introduced in the last few years, virtually all dihydropyridines. Compared with the older generation of calcium antagonists these newer drugs tend to have (1) a longer duration of action; (2) some selectivity for a specific vascular bed, such as resistance, coronary, renal or cerebral vessels; (3) a potentially useful extra component, such as diuretic or anti-atherogenic activity. Newer calcium antagonists described in this review: The newer compounds briefly characterized in this review are amlodipine, felodipine, isradipine, lacidipine, nimodipine, nisoldipine and nitrendipine. New slow-release formulations are also discussed. There is a particular emphasis on lacidipine and its potential for cardiovascular drug therapy.

Topics: Angina Pectoris; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diltiazem; Humans; Hypertension; Nifedipine; Vasodilator Agents; Verapamil

To compare the vascular effects of lacidipine with those of other calcium antagonists.. A review of published studies.. Experimental studies have shown that for a similar fall in blood pressure, lacidipine increased cardiac contractility while verapamil decreased cardiac contractility. In the rat aorta, the dose of lacidipine required to reduce a calcium-induced contraction by 50% was lower than that of all other calcium antagonists tested except nisoldipine. In human studies, especially, there are inherent limitations in the techniques available to measure regional blood flows under physiological conditions, making it difficult to compare the effects of different antihypertensive drugs. A recent study showed that renal blood flow was increased by lacidipine without any reduction in renal function. As in animals, vital organ perfusion was either preserved or increased. Further, maximal coronary vasodilation was associated with lower coronary resistance values during lacidipine treatment compared with pretreatment values. Another lacidipine study showed increased brachial artery compliance, while a study on the radial artery showed that lacidipine increased the compliance of this artery also.. Lacidipine has vascular selectivity. Although regional blood flows are difficult to measure, due to inherent limitations in the techniques available, the evidence suggests that lacidipine produces vasodilation in essential hypertensive subjects while maintaining or even increasing vital organ perfusion. This appears to be due to a regression of the structural changes that characterize hypertension.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Humans; Hypertension

Effects of calcium antagonists on left ventricular hypertrophy: The goals of antihypertensive treatment are to lower systemic blood pressure and to reverse left ventricular hypertrophy. A number of different drugs can induce a decrease in left ventricular mass, some of which are calcium antagonists. In particular, verapamil, diltiazem and a number of dihydropyridines (nifedipine, isradipine, lacidipine) have proved effective in this respect. Left ventricular systolic function: Left ventricular systolic function is often normal at rest in patients with hypertension, but is quite commonly abnormal during exercise. Calcium antagonists therefore do not affect resting systolic function in this category of hypertensive patients. In contrast, in hypertensive patients with heart failure the administration of dihydropyridines improves systolic performance. Left ventricular diastolic function: Isovolumic relaxation and rapid filling are often impaired in patients with hypertension, with or without left ventricular hypertrophy. Verapamil is effective in abolishing this diastolic dysfunction when given intravenously; in contrast, medium-term therapy with calcium antagonists such as diltiazem or dihydropyridines does not improve left ventricular filling properties. However, when antihypertensive therapy achieves a reduction in left ventricular mass, a consistent improvement in diastolic properties occurs.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Contraction; Ventricular Function, Left

To review the effects of calcium antagonists, and of the new dihydropyridine lacidipine in particular, on the glomerular filtration rate, renal plasma flow, and the sodium to water ratio in hypertensive patients.. Review of published data.. Different studies have shown a wide range of responses to all three subgroups of calcium antagonists in glomerular filtration rates and in renal plasma flows. In some studies there was a reduction and in others a rise in these two renal parameters. The administration of lacidipine was associated with a significant rise in renal plasma flow which disappeared with chronic treatment and no change in the glomerular filtration rate. There are only a few studies on the long-term natriuretic and diuretic effects of calcium antagonists. In the short term, dihydropyridine calcium antagonists appear to produce diuretic and natriuretic effects, but these effects are not seen with verapamil. Lacidipine showed no trend towards sodium and water retention.. Reported differences between calcium antagonists in glomerular filtration and renal plasma flow probably reflect differences in the baseline tone of pre- and postglomerular arterioles. Calcium antagonists do not cause sodium and water retention during chronic therapy. The new dihydropyridine derivative lacidipine lowers blood pressure without reducing renal function or causing sodium and water retention.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Renal Circulation; Water-Electrolyte Balance

To review the pharmacology, pharmacokinetic disposition, dose recommendations, adverse effects, drug interactions, and efficacy of isradipine in patients with hypertension or ischemic heart disease.. Data from scientific literature were extracted, evaluated, and summarized for presentation. A MEDLINE search was conducted using the following indexing terms: isradipine, calcium-channel blockers, hypertension, and angina pectoris. Experiences from studies evaluating isradipine reported in the form of articles, abstracts, or proceedings involving patients or healthy subjects were considered for inclusion.. Special consideration was given to clinical studies that had been designed in a blind, randomized fashion. Studies that compared the effectiveness and safety of isradipine with another antihypertensive or antianginal agent or placebo were included.. Data from human studies published in the English language were evaluated. Trials were evaluated according to sample size, design, and adequacy of description of therapeutic response.. Isradipine is a new dihydropyridine calcium-channel blocker that appears to exert less negative inotropic activity than nifedipine and to selectively inhibit sinoatrial conduction. Pharmacokinetic parameters are quite variable and considerably more work is needed to better describe the kinetic disposition of isradipine. Antihypertensive efficacy has been demonstrated extensively in a number of short-term trials. Antianginal efficacy also has been observed in a few short-term trials and is comparable to that of isosorbide dinitrate and nifedipine. Extensive experience with isradipine is minimal and no clear-cut advantages over existing compounds have been noted thus far.. The place of isradipine in the therapy of hypertension and myocardial ischemia is unclear and its routine use cannot yet be recommended based solely on clinical grounds.

Topics: Angina Pectoris; Calcium Channel Blockers; Clinical Trials as Topic; Coronary Disease; Dihydropyridines; Drug Interactions; Humans; Hypertension; Isradipine; Kidney

Renal vascular resistance is increased in essential hypertension, with a consequent reduction in renal plasma flow together with a normal or slightly reduced glomerular filtration rate. Non-specific vasodilators may exacerbate this effect while loop diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium antagonists may increase these renal hemodynamic parameters. We studied the effect of lacidipine, a new long-lasting calcium antagonist, on renal hemodynamics in 11 essential hypertensives. Lacidipine (4 mg once a day) acutely increased renal plasma flow without affecting the glomerular filtration rate. A transient, but non-significant, diuresis and natriuresis occurred. After 4 weeks of lacidipine treatment, all the parameters of renal function returned to basal levels. These results suggest that the well known renal effects of calcium antagonists are, at least in part, related to the onset of the antihypertensive effect being more pronounced with compounds such as nifedipine which have a rapid-onset, blood pressure-lowering effect.

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Evaluation; Humans; Hypertension; Kidney; Renal Circulation; Vascular Resistance

The effects of calcium antagonists in reducing blood pressure at rest and during exercise were examined in patients with mild-to-moderate essential hypertension. The haemodynamic effects of calcium antagonists were evaluated at rest and during exercise. We also examined 10 patients with mild-to-moderate essential hypertension taking lacidipine, a new dihydropyridine calcium antagonist (4 mg once a day, at 0700 h). Compared with placebo, lacidipine induced significant mean reductions in 24-h blood pressure (P less than 0.001 for systolic blood pressure; P less than 0.002 for diastolic blood pressure). After 24 h, the blood pressure reductions were still significant (P less than 0.02 for systolic blood pressure; P less than 0.04 for diastolic blood pressure). The heart rate did not change. During dynamic exercise, blood pressure at maximal effort was reduced (P less than 0.01 for systolic and diastolic blood pressure) and the external workload reached at the anaerobic threshold was significantly increased (P less than 0.001), but not at maximum effort. Ventilation and tidal volume were similar at both the anaerobic threshold and peak exercise, while oxygen uptake and carbon dioxide production were increased at the anaerobic threshold (P less than 0.02 for carbon dioxide production) but were similar at peak exercise.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Anaerobic Threshold; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Diuretics; Exercise; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male

Lacidipine is a calcium antagonist of the dihydropyridine group that is highly selective for vascular tissues. It has been tested during the last few years for the treatment of arterial hypertension. We evaluated the clinical position of this calcium antagonist on the basis of clinical results. From the dose-ranging studies carried out to determine the efficacy of lacidipine, it has been shown that the dose range of 2-6 mg of lacidipine given once daily is effective in reducing blood pressure levels. Lacidipine efficacy (4-6 mg/o.d.) also has been compared with that of the diuretic hydrochlorothiazide, the calcium-antagonist nifedipine, and the beta-blocker atenolol in three different clinical trials according to the same protocol. The results indicated that lacidipine, hydrochlorothiazide, nifedipine, and atenolol caused similar reductions both in systolic and diastolic blood pressure after 1 and 2 months of treatment. Similar blood pressure levels were also reached when another antihypertensive agent (atenolol or hydrochlorothiazide) had been added in nonresponders to monotherapy. Heart rate showed a significant decrease only under atenolol treatment, either monotherapy or associated to the previous treatment. In these comparison studies, tolerability was also evaluated. The incidence of side effects during lacidipine treatment was lower than during nifedipine or atenolol treatment, but higher than during hydrochlorothiazide therapy. Lacidipine did not cause any changes in the laboratory parameters evaluated during the 2-month monotherapy period. From a trial conducted in elderly patients, lacidipine 2 and 4 mg/o.d. has been shown to cause similar diastolic blood pressure reduction after 1 month of treatment, the effect being more gradual with the lower dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Meta-Analysis as Topic

Lacidipine is a new 1,4-dihydropyridine (DHP) that induces a potent calcium antagonistic activity on vascular preparations. It has a markedly slow rate of onset, but its effect is still apparent after 9 h of drug washout. Calcium antagonistic activity has been evaluated on nonvascular smooth muscle, and lacidipine has proved to be more vascular-selective than standard DHP derivatives. In cardiac preparations, the concentrations required to induce negative inotropic effects are approximately 100 times higher than concentrations needed to antagonize calcium-induced contractions in vascular smooth muscle. In addition, lacidipine exhibits antioxidant properties in tests based on the autoperoxidation of rat cerebral cortical membranes. In spontaneously hypertensive rats (SHRs), lacidipine induces a potent and long-acting blood pressure reduction (ED25 = 0.19 mg/kg orally and 0.006 mg/kg intravenously, with durations greater than 12 and 3 h, respectively). In saline-loaded SHRs and at antihypertensive dosages, lacidipine increases urine volume as well as urinary excretion of sodium. In one-clip, two-kidney renal hypertensive dogs, the antihypertensive properties of lacidipine after both oral and intravenous administration were confirmed. The marked vascular selectivity of lacidipine was clearly evident both in pithed rats infused with angiotensin II and in anesthetized dogs, in which preferential and long-lasting coronary and vertebral blood flow increases were also observed.

Topics: Animals; Blood Pressure; Blood Vessels; Calcium Channel Blockers; Dihydropyridines; Dogs; Hypertension; Rabbits; Rats

Selection of the appropriate dose of a new drug for initiation of treatment and then for maintenance is a complicated task. It requires the careful assessment and weighing of benefit vs. risk. A series of studies was carried out with lacidipine to determine the optimal initial dose in a general hypertensive population as well as in special populations in whom the pharmacokinetics may be different. The conclusions of these studies are that (a) in a general adult population, the initial dose should be 4 mg once daily; (b) in the elderly and in those with impaired liver function, the starting dose should be 2 mg once daily; and (c) renal dysfunction does not alter the usual starting dose of 4 mg once daily.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged

The circadian rhythm of blood pressure has been shown to be an accurate and repeatable method of characterizing blood pressure over each 24-h period, and probably provides the best index of cardiovascular risk. Many studies have confirmed that these curves can be used to define accurately the duration and degree of antihypertensive effect of drugs, and are not influenced by the administration of placebo. Furthermore, these curves represent an ideal method for testing the efficacy of once-daily drugs. Lacidipine has been tested against these curves in 12 hypertensive patients, and has been shown to be an effective antihypertensive agent throughout the day, with a 24-h duration of action after a single oral dose and without reflex tachycardia.

Topics: Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Humans; Hypertension

The clinical safety of the new dihydropyridine calcium antagonist lacidipine was assessed in 14 clinical trials, including 1,372 patients treated with lacidipine and 687 treated with an alternative antihypertensive agent. The type and incidence of adverse events seen with lacidipine were characteristic of this class of drug, being mainly those associated with the pharmacologic effect of vasodilation, but with a lower incidence of edema than seen with nifedipine. There were no unexpected adverse effects. Hence, lacidipine is likely to be well accepted in general clinical use. Furthermore, as it has the advantages of a long duration of action and once-daily dosage, the benefit/risk ratio indicates that lacidipine is a suitable agent for the first-line treatment of hypertension across a wide range of patients.

Topics: Adult; Aged; Aged, 80 and over; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Safety

Arterial diameter, blood flow, and vascular resistance of the common carotid artery were studied, using a pulsed Doppler system, in patients with uncomplicated sustained essential hypertension compared with age-matched normotensive subjects. In the hypertensive subjects, arterial diameter and blood flow remained close to the normal range while vascular resistance was increased. Following antihypertensive drug treatment with converting enzyme inhibitors, nitrates, or calcium antagonists, dilation of small or large arteries, or both, may be obtained, depending on the administered compound. Calcium blockade by lacidipine produced a predominantly carotid arteriolar dilation with no change in arterial diameter, suggesting independent consequences on cerebral circulation and baroreflex mechanisms.

Topics: Calcium Channel Blockers; Carotid Arteries; Cerebrovascular Circulation; Dihydropyridines; Humans; Hypertension; Pressoreceptors; Vasodilation

Topics: Amlodipine; Antihypertensive Agents; Delayed-Action Preparations; Dihydropyridines; Doxazosin; Humans; Hypertension; Isradipine; Nifedipine; Prazosin; Verapamil

K(+)-channel openers are a new class of drugs. They interact in a not yet identified fashion with a not yet identified population of K+ channels resulting in an increase in K+ conductance of the surface membrane. K(+)-channel openers have a high affinity for K+ channels of smooth muscle and distinctly less for cardiac or neuronal K+ channels. The cellular effects of K(+)-channel openers in smooth muscle include hyperpolarization, decrease in membrane resistance, inhibition of propagation of excitation, suppression of spontaneous electrical and mechanical activity and inhibition of agonist-induced contraction. The pharmacodynamic profile of K(+)-channel openers is reminiscent of typical vasodilators with decreases in total peripheral resistance and blood pressure and reflex increases in heart rate and cardiac output. While there is no doubt that K(+)-channel openers are effective antihypertensive agents, it is too early, at present, to define their future role in cardiovascular therapy. A satisfactory treatment of hypertension by these drugs may require the addition of diuretics and/or beta-blockers. Other potential clinical indications of K(+)-channel openers include coronary heart disease and asthma.

Topics: Antihypertensive Agents; Benzopyrans; Cromakalim; Dihydropyridines; Guanidines; Hemodynamics; Humans; Hypertension; Molecular Structure; Pinacidil; Potassium Channels; Pyrroles

Clinically used calcium antagonists are derivatives of either verapamil (verapamil), dihydropyridines (e.g. felodipine and nifedipine), or benzothiazepines (diltiazem). The principal side effects are mostly predictable, dose-dependent, and related to their main actions: vasodilatation, negative inotropic effects and antiarrhythmic effects. All calcium antagonists have demonstrated a pronounced hypotensive effect. Conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, while tachycardia, headache, ankle oedema; and flush are more frequent after felodipine and nifedipine. Another side effect is constipation, which is frequent after verapamil. Important interactions have been reported with, for instance, digoxin and beta-adrenergic blocking agents. Calcium antagonists may have favourable effects on serum lipids, and there is no indication of consistent changes in basal glucose metabolism. Uric acid is unchanged or reduced. Regarding the effects on the quality of life exerted by the different calcium antagonists, very little is known since such studies have not been performed so far.

Topics: Benzodiazepines; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Health Status; Humans; Hypertension; Quality of Life; Verapamil

This review focuses on the effects of calcium antagonists on renal function in hypertensive human subjects. Specifically assessed are the acute and chronic effects of diltiazem, verapamil, amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine on glomerular filtration rate; effective renal plasma flow/renal blood flow; renal vascular resistance; and urinary protein excretion. Among the calcium antagonists, only the dihydropyridine derivatives have been demonstrated consistently to acutely increase effective renal plasma flow/renal blood flow. The acute effects on glomerular filtration rate are variable. With respect to chronic therapy, many of the calcium antagonists have been reported to produce sustained increases in the effective renal plasma flow/renal blood flow and/or the glomerular filtration rate. Renal vascular resistance is reduced. Although calcium antagonists preserve or improve renal perfusion and glomerular filtration, long-term clinical trials are required to determine their potential therapeutic benefit to modify the natural course of hypertensive renal disease.

Topics: Calcium Channel Blockers; Dihydropyridines; Diltiazem; Humans; Hypertension; Kidney; Kidney Function Tests; Verapamil

Dihydropyridine calcium antagonists play an important role in the treatment of arterial hypertension. In many centers, they are used as first-line treatment. Since impaired renal function can be a complication of long-standing blood pressure elevation, the usefulness of dihydropyridine calcium antagonists in hypertensive patients with reduced glomerular filtration rate is an important clinical issue. Several studies of the pharmacokinetics of calcium antagonists, such as nifedipine and related compounds, clearly show that the important pharmacokinetic variables are not affected by impaired renal function. Moreover, the antihypertensive efficacy is not reduced in patients with reduced glomerular filtration rate. A matter of potentially great clinical importance is the fact that several studies have shown that treatment with dihydropyridine calcium antagonists in patients with impaired renal function has reduced the rate of deterioration in filtration rate, leading to a preservation of renal function. It can therefore be concluded that dihydropyridine calcium antagonists are useful in the treatment of hypertensive patients with impaired renal function, that the major pharmacokinetic and pharmacodynamic variables are not negatively affected, in particular that the antihypertensive effect is maintained in such patients, and that there is no retention of metabolites. Finally, the observation that the decline in renal function can be slowed down suggests that dihydropyridine calcium antagonists may be the preferential treatment in hypertensive patients with reduced renal function.

Topics: Aged; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Kidney Diseases

The calcium-channel blockers have expanded the therapeutic choices of the practicing physician. The recent changes in the recommendations regarding first-line therapy in the treatment of essential hypertension have allowed the use of a variety of different antihypertensive agents to provide safe and effective therapy.

Topics: Calcium Channel Blockers; Dihydropyridines; Diltiazem; Humans; Hypertension; Verapamil

Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonist (nifedipine, nicardipine, PN 200-110) induced opposite long-lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200-110 decreased mean blood pressure dose-dependently and stereoselectively, (+) NIC and (+) PN being 8 and 3 times more potent than their (-) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF- and NIC-induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose-dependently. The i.c.v. BAY K8644-induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (-) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c) by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K(+)-evoked ACh release but suppressed the BAY K8644-induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hypertension via sympathetic tone.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Hypertension; Rats; Rats, Inbred SHR

The combination of one of the dihydropyridine class of calcium channel antagonists with a beta-adrenoceptor blocker has particular therapeutic advantages in the management of hypertension. The beta-blocker reduces the effects of the dihydropyridine-induced reflex increases in sympathetic nervous system and renin-angiotensin system activity, while the dihydropyridine reduces the peripheral effects of beta-blockade. Numerous studies have documented additional antihypertensive effects when these two classes of agents are used as combination therapy in hypertension. This therapeutic combination is well tolerated and produces minimal alterations in clinical laboratory tests. Initial concerns that the combination may impair atrioventricular conduction and left ventricular function have not been substantiated in widespread clinical trials.

Topics: Adrenergic beta-Antagonists; Blood Pressure; Clinical Trials as Topic; Dihydropyridines; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension

Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects.

Topics: Angina Pectoris; Calcium; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Hemodynamics; Humans; Hypertension; Nifedipine; Nitrendipine

Synthetic calcium channel blockers (Ca2+ entry blockers or antagonists) have been reported to induce relaxation of smooth muscle which is not thought to be mediated by any specific action(s) on receptor sites. In addition, it has been suggested that Ca2+ channel blockers increases blood flow in a number of organ regions, including mesenteric, femoral, renal, cerebral and coronary vasculatures, via a direct action on vascular tone by inhibiting Ca2+ influx across the vascular smooth muscle membranes. Such information has prompted clinical studies with the use of Ca2+ channel blockers in the treatment of a wide variety of cardiovascular disorders. The questions, to be answered, however, are whether any of the newly-designed channel blockers can actively produce vasodilatation of arterioles and venules in regional microvasculatures, and these synthetic agents are safe and therapeutically effective. In addition, can one design site-specific (e.g., cerebral vs. coronary vasodilator) Ca2+ channel blockers. But, since the body has a natural Ca2+ antagonist, viz., magnesium ions (Mg2+), one must ask whether such divalent cations act as peripheral vasodilators and are effective as therapeutic agents. The studies reviewed herein: compare the effects of several different Ca2+ channel blockers on resistance and capacitance vessels in different regional microvasculatures (i.e., mesenteric, skeletal muscle, pial) within a single species, namely the rat, by high-resolution TV microscopy, and demonstrate the rationale, effects and mechanisms of action of Mg2+ on regional blood vessels. These data show some of the new, novel synthetic Ca2+ channel blockers (i.e., nisoldipine, nitrendipine, nimodipine) can: exert effects on both arterioles and venules in certain vasculatures; be designed to exert a wide range of potencies; and be designed to act selectively at regional microvasculatures. In addition, the data presented are consistent with the hypothesis that Mg2+ exerts a regulatory role in vascular tone, vascular reactivity and vascular resistance. Certain vascular diseases associated with a Mg2+-deficiency appear to be amenable to treatment with Mg2+.

Topics: Anesthesia; Animals; Arterioles; Blood Pressure; Calcium; Calcium Channel Blockers; Cell Membrane Permeability; Cerebrovascular Circulation; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Ketamine; Magnesium; Magnesium Deficiency; Microcirculation; Muscle, Smooth, Vascular; Muscles; Nifedipine; Nisoldipine; Nitrendipine; Nutritional Requirements; Pentobarbital; Pre-Eclampsia; Pregnancy; Pyridines; Rats; Vasoconstrictor Agents; Vasodilator Agents; Venules

Increased visit-to-visit blood pressure variability (vvBPV) has negative effects on multiple organ systems. Prior research has suggested that dihydropyridine calcium channel blockers (CCB) may reduce vvBPV, which we attempted to verify in a high-quality dataset with robust statistical methodology.. We performed a post hoc analysis of the SPRINT trial and included participants who were on a dihydropyridine CCB either 0 or 100% of follow-up study visits. The primary outcome was vvBPV, defined as residual standard deviation (rSD) of SBP from month 6 until study completion. We estimated the average treatment effect of the treated (ATET) after augmented inverse-probability-weighting (AIPW) matching.. Of the 9361 participants enrolled in SPRINT, we included 5020, of whom 1959 were on a dihydropyridine CCB and 3061 were not; mean age was 67.4 ± 9.2 years, 34.5% were men, 65.9% were white, 49.4% were randomized to intensive blood pressure control, and the rSD was 10.1 ± 4.0 mmHg. Amlodipine represented greater than 95% of dihydropyridine CCB use. After AIPW matching of demographics and other antihypertensive medications, the ATET estimation for participants on a dihydropyridine CCB was an rSD that was 2.05 mmHg lower (95% CI -3.19 to -0.91). We did not find that other antihypertensive medications classes decreased vvBPV, and several increased it.. In the SPRINT trial, consistent use of a dihydropyridine CCB was associated with a 2 mmHg reduction in vvBPV. The implication of this hypothesis-generating finding in a high-quality dataset is that future trials to reduce vvBPV could consider using dihydropyridine CCBs.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged

Cilnidipine, an upcoming anti-hypertensive drug, is a combined L- and N-type calcium channel blocker. It is proposed to be more efficacious and safer due to its two-pronged approach in treating hypertension.. The study was a randomized open-label parallel-group study, conducted in the Department of General Medicine, Sri Ramachandra Medical College Hospital, Chennai, during the period September 2014 to May 2015. 50 patients were randomized to the amlodipine group and 50 to the cilnidipine group. The blood pressure, pulse rate and adverse effects were monitored in each patient over 12 weeks. The difference in the Systolic Blood Pressure(SBP), Diastolic Blood Pressure(DBP) and Heart Rate(HR) before and after treatment within each group, and between the two groups were analyzed using paired and unpaired t tests respectively. The adverse effects reported in each group were analyzed using Chi-square test.. There was no statistically significant difference in the reduction of SBP and DBP between the two groups (p>0.05). The HR however, showed an increase of 1.07/min in the amlodipine group and decreased by 1.16/min in the cilnidipine group. The patients in the cilnidipine group experienced significantly less adverse effects such as pedal edema and palpitations when compared to those in the amlodipine group (p<0.05).. Cilnidipine therapy is an effective and safe alternative in the treatment of essential hypertension. It can be used as a first line antihypertensive drug since its efficacy is comparable to that of amlodipine with a better safety profile than amlodipine.

Topics: Adult; Amlodipine; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; India

Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension.. We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining.. Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years;. Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebral Small Vessel Diseases; Dihydropyridines; Humans; Hypertension; Magnetic Resonance Imaging; Middle Aged

We tested our hypothesis that, in hypertensive patients with higher nocturnal home systolic blood pressure (HSBP) at baseline, a valsartan/cilnidipine (80/10 mg) combination would reduce nocturnal HSBP more markedly than a valsartan/hydrochlorothiazide (80/12.5 mg) combination. Patients measured their nocturnal HSBP over three nights prior to study randomization and at the end of treatment. Sixty-three and 66 patients comprised the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups; their respective baseline nocturnal HSBP values were 124.3 ± 15.6 and 125.8 ± 15.2 mm Hg (P = .597). Nocturnal HSBPs were significantly reduced from baseline in both groups. Although the valsartan/hydrochlorothiazide group exhibited a significantly greater reduction in nocturnal HSBP compared to the valsartan/cilnidipine group (-5.0 vs. -10.0 mm Hg, P = .035), interaction between the treatment groups and the baseline nocturnal HSBP levels for the changes in nocturnal HSBP after the treatment periods was significant (P = .047). The BP-lowering effect of valsartan/cilnidipine was more dependent on baseline nocturnal HSBP than that of valsartan/hydrochlorothiazide.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hypertension; Tetrazoles; Treatment Outcome; Valine; Valsartan

Cilnidipine, a fourth-generation both L-and N-type calcium channel blocker (CCB) is safe and effective in lowering blood-pressure without reflex tachycardia compared to other dihydropyridine CCBs. However, its low solubility coupled with extensive first-pass metabolism results in very low oral bioavailability. Thus the study aimed to improve oral bioavailability of Cilnidipine by increasing its gastrointestinal transit-time and mucoadhesion. Gastroretentive tablets were prepared by direct-compression technique using gellan gum as hydrogel forming polymer and sodium bicarbonate as gas-generating agent. Statistical optimization was carried out by design approach which showed that gellan gum has significant impact on floating lag time, mucoadhesive strength, % drug release at 1 h and time to release 90% of drug. Drug release study revealed that optimized tablets prolonged drug release for 12 h and followed anomalous-diffusion indicating drug release is by coupling of both diffusion and erosion mechanism. Intragastric behaviour of formulation in human volunteers revealed that radio-opaque tablets remain buoyant in stomach for more than 6 h with sufficient mucoadhesion. Comparative pharmacokinetic profiling in human subjects revealed that relative bioavailability of Cilnidipine GR tablets was enhanced compared to reference tablets. Thus concluded that gastroretentive tablets to be promising strategy for improved oral bioavailability of Cilnidipine for effective treatment of hypertension.

Topics: Adult; Biological Availability; Blood Chemical Analysis; Calcium Channel Blockers; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Dihydropyridines; Drug Liberation; Healthy Volunteers; Humans; Hypertension; Male; Middle Aged; Polysaccharides, Bacterial; Spectroscopy, Fourier Transform Infrared; Tablets

Topics: Administration, Oral; Adult; Antihypertensive Agents; Carvedilol; Case-Control Studies; Cross-Over Studies; Cytochrome P-450 Enzyme System; Dihydropyridines; Drug Interactions; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Stereoisomerism

Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation.. Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention.. Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups.. Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Catecholamines; Dihydropyridines; Female; Humans; Hypertension; Male; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Sympathetic Nervous System; Systole

In vitro study showed that benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine.. Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(-)-α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam.. The exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(-)-α-benidipine by approximately three-fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of C. After single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-α- and (R)-(R)-(-)-α-benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients.

Topics: Adult; Antihypertensive Agents; Area Under Curve; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP3A; Dihydropyridines; Dose-Response Relationship, Drug; Drug Interactions; Healthy Volunteers; Humans; Hypertension; Male; Rifampin; Stereoisomerism; Young Adult

Whether increased serum uric acid (SUA) favours resistance to antihypertensive drugs is not clear.. The European Lacidipine Study on Atherosclerosis (ELSA) was a randomized, double-blind, multicenter trial comparing the effects of a 4-year treatment with either lacidipine or atenolol on progression of carotid atherosclerosis in patients with moderate hypertension. SUA was assessed at randomization and at the study end, office blood pressure (BP) was measured at each titration visit and every 6 months thereafter, ambulatory BP was measured at randomization and every year thereafter.. No difference was found in office and ambulatory BP reduction achieved after 1 and 4 years of treatment in baseline SUA tertiles. This was the case for both treatments. The percentage of patients with controlled office BP (<140/90 mmHg) after 1 year (36.5, 34.2 and 33.8%, P = 0.56) and 4 years (39.9, 39.4 and 38%, P = 0.82) was not different in SUA tertiles. Similar results were obtained basing the analysis on the control of ambulatory BP (<130/80 mmHg) or when data were analyzed taking into account SUA extreme values (≥7 and <3.5 mg/dl). The average and percentage changes of SUA (baseline-study end) were not different between patients who achieved or did not achieve office BP control (5.31 ± 1.26 vs. 5.4 ± 1.29 mg/dl, P = 0.22 e 0.13 ± 0.33 vs. 0.13 ± 0.68, P = 0.87, respectively). This was the case also for control of ambulatory BP.. In the ELSA study, SUA levels do not affect the responsiveness to antihypertensive treatment.

Topics: Antihypertensive Agents; Atenolol; Atherosclerosis; Blood Pressure; Carotid Artery Diseases; Dihydropyridines; Disease Progression; Double-Blind Method; Drug Resistance; Female; Humans; Hypertension; Male; Middle Aged; Uric Acid

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; β-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/β-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups.. This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, β-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Thiazides; Treatment Outcome

The authors tested the hypothesis that a valsartan/cilnidipine combination would suppress the home morning blood pressure (BP) surge (HMBPS) more effectively than a valsartan/hydrochlorothiazide combination in patients with morning hypertension, defined as systolic BP (SBP) ≥135 mm Hg or diastolic BP ≥85 mm Hg assessed by a self-measuring information and communication technology-based home BP monitoring device more than three times before either combination's administration. This was an 8-week prospective, multicenter, randomized, open-label clinical trial. The HMBPS, which is a new index, was defined as the mean morning SBP minus the mean nocturnal SBP, both measured on the same day. The authors randomly allocated 129 patients to the valsartan/cilnidipine (63 patients; mean 68.4 years) or valsartan/hydrochlorothiazide (66 patients; mean 67.3 years) combination groups, and the baseline HMBPS values were 17.4 mm Hg vs 16.9 mm Hg, respectively (P = .820). At the end of the treatment period, the changes in nocturnal SBP and morning SBP from baseline were significant in both the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups (P < .001): -5.0 vs -10.0 mm Hg (P = .035) and -10.7 vs -13.6 mm Hg (P = .142), respectively. HMBPS was significantly decreased from baseline in both groups (P < .001), but there was no significant difference between the two groups: 14.4 mm Hg vs 14.0 mm Hg, respectively (P = .892). Valsartan/cilnidipine could not significantly suppress HMBPS compared with valsartan/hydrochlorothiazide. Large-scale randomized controlled studies are needed to assess how reducing HMBPS will affect future cardiovascular outcomes. The information and communication technology-based home BP monitoring device may become an alternative to ambulatory BP monitoring, which has been a gold standard to measure nocturnal BP and the morning BP surge.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Blood Pressure Monitors; Dihydropyridines; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Medical Informatics; Middle Aged; Outcome Assessment, Health Care; Valsartan

Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress.. To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity.. A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy.. During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period.. The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Case-Control Studies; Dihydropyridines; Dinoprost; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Tetrazoles; Tumor Necrosis Factor-alpha

It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D).. A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36).. Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0±123.2 mg/g in cilnidipine group and -35.7±83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3±106.9 mg/g in cilnidipine group and -20.0±110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7±106.8 mg/g in cilnidipine group and -9.5±79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0±111.7 mg/g in cilnidipine group and 14.6±119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years.. Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes.

Topics: Adult; Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Arterial stiffness and blood pressure (BP) augmentation are independent predictors of cardiovascular events. In a randomized, open, parallel group study we compared the effect on these parameters of combination therapy with an ACE-inhibitor plus calcium channel blocker or thiazide diuretic in 76 hypertensive patients with metabolic syndrome uncontrolled by ACE-inhibitor monotherapy. After 4weeks run-in with enalapril (ENA, 20mg), patients were randomized to a combination therapy with lercanidipine (LER, 10-20mg) or hydrochlorothiazide (HCT, 12.5-25mg) for 24weeks. Aortic stiffness (carotid to femoral pulse wave velocity, PWV), central BP values and augmentation (augmentation index, AIx) were measured by applanation tonometry. The two groups showed similar office and central BP after run-in. Office (ENA/LER: from 149.1±4.9/94.5±1.5 to 131.7±8.1/82.2±5.3; ENA/HCT: from 150.3±4.7/94.7±2.1 to 133.1±7.1/82.8±5.3mmHg) and central BP (ENA/LER 127.4±17.1/85.2±12.1 to 120.5±13.5/80.0±9.5mmHg; ENA/HCT 121.6±13.4/79.3±9.5mmHg) were similarly reduced after 24weeks. PWV was comparable after run-in and not differently reduced by the two treatments (ENA/LER from 8.6±1.5 to 8.1±1.3m/s, p<0.05; ENA/HCT from 8.5±1.2 to 8.2±1.0m/s, p<0.05). Finally, both combinations reduced AIx, but its reduction was significantly greater (p<0.05) in ENA/LER (from 26.8±10.9 to 20.6±9.1%) than in ENA/HCT arm (from 28.2±9.0 to 24.7±8.7%). In conclusion, the combination with LER caused a similar PWV reduction as compared to HCT, but a greater reduction in AIx in hypertensive patients with metabolic syndrome not controlled by ENA alone. These results indicate a positive effect of the combination of ENA/LER on central BP augmentation, suggesting a potential additive role for cardiovascular protection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Italy; Male; Metabolic Syndrome; Middle Aged; Prospective Studies; Treatment Outcome; Vascular Stiffness

In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed.. For this purpose, a multivariable analysis was performed.. Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE.. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

Topics: Adult; Aged; Albumins; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Nitrobenzenes; Piperazines

We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Treatment Outcome

Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ).. BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal.. NCT02646397.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; China; Dihydropyridines; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Fosinopril; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Research Design; Treatment Outcome; Young Adult

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-β-blocker combination.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Stroke; Thiazides

To compare a combination of a dihydropyridine calcium-channel blocker with an angiotensin converting enzyme inhibitor vs. monotherapy with one or the other drug and placebo for their effects on home blood pressure (HBP).. After a 2-week placebo wash-out, patients with an elevated office blood pressure (BP) (diastolic 100-109 and systolic <180 mmHg) and HBP (diastolic ≥85 mmHg) were randomized double-blind to a 10-week treatment with placebo, lercanidipine, 10 or 20 mg daily, enalapril, 10 or 20 mg daily, or the four possible combinations. In addition to office BP, HBP was self-measured via a validated semiautomatic device twice in the morning and twice in the evening during the 7 days before randomization and at the end of treatment. Baseline and treatment HBP values were separately averaged for each day, morning, evening or the whole monitoring period, excluding the first day. Day-by-day HBP variability was defined as the SD or the variation coefficient of the daily BP averages.. Eight hundred and fifty-four patients with valid HBP recordings at baseline and at the end of treatment were analyzed (intention-to-treat population). From the baseline value (147.0±11.6 mmHg) systolic/diastolic HBP showed a small reduction (average baseline-adjusted change: -1.8/-1.6 mmHg) with placebo, a more marked significant fall with monotherapies (-8.8/-5.9 mmHg, P < 0.001/<0.001 vs. placebo) and even more with combination treatment (11.6/-7.6 mmHg, P < 0.001/ < 0.001 vs. placebo and P < 0.01/ < 0.05 vs. monotherapy). A similar pattern was observed for each of the days of the BP self-monitoring period as well as for either morning or evening values, although the difference between mono and combination treatment appeared to be consistently significant for the morning values only. Day-by-day systolic BP-SD was unaffected by placebo and slightly reduced by drug treatments, with no, however, significant changes in SBP-variation coefficient. Baseline and end of treatment HBP values showed a limited correlation with office BP values, this being particularly the case for treatment-induced changes (correlation coefficients: 0.37 for systolic and 0.45 for diastolic BP).. This large HBP database shows that the lercanidipine-enalapril combination lowers HBP more effectively than the corresponding monotherapies and placebo, and that this greater effect is consistent between days.. ClinicalTrials.gov identifier: NCT01093807.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Calcium Channel Blockers; Databases, Factual; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Intention to Treat Analysis; Male; Middle Aged; Office Visits; Self Care

Although calcium channel blockers (CCB) are expected to improve the augmentation index (AI) in CKD patients, the potential effect of benidipine on AI has been poorly studied.The present study aimed to compare the effect of benidipine and amlodipine in the treatment of CKD patients as measured through AI and urinary albumin excretion (UAE). Eligible patients with CKD were randomized to either the benidipine group or amlodipine group. Changes in UAE and AI were compared with target blood pressure level set at < 130/80 mmHg. A total of 108 patients were enrolled; 88 patients who were followed up were included in the analysis. Although no significant change in renal function was noted in either group, there was a significant improvement in AI only in the benidipine group (85.7 ± 13.3% to 81.4 ± 15.2%; P = 0.021) A subgroup analysis of 64 patients who achieved SBP < 140 mmHg at the end of follow-up (31 on amlodipine and 33 on benidipine) was carried out. Significant improvement in AI was noted only in the benidipine group (84.5 ± 13.6% to 79.5 ± 15.2%; P = 0.0138). In another subgroup of patients with UAE ≥ 300 mg/g Cr, a significant improvement in UAE in the benidipine group was found compared with the amlodipine group (-25 ± 46, 51 ± 60%, P = 0.031, respectively).These results suggest that benidipine might reduce significantly AI and might have potentially greater improvements in UAE than amlodipine in advanced CKD patients receiving RAS inhibitors.

Topics: Aged; Albuminuria; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Male; Prospective Studies; Renal Insufficiency, Chronic

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

Topics: Amlodipine; Atrial Function, Left; Atrial Remodeling; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; China; Diastole; Dihydropyridines; Down-Regulation; Echocardiography, Doppler; Female; Humans; Hypertension; Hyperuricemia; Male; Middle Aged; Time Factors; Treatment Outcome; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Felodipine; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Metabolome; Middle Aged; Norepinephrine; Obesity; Random Allocation; Sympathetic Nervous System

Essential hypertension has been extensively reported to cause endothelial dysfunction. The aim of this study was to evaluate the effects of barnidipine or lercanidipine, in addition to losartan, on some parameters indicative of endothelial damage and oxidative stress in hypertensive, type 2 diabetic patients.. One hundred and fifty one patients were randomised to barnidipine, 20 mg/day, or lercanidipine, 20 mg/day, both in addition to losartan, 100 mg/day, for 6 months. We assessed BP every month, in addition, patients underwent ambulatory blood pressure monitoring (ABPM). We also assessed: fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), some markers such as high-sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), metalloproteinase-2 (MMP-2) and -9 (MMP-9), soluble vascular adhesion protein-1 (sVCAM-1), soluble intercellular adhesion protein-1 (sICAM-1), isoprostanes and paraoxonase-1 (PON-1).. Both barnidipine and lercanidipine resulted in a significant reduction in blood pressure, even if the reduction obtained with barnidipine + losartan was greater than that obtained with lercanidipine + losartan. Data recorded with ABPM also showed a similar trend. Barnidipine + losartan reduced the levels of Hs-CRP, TNF-α, sVCAM-1, sICAM-1, and isoprostanes both compared to baseline and to lercanidipine + losartan.. Barnidipine + losartan gave an improvement of some parameters indicative of endothelial damage and oxidative stress in diabetic and hypertensive patients.. NCT02064218 , ClinicalTrials.gov.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Italy; Losartan; Male; Middle Aged; Nifedipine; Oxidative Stress; Time Factors; Treatment Outcome

The objective of this study was to compare the effectiveness of lercanidipine with felodipine in patients with mild-to-moderate hypertension on day-to-day home blood pressure variability.. This is a sub-study of a multicenter, randomized, open-label, parallel group and active controlled clinical trial. Hypertensive patients aged 18-75 (i.e. diastolic blood pressure ≥90 mmHg and <110 mmHg; systolic blood pressure ≥140 mmHg and <180 mmHg) and 24 h mean BP >130/80 mmHg) were eligible for this study. During the study, blood pressure (BP) and heart rate (HR) were recorded. The day-to-day BP variability (BPV) and HR variability (HRV) were obtained by the standard deviation (SD) of daily BP/HR average (of six readings) in 7 days.. There were 186 patients (89 and 97 patients in the lercanidipine and felodipine groups, respectively) included in this study. Lercanidipine hydrochloride 10 mg/d and felodipine sustained-release tablets 5 mg/d were given to their respective groups. After 6 weeks of treatment, SD of home BP significantly reduced compared with baseline in both groups (P < .05) while SD of home HR also changed significantly after treatment (P < .05). There was no significant difference in SD of home BPV between the lercanidipine and felodipine groups after treatment.. Treatment with lercanidipine and felodipine both resulted in reduction of BPV and HRV. There was no significant inter-group difference in reduction of BPV between the groups. Lercanidipine is an effective antihypertensive drug in improving BPV. National clinical trial: NCT01520285.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Delayed-Action Preparations; Dihydropyridines; Felodipine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

This randomized study evaluates the effects of lercanidipine - as well as its antihypertensive efficacy - on the number of circulating endothelial progenitor cells (EPCs) in elderly patients with hypertension.. In total, 61 patients with hypertension were randomly assigned to lercanidipine 10 mg/day or to other antihypertensive treatments (control group).. Cytometry analysis was conducted at baseline, at 12 weeks and at 24 weeks. Routine clinical examination was also performed.. Overall, the number of circulating EPCs had already significantly increased with lercanidipine, compared with baseline values, after 12 weeks; this increase was sustained until the end of the study. On the other hand, the number of circulating EPCs remained stable in the control group throughout the study period. At 12 weeks, a significant reduction in blood pressure, compared with baseline values, was observed in both groups. Regression analysis showed a significant negative correlation between systolic blood pressure and the number of circulating EPCs.. Although the limited number of patients and the short follow-up hamper the analysis, this study suggests that lercanidipine may increase EPC concentration independently from its anti-hypertensive effect.

Topics: Aged; Antigens, CD34; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Flow Cytometry; Hematopoietic Stem Cells; Humans; Hypertension; Male; Middle Aged

The aim of the present study was to compare the effects of the combination of lercanidipine/enalapril versus amlodipine/enalapril and hydrochlorothiazide/enalapril on blood pressure, target organ damage and sympathetic activation in patients with grade 2 essential hypertension.. This was a 3 month, randomized, blinded-endpoint study in essential hypertensive patients.. Office and ambulatory blood pressure, arterial stiffness, urinary albumin to creatinine ratio, renal arterial resistive index, and muscle sympathetic nerve activity were evaluated at baseline, after a 2 week run-in placebo period, at 1 month and at 3 months.. In total, 56 patients were assigned to lercanidipine/enalapril (n = 19), enalapril/amlodipine (n = 18) and hydrochlorothiazide/enalapril (n = 19). Each pharmacological combination tested was effective in reducing office blood pressure at 1 month and 3 months, and 24 h ambulatory blood pressure at 3 months. Renal arterial resistive index (RI) significantly improved at 1 month and 3 months compared with baseline in all groups. However in the lercanidipine/enalapril and hydrochlorothiazide/enalapril groups, RI was favorably reduced (0.53 ± 0.03 and 0.54 ± 0.04 respectively, p < 0.05) in comparison with the enalapril/amlodipine RI value (0.57 ± 0.03) at 3 months. Moreover, after 3 months of treatment, a significant decrease (by -5.47 bursts/min) (p < 0.05) in muscle sympathetic nerve activity was observed in the lercanidipine/enalapril group (50.79 ± 6.49) compared with baseline (56.26 ± 6.05), while no differences were detected in the amlodipine/enalapril and hydrochlorothiazide/enalapril groups.. Our study provides evidence of the efficacy of the lercanidipine/enalapril combination in ameliorating hypertension-related target organ damage and in reducing sympathetic overdrive.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Middle Aged; Sympathetic Nervous System; Vascular Stiffness

The RED LEVEL study (REnal Disease: LErcanidipine Valuable Effect on urine protein Losses) directly compares, in an explorative fashion, the effects of lercanidipine + enalapril and amlodipine + enalapril combinations on renal parameters in hypertensive subjects.. This was a 1 year, prospective, multi-center, randomized, open-label, blinded-endpoint (PROBE) study in hypertensive patients with albuminuria.. Renal function (albuminuria, serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria); blood pressure.. Albuminuria was significantly reduced, compared with baseline values, with the lercanidipine + enalapril combination over the entire study period; at month 3, month 6 and month 12, changes from baseline were: -162.5 (p-value = 0.0439), -425.8 (p-value = 0.0010), -329.0 (p-value = 0.0011) mg/24 h), respectively. On the other hand, this improvement was not observed with enalapril + amlodipine. Other parameters of renal function such as serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria did not change over the study. Both lercanidipine + enalapril and amlodipine + enalapril significantly reduced systolic and diastolic blood pressure values from baseline all over the study period with no significant differences between groups. Safety outcomes were comparable between the two groups.. Overall, the results of this explorative study lend support to the anti-albuminuric effect of the lercanidipine + enalapril combination and to the long term renal-protective effects of this combination in patients with hypertension.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Prospective Studies

To investigate the efficacy and safety of perindopril-lercanidipine combination versus perindopril or lercanidipine monotherapies in patients with mild essential hypertension.. A total of 180 patients with mild essential hypertension were randomly assigned to three groups: group A (perindopril 2 mg plus lercanidipine 5 mg; n = 60), group B (lercanidipine 10 mg; n = 60) and group C (perindopril 4 mg; n = 60). The treatment efficacy and the incidence of adverse events were evaluated at the end of 4, 8 and 12 weeks after treatment initiation.. The blood pressure in group A was already lower than in group B and group C at week 4 after treatment initiation. Systolic blood pressure was 148 ± 13 mmHg in group A, 151 ± 14 mmHg in group B, and 153 ± 13 in group C (p < 0.001); diastolic blood pressure was 89 ± 8, 92 ± 7 and 92 ± 6 mmHg, respectively (p < 0.001). At the end of treatment the normalization rate was significantly higher in group A, compared with group B and group C (71.7%, 68.3%, and 48.3%, respectively; p < 0.05). Four adverse events were observed in group A, while seven and nineteen adverse events occurred in group B and in group C, respectively. Statistically significant differences in adverse reaction incidence were reported among three groups.. Although its results were collected in an overall limited number of patients in a single center, this study shows that the combination of perindopril and lercanidipine, compared with lercanidipine alone or perindopril alone, was effective in improving blood pressure in mild essential hypertensive patients, and also decreased the incidence of adverse events.

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Drug Therapy, Combination; Essential Hypertension; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Perindopril; Treatment Outcome

The DUAL study evaluated the effectiveness and safety of the fixed-dose combination of lercanidipine and enalapril in a real-practice scenario; the effects of this combination on a number of markers of cardiovascular risk have been also investigated.. This was a 2 month, phase IV, open-label, single-group, prospective observational study. Adult patients with untreated or uncontrolled hypertension (blood pressure [BP] >140/90 mmHg) were eligible for this study. All patients received lercanidipine/enalapril, in a once-daily fixed combination (10 mg/10 mg).. The patients were evaluated at baseline, at 1 month and at 2 months. The following parameters were evaluated at all time points: systolic BP (SBP) and diastolic BP (DBP); heart rate (HR). A number of laboratory parameters were measured at baseline and at 2 months. Safety considerations were performed.. In total, 188 patients were enrolled (104 males; mean age 58 ± 12 years). At baseline, mean SBP was 159 ± 10 mmHg and mean DBP was 94 ± 7 mmHg. Treatment with lercanidipine/enalapril in fixed combination was associated with a reduction in both SBP and DBP already at 1 month; this reduction was sustained until month 2 (SBP: 131 ± 7 mmHg; DBP: 79 ± 5 mmHg; p < 0.05 vs baseline). At baseline HR was 78 ± 10 bpm; a significant reduction in this parameter was observed at month 2 (75 ± 7 bpm; p < 0.05 vs baseline). A significant decrease in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and fasting glucose, and a significant increase in K(+), and Ca(2+) was observed at month 2 compared with baseline values. In total, two patients (1%) experienced dry cough. No other adverse effects were reported.. Even with all the limitations of any observational study, these data show that a 2 month treatment with a fixed dose of lercanidipine/enalapril is associated with significant reductions in SBP and DBP, HR, and improvement in a number of laboratory parameters.

Topics: Adult; Antihypertensive Agents; Dihydropyridines; Drug Combinations; Enalapril; Female; Heart Rate; Humans; Hypertension; Lebanon; Lipids; Male; Middle Aged; Prospective Studies; Treatment Outcome

Lercanidipine hydrochloride and felodipine sustained-release tablets comparison for the treatment of patients with mild-to-moderate primary hypertension.. The study was designed as a multicenter, randomized, open-label, parallel-group clinical trial. A total of 281 adult patients (18-75 years) with a mild-to-moderate primary hypertension diagnosis were randomly assigned, in a 1:1 ratio, to lercanidipine hydrochloride (n = 139; 81 males) or felodipine sustained-release tablets (n = 142; 87 males). Study duration was 8 weeks, including two run-in weeks and 6 weeks of treatment.. The mean seated diastolic blood pressure (BP) change from baseline to 6 weeks of treatment was the primary endpoint. Main secondary efficacy parameters were: (i) mean seated systolic BP change from baseline to 6 weeks of treatment; (ii) normalization BP rate. The incidence of adverse events was also considered.. BP monitoring showed a significant decrease compared with baseline in diastolic BP (lercanidipine: from 96 ± 4 to 83 ± 6 mmHg, p < 0.0001; felodipine: from 96 ± 4 to 82 ± 5 mmHg, p < 0.0001). The mean systolic BP decreased, when compared with baseline values, by 18 mmHg and 19 mmHg in the lercanidipine and felodipine arm, respectively (p < 0.0001 versus baseline for both comparisons). The normalization rates of BP were 79.5% and 87.2%, in the lercanidipine and felodipine groups, respectively (in-office monitoring; p = n.s.). In total, 73 patients experienced 103 AEs: 26.6% (37/139) in the lercanidipine group and 25.3% (36/142) in the felodipine arm (p = n.s.). The analysis of safety showed no unexpected adverse events.. Although the overall short follow-up of the present study should be taken into account, lercanidipine is an effective and safe treatment option for BP control in adult patients with mild-to-moderate primary hypertension.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Delayed-Action Preparations; Dihydropyridines; Felodipine; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Treatment Outcome; Young Adult

The aim of this study was to compare the efficacy and safety of lercanidipine and amlodipine in the treatment of hypertensive patients with acute cerebral ischemic stroke.. An open label, controlled, randomized, parallel-group study was conducted on 104 hypertensive patients (blood pressure [BP] >130/80 mmHg) diagnosed with ischemic stroke. Enrolled subjects were randomly assigned to a 4 week treatment with lercanidipine 20 mg/day or amlodipine 10 mg/day. The treatment was administered during the acute phase of the stroke, either immediately after the diagnosis or during an observation period of maximum 6 days.. Both lercanidipine and amlodipine were able to significantly reduce mean clinical systolic BP (SBP)/diastolic BP (DBP), mean 24 h ambulatory BP and day-time and night-time BP. In particular, mean clinical SBP/DBP was reduced from 168.9 ± 21.6/96.2 ± 13.6 mmHg to 147.1 ± 22.0/87.1 ± 14.0 mmHg in the lercanidipine group (p < 0.001 for SBP and p < 0.01 for DBP) and from 167.1 ± 19.9/97.8 ± 14.5 mmHg to 143.3 ± 21.9/82.8 ± 14.1 mmHg in the amlodipine-treated group (p < 0.001 for both SBP and DBP). No statistical difference was observed between the two treatments in the reduction of clinical BP. The response and normalization rates registered in the two groups of patients were also similar, with no significant difference between the two drugs. In addition, both treatments reported comparable results in terms of early morning BP surge reduction and BP stabilization, measured through trough-peak ratio and smoothness index. However lercanidipine showed a better tolerability profile than amlodipine, with fewer adverse events and a lower percentage of patients suffering from side effects.. Lercanidipine is as effective as amlodipine in the reduction and stabilization of BP in hypertensive patients after a stroke, and presents some advantages in terms of safety. Larger studies are necessary to further evaluate these preliminary findings.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Brain Ischemia; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Stroke; Treatment Outcome

This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension.. In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups.. Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period.. Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension.. UMIN 000006081.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Female; Humans; Hypertension; Japan; Male; Middle Aged; Risk Factors; Treatment Outcome; Trichlormethiazide

The objective of this study was to evaluate the efficacy and safety of the lercanidipine/valsartan combination compared with lercanidipine monotherapy in patients with hypertension.. Part 1 of this study was the randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare superiority of lercanidipine 10 mg/valsartan 80 mg (L10/V80) and lercanidipine 10 mg/valsartan 160 mg (L10/V160) combinations with lercanidipine 10 mg (L10) monotherapy. At screening, hypertensive patients, whose diastolic blood pressure (DBP) was >90 mm Hg after 4 weeks with L10, were randomized to 3 groups of L10, L10/V80, and L10/V160. The primary end point was the change in the mean sitting DBP from baseline (week 0) after 8 weeks of therapy. Patients who were randomly assigned to L10/V160 and whose mean DBP was still ≥ 90 mm Hg in part 1 were enrolled to the up-titration extension study with lercanidipine 20 mg/valsartan 160 mg (L20/V160) (part 2).. Of 772 patients screened, 497 were randomized to 3 groups (166 in the L10 group, 168 in the L10/V80 group, and 163 in the L10/V160 group). Mean (SD) age was 55 (9.9) years, and male patients comprised 69%. The mean (SD) baseline systolic blood pressure (SBP)/DBP were 148.4 (15.1)/94.3 (9.5) mm Hg. No significant differences were found between groups in baseline characteristics except the percentages of previous history of antihypertensive medication. The primary end points, the changes of mean (SD) DBP at week 8 from the baseline were -2.0 (8.8) mm Hg in the L10 group, -6.7 (8.5) mm Hg in L10/V80 group, and -8.1 (8.4) mm Hg in L10/V160 group. The adjusted mean difference between the combination groups and the L10 monotherapy group was -4.6 mm Hg (95% CI, -6.5 to -2.6; P < 0.001) in the L10/V80 group and -5.9 mm Hg (95% CI, -7.9 to -4.0, P < 0.001) in the L10/V160 group, which had significantly greater efficacy in BP lowering. A total of 74 patients were enrolled in the part 2 extension study. Changes of mean (SD) DBP and SBP from week 8 to week 12 and week 16 were -5.6 (7.9)/-8.0 (12.0) mm Hg and -5.5 (7.0)/-8.5 (11.3) mm Hg, respectively. For evaluation of the safety profile, the frequencies of adverse events between groups were also not significantly different. The most frequently reported adverse events were headache (6 cases, 20.7%) in the L10 group, dizziness (8 cases, 16.3%) in L10/V80 group, and nasopharyngitis (3 cases, 9.4%) in L10/V160 group, and the incidences of adverse events were not different between groups.. Treatment of L10/V80 or L10/V160 combination therapy resulted in significantly greater BP lowering compared with L10 monotherapy. Moreover, the L20/V160 high dose combination had additional BP lowering effect compared with nonresponders with the L10/V160 combination. ClinicalTrials.gov: NCT01928628.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Essential Hypertension; Female; Headache; Humans; Hypertension; Male; Middle Aged; Treatment Outcome; Valsartan; Young Adult

The aim of this study was to evaluate the effects of lercanidipine or barnidipine on echocardiographic parameters, in hypertensive, type 2 diabetics with left ventricular hypertrophy. One hundred and forty-four patients were randomized to lercanidipine, 20 mg/day, or barnidipine, 20 mg/day, in addition to losartan, 100 mg/day, for 6 months. We evaluated: blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA(1c)), lipid profile, creatinine, estimated glomerular filtration rate (eGFR), sodium, potassium, and acid uric. Echocardiography was performed at baseline and after 6 months. Both lercanidipine and barnidipine decreased blood pressure. Left ventricular mass index was reduced to a greater extent with barnidipine + losartan. Interventricular septal thickness in diastole was reduced by barnidipine + losartan. Posterior wall thickness in diastole was decreased by both treatments, even if barnidipine + losartan were more effective. Ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction was increased by barnidipine + losartan, but not by lercanidipine + losartan. Finally, isovolumetric relaxation and time and left atrial volume index were reduced by barnidipine + losartan, while lercanidipine + losartan did not affect them. In conclusion, barnidipine + losartan provided a greater improvement of echocardiographic parameters compared to lercanidipine + losartan.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Nifedipine; Treatment Outcome

Vascular calcification is a potent predictor of plaque instability and cardiac events. Osteoprotegerin (OPG), well-known vascular calcification mediator, is a signaling molecule involved in bone remodeling, which has been implicated in the regulation of vascular calcification and atherogenesis. The purpose of this study was to compare the combination treatments of olmesartan/azelnidipine and olmesartan/diuretics on serum bone-related markers in patients with essential hypertension.. A total of 48 patients with hypertension treated with 20 mg olmesartan were randomized to receive combination treatment with 16 mg azelnidipine (O/A group) or diuretics (1 mg indapamide; O/D group) for 12 months. Osteoprotegerin, matrix metalloproteinase 2 (MMP-2), and high-sensitive CRP (hs-CRP) were measured after 3 and 12 months of treatment. Cardio-ankle vascular index (CAVI) was measured as the arterial stiffness using a VaSera CAVI instrument at the same time points. In both groups, the systolic and diastolic blood pressure reduction is similar. Serum OPG, MMP-2, and hs-CRP were significantly decreased at 12 months in the O/A group (P < .05), while there were no significant reductions in the O/D group. CAVI was significantly improved at 12 months in both the treatment groups. The improvement in CAVI was significantly greater in the O/A group than in the O/D group.. Azelnidipine, but not indapamide, combined with olmesartan, improved arterial stiffness and were associated with significant decrease in OPG, MMP-2, and hs-CRP concentrations. These results suggest that the beneficial effects of the combination treatments of olmesartan/azelnidipine on arterial stiffness are mediated by alteration in bone-remodeling and inflammatory markers.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Biomarkers; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Essential Hypertension; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Matrix Metalloproteinase 2; Middle Aged; Osteoprotegerin; Prospective Studies; Tetrazoles

The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of 11 140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril-indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%-43%) among patients with CCB at baseline compared with 5% (-12% to 20%) among those without CCB (P homogeneity=0.02) and 14% (2%-25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% (-8% to 28%) versus 6% (-10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant (P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Female; Gliclazide; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Proportional Hazards Models

To examine effects of a long-acting calcium channel blocker (CCB) azelnidipine on uric acid metabolism in hypertensive patients.. Azelnidipine was administered to 72 patients at a daily dose of 8 mg or 16 mg. In 22 cases out of the 72 patients, a different CCB was switched to azelnidipine. Blood pressure was measured and biochemical parameters of blood and urine were evaluated before and 2-3 months after the administration.. Azelnidipine significantly decreased both systolic and diastolic blood pressure and the heart rate. It decreased both serum urate levels and the urinary uric acid to creatinine ratio (Uur/Ucr), but did not affect the uric acid clearance to creatinine clearance ratio (Cur/Ccr). Azelnidipine decreased both Uur/Ucr and Cur/Ccr in patients with Uur/Ucr ≥ 0.5 or ≥ 0.34, although it did not change these clearance parameters in patients with Uur/Ucr <0.5 or <0.34. Azelnidipine decreased the serum urate levels and Uur/Ucr in hyperuricemic patients with uric acid levels ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females. It did not change these parameters in normouricemic patients with serum urate levels <7.0 mg/dL in males and <6.0 mg/dL in females. Azelnidipine decreased Uur/Ucr and Cur/Ccr in hyperuricemic patients with normal or over excretion of uric acid, although it did not change these clearance parameters in hyperuricemic patients with uric acid hypoexcretion.. Azelnidipine decreased the serum urate acid levels and Uur/Ucr, and this response was most prominent in hyperuricemic patients or patients with normal and over excretion of uric acid.

Topics: Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Essential Hypertension; Female; Humans; Hypertension; Hyperuricemia; Male; Uric Acid

The OlmeSartan Calcium Antagonists Randomized (OSCAR) study is a multicenter, prospective, randomized, open-label, blinded, end point study of elderly hypertensive Japanese patients that compared the efficacy of a high-dose angiotensin II receptor blocker (ARB) treatment to an ARB plus calcium channel blocker (CCB) combination. In this pre-specified subgroup analysis, we compared the response to such therapy according to sex. A total of 1164 patients (515 (44%) men and 649 (56%) women) were included, and each gender was split into two nearly equal treatment groups. The primary end point was a composite of cardiovascular events and non-cardiovascular death. The baseline characteristics between the two treatment groups in each sex were similar, except for some variables. Male patients had lower systolic and higher diastolic blood pressure than female patients (156.8/85.7 vs. 158.5/84.2 mm Hg). At the end of the study, the mean systolic pressure was higher in the ARB group (134.4 mm Hg) than in the ARB plus CCB group (131.5 mm Hg; P=0.03) for men but not for women (135.4 vs. 133.4 mm Hg; P=0.12). For men, the primary outcome events tended to be higher in the ARB group than in the ARB plus CCB group (hazard ratio (HR)=1.66; P=0.055) but not for women (HR=0.97; P=0.92). This difference in men was due to cardiovascular events (HR=1.86; P=0.03). The interaction between sex and treatment group was not significant (P=0.17). These findings suggest that, in addition to blood pressure control, appropriate patient risk assessment is important for the treatment of hypertension, especially in male patients, as opposed to possible sex differences in treatment effects.

Topics: Age Factors; Aged; Aged, 80 and over; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Asian People; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Japan; Male; Prospective Studies; Risk Factors; Sex Factors; Tetrazoles; Treatment Outcome

There is considerable interest in pharmacogenetic and molecular biomarkers. Our aim was to evaluate the effects of enalapril/lercanidipine combination on some emerging biomarkers for cardiovascular risk stratification of hypertensive patients, such as lipoprotein(a) [Lp(a)], soluble advanced glycation end products (sRAGE), soluble CD40 ligand (sCD40L) and serum myeloperoxidase (MPO).. Three hundred and forty-five patients were enrolled in this randomized, double-blind, clinical trial: 120 hypertensive patients were randomized to enalapril 20 mg, 110 to lercanidipine 10 mg and 115 to enalapril/lercanidipine 20/10 mg fixed combination. We measures the following markers at baseline and after 6, 12, 18 and 24 months: blood pressure, fasting plasma glucose (FPG), lipid profile, Lp(a), sRAGE, sCD40L and MPO.. There was a decrease in blood pressure in all groups compared with baseline, even if, as expected, enalapril/lercanidipine combination was more effective in reducing blood pressure compared with the monotherapies. No variations in lipid profile or FPG were recorded in any of the groups. Lercanidipine, but not enalapril, improved Lp(a) levels compared with baseline. The combination enalapril/lercanidipine improved it more than the single therapies. All treatments increased sRAGE levels, and decreased sCD40L and MPO, with a better effect seen with the enalapril/lercanidipine combination compared with single monotherapies.. The combination enalapril/lercanidipine seems to be better than the single monotherapies in reducing not only blood pressure, but also the levels of some emerging biomarkers, potentially useful for cardiovascular risk stratification of hypertensive patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; CD40 Ligand; Dihydropyridines; Double-Blind Method; Drug Combinations; Enalapril; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Peroxidase; Risk Factors

The impact of long-acting calcium channel blocker (CCB) administration on serial changes in left ventricular (LV) function and morphology in hypertensive patients with LV hypertrophy remains unclear. This study attempted to clarify this impact by comparing the effects of administration of azelnidipine with that of amlodipine using conventional and speckle tracking echocardiography.. An equal number (16) of 32 hypertensive patients was prospectively assigned to a group administered 5 mg of amlodipine/day or a group administered 16 mg of azelnidipine/day. LV function and morphology was examined by conventional and speckle tracking echocardiography at baseline and at 1, 3, 6, and 12 months after treatment initiation.. Both groups were found to have experienced a significant decrease in systolic blood pressure by 1 month after treatment initiation; a significant reduction in septal thickness and LV mass index at 6 and 12 months. Transmitral flow E/A ratio and early diastolic mitral annular velocity at lateral wall significantly improved at 12 months. On the other hand, a significant improvement of global longitudinal strain was observed earlier than the above indexes at 3, 6, and 12 months. Ar-A duration difference was significantly decreased at 3 months. The global circumferential strain improved significantly at 3 months, but there were no significant changes in mid-/apical circumferential and radial strains throughout the study period.. Azelnidipine has beneficial effects on LV mass regression, transmitral flow, tissue Doppler, and LV longitudinal strain that are comparable to those of amlodipine on the same parameters.

Topics: Adult; Aged; Amlodipine; Analysis of Variance; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography, Doppler, Pulsed; Female; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Image Interpretation, Computer-Assisted; Male; Middle Aged; Prospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

The aim of this study was to evaluate enalapril/lercanidipine combination effects on markers of cardiovascular risk stratification in hypertensive patients. A total of 359 patients were randomized to enalapril 20 mg, lercanidipine 10 mg, or enalapril/lercanidipine 20/10 mg fixed combination. We evaluated blood pressure (BP), fasting plasma glucose (FPG), lipid profile, lipoprotein(a) (Lp[a]), soluble receptor for advanced glycation end products (sRAGE), soluble CD40 ligand (sCD40 L), serum myeloperoxidase (MPO), high sensitivity C-reactive protein (Hs-CRP), and tumor necrosis factor-α (TNF-α). We recorded a decrease of BP in all groups, with the enalapril/lercanidipine combination being more effective in reducing BP compared with single monotherapies. Lipid profile or FPG were not affected by various treatments. Lercanidipine, but not enalapril, improved Lp(a) levels compared with baseline, with enalapril/lercanidipine having a greater effect on Lp(a) reduction. All treatments increased sRAGE levels, and decreased sCD40 L and MPO, even if enalapril/lercanidipine combination was more effective than single monotherapies. TNF-α and Hs-CRP were greater reduced by enalapril/lercanidipine combination compared with enalapril (P < .05 for both). The enalapril/lercanidipine fixed combination was more effective than single monotherapies in decreasing BP, but also in improving markers of cardiovascular risk stratification in hypertensive patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Italy; Lipids; Male; Risk Factors; Survival Rate; Treatment Outcome

The aim of this study was to evaluate the efficacy and safety of combinations of lercanidipine (L) and enalapril (E) at different doses on office and home blood pressure (BP) in patients with Stage 2 hypertension.. This was a randomized, double-blind, placebo-controlled, factorial study conducted in 100 centres from seven countries. Patients with office DBP 100-109 mmHg and home DBP at least 85 mmHg at the end of a 2-week placebo run-in period were randomized to a 10-week treatment with placebo, L (10 or 20 mg), E (10 or 20 mg) or the four L-E combinations. The efficacy parameters were office DBP at trough (primary), SBP at trough and home SBP and DBP. Office BP was measured at each visit in both the sitting and the standing position, while home BP was measured twice in the morning and twice in the evening for at least 3 days before treatment and at study end. Safety parameters included adverse events, laboratory tests and 12-lead ECG.. A total of 1039 patients were randomized (48% men, mean age 54 years, mean BMI 30 kg/m, 40% obese patients). Baseline BP was similar in all groups and lower for home than for office values (149/95 and 159/103 mmHg, respectively). A marked placebo effect was observed on office but not on home BP. Combination therapy was superior to placebo at all doses for both office and home BP. The greatest effect was observed in the L20/E20 group, in which the SBP/DBP fall amounted to -19.2/-15.2 and -13.2/-7.5 mmHg for sitting office and home BP, respectively. Similar reductions were observed on standing office BP. The L20/E20 combination was associated with less cough, palpitations and leg oedema than monotherapies, with no increased rate of dizziness or hypotension.. In Stage 2 hypertension, a fixed-dose combination of L and E ensures a control of both office and out-of-office BP, with a favourable tolerability profile.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Combinations; Enalapril; Female; Humans; Hypertension; Male; Medication Adherence; Middle Aged

Calcium channel blockers (CCBs) are used as antihypertensive agents and have a strong vasodilatory effect; however, the sympathetic activation mediated by baroreflex might cause adverse effects. A recently developed CCB, azelnidipine, decreases the heart rate (HR) while lowering blood pressure (BP), possibly by inhibiting sympathetic nerve activity in animal models. In this study, we evaluated whether azelnidipine inhibited sympathetic nerve activity, compared to amlodipine, in primary hypertensive patients.. We conducted a prospective, randomized, open-label, and crossover study of 14 patients. We measured the patients' BP, HR and baroreflex sensitivity, and directly recorded muscle sympathetic nerve activity (MSNA), via microneurography, after treatment with either CCB for 8 weeks.. Although systolic and diastolic BPs did not differ between the azelnidipine and amlodipine groups, the HR in the azelnidipine group significantly decreased compared with that in the amlodipine group. MSNA was significantly reduced in the azelnidipine compared with the amlodipine group (47.7 ± 14.9 vs. 61.5 ± 10.7  bursts per 100 beats, P < 0.05). However, no significant difference was observed in terms of the baroreflex control of HR, or MSNA, between the two groups.. Our data show, first, that azelnidipine, compared with amlodipine, exerted a favorable effect on sympathetic nerve activity, without affecting baroreflex sensitivity, in hypertensive patients. These results indicate that azelnidipine might be useful for treating hypertensive patients, in whom hypertension is complicated by heart failure and ischemic heart disease.

Topics: Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Baroreflex; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Essential Hypertension; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Sympathetic Nervous System

This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD).. In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months.. Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)).. The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

Topics: Adult; Aged; Albuminuria; Amlodipine; Blood Pressure; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System

We previously demonstrated that a calcium channel blocker, azelnidipine, improves left ventricular relaxation in patients with hypertension and diastolic dysfunction in a multicentre, Clinical impact of Azelnidipine on Left VentricuLar diastolic function and OutComes in patients with hypertension (CALVLOC) trial. The objectives of the present subanalysis were to investigate the differences in diastolic function in hypertensive patients with and without diabetes, and the efficacy of azelnidipine on diastolic function among them.. Subanalysis of a prospective single-arm multicentre study.. 228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e' velocity<8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes.. Administration of 16 mg of azelnidipine for 8 months (range 6-10 months).. Septal e' velocity before and at the end of the study.. Whereas patients with diabetes (n=53, 23.2%) had lower systolic blood pressure (BP) than patients without diabetes (155±17 vs 161±16 mm Hg, p=0.03), they had lower e' velocity (5.7±1.5 vs 6.1±1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e' velocity similarly in patients with diabetes (5.7±1.5 to 6.3±1.5 cm/s, p=0.0003) and without diabetes (6.1±1.4 to 6.9±1.4 cm/s, p<0.0001). Increase in e' velocity was not influenced by presence of diabetes, and patients with diabetes still had lower e' velocity after treatment (p=0.006). There was a significant correlation between increase in e' velocity and decrease in systolic BP (R=0.25, p=0.0001), which was not influenced by diabetes.. Comorbid diabetes could impair left ventricular relaxation independently in patients with hypertension, which might not be improved solely by BP lowering.

Topics: Adult; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetic Cardiomyopathies; Dihydropyridines; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ventricular Dysfunction, Left; Ventricular Function, Left

Albuminuria and a high plasma aldosterone concentration (PAC) are prognosis factors predicting a poor outcome for cardiovascular disease. We examined here the effects of benidipine, a T/L-type calcium channel blocker (CCB), on albuminuria and PAC.Thirty-one patients with essential hypertension who received an L-type CCB and achieved the target blood pressure (BP) indicated by the Treatment Guidelines of the Japan Society of Hypertension (JSH2009) were investigated. The Ltype CCB under treatment was switched to benidipine at a dose in which equivalent BP reduction was expected. BP and estimated glomerular filtration rate at 6 months after switching to benidipine were not significantly different from those at baseline. The urinary-albumin-creatinine ratio (UACR) decreased significantly by 36.9% (P = 0.001). No significant change was observed in plasma renin activity (P = 0.063). The PAC of all patients decreased significantly by 11.8% (P = 0.002). When analyzed by daily doses of benidipine, the PAC appeared to have decreased in patients who received 4 mg per day of benidipine (n = 14), although statistical significance was not reached (P = 0.096). The PAC in patients who received 8 mg per day of benidipine (n =17) was significantly reduced by 13.2% (P = 0.017).In hypertensive patients whose BP is controlled by L-type CCB, switching to the T/L-type CCB benidipine maintained BP control and reduced UACR. In addition, the high dose of benidipine reduced the PAC independent of BP control. These results suggest the T/L-type CCB benidipine may contribute to cardio-renal protection in addition to lowering BP.

Topics: Aged; Albuminuria; Aldosterone; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Prospective Studies; Renin

A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved.. Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization.. At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period.. Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Kidney Diseases; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Tetrazoles; Young Adult

To compare the long-term effects of olmesartan combined with either azelnidipine or amlodipine on central blood pressure (CBP), left ventricular (LV) mass index (LVMI), LV diastolic function (e' velocity, E/e' ratio, E/A ratio) and arterial stiffness (brachial-ankle pulse wave velocity [baPWV] and augmentation index normalized for a heart rate of 75 bpm [AIx]).. Patients with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg received olmesartan monotherapy (20 mg/day) for 12 weeks. They were then randomly assigned to fixed-dose add-on therapy with azelnidipine (16 mg/day; n = 26) or amlodipine (5 mg/day; n = 26) for a further 2 years. CBP, LVMI, e' velocity, E/e' ratio, E/A ratio, baPWV, and AIx were measured at baseline, 6 months, and 2 years.. Baseline characteristics of both groups were similar. The decrease in brachial BP over 2 years was similar in both groups. CBP, LVMI, E/e' ratio, baPWV, and AIx decreased significantly, and the E/A ratio and e' velocity increased significantly in both groups. The decreases in CBP (P < 0.001), AIx (P < 0.001), baPWV (P < 0.001), LVMI (P < 0.001), and E/e' (P = 0.002) as well as the increase in E/A ratio (P = 0.03) over 2 years were significantly greater in the olmesartan/azelnidipine group than in the olmesartan/amlodipine group. Multivariate linear regression analyses showed that the changes in baPWV (β = 0.41, P < 0.001) and CBP (β = 0.47, P = 0.01) were independently associated with the change in LVMI, the change in baPWV (β = 0.25, P < 0.001) was independently associated with the change in E/e' ratio, and the changes in baPWV (β = 0.21, P = 0.001) and AIx (β = 0.25, P = 0.03) were independently associated with the change in E/A ratio.. Treatment with olmesartan/azelnidipine for 2 years resulted in greater improvements in CBP, LVMI, and LV diastolic function, and arterial stiffness compared with olmesartan/amlodipine. Improvements in LV diastolic function were associated with improvements in arterial stiffness.

Topics: Aged; Amlodipine; Azetidinecarboxylic Acid; Diastole; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Male; Middle Aged; Pulse Wave Analysis; Tetrazoles; Vascular Stiffness; Ventricular Function, Left

Central blood pressure (BP) is pathophysiologically more important than peripheral BP for the pathogenesis of cardiovascular disease. Arterial stiffness is also a good predictor of cardiovascular morbidity and mortality. The effects of benidipine, a unique dual L-/T-type calcium channel blocker, on central BP have not been reported. This study aimed to compare the effect of benidipine and losartan on the central BP and arterial stiffness in mild to moderate essential hypertensives.. This 24 weeks, multi-center, open label, randomized, active drug comparative, parallel group study was designed as a non-inferiority study. The eligible patients (n = 200) were randomly assigned to receive benidipine (n = 101) or losartan (n = 99). Radial artery applanation tonometry and pulse wave analysis were used to measure the central BP, pulse wave velocity (PWV) and augmentation index (AIx). We also measured the metabolic and inflammatory markers.. After 24 weeks, the central BP decreased significantly from baseline by (16.8 ± 14.0/10.5 ± 9.2) mmHg (1 mmHg = 0.133 kPa) (systolic/diastolic BP; P < 0.001) in benidipine group and (18.9 ± 14.7/12.1 ± 10.2) mmHg (P < 0.001) in losartan group respectively. Both benidipine and losartan groups significantly lowered peripheral BP (P < 0.001) and AIx (P < 0.05), but there were no significant differences between the two groups. The mean aortic, brachial and femoral PWV did not change in both groups after 24-week treatment. There were no significant changes of the blood metabolic and inflammatory biomarkers in each group.. Benidipine is as effective as losartan in lowering the central and peripheral BP, and improving arterial stiffness.

Topics: Adolescent; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Essential Hypertension; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Vascular Stiffness

Combination therapy is an effective method to reduce the blood pressure (BP) for patients with hypertension. This study was performed to evaluate the efficacy and safety of benazepril/lercanidipine compared with benazepril alone in patients with mild-to-moderate hypertension.. One hundred and eighty-one patients with mild-to-moderate primary hypertension were assigned in this randomized, single-blind, parallel-group study and were randomly divided into group A (benazepril 10 mg/lercanidipine 10 mg) and group B (benazepril 10 mg) for 8 weeks. At 4 weeks, the dosage of Benazepril was titrated up to 20 mg if the diastolic blood pressure (DBP) remained ≥ 90 mmHg. BP control and side effects were evaluated at the end of 1, 4 and 8 weeks.. The baseline characteristics of the two groups were similar. The BP in both groups decreased from the baseline (P < 0.05). At the end of 4 and 8 weeks, Benazepril/Lercanidipine produced greater BP reduction than Benazepril alone (P < 0.05). The comparison of the rate of BP control for the benazepril/lercanidipine and benazepril groups at the end of 1, 4, and 8 weeks were 41.2% vs. 37.6% (P > 0.05), 67.1% vs. 44.7% (P < 0.05), and 71.8% vs. 45.9% (P < 0.05). There was no significant difference of side effects between the two groups.. The benazepril/lercanidipine combination is more effective in reducing BP than benazepril alone, while it does not increase the incidence of side effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Single-Blind Method

The authors examined the effect of cilnidipine, a unique L/N-type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N-Channel Blocker Cilnidipine (ACHIEVE-ONE), a large-scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24-hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12-week treatment with cilnidipine significantly reduced 24-hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were -17.9 mm Hg from 154.6 mm Hg in risers and -11.9 mm Hg from 142.1 mm Hg, -6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but -7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (-0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

Topics: Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Edema; Female; Humans; Hypertension; Hypotension; Incidence; Japan; Male; Middle Aged; Treatment Outcome

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR <60 ml min(-1) per 1.73 m(2) regardless of the treatment group, although the eGFR decreased over time in all patients in the three groups. In conclusion, in patients with CKD, all of the tested combination therapies demonstrated comparable efficacy in terms of prevention of cardiovascular events as well as maintenance of eGFR.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Sodium Chloride Symporter Inhibitors; Treatment Outcome

To clarify whether the L-/N-type calcium channel blocker (CCB) cilnidipine is more renoprotective than the L-type CCB amlodipine in patients with early-stage diabetic nephropathy.. In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of cilnidipine and amlodipine were examined in renin-angiotensin system (RAS) inhibitor-treated patients with hypertension (blood pressure [BP]: 130-180/80-110 mmHg), type 2 diabetes, and microalbuminuria (urinary albumin to creatinine [Cr] ratio [UACR]: 30-300 mg/g).. Patients received cilnidipine (n = 179, final dose: 10.27 ± 4.13 mg/day) or amlodipine (n = 186, 4.87 ± 2.08 mg/day) for 12 months. Cilnidipine and amlodipine equally decreased BP. The UACR values for the cilnidipine and amlodipine groups were 111.50 ± 138.97 and 88.29 ± 63.45 mg/g, respectively, before treatment and 107.93 ± 130.23 and 89.07 ± 97.55 mg/g, respectively, after treatment. The groups showed similar changes for the natural logarithm of the UACR, serum Cr, and estimated glomerular filtration rate.. Cilnidipine did not offer greater renoprotection than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, -12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomegaly; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Outcome

To evaluate the effect of aranidipine enteric-coated capsules on 24 h blood pressure and blood pressure variability (BPV) in patients with mild to moderate essential hypertension.. This was an open clinical trial with 2 weeks of placebo run-in period. A total of 74 patients with blood pressure (140-180/95-110 mm Hg (1 mm Hg = 0.133 kPa) were treated by aranidipine (5 mg/d) for 4 weeks.If clinical sitting blood pressure < 140/90 mm Hg at 4th week, aranidipine at 5 mg/d would be continued for another 8 weeks.If not, the dosage would be increased to 10 mg/d.If blood pressure <140/90 mm Hg at 8th week, aranidipine at 5 mg/d or 10 mg/d would be given constantly.If not, the dosage would be increased to 20 mg/d and given for another 4 weeks. All patients performed 24 h ambulatory blood pressure monitoring (ABPM) before and after the treatment with BPV evaluated by the average 24 h per unit time blood pressure standard deviation and morning blood pressure surge (MBPS).. (1) After 12 weeks' treatment with aranidipine, the mean 24 h blood pressure was reduced significantly compared with the baseline [(14 ± 13)/(11 ± 9) mm Hg, both P < 0.05] with trough/peak (T/P) ratio of SBP and DBP in responders of 75.31% and 78.15%, respectively.(2) After 12 weeks' treatment, standard deviations of 24 h, daytime SBP/DBP and nighttime SBP/DBP were reduced significantly[(25 ± 3)/(14 ± 4) mm Hg vs (11 ± 3)/(8 ± 2) mm Hg, (24 ± 5)/(14 ± 4) mm Hg vs (11 ± 3)/(8 ± 2) mm Hg, (10 ± 3)/(8 ± 4) mm Hg vs (8 ± 3)/(6 ± 3) mm Hg], respectively with all P < 0.05.Significant decrease was shown in MBPS compared to the baseline [(27 ± 11) mm Hg vs (19 ± 9) mm Hg, P < 0.05]. (3) The incidence of adverse events was 13.4%, including mild dizziness, flushing and palpitation.. Administration of aranidipine enteric-coated capsules can control 24 h blood pressure effectively and reduce BPV significantly in patients with mild to moderate essential hypertension with good safety profile.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Essential Hypertension; Female; Humans; Hypertension; Male; Middle Aged; Young Adult

To assess the efficacy and safety of aranidipine versus retard-released felodipine in Chinese patients with mild-to-moderate essential hypertension.. This was a multicenter, randomized, double-blind, placebo and active antihypertensive drug parallel-controlled study. After 2 weeks of placebo run-in period, 315 patients at 6 centers with diastolic blood pressure (DBP) between 95 to 109 mm Hg (1 mm Hg = 0.133 kPa) while systolic blood pressure (SBP) below 180 mm Hg were randomized to receive aranidipine 5-20 mg/d (n = 126) or retard-released felodipine 5-10 mg/d (n = 126) for 12 weeks. Others (n = 63) received placebo for 4 weeks. Their blood pressures were evaluated at baseline and the end of Weeks 4, 8 and 12.. After a 12-week treatment, SBP decreased from 148.8 ± 10.7 mm Hg to (132.8 ± 11.2) mm Hg while DBP dropped from ( 98.4 ± 2.8) mm Hg to (83.9 ± 7.5) mm Hg. There were significant differences with the baseline values (P < 0.0001). After a 4-week treatment, the reductions of SBP in aranidipine and retard-released felodipine groups were (12.1 ± 11.0) mm Hg and (12.2 ± 11.2) mm Hg while the reductions of DBP in two groups (11.8 ± 6.9) mm Hg and (12.1 ± 7.9) mm Hg respectively. The reductions of SBP and DBP in two groups were (2.3 ± 8.4) mm Hg and (4.0 ± 5.1) mm Hg and they were significantly superior to that in placebo group (P < 0.0001). But no significant difference existed between aranidipine and retard-released felodipine groups. Also no significant differences were found between these two antihypertensive therapy groups at the end of Weeks 4, 8 and 12 in the reduction of blood pressure, total response rate and blood pressure control rate. But 20 mg daily aranidipine was significantly superior to 10 mg daily retard-released felodipine in the control rates of SBP and DBP. Adverse events occurred at 24.22% and 29.92% in aranidipine and retard-released felodipine groups respectively (P = 0.305).. Administration of aranidipine 5-20 mg/d can effectively control blood pressure and is not inferior to retard-released felodipine 5-10 mg/d. The efficacy of 20 mg/d aranidipine is superior to that of retard-released felodipine 5-10 mg/d. And the effectiveness and safety of aranidipine are similar to those of retard-released felodipine.

Topics: Antihypertensive Agents; Dihydropyridines; Double-Blind Method; Essential Hypertension; Felodipine; Female; Humans; Hypertension; Male; Middle Aged

At the intervention for cardiovascular disease (CVD), albuminuria is a new pivotal target. Calcium channel blocker (CCB) is one of the most expected agents. Currently CCBs have been classified by delivery system, half-life and channel types. We tested anti-albuminuric effect among 4 types of CCBs.. Subjects were 50 hypertensives (SBP/DBP 164.7±17.1/92.3±12.2mmHg, s-Cr 0.81±0.37mg/dl, urinary albumin excretion (UAE) 69.4 (33.5-142.6) mg/gCr). Four CCBs were administered in a crossover setting: nifedipine CR, a long biological half-life L type by controlled release; cilnidipine, an N/L type; efonidipine, a T/L type; and amlodipine, a long biological half-life L type.. Comparable BP reductions were obtained. UAE at endpoints ware as follows (mg/gCr, *P<0.01): nifedipine CR 30.8 (17.3-81.1),* cilnidipine 33.9 (18.0-67.7),* efonidipine 51.0 (21.2-129.8), amlodipine 40.6 (18.7-94.7). By all agents, significant augmentations were observed in PRA, angiotensin I and angiotensin II (AngII). AngII at cilnidipine was significantly lower than that at amlodipine. PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine. Nifedipine CR significantly reduced ANP concentration.. It is revealed that only nifedipine CR and cilnidipine could reduce albuminuria statistically. Thus, it is suggested that the 2 CCBs might be favorable for organ protection in hypertensives.

Topics: Aged; Aged, 80 and over; Albuminuria; Biomarkers; Calcium Channel Blockers; Cardiovascular Diseases; Cross-Over Studies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine

Cilnidipine inhibits both L- and N-type calcium channels and has been shown to dilate efferent arterioles as effectively as afferent arterioles. We conducted an open-label, randomized trial to compare the effects of cilnidipine against those of amlodipine on blood pressure (BP), albuminuria, and plasma aldosterone concentration in hypertensive patients with mild- to moderate-stage chronic kidney disease. Patients with BP ≥130/80 mmHg, an estimated glomerular filtration rate of 90-30 ml/min/1.73 m(2), and albuminuria ≥30 mg/g, despite treatment with the maximum recommended dose of angiotensin II receptor blockers, were randomly assigned to two groups. Patients received either 10 mg/day cilnidipine (increased to 20 mg/day; n = 35) or 2.5 mg/day amlodipine (increased to 5 mg/day; n = 35). After 48 weeks of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The percent reduction in the urinary albumin to creatinine ratio and liver-type fatty acid binding protein (L-FABP) in the cilnidipine group was significantly greater than in the amlodipine group. Although plasma renin activity did not differ between the two groups, the plasma aldosterone level was significantly decreased in the cilnidipine group. Cilnidipine therefore appears to reduce albuminuria, urinary L-FABP, and plasma aldosterone levels more than amlodipine, and these effects are independent of BP reduction.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Down-Regulation; Fatty Acid-Binding Proteins; Female; Humans; Hypertension; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

To compare the effect of manidipine 20 mg plus rosuvastatin 10 mg versus olmesartan 20 mg plus rosuvastatin 10 mg on markers of insulin resistance in patients with mixed dyslipidemia, hypertension, and impaired fasting glucose (IFG).. This study had a prospective, randomized, open-label, blinded endpoint (PROBE) design. A total of 40 patients with IFG, mixed dyslipidemia, and stage 1 hypertension were included. Following dietary intervention, patients were randomly allocated to rosuvastatin (10 mg/d) plus olmesartan (20 mg/d) or manidipine (20 mg/d). The primary end point was the between-group difference in changes in the Homeostasis Model Assessment Insulin Resistance (HOMA-IR) index following 3 months of treatment. Secondary end points included changes in fasting plasma glucose (FPG), fasting insulin levels, and glucosylated hemoglobin.. At the end of the 3-month treatment period, a significant increase in HOMA-IR index by 14% (from 2.4 [0.5-7.9] to 2.7 [0.5-5.2], P = .02 versus baseline) was seen in the olmesartan plus rosuvastatin group. On the contrary, no significant change in HOMA-IR index was observed in the manidipine plus rosuvastatin group (1.7 [0.5-5.2] to 1.7 [0.8-6.0], P = NS versus baseline, P = .04 versus olmesartan plus rosuvastatin group). An increase in fasting insulin levels was observed in the olmesartan plus rosuvastatin group (+8%, from 10.1 [2.0-29.6] to 10.9 [2.0-19.1] μU/mL, P < .05 versus baseline), while no significant change was seen in the manidipine plus rosuvastatin group (+3%, from 7.3 [2.0-17.6] to 7.5 [1.9-15.6] μU/mL, P = NS versus baseline, P = .02 versus olmesartan plus rosuvastatin group). Fasting plasma glucose and glycosylated hemoglobin did not change significantly in any group.. Manidipine seems to ameliorate the possible statin-associated increase in insulin resistance as compared with olmesartan in patients with IFG, hypertension, and mixed dyslipidemia.

Topics: Aged; Blood Glucose; Dihydropyridines; Drug Therapy, Combination; Dyslipidemias; Endpoint Determination; Fasting; Female; Fluorobenzenes; Humans; Hypertension; Imidazoles; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Pyrimidines; Rosuvastatin Calcium; Single-Blind Method; Sulfonamides; Tetrazoles; Treatment Outcome

Intraglomerular pressure is one of the main drivers of progression of renal failure. Experimental data suggest that there are important differences between calcium channel blockers (CCBs) in their renal haemodynamic effects: manidipine reduces, whereas amlodipine increases intraglomerular pressure. The aim of this study was to investigate the effects of manidipine and amlodipine treatment on intragomerular pressure (P(glom)) in patients with mild to moderate essential hypertension.. In this randomized, double-blind, parallel group study, hypertensive patients were randomly assigned to receive manidipine 20 mg (n = 54) or amlodipine 10 mg (n = 50) for 4 weeks. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant-infusion input-clearance technique with p-aminohippurate (PAH) and inulin. P(glom) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the model established by Gomez.. P(glom) did not change in the manidipine group (P = 0.951), whereas a significant increase occurred in the amlodipine group (P = 0.009). There was a significant difference in the change of P(glom) by 1.2 mmHg between the manidipine and amlodipine group (P = 0.042). In both treatment arms, R(A) was reduced (manidipine P = 0.018; amlodipine P < 0.001). The reduction of R(A) was significantly more pronounced with amlodipine compared with manidipine treatment (P < 0.001). R(E) increased in both treatment arms (manidipine P = 0.012; amlodipine P = 0.002), with no difference between the treatment arms. Both CCBs significantly reduced systolic and diastolic blood pressure (BP) (both P < 0.001). However, amlodipine treatment resulted in a significantly greater decrease of BP compared with manidipine (P < 0.001).. In accordance with experimental data after antihypertensive treatment of 4 weeks, intraglomerular pressure was significantly lower with the CCB manidipine than with amlodipine, resulting and explaining their disparate effects on albuminuria.

Topics: Adult; Aged; Albuminuria; Amlodipine; Creatinine; Dihydropyridines; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Nitrobenzenes; Piperazines

The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering By N-Channel Blocker Cilnidipine (ACHIEVE-ONE) trial is a large-scale clinical study on blood pressure (BP) and pulse rate (PR) in the real world with use of cilnidipine, a unique L/N-type Ca channel blocker, possessing a suppressive action on increased sympathetic activity in patients with essential hypertension. The effects of cilnidipine on morning hypertension were examined. The authors examined 2319 patients treated with cilnidipine for 12 weeks. Clinic systolic BP (SBP) decreased by 19.6 mm Hg from 155.0 mm Hg, whereas morning SBP decreased by 17.0 mm Hg from 152.9 mm Hg after 12-week cilnidipine treatment. Cilnidipine reduced both morning SBP and PR more markedly in patients with higher baseline morning SBP (-3.2 mm Hg and -1.3 beats per minute in the first quartile of morning SBP, -30.9 mm Hg and -3.2 beats per minute in the fourth quartile), and also reduced both morning PR and SBP more markedly in patients with higher baseline morning PR (0.6 beats per minute and -15.6 mm Hg in <70 beats per minute, and -9.7 beats per minute and -20.2 mm Hg in ≥85 beats per minute). Cilnidipine significantly reduced BP and PR in hypertensive patients at the clinic and at home, especially with higher BP and PR in the morning.

Topics: Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Circadian Rhythm; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Japan; Male; Middle Aged; Sympathetic Nervous System; Treatment Outcome

The aim of this study is to assess the blood pressure (BP) and metabolic effects of lercanidipine when combined with other classes of first-line antihypertensive drugs in day-to-day clinical practice. For this study, we consecutively enrolled 162 patients with uncomplicated primary hypertension, who are partial responders to the treatment with lercanidipine over a period of 24 months. Patients were then allocated to the combination of lercanidipine (10-20 mg/day) with β-blockers, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin-II receptor blockers according to compelling indications (if any) and/or suggestions of European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines. All the enrolled patients completed the study and no adverse drug reaction was registered during the research period. The association of a second drug with lercanidipine determined an additional BP decrease of either systolic BP or diastolic BP independently from the type of drug added (P always <.05). The additional effect of lercanidipine appears widely distributed with no significant differences in the size of BP decrease. From the metabolic point of view, the addition of a second drug did not determine a significant variation in the serum levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (P always >.05). Conversely, a significant decrease in fasting plasma glucose and serum levels of triglycerides has been observed in patients where lercanidipine has been combined with an angiotensin-converting enzyme inhibitor or an angiotensin-II receptor blocker. In conclusion, in our study we observed that lercanidipine-based protocols are well tolerated and efficacious in reducing BP. Moreover, the association of lercanidipine with renin-angiotensin system blockers is also associated with significant improvements in triglycerides and fasting plasma glucose.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Middle Aged; Triglycerides

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90 mm Hg). We further evaluated the efficacy and safety of these combination therapies in older (65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (153365 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Treatment Outcome

This is a multicenter, randomized, double-blind, parallel-controlled study, conducted in Chinese patients with mild to moderate essential hypertension. After a 2-week washout period, 236 eligible patients were randomly to receive aranidipine 5-10 mg/d (n = 118) or amlodipine 5-10 mg/d (n = 118) for 10 weeks. The blood pressure and heart rate were evaluated in outpatient clinics, and ambulatory blood pressure monitoring was performed in 24 patients in each group. The blood pressure was significantly decreased in both groups. Compared with amlodipine, the patients who received aranidipine had less response in blood pressure (P < 0.01). The trough/peak ratios of diastolic blood pressure in aranidipine and amlodipine groups were 0.57 ± 0.20 and 0.68 ± 0.19, respectively (P = 0.119). Adverse events occurred at 11.86% and 7.63% in the aranidipine and amlodipine groups, respectively (P = 0.348). Headache was observed at an incidence of >3.0% in both groups, and the serum glucose and lipid profile had no significant change in the amlodipine group. In conclusion, once-daily administration of aranidipine (5-10 mg) effectively controlled blood pressure, and the short-term treatment might result in it being less effective than amlodipine. It had a stable action over 24-hour period, and the mechanism of that is not yet clear. Aranidipine had a good safety similar to that of amlodipine.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Tablets, Enteric-Coated

Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion.. Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination.. Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline.. This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Half-Life; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Pyridines; Single-Blind Method

Recent studies have reported that in patients under antihypertensive treatment visit-to-visit (or long-term) variability of clinic BP within a given patient has an independent prognostic significance. Partly based on between-patient dispersion of BP values during treatment (interindividual variability) it has also been reported that long-term clinic BP variability is greater for β-blocker than for calcium antagonist and other types of treatment.. To measure visit-to-visit intraindividual variations of both clinic and 24-h mean BP in the hypertensive patients of the European Lacidipine Study on Atherosclerosis (ELSA) trial treated for 4 years with either atenolol or lacidipine, and to check whether interindividual clinic and 24-h BP variabilities during treatment can really be considered a surrogate of intraindividual variabilities in exploring differences between β-blocker and calcium antagonist treatments.. Long-term intraindividual BP variability was defined as the coefficient of variation of the average systolic or diastolic values of clinic and 24-h BP measured at each visit throughout the treatment period. Patients in whom at least seven clinic (6-month intervals) or at least three (yearly intervals) 24-h values were available from the end of the drug titration phase to the end of the study were considered.. Visit-to-visit 24-h SBP/DBP variabilities were 20-25% smaller than, and loosely correlated with clinic BP variability (r(2) < 0.022). There was also a very limited relationship (r (2)< 0.026) between visit-to-visit and within 24-h ambulatory BP variabilities, the latter being two to three times greater than the former. Visit-to-visit intraindividual clinic SBP variability was only slightly lower on calcium antagonist than on β-blocker treatment but little or no between-treatment difference was found for visit-to-visit clinic DBP and ambulatory SBP/DBP particularly in patients under monotherapy throughout the study. Interindividual BP variability was markedly greater than the intra-individiual one of which it did not precisely reflect the treatment-induced changes.. In mild-to-moderate hypertensive patients, visit-to-visit BP variability does not differ substantially between β-blocker and calcium antagonist treatment. Major discrepancies exist between visit-to-visit BP variability as quantified by 24-h vs. clinic BP, making investigation of which of these indices is clinically more relevant important. Interindividual BP variability during treatment shows marked quantitative differences with intraindividual BP variability questioning whether its use can accurately reflect individual BP variations from one visit to another.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Europe; Humans; Hypertension

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients.. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death.. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02).. The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.

Topics: Aged; Aged, 80 and over; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Imidazoles; Japan; Male; Prospective Studies; Single-Blind Method; Survival Analysis; Tetrazoles; Treatment Outcome

Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD).. The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure.. Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. -2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (-29 ± 2 vs. -38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (-4 ± 1 vs. -9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period.. In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection.

Topics: Aged; Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Time

Day-by-day home blood pressure (BP) variability (BPV) was reported to be associated with increased cardiovascular risk. We aimed to test the hypothesis that the angiotensin II receptor blocker/calcium-channel blocker combination decreases day-by-day BPV more than the angiotensin II receptor blocker/diuretic combination does and investigated the mechanism underlying the former reduction. We enrolled 207 hypertensive subjects treated with olmesartan monotherapy for 12 weeks. The subjects were randomly assigned to treatment with hydrochlorothiazide (n = 104) or azelnidipine (n = 103) for 24 weeks. Home BP was taken in triplicate with a memory-equipped device in the morning and evening, respectively, for 5 consecutive days before each visit. Visits occurred at 4-week intervals. Home BPV was defined as within-individual SD of the 5-day home BP. Arterial stiffness was assessed by aortic pulse wave velocity at baseline and 24 weeks later. The reductions in home systolic BP were similar between the 2 groups, whereas the SD of home systolic BP decreased more in the azelnidipine group than in the hydrochlorothiazide group during the follow-up period (follow-up mean: 6.3 versus 7.1 mm Hg; P = 0.007). In the azelnidipine group, the change in aortic pulse wave velocity was independently associated with the change in SD of home systolic BP (regression coefficient ± SE = 0.79 ± 0.37; P = 0.036). This study demonstrated that the angiotensin II receptor blocker/calcium-channel blocker combination improved home BPV in addition to home BP reduction and that the reduction in home BPV was partly attributable to the arterial stiffness reduction by this combination.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Tetrazoles; Treatment Outcome

We aimed to investigate the association of the change in the ambulatory arterial stiffness index (AASI) with that in carotid-femoral pulse wave velocity (cfPWV) during treatment with antihypertensive medication.. We enrolled 207 hypertensive patients treated with olmesartan monotherapy for 12 weeks. Patients were randomly assigned to treatment with hydrochlorothiazide (HCTZ; n = 104) or azelnidipine (n = 103) for 24 weeks. The cfPWV and 24-h ambulatory blood pressure monitoring (ABPM) results were assessed at baseline and 24 weeks later. The AASI was defined as 1 minus the regression slope of diastolic blood pressure (DBP) on systolic BP (SBP), and was calculated by standard and symmetric regression.. The changes in the AASI and symmetrical AASI were similar between the two groups, while cfPWV in the azelnidipine group decreased more than in the HCTZ group (P < 0.001). The change in AASI was not significantly correlated with change in cfPWV (r = 0.08, P = 0.26), whereas the change in symmetrical AASI was significantly but weakly correlated with change in cfPWV (r = 0.22, P < 0.001). The multivariable linear regression analysis revealed that the association of the change in symmetrical AASI with change in cfPWV remained significant even after adjustments for covariates derived from ABPM (regression coefficient (95% confidence interval): 1.33 (0.35-2.30), P = 0.01).. The present study demonstrated that neither AASI nor symmetrical AASI may be an unequivocal marker of arterial stiffness during antihypertensive treatment.

Topics: Aged; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Middle Aged; Pulse Wave Analysis; Tetrazoles; Vascular Stiffness

Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Imidazoles; Japan; Male; Middle Aged; Tetrazoles; Time Factors; Treatment Outcome

Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

Topics: Aged; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cross-Over Studies; Dihydropyridines; Female; Heart; Heart Conduction System; Hemodynamics; Humans; Hypertension; Male; Nitrophenols; Norepinephrine; Organophosphorus Compounds; Prospective Studies; Sympathetic Nervous System

In high-cardiovascular-risk treated hypertensive patients, the incidence of cardiovascular events has been reported to relate to visit-to-visit blood pressure (BP) variability. We investigated whether visit-to-visit BP variability is prognostically important in treated mildly to moderately hypertensive patients in whom treatment aims at avoiding events but also at preventing or delaying progression of organ damage.. We analyzed the pooled data from the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind 4-year trial of the effect of lacidipine or atenolol on echographic carotid intima-media thickness. Visit-to-visit BP variability was assessed by the coefficient of variation or the SD of the mean on-treatment systolic BP (SBP) obtained at 6- (clinic BP) and 12- (24 hours BP) month intervals, respectively (1521 and 1264 patients, respectively). In a multivariable linear regression model, mean on-treatment clinic or 24-hour SBP, but not SBP coefficient of variation or SD, was associated with end-of-treatment carotid intima-media thickness. Intima-media thickness increased progressively from the lowest to highest quartile of mean on-treatment clinic or 24-hour SBP (adjusted P for trend=0.046 and 0.048) but not along similar quartiles of SBP coefficient of variation or SD. In a multivariable logistic regression model, mean BP, but not variability, was associated with cardiovascular outcomes.. In mildly to moderately hypertensive patients, carotid intima-media thickness and cardiovascular outcomes were related to the mean clinic or ambulatory SBP achieved by treatment but not to on-treatment visit-to-visit clinic or 24-hour BP variability. Thus, when BP is modestly elevated, inconsistency of BP control between visits plays a less important prognostic role than long-term average BP levels.

Topics: Adrenergic Antagonists; Aged; Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Circadian Rhythm; Dihydropyridines; Double-Blind Method; Europe; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Office Visits; Prognosis; Prospective Studies; Treatment Outcome

Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin-angiotensin system inhibitor were randomly assigned to a cilnidipine (n=18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine (n=17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2'-deoxyguanosine (OHdG) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group (P<0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Antioxidants; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Heart Rate; Humans; Hypertension; Incidence; Male; Middle Aged; Oxidative Stress; Prospective Studies; Renal Insufficiency, Chronic

This open-label, randomized controlled trial investigated the effects of cilnidipine, an L/N-type calcium channel blocker (CCB), in patients with chronic kidney disease (CKD).. Sixty patients with CKD and well-controlled hypertension being treated with a renin- angiotensin system (RAS) inhibitor and an L-type CCB (L-CCB) were randomly assigned either to switch from the L-CCB to cilnidipine after a 4-week observation period or to continue with L-CCB treatment. Blood pressure, heart rate and renal function were monitored for 12 months. Data were available for analysis from 50 patients: 24 from the cilnidipine group and 26 from the L-CCB group.. Blood pressure was well controlled in both groups. After 12 months, proteinuria and heart rate were significantly decreased in the cilnidipine group, but proteinuria increased and heart rate remained unchanged in the L-CCB group. There was a significant positive correlation between the percentage changes in proteinuria and heart rate.. Cilnidipine has antihypertensive effects equivalent to those of L-CCBs. In patients with CKD, proteinuria can be decreased by switching from an L-CCB to cilnidipine, thereby improving renal function.

Topics: Adrenergic alpha-1 Receptor Antagonists; Aged; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Diuretics; Drug Substitution; Female; Heart Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Proteinuria; Regression Analysis; Renal Insufficiency, Chronic

Topics: Aged; Amlodipine; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Coronary Artery Disease; Dihydropyridines; Female; Humans; Hypertension; Male; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Preoperative Period; Prospective Studies; Ultrasonography, Interventional

Acute and severe hypertension is common, especially in patients with renal dysfunction (RD). Clevidipine is a rapidly acting (t½∼1 min) intravenous (IV) dihydropyridine calcium-channel blocker metabolized by blood and tissue esterases and may be useful in patients with RD. The purpose of this analysis was to assess the safety and efficacy of clevidipine in patients with RD.. VELOCITY, a multicenter open-label study of severe hypertension, enrolled 126 patients with persistent systolic blood pressure (SBP) >180 mmHg. Investigators pre-specified a SBP initial target range (ITR) for each patient to be achieved within 30 min. Blood pressure monitoring was by cuff. Clevidipine was infused via peripheral IV at 2 mg/h for at least 3 min, then doubled every 3 min as needed to a maximum of 32 mg/h (non-weight-based treat-to-target protocol). Per protocol, clevidipine was continued for at least 18 h (96 h maximum). RD was diagnosed and reported as an end-organ injury by the investigator and was defined as requiring dialysis or an initial creatinine >2.0 mg/dl. Primary endpoints were the percentage of patients within the ITR by 30 min and the percentage below the ITR after 3 min of clevidipine infusion.. Of the 24 patients with moderate to severe RD, most (13/24) were dialysis dependent. Forty-six percent were male, with mean age 51 ± 14 years; 63% were black and 96% had a hypertension history. Median time to achieve the ITR was 8.5 min. Almost 90% of patients reached the ITR in 30 min without evidence of overshoot and were maintained on clevidipine through 18 h. Most patients (88%) transitioned to oral antihypertensive therapy within 6 h of clevidipine termination.. This report is the first demonstrating that clevidipine is safe and effective in RD complicated by severe hypertension. Prolonged infusion maintained blood pressure within a target range and allowed successful transition to oral therapy.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Pyridines; Severity of Illness Index; Treatment Outcome

The blood pressure goals set for the treatment of hypertensive patients have been lowered in recent guidelines. To reduce blood pressure levels sufficiently, combination therapies are often needed, but there is little evidence about which combination should be chosen. The present study was carried out to compare the effects of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker (CCB) or a thiazide diuretic, in elderly patients with hypertension. A total of 65 patients aged 65-85 years, with blood pressures of 140/90 mmHg or higher for those taking antihypertensive medication or 160/100 mmHg or higher for those not on medication, were randomly assigned to either the group treated with olmesartan plus a dihydropyridine CCB or the group treated with olmesartan plus a thiazide diuretic; 58 patients completed the treatment for 6 months. Systolic and diastolic blood pressures (SBP and DBP) were reduced during the treatment period in both the groups. The reductions in SBP at 1 and 6 months were significantly (P<0.05) greater in the CCB combination group than in the diuretic group (-29 vs. -18 mmHg, respectively, at 1 month; -32 vs. -23 mmHg, respectively, at 6 months). Despite greater reduction in SBP in the CCB group, the serum creatinine level and the estimated glomerular filtration rate (eGFR) remained unchanged, whereas in the diuretic group, creatinine was elevated (+0.06 mg per 100 ml, P<0.05) and eGFR was reduced (-4.5 mlmin(-1) per 1.73 m(2)). In addition, high-density lipoprotein cholesterol levels were reduced in the diuretic group (-5.0 mg per 100 ml, P<0.01). These results suggest that olmesartan plus a CCB is the preferable combination therapy in comparison with olmesartan plus a thiazide diuretic for elderly patients with hypertension.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Cholesterol, HDL; Creatinine; Dihydropyridines; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Male; Sodium Chloride Symporter Inhibitors; Tetrazoles; Treatment Outcome

Benidipine inhibits both L- and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-to-moderate stage chronic kidney disease (CKD). Patients with BP ≥ 130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30-90 ml min(-1) per 1.73 m(2), and with albuminuria>30 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n=52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10  mg per day (n=52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin Receptor Antagonists; Blood Pressure; Calcium Channel Blockers; Chronic Disease; Diabetic Nephropathies; Dihydropyridines; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension; Male; Middle Aged; Nephrosclerosis; Potassium; Severity of Illness Index; Sodium

Metabolic syndrome is common in patients with hypertension and increases the risk of developing diabetes mellitus. The objective of this study (the MARCADOR study) was to compare the effects of manidipine 20  mg with the extemporary combination of manidipine 10  mg/lisinopril 10  mg, amlodipine 10  mg and telmisartan 80  mg on insulin sensitivity, as well as metabolic, inflammatory and prothrombotic markers, in hypertensive non-diabetic patients with metabolic syndrome.. This study had a prospective, randomized, open-label, blinded endpoint (PROBE) design. A total of 120 patients aged 35-75 years with stage I-II essential hypertension (systolic blood pressure [BP] 140-179  mmHg, diastolic BP 90-109  mmHg) and metabolic syndrome were recruited from general practitioner clinics in Northern Gran Canaria Island, Spain and randomized to receive amlodipine 10  mg (n = 30), telmisartan 80  mg (n = 30), manidipine 20  mg (n = 30) or (low-dose) manidipine 10  mg/lisinopril 10  mg (n = 30), all administered once daily. At baseline and after 14 weeks of treatment, BP, insulin sensitivity, lipid profile, and albumin and metanephrin excretion as well as several other metabolic, inflammatory, prothrombotic and growth/adhesion markers were measured. The primary endpoint was the change in insulin sensitivity.. A total of 115 patients completed the study. All treatments significantly lowered BP from baseline. Compared with amlodipine, manidipine had significantly superior effects (p < 0.05) on insulin resistance (-26.5% vs -3.0%), albumin/creatinine ratio (-28.2% vs -3.6%), low-density lipoprotein (LDL) cholesterol (-6.8% vs +1.7%), and several other metabolic, inflammatory and prothrombotic markers. Manidipine was associated with a slightly greater increase in insulin sensitivity than manidipine/lisinopril, but manidipine/lisinopril was significantly more effective than manidipine and telmisartan for improving a number of metabolic, inflammatory, prothrombotic and growth/adhesion markers. Amlodipine was associated with a significantly greater incidence of adverse effects compared with telmisartan, manidipine and manidipine/lisinopril (26.7% vs 3.3%, 3.3% and 13.3%, respectively).. In patients with hypertension and metabolic syndrome, manidipine, both alone and in combination with the ACE inhibitor lisinopril, is significantly superior to amlodipine for improving insulin sensitivity as well as several metabolic, inflammatory and prothrombotic markers. Furthermore, the combination of manidipine and lisinopril appears to have greater efficacy than manidipine alone and telmisartan with respect to the improvement of metabolic, inflammatory and prothrombotic markers.

Topics: Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biomarkers; Blood Pressure; Dihydropyridines; Drug Combinations; Female; Humans; Hypertension; Insulin Resistance; Lisinopril; Male; Metabolic Syndrome; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Spain; Telmisartan

There is a growing body of evidence that advanced glycation end products (AGE) and their receptor (RAGE) system are implicated in chronic kidney disease (CKD). We have previously found that a long-acting calcium channel blocker, azelnidipine, but not amlodipine, improves renal injury in CKD patients. However, little is known about the effect of azelnidipine on the AGE-RAGE axis in humans. In this study, we examined whether azelnidipine addition could have renoprotective properties in hypertensive CKD patients by reducing serum levels of AGE and soluble form of RAGE (sRAGE). Thirty nondiabetic stage I or II CKD patients who had already been treated with angiotensin II receptor blockers were enrolled in this study.. We hypothesized that azelnidipine treatment could limit renal injury partly by blocking the AGE-RAGE axis.. Patients were randomly divided into 2 groups; one group was treated with 16 mg azelnidipine and the other with 5 mg amlodipine once daily. They were followed up for 6 months.. Proteinuria was positively correlated with circulating AGE and sRAGE levels in our subjects. Both drugs exhibited comparable and significant blood pressure (BP)-lowering effects. Although neither of them affected glucose, glycated hemoglobin, lipid levels, and estimated glomerular filtration rate, treatment with azelnidipine, but not amlodipine, decreased circulating AGE, sRAGE, proteinuria, and urinary levels of liver-type fatty acid binding protein, a marker of tubular injury, in a BP-lowering-independent manner.. Our present results suggest that azelnidipine may exert renoprotective properties in nondiabetic hypertensive CKD patients via its unique inhibitory effects on the AGE-RAGE axis.

Topics: Adult; Amlodipine; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Chronic Disease; Dihydropyridines; Female; Glycation End Products, Advanced; Humans; Hypertension; Japan; Kidney; Kidney Diseases; Male; Middle Aged; Proteinuria; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Time Factors; Treatment Outcome

A previous study reported that amlodipine retarded coronary plaque progression in patients with coronary artery disease. The goal of this multicenter study was to determine which calcium-channel blockers (CCBs) other than amlodipine attenuated the progression of plaque volume (PV) accessed by intravascular ultrasound (IVUS).. ALPS-J was a prospective, randomized open-label study conducted at 5 centers. Patients who had hypertension and were scheduled for coronary intervention were enrolled. Subjects were randomly assigned to receive 16 mg/day of azelnidipine or 5mg/day of amlodipine administered for 48 weeks. The primary endpoint was the percent change in coronary PV measured by IVUS. Between 2007 and 2009, 199 patients were enrolled; 115 had evaluable IVUS images at both baseline and after 48 weeks of treatment. Blood pressure significantly reduced to 128/68 mmHg at follow-up. The lipid profiles in the 2 groups were comparable (low-density lipoprotein cholesterol: 97 mg/dl). The %change in PV showed a significant regression of 4.67 and 4.85% in the azelnidipine and amlodipine groups, respectively. The upper limit of the 95% confidence interval of the mean difference in %change PV between the 2 groups (0.18%, 95% confidence interval 4.62 to 4.98%) did not exceed the pre-defined non-inferiority margin of 6.525%.. ALPS-J demonstrated that azelnidipine was not inferior to amlodipine for primary efficacy. In addition to standard medical therapy, dihydropyridine CCBs will retard PV progression in hypertensive patients.

Topics: Amlodipine; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Coronary Artery Disease; Dihydropyridines; Humans; Hypertension; Lipids; Plaque, Atherosclerotic; Ultrasonography, Interventional

Benidipine (CAS 91599-74-5) has been reported as an effective antihypertensive treatment and its cardioprotective effects have been shown in several basic and clinical studies. However, the long-term efficacy and safety of benidipine remain unknown in elderly Chinese patient with hypertension. In this prospective, multicenter, open-label clinical trial, 152 eligible patients aged 60 to 75 years with mild to moderate essential hypertension (sitting systolic blood pressure (BP) > or = 140 mmHg and/or sitting diastolic BP > or = 90 mmHg) entered a 52-week study. All patients initially received benidipine 2-4 mg once a day, followed by titration to benidipine 8 mg/day to achieve the target BP (< 140/90 mmHg in non-diabetics and <130/80 mmHg in diabetics). Add-on hydrochlorothiazide (CAS 58-93-5) and/or metoprolol tartaric acid (CAS 3750-58-6) were permitted during the study. Overall, 132 patients completed the 52-week treatment with benidipine as monotherapy or combination therapy. It showed that the regimen based on benidipine provided an obvious mean trough BP reduction of 13.8 +/- 12.4/8.3 +/- 9.2 mmHg (p < 0.001), and 62.5% of patients reached the target BP. In patients with left ventricular hypertrophy, the left ventricular mass index significantly decreased from 147.1 +/- 27.6 g/m2 at baseline to 136.0 +/- 17.5 g/m2 at 52 weeks (p = 0.036). Clinical adverse events (AEs) were found in 15.1% of all patients, and six patients discontinued the treatment due to drug-related AEs during the entire trial. Patients' compliance was an average of 98.7%. Benidipine, with a favorable tolerability profile, provides a long-term antihypertensive effect and potential benefit for the heart in elderly patients with mild to moderate hypertensive, suggesting that it is suitable for elderly patients with hypertension.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; China; Dihydropyridines; Echocardiography; Female; Heart; Heart Function Tests; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Function Tests; Male; Middle Aged; Myocardium; Patient Compliance; Prospective Studies

Little is known about the effects of the calcium channel antagonist manidipine when it is added as a third drug in non-controlled hypertensive patients with diabetes mellitus receiving dual antihypertensive therapy. The aim of this study was to evaluate the response in terms of blood pressure (BP) and microalbuminuria when manidipine is administered to patients with type 2 diabetes and uncontrolled hypertension who are already being treated with a combination of a low-dose diuretic plus an ACE inhibitor or an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]). We also evaluated the effects of addition of manidipine on plasma fasting glucose, glycosylated haemoglobin (HbA(1c)), serum uric acid, the lipid profile, serum creatinine and creatinine clearance.. This was a non-comparative, open-label study of hypertensive diabetic patients with systolic/diastolic BP >130/80 mmHg. All patients had been receiving treatment for ≥3 months with stable doses of a diuretic plus an ACE inhibitor or ARB. Manidipine 10 mg/day was added, increasing to 20 mg/day if the target BP was not reached after 3 months' treatment. The follow-up period was 6 months. Patient compliance was verified by tablet count. The doses of statins being taken by patients prior to commencement of the trial were not modified during the study. All patients were treated with oral antihyperglycaemic agents only; patients receiving insulin were excluded from the study.. 136 patients were enrolled in the trial and completed the study; 41.9% of the patients were males, the mean ± SD age of the study population was 64.4 ± 12.3 years, and the mean ± SD body mass index was 30.2 ± 4.9 kg/m(2). The mean ± SD BP at baseline was 158.6 ± 15.6/86.7 ± 11.2 mmHg compared with 136.8 ± 12.0/78.0 ± 11.2 (-21.8/-8.7, respectively) mmHg at the end of the study period (p < 0.001). A total of 63.6% of the patients attained a BP of <140/90 mmHg and 20.9% attained a BP of <130/80 mmHg. The mean ± SD heart rate decreased from 75.1 ± 11.2 at baseline to 72.8 ± 11.2 beats/min at the end of the study (p = 0.06; not significant). Fifty percent (95% CI 41.6, 58.4) of the patients had microalbuminuria at baseline compared with 31.3% (95% CI 23.0, 39.6) at study end (p = 0.006). Reductions in mean ± SD fasting glucose levels (-10.2 ± 50.3 mg/dL; p < 0.05), HbA(1c) (-0.19 ± 0.97%; p = 0.05), total cholesterol (-11.9 ± 35.2 mg/dL; 95% CI -18.1, -5.8; p < 0.005), triglycerides (-10.8 ± 51.1 mg/dL; 95% CI -19.7, -1.8; p = 0.018) and low-density lipoprotein-cholesterol (-8.1 ± 27.7 mg/dL; 95% CI -13.2, -2.9; p = 0.002) were observed. No patients dropped out of the study because of adverse effects. The most frequent adverse effect encountered was malleolar oedema (9%).. Manidipine added as the third drug to a renin-angiotensin system inhibitor plus a low dose of diuretic significantly reduces BP, improves renal function, has favourable effects on the lipid and glucose profiles, and reduces microalbuminuria in uncontrolled hypertensive patients with type 2 diabetes. Long-term trials are necessary to evaluate time-related effects.

Topics: Aged; Antihypertensive Agents; Diabetes Complications; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines

Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events.. We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), β-blocker, or thiazide diuretic in addition to benidipine.. Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-β-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-β-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P  = 0.3505) and 1.54 in the benidipine-β-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and β-blocker. All trial treatments were safe and well tolerated.. CCB combined with ARB, β-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Risk Factors; Single-Blind Method; Sodium Chloride Symporter Inhibitors; Stroke; Treatment Outcome

Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine.. A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8-16 mg/day) and amlodipine (2.5-5 mg/day) in olmesartan-treated hypertensive (blood pressure 130-180/80-110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment.. The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy.

Topics: Adult; Aged; Albuminuria; Amlodipine; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Imidazoles; Middle Aged; Research Design; Sympatholytics; Tetrazoles

Recently, it has been demonstrated that L-/N-type calcium channel blockers (CCBs), cilnidipine, but not L-type CCB, decreased urinary protein in renin-angiotensin system (RAS), inhibitor-treated hypertensive patients with macroproteinuria. However, the antiproteinuric effect of cilnidipine was weaker in diabetic patients than in nondiabetic patients with macroproteinuria. This may be due to the fact that diabetic neuropathy was also developed in patients with advanced diabetic nephropathy because L-/N-type CCB has been considered to exert its renoprotetive effects through sympatholytic action. If so, the antiproteinuric effect of cilnidipine may be potent in patients with early stages of diabetic nephropathy. To elucidate our hypothesis, we designed a multi-center, open-labeled, randomized trial to compare the antialbuminuric effect between cilnidipine and amlodipine in RAS inhibitor-treated hypertensive (blood pressure [BP]: 130-180/80-110 mmHg) patients with type 2 diabetes and microalbuminuria (urinary albumin/creatinine [Cr] ratio: 30-300 mg/g). The primary study endpoint is the change in the urinary albumin/Cr ratio after a 1-year treatment. Enrollment began in April 2008 and was completed in March 2010. A total of 367 patients were randomly allocated to receive cilnidipine or amlodipine. At baseline, study subjects had 63.3± 8.5 years of age, 145.9 ± 12.2/80.8 ± 10.0 mmHg of BP, 101.0 ± 111.6 mg/g of urinary albumin/Cr. The trial is expected to show whether cilnidipine can exert an antialbuminuric effect in RAS inhibitor-treated hypertensive patients with early stages of diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Renin-Angiotensin System

The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n=34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n=33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine.

Topics: Aged; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Tetrazoles

Whether the strict control of blood pressure (BP) of patients with hypertension who are aged 85 years or older is beneficial is unclear. The Japan's Benidipine Research on Antihypertensive Effects in the Elderly study is a prospective, observational 3-year study to evaluate the safety and effectiveness of treatment with a calcium channel blocker benidipine in 8897 hypertensive patients aged 65 years or older as a post-marketing surveillance. We examined the relationship between the achieved BP and cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) in a subgroup of 415 patients aged 85 years or older (mean age 88 years). BP decreased significantly from 165 ± 14/84 ± 10 mmHg to 130 ± 11/71 ± 10 mmHg during treatment in patients with a treated systolic BP (SBP) < 140 mmHg (n = 230) and BP decreased significantly from 169 ± 16/86 ± 12 mmHg to 143 ± 13/75 ± 10 mmHg in those with a treated SBP ≥ 140 mmHg (n = 185). There was a nonsignificant trend toward a lower rate of cardiovascular events and higher rate of total death in patients with a treated SBP < 140 mmHg. On-treatment SBP ≥ 160 mmHg is tended to associate with a higher incidence of cardiovascular events. There was no significant difference in the incidence of adverse reactions between the controlled BP group (3.04%) and the less well controlled BP group (3.24%). In conclusion, although this study was not powered for definitive conclusion, there was a nonsignificant trend toward a lower rate of cardiovascular events and higher total death in patients aged 85 years or older with a treated SBP < 140 mmHg.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Prospective Studies

The aim of this study was to compare the effects of olmesartan combined with either azelnidipine or amlodipine on central blood pressure (CBP) and left ventricular mass index (LVMI) in hypertensive patients.. Patients with brachial systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg received olmesartan monotherapy (20 mg daily) for 12 weeks. The patients were then randomly assigned to fixed-dose add-on therapy with azelnidipine (16 mg daily) or amlodipine (5 mg daily) (25 patients/group) for a further 24 weeks. CBP and LVMI were measured at baseline and at the end of the study.. Baseline characteristics were similar in both groups. The decrease in brachial BP was similar in both groups. CBP and LVMI decreased significantly in both groups (both, P < 0.001). However, the decreases in CBP and LVMI were significantly greater with olmesartan/azelnidipine than with olmesartan/amlodipine (CBP, P < 0.001; LVMI, P = 0.002).. These findings indicate that olmesartan/azelnidipine had greater effects on CBP and LVMI than did olmesartan/amlodipine, even though the reduction in brachial BP was similar in both groups. These differential effects on CBP and LVMI may have important implications for cardiovascular risk reduction.

Topics: Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Japan; Male; Middle Aged; Prospective Studies; Tetrazoles; Time Factors; Treatment Outcome; Ultrasonography

The impact of the metabolic syndrome (MS) on cardiovascular events in elderly subjects has not been clarified. We hypothesized that the impact differs between patients with and without strictly controlled blood pressure (BP) and also between early elderly (<75 years) and late (≥75 years) elderly patients.. Elderly hypertensive patients (65-85 years old) were randomly assigned to strict (target systolic BP <140 mm Hg) or mild (140-159 mm Hg) BP target, and were treated for 2 years with efonidipine-based regimen. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, except for the use of body mass index (BMI) ≥25 kg/m(2) instead of waist circumference. Primary endpoint was combined incidence of cardiovascular and renal events. Data were obtained from 2,865 patients.. The prevalence of MS was 31.4%. The incidence of primary endpoint in patients with and without MS was 4.0% and 3.1%, respectively. MS was a significant risk factor for cardiovascular events in patients <75 years old (adjusted hazard ratio (HR) 2.17, P = 0.01), but not in patients ≥75 years old (adjusted HR 0.98, P = 0.94). In patients with MS, the event rate was significantly lower with strict treatment than with mild treatment among patients aged <75 years (P = 0.0006) but not in those aged ≥75 years (P = 0.82).. MS was associated with cardiovascular risk in elderly hypertensive patients <75 years old, and strict BP control was beneficial for those with MS. However, MS and intensive control of BP may have little effect on cardiovascular events in elderly patients ≥75 years old.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Asian People; Blood Pressure; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Metabolic Syndrome; Nitrophenols; Organophosphorus Compounds; Prevalence; Risk Factors

Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice.. Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT.. Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016).. These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

Topics: Adult; Aged; Amlodipine; Azetidinecarboxylic Acid; Blood Glucose; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Endothelium, Vascular; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Prospective Studies; Stem Cells

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Body Mass Index; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Kidney Function Tests; Male; Middle Aged; Nitrobenzenes; Piperazines; Prognosis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Azelnidipine, a long-acting calcium channel blocker, is highly lipid soluble and selective for the vascular wall, and is expected to have an increasing effect on cerebral blood flow (CBF). The aim of this study is to investigate its safety and efficacy in stroke patients in the chronic stage as far as CBF is concerned using N-isopropyl-p-(123)I-iodo amphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). The patients were orally administered 8 or 16 mg of azelnidipine. Regional CBF was evaluated by (123)I-IMP SPECT using three-dimensional stereotactic region-of-interest (ROI) template (3D-SRT), a technique using anatomical standardization and ROI template consisting of 636 ROIs for the whole brain. Mean hemispheric CBF was defined as the mean value of the corpus callosum, and the precentral, central, parietal, angular and temporal gyri. Mean hemispheric and regional CBF after 1, 3 and 6 months were analyzed using a one-way repeated-measures analysis of variance. Ten post-ischemic stroke patients with hypertension were enrolled between October 2005 and October 2007, and all of them were well controlled with normal blood pressure (before: 172.3+/-16.6/88.4+/-14.0 mm Hg; 6 months: 128.7+/-15.9/70.9+/-10.1 mm Hg). No vascular events were observed during the study period. The mean hemispheric CBF was maintained during the study period (before: 46.0+/-9.7 ml per 100 g per min; 6 months: 49.3+/-11.1 ml per 100 g per min). The regional CBF was also maintained. In the chronic stage of ischemic stroke, azelnidipine could safely decrease systemic blood pressure without decreasing CBF.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Female; Follow-Up Studies; Functional Laterality; Heart Rate; Humans; Hypertension; Image Processing, Computer-Assisted; Iofetamine; Male; Middle Aged; Prospective Studies; Radiopharmaceuticals; Stroke; Tomography, Emission-Computed, Single-Photon

The aim of this study was to compare the effects of antihypertensive agents on cerebral blood flow (CBF) in hypertensive patients with previous ischemic stroke.. In this double-blind, multi-center, non-inferiority trial, 196 patients were randomized to cilnidipine 10-20 mg or losartan 50-100 mg once daily for 4 weeks. Baseline and follow-up CBF as measured by single photon emission computed tomography were obtained in 167. The primary endpoint was the global CBF change. The secondary endpoints were the CBF change in the hemisphere ipsilateral to the index stroke, non-impairment of global CBF and blood pressure (BP) reduction.. Global CBF increased significantly in the cilnidipine arm (9.0 +/- 29.6%, P = 0.0071) and the losartan arm (11.4 +/- 31.4%, P = 0.0012), and these changes were not different between the two groups (P = 0.607). However, the estimated difference in percentage global CBF change between the two groups was -2.43% (97.5% CI, -13.06% to 8.21%), which crossed the predetermined non-inferiority margin of -8.6%. Ipsilesional hemispheric CBF change, non-impairment of global CBF and BP reduction were similar in the two groups.. This trial failed to prove the non-inferiority of cilnidipine to losartan regarding global CBF change. Both the treatments, however, increase the global CBF despite BP lowering.

Topics: Acute Disease; Aged; Angiotensin II Type 1 Receptor Blockers; Brain; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Tomography, Emission-Computed, Single-Photon

Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

Topics: Aged; Aged, 80 and over; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Renal Insufficiency, Chronic; Tetrazoles

The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients.. Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined.. Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95%CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (micromol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95%CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group.. The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Trichlormethiazide

To compare the renal protective effects between calcium channel blocker benidipine and angiotensin II receptor blocker valsartan in primary hypertension patients with proteinuria.. A total of 236 patients were divided to low (< 1 g/24 h) and high (1 - 3 g/24 h) proteinuria groups and treated with benidipine (8 mg/d) or valsartan (80 mg/d) for 48 weeks. Blood pressure, glomerular filtration rate (GFR) and 24 h protein were measured at baseline, 12, 24 and 48 weeks.. Blood pressure was significantly and equally reduced in all treated groups (all P < 0.05 vs. baseline). GFR was also significantly and equally improved in all treated groups after 24 weeks treatments (all P < 0.05 at 24 weeks and 48 weeks). Proteinuria reduction at 24 and 48 weeks was more significant in patients treated with valsartan compared to patients treated with benidipine in low proteinuria group [24 weeks: (0.27 +/- 0.07) g/24 h vs. (0.39 +/- 0.06) g/24 h, P < 0.01; 48 weeks: (0.18 +/- 0.01) g/24 h vs. (0.30 +/- 0.05) g/24 h, P < 0.01].. The renal protection efficacy of valsartan and benidipine was similar in primary hypertensive patients with proteinuria.

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Proteinuria; Tetrazoles; Valine; Valsartan

The purpose of this first prospective observational cohort study after launch was to document the efficacy and tolerability of therapy with the fixed combination of lercanidipine HCl (CAS 132866-11-6), a third-generation calcium antagonist, and the angiotensin converting enzyme (ACE) inhibitor enalapril maleate (CAS 76095-16-4) in patients with essential hypertension in daily practice. Both parts of the observational study were conducted with the fixed combination of enalapril maleate 10 respectively 20 mg and lercanidipine HCl 10 mg, one part with Zaneril and the other with Zanipress. The fixed combination is marketed under these product names in Germany. The data of 8,440 patients with a mean age of 62 years and a mean body mass index (BMI) of 28 kg/m2 were evaluated. 84% of the patients had already received pre-treatment for essential hypertension. 26% of all the patients were known to have had hypertension for at least 10 years. Around 70% had further concomitant diseases. The mean blood pressure before the beginning of the study was 162.5/ 94.5 mmHg, the mean reduction after around three months was 28.4/ 13.5 mmHg. Just under 80% of the patients reached the desired target blood pressure after the observation period. The global assessment of the physicians shows that the efficacy of the drugs was "very good" to "good" for 94% of the patients. Global tolerability was assessed as "very good" and "good" for 97% of the patients. Compliance was stated as "very good" and "good" for 97% of the patients. Adverse drug reactions were documented for 2% of all patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Drug Combinations; Enalapril; Female; Heart Rate; Humans; Hypertension; Lipids; Male; Middle Aged; Prospective Studies

Calcium channel blocker (CCB) is one of the most useful antihypertensive agents. However, the activation of the renin-angiotensin system (RAS) is an unfavorable characteristic. N-type calcium channel is thought to be involved in catecholamine's release. Accordingly, N/L-type CCB has a probability of less activation of the RAS. We substantiated the hypothesis that N/L-type CCB, cilnidipine, leads to less activation of the RAS compared with conventional L-type CCB, amlodipine.. Randomized, cross-over study.. Outpatient study.. Participants were 110 hypertensive patients [male/female 46/64, age 66.3 ± 10.8 years, systolic blood pressure (SBP)/diastolic blood pressure (DBP) 161.8 ± 16.9/92.9 ± 12.4 mmHg, s-Cr 0.77 ± 0.32 mg/dl, plasma renin activity (PRA) 0.65 ± 0.63 ng/ml per h, angiotensin I (AngI) 70.5 ± 77.3 pg/ml, angiotensin II (AngII) 5.2 ± 3.9 pg/ml, plasma aldosterone concentration (PAC) 76.3 ± 35.9 pg/ml, urinary albumin excretion (UAE) 108.1 ± 284.2 mg/gCr]. Amlodipine besilate or cilnidipine was administered for 12 weeks in a cross-over manner as a monotherapy with an intention-to-treat fashion by titrating doses. Final doses of amlodipine besilate and cilnidipine were 6.6 ± 2.7 and 13.7 ± 5.1 mg/day, respectively.. Changes in blood pressure, PRA, AngI, AngII, PAC, UAE of baseline and each end of amlodipine besilate and cilnidipine administration.. Results were as follows (amlodipine vs. cilnidipine): SBP/DBP (mmHg): 135.2 ± 11.7/79.8 ± 9.6 vs. 136.7 ± 13.2/79.5 ± 10.9, P = 0.22/0.74; PRA (ng/ml per h): 1.16 ± 1.03 vs. 0.95 ± 0.78, P < 0.01; AngI (pg/ml): 155.0 ± 306.4 vs. 101.8 ± 92.0, P < 0.05; AngII (pg/ml): 12.0 ± 12.3 vs. 7.1 ± 4.5, P < 0.001; PAC (pg/ml): 81.6 ± 37.9 vs. 74.3 ± 36.2, P < 0.05; UAE (mg/gCr): 145.4 ± 424.5 vs. 58.8 ± 125.1, P < 0.05. Thus, in spite of the comparable blood pressure reductions, each level of components of the RAS at cilnidipine administration was significantly lower than those at amlodipine. Apart from this, UAE at cilnidipine administration was also significantly lower than that at amlodipine.. It is suggested that cilnidipine leads to less activation of the RAS compared with amlodipine for the first time in human clinical patients and therefore cilnidipine might be expected to be superior in organ protection in addition to the antialbuminuric effect.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin I; Angiotensin II; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System

Benidipine, an L-/T-type calcium channel blocker, dilates renal efferent and afferent arterioles and reduces glomerular pressure; therefore, it may exert renoprotective effects. We conducted an open-labeled randomized trial to compare the effects of benidipine with cilnidipine in hypertensive patients with chronic kidney disease (CKD).. The patients who were already being treated with angiotensin receptor blockers (ARBs) received one of the following treatment regimens: benidipine at a dose of 2 mg/day that was increased up to a dose of 8 mg/day (benidipine group; n=118) or cilnidipine at a dose of 5 mg/day that was increased up to a dose of 20 mg/day (cilnidipine group; n=115).. After 12 months of treatment, we observed a significant and comparable reduction in the systolic and diastolic blood pressure in both groups. The urinary protein:creatinine ratio was significantly decreased in both groups after 3 months of treatment and thereafter; however, the difference between both groups was not significant after 12 months of treatment. Benidipine exerted an antiproteinuric effect to a greater extent than cilnidipine in patients with diabetes.. The addition of benidipine as well as cilnidipine reduces urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Proteinuria; Receptors, Angiotensin; Renal Insufficiency, Chronic

In a previously reported randomized, double-blind, parallel-group study of the efficacy and tolerability of olmesartan medoxomil (OLM) and azelnidipine (AZL) combination therapy compared with monotherapy with each agent in Japanese patients with essential hypertension (the REZALT study), the use of a combination of OLM, an angiotensin II receptor blocker, plus AZL, a dihydropyridine calcium channel blocker, was associated with significantly greater reductions in office sitting blood pressure (BP) and 24-hour ambulatory BP compared with monotherapy with either agent, and was well tolerated.. This article reports the results from an a priori planned analysis and post hoc analyses of the diurnal BP and pulse rate (PR) profiles of OLM/AZL versus monotherapy with either agent from the REZALT study.. Male and female Japanese outpatients with essential hypertension were eligible if they met the following inclusion criteria: age > or = 20 years; systolic BP (SBP) > or = 140 to <180 mm Hg and diastolic BP (DBP) > or = 90 to <110 mm Hg; and 24-hour ambulatory SBP/DBP > or = 135/> or = 80 mm Hg. Patients were randomly assigned to receive OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM 20 mg, or AZL 16 mg, once daily for 12 weeks. The effectiveness of the treatments was assessed using 24-hour ambulatory BP monitoring (ABPM) and PR, analyzed by time period (BP and PR, 24 hours, daytime [7 AM-<10 PM], nighttime [10 PM-<7 AM], and early morning [6 AM-<9 AM]; PR, morning [6 AM -<11 AM]) and dipping status at baseline (dippers [(Daytime BP - Nighttime BP)/Daytime BP > or = 10%] or nondippers [(Daytime BP - Nighttime BP)/Daytime BP <10%]).. A total of 867 patients were enrolled, and 862 randomized patients were included in the full analysis set (590 men, 272 women; mean age, 56.6 years). A total of 839 patients had assessable ABPM data (213, 211, 206, and 209 patients in the OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM, and AZL groups, respectively). No clinically significant between-group differences were observed in baseline demographic and clinical characteristics. Combination therapy was associated with significantly greater antihypertensive effects on 24-hour ABPM compared with either monotherapy in all of the time periods, as follows: SBP/DBP reductions with OLM/AZL 20/16 mg in the daytime, nighttime, and early morning were -22.6/-14.1, -21.2/-12.5, and -20.6/-11.9 mm Hg, respectively (all, P < 0.05 vs the other 3 treatment groups). The SBP/DBP reductions with OLM/AZL 10/8 mg (daytime, -18.2/-11.0 mm Hg; nighttime, -18.1/-10.0 mm Hg; and early morning, -15.6/-9.3 mm Hg) were also significantly greater than with OLM 20 mg (-11.8/-6.7, -12.8/-7.2, and -11.0/ -6.9 mm Hg, respectively; all, P < 0.01) and AZL 16 mg (-13.1/-7.8, -10.2/-5.5, and -9.9/-6.1 mm Hg; all, P < 0.001) in all of the time periods. The antihypertensive effects associated with OLM/AZL 10/8 mg or 20/16 mg were significantly greater than those with monotherapies regardless of dipping pattern at baseline (all, P < 0.05) in all of the time periods, with the exception of nighttime reduction with OLM/AZL 10/8 mg versus OLM in dippers. The numbers of patients who had any increase in BP were 12/213 (5.6%) with OLM/AZL 10/8 mg, 13/211 (6.2%) with OLM/AZL 20/16 mg, 35/206 (17.0%) with OLM, and 36/209 (17.2%) with AZL. The AZL-containing regimens were associated with reduced morning PR (mean [95% CI] changes from baseline to week 12: -1.5 beats/min [-2.5 to -0.4] with OLM/AZL 10/8 mg, -2.1 beats/min [-3.0 to -1.1] with OLM/AZL 20/16 mg, 0.4 beat/min [-0.5 to 1.3] with OLM, and -1.9 beats/min [-2.8 to -1.0] with AZL).. In this study in Japanese patients with essential hypertension, the reductions in daytime, nighttime, and early-morning BP assessed using 24-hour ABPM were significantly greater with combination OLM/AZL than with either monotherapy, regardless of dipping pattern at baseline. Japan Pharmaceutical Information Center registration number: JapicCTI-060286.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Imidazoles; Male; Middle Aged; Olmesartan Medoxomil; Tetrazoles

High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension.. We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine).. Sequential home BP and UACR data were fitted to a simple exponential function as follows: where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; beta (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine).. Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean +/- SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p < 0.01) but not with BP decrease.. The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

Topics: Albuminuria; Antihypertensive Agents; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Creatinine; Dihydropyridines; Humans; Hypertension; Models, Statistical; Nephelometry and Turbidimetry; Time Factors; Treatment Outcome

Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin-angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Proteinuria; Treatment Outcome

This study evaluated the impact of renal function on cardiovascular outcomes in elderly hypertensive patients enrolled in the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive patients. The patients were randomly assigned to either a strict-treatment group (target systolic blood pressure (BP) <140 mm Hg, n=2212) or a mild-treatment group (target systolic BP, 140 to <160 mm Hg, n=2206), each with efonidipine (a T/L-type Ca channel blocker)-based regimens. Cardiovascular events (stroke, cardiovascular disease and renal disease) were evaluated during the 2-year follow-up period following the prospective randomized open-blinded end-point method. Estimated glomerular filtration rate (eGFR) was elevated throughout the trial period in both the strict-treatment (59.4-62 ml min⁻¹ per 1.73 m²) and the mild-treatment group (58.8-61.4 ml min⁻¹ per 1.73 m²). This tendency was also observed in diabetic patients and patients aged ≥75 years, with baseline eGFR<60 ml min⁻¹ per 1.73 m². Baseline eGFR (<60 vs. ≥60 ml min⁻¹ per 1.73 m²) had no definite relationship with the incidence of cardiovascular events, nor did the level of BP control. Proteinuria at the time of entry into the study, however, was significantly correlated with cardiovascular event rates (7.1%), an association that was more apparent in patients with eGFR<60 ml min⁻¹ per 1.73 m² (8.2%). Furthermore, the event rate was more elevated in patients with greater declines in eGFR and was amplified when the baseline eGFR was <60 ml min⁻¹ per 1.73 m². In conclusion, the rates of decline of renal function and proteinuria constitute critical risk factors for cardiovascular events in elderly hypertensive patients, trends that are enhanced when baseline eGFR is diminished. Furthermore, the fact that efonidipine-based regimens ameliorate renal function in elderly hypertensive patients with chronic kidney disease may offer novel information on the mechanisms of cardiovascular protection.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Cardiovascular Diseases; Chronic Disease; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Nitrophenols; Organophosphorus Compounds; Prospective Studies

The purpose of this study is to compare the effects and safety of azelnidipine and amlodipine in Chinese essential hypertensive patients. Patients were randomized to receive administration of azelnidipine 8-16 mg/day or amlodipine 2.5-5 mg/day for 8 weeks. The blood pressure and pulse rate were evaluated in an outpatient clinic and by ambulatory blood pressure monitoring. There were 220 patients enrolled to the study. The blood pressure in both groups was decreased significantly (P < 0.001). Compared with amlodipine, the patients received azelnidipine had better response in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P < 0.01). No significant changes of pulse rate were observed in either group. For the ambulatory blood pressure monitoring, both drugs had stable anti-hypertensive effects over 24 h. The trough/peak ratios of DBP for the azelnidipine and amlodipine groups were, respectively, 46% and 40%. Adverse events occurred at 7.3% and 10.0%, respectively in the azelnidipine and amlodipine groups (P = 0.485). Headache and dizziness were observed at an incidence of more than 1% in both groups. Once-daily administration of azelnidipine effectively controlled blood pressure and had a stable action over 24 h. Azelnidipine had good safety and compliance similar to amlodipine.

Topics: Adolescent; Adult; Aged; Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure Monitoring, Ambulatory; China; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

To compare changes of body water measured by using bioelectrical impedance analysis (BIA), between lercanidipine and amlodipine therapy.. This is a prospective randomized open-label study in hypertensive outpatients. Eighty patients were randomized into two groups; 1) amlodipine 5 mg/d and 2) lercanidipine 10 mg/d. Patients were assessed for changes in total body water (TBW), extracellular water (ECW) and intracellular water (ICW) at week 4 and 8 after treatment.. At baseline body water in both groups were similar. After treatment, both groups did not have significant changes in body water from baseline. Seven patients in amlodipine group (17.5%) and none of lercanidipine group developed edema; p = 0.012. Among those seven patients, TBW, ECW and ICW all increased significantly from baseline.. BIA did not detected changes of body water in most patients. However, in patients who developed edema, TBW, ECW and LCW significantly increased from baseline with the greatest changes seen in extracellular compartment.

Topics: Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Body Composition; Body Water; Dihydropyridines; Edema; Electric Impedance; Extracellular Fluid; Female; Humans; Hypertension; Intracellular Fluid; Male; Middle Aged; Outpatients; Prospective Studies; Thailand; Treatment Outcome

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being <140 mm Hg for systolic BP and <90 mm Hg for diastolic BP. Safety and tolerability will also be investigated. A total of more than 4000 patients were recruited and will be followed up for at least 3 years.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diuretics; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Humans; Hypertension; Imidazoles; Japan; Male; Prospective Studies; Risk; Tetrazoles

Benidipine, an L- and T-type calcium channel blocker, dilates both efferent and afferent arterioles and reduces glomerular pressure. Thus, it may exert renoprotective effects. We conducted an open-labeled, randomized trial to compare the blood pressure (BP)-lowering effect and antiproteinuric effect of benidipine with those of amlodipine in hypertensive patients with moderate-to-advanced-stage chronic kidney disease (CKD) (stages 3-5). These patients were already being administered the current maximum recommended doses of angiotensin receptor blockers (ARBs). Patients with BP >or=140/90 mm Hg, despite treatment with the maximum recommended dose of ARBs, were randomly assigned to two groups. The patients received either of the following treatment regimens: 4 mg day(-1) of benidipine, which was increased up to a dose of 16 mg day(-1) (B group; n=24), and 2.5 mg day(-1) of amlodipine, which was increased up to a dose of 10 mg day(-1) amlodipine (A group; n=23). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was seen in both groups. The decrease in the urinary protein to creatinine ratio in the B group was significantly lower than that in the A group. Benidipine exerted antiproteinuric effect to a greater extent than did amlodipine, even in patients with diabetic nephropathy. We conclude that the addition of benidipine, rather than amlodipine, ameliorates urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs. Therefore, we propose a combination therapy with benidipine and ARBs, even for patients with moderate-to-advanced-stage CKD.

Topics: Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Protective Agents; Proteinuria

Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria.. Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56).. Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group.. A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

Topics: Aged; Aged, 80 and over; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines

N-type calcium channel blocker, cilnidipine, is reported not to increase the heart rate in spite of the strong depressor effect. However, it has not been determined whether cilnidipine has the sympatho-inhibitory effects or not. Moreover, the effect of cilnidipine on the baroreflex control has not been determined. The aim of this study was to determine the effect of cilnidipine on sympathetic and parasympathetic nerve activity, and baroreflex sensitivity. We studied five hypertensive patients treated with 10 mg cilnidipine (10-mg group) and five hypertensive patients treated with 20 mg cilnidipine (20-mg group). Before the treatment and 6 months after the treatment, we measured the blood pressure, spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV), and blood pressure variability (BPV). After 6 months, systolic blood pressure (SBP) and the low-frequency component of systolic BPV expressed in normalized units (LFnuSBP), as the parameter of sympathetic nerve activity, was significantly decreased in both groups, and the suppressive effects were stronger in the 20-mg group than in the 10-mg group. The high-frequency component of HRV expressed in normalized units, as the parameter of parasympathetic nerve activity, and BRS were significantly increased in 20-mg group, but not significant in 10-mg group. These results suggest that 6 months treatment with cilnidipine for hypertension has the sympatho-inhibtory effect, and that high-dose cilnidipine improves the parasympathetic nerve activity and baroreflex control in patients with hypertension.

Topics: Adult; Aged; Baroreflex; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Parasympathetic Nervous System; Prospective Studies; Sympathetic Nervous System

Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening. Although various drug therapies are used to lower peripheral blood pressure (BP) in patients with isolated systolic hypertension, the effects of the 4 major classes of antihypertensive agents on central BP, pulse pressure (PP) amplification, and arterial stiffness in this condition are not clear. Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension (systolic BP > or =140 mm Hg and diastolic BP

Topics: Administration, Oral; Aged; Analysis of Variance; Antihypertensive Agents; Arteries; Atenolol; Bendroflumethiazide; Blood Pressure Determination; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Elasticity; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Patient Compliance; Perindopril; Probability; Regression Analysis; Risk Assessment; Systole; Treatment Outcome

A certain percentage of aldosterone (ALD) breakthrough generally occurs in patients with hypertension and chronic heart failure and is an important issue during long-term treatment with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). It has been reported that efonidipine decreases the plasma levels of ALD. However, the long-term effects of efonidipine on the plasma levels of ALD and the left ventricular mass index (LVMI) remain unknown in patients with hypertension. Sixty stable outpatients with essential hypertension who had received amlodipine and ACE-I or ARB for more than 1 year were randomized into two groups (amlodipine group (n=30): continuous amlodipine treatment at a stable dose; efonidipine group (n=30): amlodipine (5 mg day(-1)) was changed to efonidipine at a dose of 40 mg day(-1)). There was no difference in their baseline characteristics including the LVMI and plasma levels of ALD. In the amlodipine group, there were no significant changes in blood pressure, LVMI or plasma levels of ALD for 18 months. In the efonidipine group, blood pressure did not change after replacement of amlodipine with efonidipine, although there was a significant decrease in the plasma levels of ALD after 6 months. The decrease in ALD was sustained for 18 months and LVMI was significantly decreased after 18 months (121+/-25 vs. 114+/-21 g m(-2), P<0.05). There was a significant correlation between the changes in LVMI and % changes of ALD in the efonidipine group. These findings indicate that the effect of efonidipine on the suppression of plasma ALD was sustained for at least 18 months and that long-term efonidipine therapy decreases LVMI in patients with essential hypertension.

Topics: Aged; Aldosterone; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Nitrophenols; Organophosphorus Compounds; Renin; Time Factors

To evaluate the effects of manidipine versus amlodipine on blood pressure, albuminuria, insulin sensitivity, adiponectin, TNF-alpha and C-reactive protein in nondiabetic subjects with metabolic syndrome (ATP-III definition), including impaired fasting glucose (>5.6 mmol/l) and hypertension.. In total, 64 patients were recruited and randomly assigned to manidipine 20 mg versus amlodipine 10 mg (for 12 +/- 2 weeks).. Blood pressure was reduced to a similar extent (p < 0.001) by both treatments. Albuminuria was significantly reduced by manidipine (-37.3%; p = 0.003), but not by amlodipine. C-reactive protein was reduced similarly (p < 0.01) by both treatments. Plasma adiponectin was increased (32.9%; p = 0.011) and plasma TNF-alpha was reduced by manidipine (-37.1%; p = 0.019), but neither was significantly changed by amlodipine. The HOMA insulin resistance index was significantly reduced by manidipine (-21.3%; p = 0.007), but not by amlodipine (-8.3%; p = 0.062). Tolerability with manidipine was superior to that with amlodipine (p = 0.04).. These data support the added value of manidipine in renal and metabolic protection beyond blood pressure reduction in the treatment of hypertensive patients with metabolic syndrome.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Single-Blind Method; Tumor Necrosis Factor-alpha

The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (n=103) or hydrochlorothiazide (n=104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P=0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: -2.2 to 7.5 mm Hg; P=0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; P<0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan (20.0 mg) and azelnidipine (16.0 mg) had a more beneficial effect on central systolic BP and arterial stiffness than the combination of olmesartan (20.0 mg) and hydrochlorothiazide (12.5 mg), despite the lack of a significant difference in brachial systolic BP reduction between the 2 treatments.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Aorta; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Japan; Male; Middle Aged; Prospective Studies; Single-Blind Method; Tetrazoles; Time Factors; Treatment Outcome

We investigated the impact of lowering blood pressure (BP) with azelnidipine, a newly developed calcium channel blocker, generation on the left ventricular (LV) diastolic function and LV filling pressure by assessing non-invasive indices derived from echo Doppler study. This study evaluated 232 hypertensive patients with diastolic dysfunction. This study had two groups: (1) in which azelnidipine was administered to patients as a first-line therapy, and (2) in which amlodipine was converted to azelnidipine. Early diastolic mitral annulus velocity (e', cm s(-1)), the ratio of peak E velocity to e' velocity (E/e' ratio) and level of brain natriuretic peptide (BNP) were measured before and, an average of, 8 months after azelnidipine treatment. In the first-line azelnidipine group, the systolic and diastolic BP reduced by 26 and 11 mm Hg, respectively. The e' increased, and E/e' ratio and BNP level decreased significantly. In the converted-from-amlodipine group, the systolic and diastolic BP decreased by 14 and 6 mmHg, respectively. The e' velocity increased, but the E/e' ratio and BNP level did not change. In both groups, azelnidipine lowered BP and improved LV diastolic function (an increase in the e' velocity). Possible reduction in LV filling pressure (a decrease in the E/e' ratio and BNP level) is observed only in the first-line azelnidipine group.

Topics: Adult; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Function, Left; Young Adult

It is known that the risk of cerebral stroke recurrence in post-stroke patients is comparatively higher than in normal subjects, and it is suggested that autonomic nervous system dysfunctions elevate this risk. We investigated the anti-hypertensive effects of cilnidipine, a Ca antagonist which suppresses sympathetic nerve activation, in hypertensives with chronic-stage cerebrovascular disease in a comparison with amlodipine.. Amlodipine 5-7.5 mg/day, or cilnidipine 5-10 mg/day was administered to 78 hypertensive subjects (greater than 140 mmHg systolic, or 90 mmHg diastolic) undergoing outpatient treatment. Amlodipine or cilnidipine was also administered similarly, to 30 subjects having hypertension associated with a cerebral infarct which occurred more than one month earlier due to cerebral thrombosis or embolism. After 3 months administration, the subjects' blood pressures and pulse rates were recorded with an ambulatory blood pressure monitor over 24 hours.. No difference was recognized in patient age, gender, and systolic and diastolic blood pressure before treatment between the groups. In the cilnidipine groups, no difference in average 24-hour or waking systolic blood pressure values was seen between cerebrovascular disease (CVD) subjects and non-CVD subjects, although in the amlodipine groups, CVD subjects had significantly higher blood pressure values than non-CVD subjects. In the cilnidipine group, the coefficient of variation values of pulse rate were significantly higher in CVD subjects than in non-CVD subjects (p<0.05).. In patients with recent stroke, a Ca antagonist with no sympathetic nerve suppression had weaker blood pressure-lowering effects. Significantly increased pulse rate variability, shown in the CVD subjects administered cilnidipine, suggests that cilnidipine enhanced the parasympathetic function in hypertensive patients with CVD.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cerebrovascular Disorders; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

To achieve the target blood pressure recommended by the latest guidelines, multiple antihypertensive drugs are needed in most patients. In this study, the efficacy of treatment using an angiotensin II receptor antagonist (ARB) combined with a calcium channel blocker (CCB) or a diuretic was compared from multiple perspectives in patients with hypertension. Twenty-nine patients with essential hypertension, who had failed to achieve their target blood pressure (<130/85 mm Hg for patients <65 years old and <140/90 mm Hg for those >/=65 years) when treated with the ARB olmesartan at 20 mg day(-1), were additionally given 8-16 mg day(-1) of the CCB azelnidipine or 1-2 mg day(-1) of trichlormethiazide (a thiazide diuretic) in a randomized crossover manner for 4 months each. At the end of each combination therapy period, blood and urine samples were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity. Compared with monotherapy, the blood pressure was reduced similarly by adding azelnidipine (-12/-10 mm Hg) or trichlormethiazide (-14/-9 mm Hg). The heart rate was decreased with the CCB by 4 b.p.m. (P<0.05), whereas it was unchanged with the thiazide. Serum K, lipids and blood glucose were not significantly changed with either combination, whereas serum uric acid was increased with the thiazide (P<0.01) but was unchanged with azelnidipine. Plasma levels of renin, angiotensin II and aldosterone were also increased with the thiazide period, whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine. In addition, the cardio-ankle vascular index, a parameter of arterial stiffness, was decreased with the azelnidipine period but was unchanged with the thiazide period (P<0.01). It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia, sympathetic activation, renin-angiotensin-aldosterone system stimulation, inflammation, oxidative stress, and increased arterial stiffness in patients with moderate hypertension. These properties may provide cardiovascular protection in addition to the hypotensive effect.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Ankle Brachial Index; Azetidinecarboxylic Acid; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Lipoproteins, LDL; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Tetrazoles; Trichlormethiazide

The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E(max)) of olmesartan, whereas azelnidpine E(max) was independent of patient background characteristics investigated. No patient was found to have a high E(max) to one agent who also had a high E(max) to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Clinical Laboratory Techniques; Cross-Over Studies; Dihydropyridines; Female; Humans; Hypertension; Imidazoles; Individuation; Male; Middle Aged; Olmesartan Medoxomil; Population Groups; Tetrazoles

The three types of calcium channel blocker (CCB), L-, T- and N-type, possess heterogeneous actions on endothelial function and renal microvascular function. In the present study, we evaluated the effects of two CCBs, efonidipine and amlodipine, on renal function and arterial stiffness.. Forty type 2 diabetic patients with hypertension and nephropathy receiving angiotensin receptor II blockers were enrolled and randomly divided into two groups: the efonidipine group was administered efonidipine hydrochloride ethanolate 40 mg/day and the amlodipine group was admin-istered amlodipine besilate 5 mg/day for 12 months. Arterial stiffness was evaluated by the cardio-ankle vascular index (CAVI).. Changes in blood pressure during the study were almost the same in the two groups. Sig-nificant increases in serum creatinine and urinary albumin and a significant decrease in the esti-mated glomerular filtration rate were observed in the amlodipine group, but not in the efonidipine group. On the other hand, significant decreases in plasma aldosterone, urinary 8-hydroxy-2'-deoxy-guanosine and CAVI were observed after 12 months in the efonidipine group, but not in the amlo-dipine group.. These results suggest that efonidipine, which is both a T-type and L-type calcium chan-nel blocker, has more favorable effects on renal function, oxidative stress and arterial stiffness than amlodipine, an L-type calcium channel blocker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aldosterone; Amlodipine; Arteries; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Kidney; Lipids; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds

Many trials have shown that calcium channel blockers (CCBs) can reduce the cardiovascular (CV) events in patients with coronary artery disease (CAD). The mechanisms of this effect could be associated with plaque regression due to the anti-atherosclerotic properties of CCBs. The goal of this study is to determine the effects of CCB on volumetric quantitative changes of coronary plaques accessed by intravascular ultrasound (IVUS). To confirm this hypothesis, a multicenter randomized trial of CCBs treatment with azelnidipine or amlodipine will be conducted in hypertensive CAD patients undergoing elective percutaneous coronary intervention (PCI).. Patients who have hypertension and are scheduled for PCI will be enrolled. Subjects will be randomized to azelnidipine or amlodipine and observed for 48 weeks. The primary endpoint will be the percent change of coronary plaque volume. The secondary endpoint will include inflammatory markers, antioxidant activity, and incidence of composite cardiovascular events.. In this study, we will investigate the improvement of coronary plaque with IVUS by treatment with two dihydropyridine CCBs in hypertensive patients undergoing elective PCI. This result will lead to the discovery of more effective drug therapy for inhibition of coronary events.

Topics: Adult; Aged; Amlodipine; Azetidinecarboxylic Acid; Calcium Channel Blockers; Coronary Artery Disease; Dihydropyridines; Disease Progression; Double-Blind Method; Endpoint Determination; Female; Humans; Hypertension; Male; Middle Aged; Ultrasonography; Young Adult

Left ventricular (LV) diastolic dysfunction is related to increased cardiac sympathetic activity. We investigated the effect of cilnidipine, an L/N-type calcium channel blocker, on LV diastolic function and cardiac sympathetic activity in patients with hypertensive heart disease (HHD) using radionuclide myocardial imaging.. Thirty-two frame electrocardiography (ECG) -gated (99m)Tc-sestamibi (MIBI) myocardial single photon emission computed tomography (SPECT), and (123)I-metaiodobenzylguanidine (MIBG) imaging were performed before and 6 months after drug administration in 32 outpatients with HHD. Sixteen of the patients were treated with cilnidipine and the other 16 were treated with nifedipine retard. The parameters for assessing LV diastolic function evaluated using ECG-gated (99m)Tc-MIBI SPECT were peak filling rate (PFR), first-third filling rate (1/3FR), and time to peak filling (TPF). Cardiac sympathetic activity was assessed as early and delayed heart to mediastinum (H/M) ratios and a washout rate (WR), using (123)I-MIBG imaging. The PFR and 1/3FR significantly increased after 6 months of treatment with cilnidipine (p<0.05 for both), but did not with nifedipine retard. The H/M ratios significantly increased (p<0.05 for both) in conjunction with a decreased WR (p<0.05) in the cilnidipine group. Moreover, a significant positive correlation was seen between the rate of change in PFR and the rate of change in early and delayed H/M ratios in the cilnidipine group (p<0.05 for both). The same results were obtained for the relationship between the rate of change in 1/3FR and the rate of change in H/M ratios (p<0.05 for both). However, no such relationship was seen in the nifedipine group.. These data indicate that cilnidipine seems to suppress cardiac sympathetic overactivity via blockade of N-type calcium channels and improves LV diastolic function in patients with HHD.

Topics: Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Female; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nicardipine; Prospective Studies; Sympathetic Nervous System; Tomography, Emission-Computed, Single-Photon; Ventricular Function, Left

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Asian People; Azetidinecarboxylic Acid; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Olmesartan Medoxomil; Tetrazoles; Treatment Outcome

The current study was conducted to examine the effects of cilnidipine, a dual L/N-type calcium channel blocker, on blood pressure, pulse rate, and autonomic functions in patients with mild-to-moderate hypertension. Sixteen patients with mild-to-moderate hypertension (8 males and 8 females; 44-72 years of age) were treated with cilnidipine (10 mg/day) for 3 months. Before and after the treatment, the following measurements were conducted; beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver, the Valsalva ratio, heart rate response to deep breathing, systolic and diastolic blood pressure, and pulse rate. The head-up tilt test was also performed before and after the treatment. Cilnidipine significantly decreased either the systolic or diastolic blood pressure from 151 +/- 15 mmHg to 129 +/- 14 mmHg or 84 +/- 11 mmHg to 71 +/- 9 mmHg, respectively. For pulse rate, there were no significant changes during therapy. Beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver indicated significant improvements in both figures. The heart rate response to deep breathing and the Valsalva ratio indicated no significant differences during therapy. Before and after the treatment, no orthostatic hypotension was observed during the head-up tilt test. The current study revealed that cilnidipine significantly decreases blood pressure with improving autonomic functions while having no adverse effects on heart rate response and pulse rate.

Topics: Adult; Aged; Antihypertensive Agents; Autonomic Nervous System; Blood Pressure; Calcium Channel Blockers; Diastole; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Systole; Tilt-Table Test; Valsalva Maneuver

To compare the renoprotective effects of the calcium channel blocker (CCB) benidipine (CAS 105979-17-7) and the angiotensin II receptor blocker (ARB) valsartan (CAS 137862-53-4) in primary hypertensive patients with proteinuria.. 236 patients with primary hypertension were randomly divided into different groups and were administered either benidipine or valsartan. The alterations of the glomerular filtration rate (GFR) and proteinuria were compared between the different groups.. Valsartan could decrease the level of proteinuria significantly as compared with that in benidipine-treated hypertensive patients with proteinuria at levels <1 g/24 h (P < 0.01). There was no significant difference of the effects of benidipine and valsartan on proteinuria reduction in hypertensive patients with proteinuria at levels 1-3 g/24 h. There was no significant difference of the effects of benidipine and valsartan on GFR in benidipine- and valsartan-treated patients.. The results showed that valsartan was more effective in decreasing the levels of proteinuria in hypertensive patients with proteinuria at an early stage of nephropathy. The renoprotective effects of benidipine and valsartan in primary hypertensive patients with proteinuria were similar.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Proteinuria; Renal Circulation; Tetrazoles; Valine; Valsartan

The present study was conducted to clarify whether azelnidipine might have beneficial effects on autonomic functions, and whether such beneficial effects might affect the vascular functions (i.e., arterial stiffness and endothelial function).. This study with a cross-over design was conducted in 21 hypertensive patients (65 +/- 9 years old) being treated with calcium channel blockers (CCBs) other than azelnidipine or benidipine (i.e., during the study period, the CCB was switched to either azelnidipine 16 mg/day or benidipine 4 mg/day, administered alternately for 8 weeks each). Blood examinations were conducted and the heart rate variability, baro-receptor sensitivity (BRS), brachial-ankle pulse wave velocity (baPWV) and flow-mediated vasodilatation (FMD) in the brachial artery were measured after treatment with each of the two drugs. While the blood pressure levels decreased to a similar degree after both treatments, the BRS (8.8 +/- 5.5 ms/mmHg vs. 6.4 +/- 2.9 ms/mmHg, p < 0.01) and high-frequency power component (HF: 139 +/- 152 ms2/Hz vs. 88 +/- 97 ms2/Hz) were higher after treatment with azelnidipine than after treatment with benidipine (p < 0.05). However, the baPWV, FMD and plasma levels of malonyldialdehyde low-density lipoprotein cholesterol and nitric oxides were similar after treatment with both drugs.. Azelnidipine has greater beneficial effects on the autonomic functions than benidipine although the degree of reduction of blood pressure induced by the two drugs was similar. However, this greater beneficial effect of azelnidipine on the autonomic functions did not produce any distinguishable differences in effects of azelnidipine and benidipine on the arterial stiffness and endothelial functions.

Topics: Aged; Arteries; Autonomic Pathways; Azetidinecarboxylic Acid; Brachial Artery; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Endothelium, Vascular; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Pulse; Vasodilation

The influence of oxidative stress (OS) and inflammation on up-regulation of blood pressure (BP) has been well established. Peripheral polymorphonuclear leukocytes (PMNLs) are primed in essential hypertension (EH) patients, releasing uncontrolled superoxide anion contributing to OS in these patients. PMNL priming correlates with PMNL intracellular calcium [Ca2+]i. Previous studies have shown that treatment by calcium channel blockers lowers BP, OS and inflammation. In the same time, there are some trials showing down regulation influence of ''anti-oxidative'' drugs as Vitamin E and C to inflammation and OS. The data of clinical significance of anti-oxidative drugs to BP is controversial. The aim of this paper was to evaluate the benefit of combined treatment by calcium channel blockers (Lercanidipine) and antioxidative drugs (Vitamins C and E) on BP and on parameters of inflammation and OS.. Sixteen new diagnosed patients with mild to moderate BP were sampled to 2 groups after randomization by age, sex, and mean arterial pressure (MAP), cholesterol and glucose level. The first group was treated by Lercanidip-ine only, the second group by combination of Lercanidipine and antioxidative drugs both for 6 months. PMNL priming was assessed by the rate of superoxide release from separated, phorbol ester-stimulated PMNLs and by PMNL-CD11b level. Inflammation was reflected by plasma C-reactive protein (CRP) and albumin levels, white blood cells (WBC) and PMNL counts and by PMNL apoptosis.. In both groups, BP decreased after 6 months of treatment, and in a more pronounced manner following the combined treatment. In both groups PMNL priming parameters remained unchanged after 6 months of treatment, with transient differences between the two groups during the experimental period. In both groups inflammation parameters remained unchanged after 6 months of treatment, without difference between the two groups, except a pronounced decrease in the percentage of apoptotic PMNLs in the combined treatment group.. Our trial shows a clinical benefit combining calcium channel blockers treatment with antioxidants in BP treatment, although it did not reveal significant influence of complementation of antioxidants to calcium channel blockers on OS and inflammation parameters. Additional clinical and laboratory investigations are needed to clear this issue. Conflicting data are reported on the influence of vitamins E and C on OS and inflammation together with controversy regarding anti-oxidative drugs and their effect on BP.

Topics: Adult; Antioxidants; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Inflammation; Male; Middle Aged

The aim of this study was to compare the efficacy and safety of adding manidipine 20 mg versus amlodipine 10 mg to the treatment of diabetic patients with uncontrolled hypertension and microalbuminuria despite full-dose treatment with a renin-angiotensin system blocker for at least 6 months. Patients were randomized to receive manidipine (n = 61) or amlodipine (n = 30) in a 2:1 ratio for 6 months and monitored for microalbuminuria for an additional extension phase of 18 months. Manidipine and amlodipine decreased blood pressure values to a similar extent. Urinary albumin excretion was reduced by 65.5% with manidipine versus 20% with amlodipine (p < 0.01) at 6 months and 62.7 versus 16.6% (p < 0.01) at the end of the extension phase. Manidipine was better tolerated than amlodipine. Thus, the addition of manidipine, but not amlodipine, resulted in a large reduction in the urinary albumin excretion rate despite similar blood pressure reductions.

Topics: Adult; Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Renin-Angiotensin System

Benidipine (CAS 105979-17-7) is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris.. To examine the efficacy and safety of therapy with benidipine in elderly hypertensive patients.. Chinese patients >60 years of age with mild to moderate essential hypertension were enrolled. The patients were prescribed benidipine at the dose of 8 mg once daily for 12 weeks. Detailed laboratory examinations and 24-h ambulatory blood pressure monitoring were performed before and after the treatment.. One hundred and sixty-four of the 180 patients enrolled completed the 12-week active treatment phase. Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) reductions at the end of treatment were 21.50 +/- 12.83 and 10.60 +/- 8.04 mmHg, respectively; the proportion of patients showing a good treatment response was 95.1% for SBP and 96.9% for DBP. Benidipine significantly reduced the mean 24-h ambulatory blood pressure (p < 0.001 vs. baseline) exhibiting smooth, sustained effects and high trough-to-peak ratios (T/P ratio) (0.87 for SBP and 0.72 for DBP). Moreover, benidIpine significantly reduced the systolic morning blood pressure surge and urinary albumin, and it was well tolerated. No serious adverse events were noted.. Benidipine was welltolerated and effective in elderly Chinese patients with essential hypertension.

Topics: Aged; Albuminuria; Antihypertensive Agents; Arteries; Blood Pressure; China; Dihydropyridines; Female; Humans; Hypertension; Male

Calcium channel blockers have been widely used for the treatment of hypertension because several clinical trials have demonstrated their strong action on lowering blood pressure and their role in preventing cardiovascular events such as stroke and coronary heart disease. However, there have been few reports on the effects on cerebral hemodynamics when blood pressure is lowered with this class of drug. In this study, we used positron emission tomography and acetazolamide challenge tests to measure cerebral blood flow and cerebrovascular reserve before and after administration of a novel calcium channel blocker, azelnidipine, in nine hypertensive patients (mean age, 66.1 years) with ischemic white matter lesions. Systemic blood pressure was significantly decreased from baseline (153.8+/-15.5/92.1+/-8.5 mmHg) after treatment with azelnidipine (138.4+/-16.3/81.8+/-6.2 mmHg). The baseline global cerebral blood flow values before and after treatment were 40.1+/-7.2 mL/min/100 g and 39.2+/-8.2 mL/min/100 g, respectively. The cerebrovascular reserve values before and after treatment were 58.6+/-21.7% and 56.3+/-21.3%, respectively. Differences in these parameters were not significant. A regional analysis showed no statistical differences in regional cerebral blood flow or cerebral perfusion reserve throughout the brain before and after treatment. No associations between the decreased blood pressure and the changes in cerebral blood flow or cerebrovascular reserve were found in the whole brain or in the deep white matter with ischemic lesions. In conclusion, we found that the cerebral blood flow and cerebral vascular reserve were preserved after blood pressure lowering with azelnidipine administration in hypertensive patients with ischemic white matter lesions. Azelnidipine, a novel calcium channel blocker, could be a feasible antihypertensive regimen in terms of cerebral circulation in patients with ischemic white matter lesions.

Topics: Acetazolamide; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Positron-Emission Tomography; Regional Blood Flow

The benefits of lowering a systolic blood pressure below 140 mmHg in elderly hypertension remain controversial. This study is a prospective, randomized, open-label study with blinded assessment of endpoints to compare the 2-year effect of strict treatment to maintain systolic blood pressure below 140 mmHg with that of mild treatment to maintain systolic blood pressure below 160 but at or above 140 mmHg in elderly hypertensive patients. Patients with essential hypertension (65-85 years old, with a pretreatment systolic blood pressure of above 160 mmHg) were randomly assigned to receive strict treatment (n=2,212) or mild treatment (n=2,206). The baseline drug was efonidipine hydrochloride, a long-acting calcium antagonist. The primary endpoint was the combined incidence of cardiovascular disease and renal failure, and the secondary endpoints were total deaths and any safety problems. Although final blood pressures (systolic/diastolic) were significantly lower in the strict-treatment group compared with the mild-treatment group (135.9/74.8 vs. 145.6/78.1 mmHg; p<0.001), the incidence of the primary endpoint was similar in the two groups (86 patients in each group; p=0.99). Total deaths were 54 in the strict-treatment group vs. 42 in the mild-treatment group (p=0.22), and treatment was withdrawn because of adverse events in 36 patients in each group (p=0.99). An interaction between age and treatment for the primary endpoints (p=0.03) was seen. Complex clinical features associated with aging seem to have obscured the difference in effect between the two treatments. Further studies are needed to assess the optimal treatment strategy for hypertension in the elderly.

Topics: Aged; Aged, 80 and over; Aging; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Diuretics; Dose-Response Relationship, Drug; Endpoint Determination; Female; Humans; Hypertension; Japan; Male; Nitrophenols; Organophosphorus Compounds; Single-Blind Method; Systole

We investigated whether mental stress-induced blood pressure elevation was related to cognitive function in the elderly, and further examined the effects of the dual-type calcium channel blocker, cilnidipine, on stress induced hypertension in subjects with mild cognitive impairment.. In study I, 39 consecutive outpatients (mean age +/- standard deviation, 77 +/- 8 years), who were referred to our memory clinic and were not taking any medications, were studied. They were divided into three groups according to cognitive function on the Hasegawa Dementia Scale-Revised (HDSR): group 1 (n = 8), 28 points or more; group 2 (n = 18), 21-27 points; and group 3 (n = 13), 20 points or less. In study II, 14 outpatients with hypertension and mild cognitive impairment (aged 79 +/- 8 years; HDSR score, 24 +/- 4) were assigned to receive cilnidipine (10-20 mg/day). The control group (n = 10) matched for age, HDSR and blood pressure was followed without cilnidipine.. In study I, although age and basal blood pressure were similar among the three groups, the blood pressure response to a mental arithmetic test was twice as large in group 2 (26 +/- 12 mmHg in systolic pressure and 11 +/- 8 mmHg in diastolic pressure) as those in groups 1 and 3. In study II, after 4 weeks, cilnidipine treatment significantly decreased the blood pressure responses to the mental arithmetic test compared to the baseline as well as to those of the control group.. Stress-induced blood pressure elevations are exaggerated in subjects with mild cognitive impairment. Cilnidipine may have inhibitory effects on stress-induced hypertension.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Case-Control Studies; Cognition Disorders; Dihydropyridines; Humans; Hypertension; Stress, Psychological

To compare the effect of delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients.. After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and <110 mmHg) outpatients were randomized to delapril 30 mg/manidipine 10 mg combination or to olmesartan 20 mg/HCTZ 12.5 mg combination for 24 weeks according to a prospective, randomized, open-label, blinded endpoint, parallel group design. At the end of the placebo period and treatment period, clinical BP, fasting plasma glucose (FPG), plasma insulin, insulin sensitivity (by euglycemic hyperinsulinemic clamp) and plasma fibrinogen were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 minutes (glucose infusion rate, GIR) in mg/Kg/min. The total glucose requirement (TGR) to maintain a steady-state blood glucose level in response to a defined increase in plasma insulin concentration was also evaluated.. Both combinations significantly reduced SBP/DBP values (-22.3/16.4 mmHg and -22.6/17.2 mmHg, respectively, all p <0.001 vs placebo). GIR was significantly increased only by delapril/manidipine (+3.01 mg/min/Kg, p=0.038 vs placebo), the difference between treatments being significant (p <0.05). TGR was significantly increased by delapril/manidipine (+9.7 g, p=0.034), while it was unaffected by olmesartan/HCTZ. Plasma insulin as well as fibrinogen were significantly reduced by delapril/manidipine (-17.8 pmol/l, p=0.047 and -67.5 mg/dl, p=0.021, respectively), but not by olmesartan/HCTZ, the difference between the two treatments being statistically significant (p <0.05).. In obese hypertensive patients the delapril/manidipine combination but not the olmesartan/HCTZ combination significantly decreased insulin resistance and plasma fibrinogen levels, despite the similar BP lowering efficacy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Female; Fibrinogen; Glucose Clamp Technique; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Tetrazoles

Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes.. This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment.. Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups.. The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

The TOlerabilidad de LERcanidipino 20 mg frente a Amlodipino y Nifedipino en CondicionEs normales de uso study was aimed to compare the tolerability of high doses of lercanidipine with amlodipine and nifedipine gastro-intestinal therapeutic system (GITS) in the treatment of hypertension in daily clinical practice.. Essential hypertensives >or= 18 years, treated during at least 1 month with lercanidipine 20 mg, amlodipine 10 mg or nifedipine GITS 60 mg, after a previous treatment course of at least 1 month with half the dose of the corresponding drugs were included. We present the data of the subgroup of patients with metabolic syndrome (MetS).. Three hundred and thirty-seven of the 650 study population fulfilled criteria of MetS, 233 (69.1%) on lercanidipine and 104 (30.9%) on amlodipine/nifedipine GITS. Overall, a significantly lower proportion of lercanidipine-treated patients showed adverse reactions (ARs) when compared with patients receiving other-dihydropyridines (DHPs) (60.1% vs. 73.1%, p = 0.003). Similarly, the most common vasodilation-related ARs (oedema, swelling, flushing and headache) were significantly less frequent in lercanidipine group (all p < 0.01).. In conclusion, lercanidipine appears to exhibit a better tolerability profile and less vasodilation-related ARs compared with other DHPs in hypertensive patients with MetS.

Topics: Adolescent; Adult; Aged; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Cross-Sectional Studies; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Nifedipine

The purpose of this study was to compare the combination treatments of manidipine/delapril and olmesartan/hydrochlorothiazide (HCTZ) in elderly diabetic hypertensives. After a 4-week placebo period, 158 hypertensive patients with type 2 diabetes (age range: 66 to 74 years) were randomized to receive combination treatment of 10 mg manidipine plus 30 mg delapril or 20 mg olmesartan plus 12.5 mg HCTZ for 48 weeks in a prospective, parallel arm trial. After 12 weeks, manidipine or HCTZ was doubled in nonresponders (systolic blood pressure [SBP] > or =130 mmHg and/or diastolic blood pressure [DBP] > or =80 mmHg). Patients were checked at the end of the placebo period and every 12 weeks thereafter. At each visit, lying, sitting and standing BP as well as fasting glycemia, glycosylated hemoglobin (HbA1c), electrolytes, uric acid, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) were evaluated. Both combinations reduced sitting SBP (-27.7 and -28.3 mmHg, respectively; both p<0.001) and DBP (-15.1 and -14.8 mmHg, respectively; both p<0.01) with no difference between the two treatments. Standing DBP was more markedly reduced by olmesartan/HCTZ (-19.5 mmHg; p<0.001) than by manidipine/delapril (-14.7 mmHg; p<0.05 vs. olmesartan/HCTZ). No changes in metabolic parameters were observed with manidipine/delapril, whereas an increase in HbA1c (+0.7%; p<0.05), uric acid (+0.4 mg/dL; p<0.05) and TG (+41.3 mg/dL; p<0.05), and a decrease in serum potassium (-0.3 mmol/L; p<0.05) and HDL-C (-3.4 mg/dL; p<0.05) were found in the olmesartan/HCTZ group. In conclusion, both combinations were similarly effective in reducing BP in elderly hypertensive diabetic patients. However, manidipine/delapril offered some advantages in terms of the less-pronounced BP orthostatic changes and absence of metabolic adverse effects.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Combinations; Endpoint Determination; Female; Humans; Hydrochlorothiazide; Hypertension; Hypotension, Orthostatic; Imidazoles; Indans; Male; Nitrobenzenes; Piperazines; Posture; Prospective Studies; Tetrazoles

It has been shown that benidipine, a long-lasting calcium (Ca) channel blocker, may exert its protective effect against vascular disorders by increasing nitric oxide (NO) production. The purpose of the present study was to investigate whether orally administered benidipine might influence the membrane function in patients with essential hypertension. We measured the membrane fluidity of erythrocytes by using an electron paramagnetic resonance (EPR) and spin-labeling method. In the preliminary study using erythrocytes obtained from healthy volunteers, benidipine decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS in the EPR spectra in vitro. The finding indicated that benidipine increased the membrane fluidity and improved the microviscosity of erythrocytes. In addition, it was demonstrated that the effect of benidipine on membrane fluidity of erythrocytes was significantly potentiated by the NO-substrate, L-arginine. In the separate series of the study, we observed that orally administered benidipine for 4 weeks significantly increased the membrane fluidity of erythrocytes with a concomitant increase in plasma NO metabolite levels in hypertensive subjects. The results of the present study demonstrated that benidipine might increase the membrane fluidity and improve the microviscosity of erythrocytes both in vitro and in vivo, to some extent, by the NO-dependent mechanism. Furthermore, it is strongly suggested that orally administered benidipine might have a beneficial effect on the rheologic behavior of erythrocytes and the improvement of the microcirculation in hypertensive subjects.

Topics: Administration, Oral; Aged; Antihypertensive Agents; Arginine; Blood Pressure; Blood Viscosity; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Erythrocyte Membrane; Female; Humans; Hypertension; Male; Membrane Fluidity; Middle Aged; Nitric Oxide; Treatment Outcome

The TOLERANCE study was aimed to compare the tolerability of high doses of lercanidipine (20 mg) with that of other frequently used dihydropyridines (amlodipine 10 mg/nifedipine GITS 60 mg) in the treatment of essential hypertension in daily clinical practice. It was an observational, transversal, multicentre study performed in a Primary Care Setting. A total of 650 evaluable patients with essential hypertension and age > or = 18 years were included. They had been treated with high doses of lercanidipine (n= 446) or amlodipine/nifedipine GITS (n= 204) during at least 1 month and previously with low doses (10 mg, 5 mg, and 30 mg, respectively) of the same drugs. The main objective was to compare the rates of vasodilation-related adverse events between both groups. Rates of signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine GITS group (76.8%, CI 95%[70.7; 82.9]) than in lercanidipine group (60.8%, [56.1;65.5]). Blood pressure control (< 140/90 mmHg or <130/80 for diabetics) and type of concomitant antihypertensive medications were similar in both groups. Treatment compliance was good (around 93%) and fairly comparable in both groups. Most adverse events with lercanidipine were mild (74.5% vs. 64% in amlodipine/nifedipine GITS group, P= 0.035) whereas severe adverse event rates did not differ significantly between groups (2.8% vs. 3.6%). In conclusion, treatment with lercanidipine at high doses is associated with a lower rate of adverse events related to vasodilation compared to high doses of amlodipine or nifedipine GITS in clinical practice.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Sectional Studies; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Logistic Models; Male; Middle Aged; Nifedipine; Primary Health Care; Spain; Vasodilation

Topics: Adiponectin; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cholesterol, HDL; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Leptin; Nitrophenols; Organophosphorus Compounds; Placebos; Vasodilation

Information on the features of long-term modifications of clinic and 24-h ambulatory blood pressure (ABP) by treatment is limited. The present study aimed to address this issue.. Ambulatory BP monitoring and clinic BP (CBP) measurements were performed at baseline and at yearly intervals over a 4-year follow-up period in 1523 hypertensives (56.1 +/- 7.6 years) randomized to treatment with lacidipine or atenolol in the European Lacidipine Study on Atherosclerosis (ELSA).. CBP was always greater than ABP, while reductions in all BP values (greater for CBP than for ABP) were on average maintained throughout 4 years, CBP changes showing limited relationship with ABP changes (r = 0.14-0.27). BP reductions by treatment during daytime and night-time were correlated (r = 0.63-0.73). BP normalization was achieved in a greater percentage of patients for CBP (41.7%) than for ABP (25.3%), with systolic BP control being always less common than diastolic BP control. BP normalization was more frequent at single yearly visits than throughout the 4 years. Twenty-four-hour BP variability was reduced by treatment over 4 years in absolute but not in normalized units.. The present study provides the best evidence available on long-term effect of antihypertensive treatment on both ABP and CBP. On average, ABP was sustainedly reduced by treatment throughout the follow-up period, but 24-h BP was more difficult to control than CBP. In several patients, ABP control was unstable between visits, the percentage of patients under control over 4 years being much less than that of those controlled at each year. Treatment induced a reduction in absolute but not in normalized BP variability estimates. This has clinical implications because of the prognostic importance of ABP mean values and variability.

Topics: Antihypertensive Agents; Atenolol; Atherosclerosis; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

In hypertensive patients with chronic renal disease, angiotensin receptor blockers (ARBs) are among the first-line drugs, and calcium channel blockers (CCBs) are recommended as a second line. We examined the effects of two therapeutic strategies using ARBs and benidipine, a CCB, on blood pressure (BP), urinary albumin excretion (UAE), and cost-effectiveness in hypertensive patients with albuminuria. Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned randomly to two groups. In Group A (n=14), the ARB dose was maximized and then benidipine was added until BP targets were reached (<130/85 mmHg). In Group B (n=18), benidipine was administered first and then the ARB dose was increased until BP targets were reached. The BP targets were achieved by ARB alone in 36% of Group A patients and by the addition of benidipine in 83% of Group B patients. Finally, BP decreased in each group, reaching the targets in 93% of Group A patients and 94% of Group B patients after a 4-month therapeutic period. UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period (-33+/-6% in Group A, -31+/-6% in Group B; p<0.001, respectively). The monthly drug cost was higher (11,426+/-880 vs. 8,955+/-410 yen, p=0.012) and the cost-effectiveness of antihypertensive treatment was lower (p=0.003) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is, in light of the renal protection and the cost-effectiveness of this approach, a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Cost-Benefit Analysis; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Kidney; Male; Middle Aged

Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD).. Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period.. Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period.. Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amlodipine; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Heart Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria

The effect of dihydropyridine calcium channel blocker (CCB) on baroreflex sensitivity (BRS) is not well described. We studied the effect of a new CCB, azelnidipine, compared with amlodipine, on BRS and ambulatory blood pressure (BP) in newly diagnosed untreated hypertension. This study was a prospective, randomized, and open-label study. We randomized patients to either azelnidipine or amlodipine treatment. Azelnidipine 8 to 16 mg (average 14.5 mg) and amlodipine 2.5 to 7.5 mg (average 4.9 mg) were used to lower the clinical BP <140/90 mm Hg. BRS, evaluated by the spontaneous and the Valsalva methods, and clinical and ambulatory BP were evaluated at baseline and after 13 weeks of each treatment. A total of 47 patients (age 53.1 +/- 10.8 years, 51% male), 26 in the azelnidipine group and 21 in the amlodipine group, completed the study. For baseline and after therapy respectively, both Valsalva-BRS (4.8 +/- 1.7 vs. 8.4 +/- 3.1 msec/mm Hg, P = 0.001) and spontaneous-BRS (5.5 +/- 2.5 vs. 8.2 +/- 5.6 msec/mm Hg, P = 0.019) were increased by azelnidipine, but amlodipine did not change them. Clinical and awake BPs were similarly reduced by each drug therapy. In conclusion, BRS was increased by azelnidipine therapy, but not by amlodipine therapy. This differential effect may be important in cardiovascular risk reduction.

Topics: Adult; Aged; Aged, 80 and over; Amlodipine; Azetidinecarboxylic Acid; Baroreflex; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies

Use of the combination of an angiotensin-converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives.. The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension.. Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period.. The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P<0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P<0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P<0.001) and DBP (-18.6 [4] mm Hg; P<0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P<0.001) and PSTP (36.6%; P<0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P<0.05) and PSTP (10.4%; P<0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment.. In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Ankle; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

This double-blind, placebo-controlled, four-way balanced design crossover study included hypertensive patients aged 60-85 years with mean office-measured sitting systolic blood pressure (SBP) 160-179 mm Hg and daytime SBP > or =135 mm Hg. After a 2-week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomized order for 4 weeks each: lercanidipine 10 mg (L), enalapril 20 mg (E), lercanidipine 10 mg plus enalapril 20 mg (L/E) and placebo (P). At the end of each treatment period, office trough blood pressure (BP) was measured and a 24-h Ambulatory Blood Pressure Monitoring (ABPM) was performed. Seventy-five patients (mean age 66 years, office BP 168/92 mm Hg, daytime SBP 151 mm Hg) were randomized and 62 completed the study with four valid post-baseline ABPMs. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133 and 127 mm Hg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but L/E was significantly more effective than L and E alone. Similarly, office SBP was significantly more reduced with L/E (-16.9 mm Hg) than with L (-5.0 mm Hg) or E (-5.9 mm Hg). A BP <140/90 mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events. In conclusion, combination therapy with L/E has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated.

Topics: Aged; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diastole; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Placebos; Systole; Time Factors

Isolated systolic hypertension (ISH) affects 10-20% of the elderly population and is strongly related to the risk of cardiovascular events. Elevated systolic BP values are primarily caused by reduced large vessel compliance with a consequent increase in total peripheral resistance. Vasodilating drugs, such as calcium channel antagonists, have proven to be effective in controlling ISH in elderly patients. This study set out to compare the antihypertensive efficacy and safety of two different calcium channel antagonists, manidipine and amlodipine, administered once daily in elderly subjects with ISH.. In a European, randomised, double-blind, multicentre, parallel-group study, after a 2-week placebo run-in period, 195 patients aged >or=60 years with ISH received manidipine 10-20 mg once daily or amlodipine 5-10 mg once daily. Chlortalidone 25mg once daily could be added to the high dose of test drug in the event of insufficient antihypertensive control. The primary efficacy parameter was the proportion of patients with a reduction in office sitting systolic BP (SBP) >or=15 mm Hg, measured at trough, at the final visit. Secondary efficacy parameters included: the proportion of patients with a normal sitting SBP value (<140 mm Hg) at the final visit; a change from baseline to the final visit in mean office trough sitting SBP; a change from baseline to the final visit in the cardiovascular risk score as measured by the INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project score; the proportion of patients with at least a two-point reduction in the cardiovascular risk score; the percentage of patients requiring upward dose titration and diuretic add-on treatment and the investigator's final judgement. Safety and tolerability evaluations were based on adverse events, ECG and laboratory tests, and clinically relevant reports of abnormalities.. In the intention-to-treat population (n = 189), 76% and 72% of patients in the manidipine and amlodipine groups, respectively, had a reduction in sitting SBP of >or=15 mm Hg (p-value not significant for between-group comparison). The percentage of patients with a normal sitting SBP value was 52% in the manidipine group and 51% in the amlodipine group (p-value not significant for between-group comparison). Sitting SBP reductions at the end of treatment were -19.5 +/- 11.8 mm Hg in patients receiving manidipine and -18.4 +/- 11.1 mm Hg in patients receiving amlodipine. Both treatments induced a small reduction in cardiovascular risk score, with 45% of patients in both treatment groups having a two-point reduction in the final score. At the final visit, approximately half of the patients in both treatment groups were still being treated with the low dose of one of the test drugs (manidipine 10mg or amlodipine 5mg). Chlortalidone was added to the high dose of test drugs in 7% and 11% of patients in the amlodipine and manidipine groups, respectively. Both drugs were well tolerated, with a higher incidence of oedema in the amlodipine group (9% vs 4%). No clinically relevant changes in heart rate were induced by either treatment.. In elderly patients with ISH, treatment with manidipine for 12 weeks was well tolerated and effective and the antihypertensive effects obtained with manidipine were the same as those obtained with amlodipine.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Chlorthalidone; Dihydropyridines; Diuretics; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Risk Assessment; Risk Factors; Systole; Time Factors; Treatment Outcome

Cilnidipine is a calcium channel blocker that blocks both L and N-type calcium channels. L/N-type calcium channel blockers exhibit sympatholytic action and a renal protective effect via dilation of afferent and efferent arterioles of the renal glomerulus, and afford more potent protection against hypertension-related organ damage than L-type calcium channel blockers. Few studies, however, have directly compared the organ protective effects of L-type calcium channel blocker monotherapy and L/N-type calcium channel blocker monotherapy. This study compares the effects on renal and vascular endothelial functions and arterial stiffness of monotherapy regimens of amlodipine, an L-type calcium antagonist, and cilnidipine, in patients with essential hypertension.. Fifty patients with untreated essential hypertension were randomized to receive 5 mg of amlodipine (n = 25) or 10 mg of cilnidipine (n = 25) once daily in the morning for 24 weeks. The patients were evaluated before and after the therapy to assess changes in renal function, flow-mediated vasodilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (a parameter of arterial stiffness).. Before treatment, the above parameters showed no significant differences between groups. After treatment, urinary albumin excretion was decreased significantly in the cilnidipine group compared with the amlodipine group, and the decrease of brachial-ankle pulse wave velocity was significantly larger in the cilnidipine group than in the amlodipine group.. These results suggest that cilnidipine is more effective than amlodipine at improving renal function and arterial stiffness in patients with essential hypertension.

Topics: Albuminuria; Amlodipine; Antihypertensive Agents; Arteries; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Safety; Vasodilation

Anti-hypertensive agents with antioxidative effects are potentially useful for diabetic patients with hypertension to prevent the onset and progression of their complication. While dihydropyridine-type calcium antagonists are among the frequently used anti-hypertensive drugs, azelnidipine, a novel calcium antagonist, has been reported to have a unique anti-oxidative effect in vitro and in animals. In this study, we measured lipid hydroperoxides in human sample using diphenyl-1-pyrenylphosphine for the first time, and used the value of lipid hydroperoxides as an index of oxidative stress. Then, we compared the antioxidative properties of azelnidipine and amlodipine, a frequently used calcium antagonist in hypertensive diabetic patients. Administration of vitamin C and E for 8 weeks significantly reduced lipid hydroperoxides in erythrocyte membrane in normal subjects. In hypertensive diabetic patients, azelnidipine treatment for 12 weeks induced a more significant fall in erythrocyte lipid hydroperoxide level than amlodipine, though blood pressure during each treatment was comparable. Our data confirm the usefulness of lipid hydroperoxides in erythrocyte membrane as a marker of oxidative stress in vivo, and indicate that azelnidipine has a unique antioxidative property in human.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Ascorbic Acid; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Erythrocytes; Female; Humans; Hypertension; Lipid Peroxides; Male; Middle Aged; Organophosphorus Compounds; Pyrenes; Vitamin E

We sought to compare the effect of manidipine versus hydrochlorothiazide (HCTZ) in addition to candesartan on the urinary albumin excretion rate (UAER) in hypertensive patients with type II diabetes and microalbuminuria.. After a 2-week washout and run-in period, and 8-week monotherapy with candesartan 16 mg every day, 174 microalbuminuric diabetic hypertensive patients with uncontrolled blood pressure (BP) (>130/80 mm Hg) were randomized to addition of manidipine 10 mg every day (n = 87) or HCTZ 12.5 mg every day (n = 87) for 24 weeks, with a titration after 4 weeks (manidipine or HCTZ dose-doubling) in nonresponder patients. Blood pressure, UAER, creatinine clearance, serum electrolytes, fasting plasma glycemia, and glycosylated hemoglobin were evaluated at baseline (end of run-in period), after candesartan monotherapy, and at the end of the combination treatment period.. Both combinations produced greater systolic BP/diastolic BP reduction than candesartan monotherapy (-28/21 mm Hg versus -16/11 mm Hg and -28/20 mm Hg versus -15/11 mm Hg, respectively; all P < .05 versus monotherapy), with no significant difference between the two combinations. The addition of manidipine produced a greater reduction in UAER than candesartan monotherapy (-55.4 mg/24 h v -36.1 mg/24 h, P < .05), whereas the addition of HCTZ did not significantly modify UAER; the difference between the two combinations was statistically significant (P < .05). Similarly, the percentage of patients moving to a normoalbuminuric state (UAER <30 mg/24 h) was increased by the addition of manidipine to candesartan (from 35% to 64%, P < .05), but not by the addition of HCTZ (from 34% to 39%, NS), with a statistical difference between the two combinations (P < .05).. These findings show that, despite equivalent reduction in BP, the addition of manidipine to candesartan further reduced the UAER, whereas the addition of HCTZ did not modify the UAER. This suggests that the antiproteinuric effect of manidipine is partially independent of BP reduction, and is attributable to mechanisms different from those mediated by angiotensin receptor blockade.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Proteinuria; Single-Blind Method; Tetrazoles

To prevent cardiovascular disease, targeting aldosterone synthesis and release may be clinically important. Aldosterone production in the adrenal gland is mediated mainly by the T-type calcium channel in vitro. Efonidipine inhibits both L- and T-type Ca channels. To compare the effects of efonidipine on neurohumoral factors with those of amlodipine, an L-type Ca channel blocker, we studied 40 essential hypertensive outpatients. Forty patients who had been administered amlodipine for more than 1 year were treated with efonidipine for 6 months in place of amlodipine. Substituting efonidipine for amlodipine had no significant effect on clinic systolic blood pressure or the plasma levels of brain natriuretic peptide, norepinephrine or active renin. However, the heart rate was significantly decreased (72.0+/-1.3 vs. 69.8+/-1.3 beats/min, p<0.01) and the plasma aldosterone level was also significantly decreased after efonidipine treatment (97.7+/-7.9 vs. 79.7+/-5.6 pg/mL, p<0.0001). Changes in the aldosterone level correlated with the baseline value before the replacement of amlodipine by efonidipine (r=-0.769, p<0.0001). These findings indicate that at the effective antihypertensive doses of efonidipine and amlodipine, efonidipine significantly decreases heart rate and plasma aldosterone level compared with those under amlodipine treatment in hypertensive patients.

Topics: Aged; Aged, 80 and over; Aldosterone; Amlodipine; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nitrophenols; Norepinephrine; Organophosphorus Compounds

Calcium antagonists are very effective drugs, recommended as first-line therapy in hypertension. However, their large use in clinical practice is often limited by a high incidence of peripheral oedema. Calcium antagonists of the third generation, such as lercanidipine, have been shown to be as effective as first- and second-generation calcium antagonists, while showing a better side-effect profile.. The purpose of the present Phase IV study was to investigate the efficacy and tolerability of lercanidipine in a large unselected population of hypertensive patients managed in private practice in Switzerland. A total of 504 physicians participated in this survey and 2199 patients were included. Treatment with lercanidipine was introduced at a dose of 10 mg and titration to 20 mg was optional according to the physician's decision. Evaluations of blood pressure control and tolerability were made after 4 and 8 weeks.. The results of the present study show that lercanidipine is an effective and well tolerated antihypertensive agent in newly treated hypertensive patients. In this group of patients, 63% reached the target blood pressure (< or = 140/90 mmHg) with lercanidipine alone. Lercanidipine is also an effective alternative in patients who are insufficiently controlled with another therapy, or in patients not tolerating other calcium channel blockers. Finally, lercanidipine is well-tolerated, with a very low rate of drop-out (1-2%) because of adverse events, and a low occurrence of peripheral oedema.. Lercanidipine is an effective and well tolerated calcium channel blocker of the third generation. This new calcium antagonist represents a very useful tool to improve blood pressure control in the community.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Pressure; Dihydropyridines; Family Practice; Female; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Sexual Dysfunction, Physiological; Sleep Wake Disorders

The European Lacidipine Study on Atherosclerosis (ELSA) randomized 2334 hypertensive patients to either the lipophilic calcium antagonist lacidipine or the beta-blocker atenolol for 4 years. About 35% of subjects in both groups received additional hydrochlorothiazide (12.5-25 mg/day). The patients were followed up for carotid intima-media thickness (IMT) changes for 3.7 years.. The present post-hoc analyses were aimed at: describing the prevalence of the metabolic syndrome (MS) at baseline; investigating the effect of long-term antihypertensive therapy (and separately of atenolol and lacidipine) on MS prevalence; exploring whether MS at baseline influenced changes in carotid IMT and incidence of cardiovascular events during treatment; and describing the relations between MS and new cases of diabetes developing during treatment.. At baseline 2034 patients had, in addition to blood pressure (BP), measurements of blood glucose, serum high-density lipoprotein (HDL)-cholesterol, triglycerides and body mass index (BMI > 28.8 for men and > 26.2 for women were taken to correspond to waist circumference > 102 and > 88 cm, respectively). These measurements were repeated after 4 years of treatment in 1444 patients. MS was defined according to Adults Treatment Panel III (ATP III).. A high proportion of ELSA patients (33.3%) had MS at baseline, with no difference between atenolol and lacidipine. Baseline IMT was slightly greater in MS patients, but only the difference in mean maximum IMT at common carotids and bifurcations (CBMmax) achieved significance (P = 0.0325). Progression of CBMmax was also slightly greater in MS patients (P = 0.0241), but significance was lost when adjusted for covariates. No significant difference was found in the incidence of new cardiovascular events between patients with and without MS. The incidence of new MS was 21.4%, and significantly greater in patients under atenolol (25.2%) than lacidipine (17.7%; P = 0.0045). New-onset diabetes occurred in 5.54% of ELSA patients, and was three times higher among patients with than those without MS (10.28 versus 3.43%, P > 0.0001).. Our analyses show a high prevalence of MS in ELSA hypertensives, a substantial incidence of new cases of MS and diabetes, the latter mostly among patients with MS. These analyses also show that in ELSA lacidipine was superior to atenolol, not only in showing a lower progression of carotid atherosclerosis, but also in causing a significantly lower incidence of new MS.

Topics: Aged; Antihypertensive Agents; Atenolol; Atherosclerosis; Calcium Channel Blockers; Carotid Arteries; Cohort Studies; Diabetes Complications; Dihydropyridines; Europe; Female; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.

Topics: Aged; Aged, 80 and over; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Both strict blood pressure control and efferent artery dilatation are critical in reducing proteinuria, which in turn helps to regulate blood pressure. Benidipine, an L- and T-type calcium channel blocker, has the potential for increased effectiveness compared with L-type-dominant calcium channel blockers such as amlodipine. Therefore, we evaluated blood pressure and proteinuria after changeover from amlodipine to benidipine in poorly controlled hypertensive patients. Fifty-eight hypertensive outpatients undergoing amlodipine treatment and unable to achieve optimal blood pressure as determined by Japanese Society of Hypertension Guidelines for the Management of Hypertention (JSH 2004) were changed over to benidipine treatment. We measured blood pressure and pulse rate and assessed urinary protein excretion before and after changeover. Systolic and diastolic blood pressure dropped from 151/90 mmHg to 140/81 mmHg (p<0.0001). Mean blood pressure (p<0.0001) and pulse pressure (p=0.0069) were also reduced, but pulse rate increased from 75 bpm to 78 bpm (p=0.0047). Urinary protein excretion adjusted for urinary creatinine was reduced from 0.35 +/- 0.82 to 0.22 +/- 0.55 g/g creatinine (p=0.0119). The urinary protein reduction was observed only in patients with renin-angiotensin inhibition (p=0.0216). By switching from amlodipine to benidipine treatment, more than 80% of patients reduced their blood pressure, and more than 40% achieved optimal blood pressure. Higher urinary protein excretion (p<0.0001), lower glomerular filtration rate (p=0.0011) and presence of diabetes (p=0.0284) were correlated with reduction of urinary proteins during changeover. Taken together, our results suggest that benidipine may have greater efficacy than amlodipine in reducing blood pressure and proteinuria.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Dihydropyridines; Female; Guideline Adherence; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Middle Aged; Proteinuria; Pulse; Renin-Angiotensin System

Recently, the use of combination therapy with a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) has been rapidly increasing. Although this combination therapy is accepted as a standard treatment hypertension, there have been few large-scale, multicenter studies examining its safety and efficacy. The present study was designed to investigate the safety and efficacy of adding cilnidipine, a dual L/N-type CCB, to the regimen of patients whose blood pressure had been poorly controlled (systolic blood pressure [SBP] >140 mmHg or diastolic blood pressure [DBP] >90 mmHg) by antihypertensive monotherapy with an ARB. The percentage achievement of the blood pressure goals recommended by the JSH 2000 guidelines was also assessed for at least 12 weeks of treatment. A total of 2,920 patients were enrolled in the study at 471 institutions in Japan from February 2003 to July 2004. The incidence of adverse reactions related to cilnidipine was as low as 2.5%. A significant reduction from the baseline was found both in SBP (from 164.1 +/- 15.3 to 139.2 +/- 15.3 mmHg, p<0.0001) and DBP (from 91.7 +/- 11.4 to 79.3 +/- 10.7 mmHg, p<0.0001). A total of 31.5% of the patients achieved the blood pressure goals recommended by the JSH 2000 guidelines. Moreover, the heart rate also significantly decreased in these patients, particularly in those with a higher baseline heart rate. Our results indicate that cilnidipine can be used in combination with an ARB to control blood pressure without any significant adverse effects, and also that cilnidipine successfully reduces elevated heart rate, which is a possible risk factor for cardiovascular events.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Asian People; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Guideline Adherence; Heart Rate; Humans; Hypertension; Japan; Male; Middle Aged; Treatment Outcome

Persistence on treatment affects the efficacy of antihypertensive treatment. We prospectively investigated the persistence on therapy and the extent of blood pressure (BP) control in 347 hypertensive patients (age 59.4 +/- 6 years) randomly allocated to a first-line treatment with: angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers (CCBs), beta-blockers, angiotensin-II receptor blockers (ARBs), or diuretics and followed-up for 24-months. Persistence on treatment was higher in patients treated with ARBs (68.5%) and ACE inhibitors (64.5%) vs CCBs (51.6%; p < 0.05), beta-blockers (44.8%, p < 0.05), and diuretics (34.4%, p < 0.01). No ARB, ACE inhibitor, beta-blocker, or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class. The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs (59.3% vs 46.6%, p < 0.05). Systolic and diastolic BP was decreased more successfully in patients treated with ARBs (-11.2/-5.8 mmHg), ACE inhibitors (-10.5/-5.1 mmHg), and CCBs (-8.5/-4.6 mmHg) compared with beta-blockers (-4.0/-2.3 mmHg p < 0.05) and diuretics (-2.3/-2.1 mmHg, p < 0.05). No ARB, ACE inhibitor, beta-blocker, or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class. A trend toward a better BP control was observed in response to lercanidipine vs other CCBs (p = 0.059). The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice.

Topics: Adrenergic beta-Antagonists; Age Factors; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Diuretics; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Sex Factors

Topics: Adult; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nifedipine; Obesity; Treatment Outcome; Verapamil

Angiotensin-converting enzyme inhibitors plus dihydropyridine calcium channel blockers or low-dose thiazide diuretics are considered first-line therapies in hypertensive diabetic patients as glucose metabolism is not relevantly affected. Most diabetic patients require at least two different drug classes to achieve the recommended target blood pressure of 130/85 mmHg. This controlled clinical trial investigated the calcium channel blocker lercanidipine versus hydrochlorothiazide (HCTZ) as add-on in diabetic patients with uncontrolled hypertension on enalapril monotherapy.. Overall, 174 patients (18-80 years old, well-controlled diabetes type 1 or 2, mild to moderate hypertension) were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 non-responders (90 mmHg < or = mean sitting diastolic blood pressure < or = 109 mmHg) were randomized to 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or HCTZ 12.5 mg (n = 66). The primary study objective was to prove non-inferiority of lercanidipine add-on versus HCTZ add-on in reducing sitting diastolic blood pressure; response rates and tolerability data were also observed.. Both add-on treatments clearly decreased diastolic blood pressure to a greater extent than enalapril monotherapy (mean +/- SD changes at study end: lercanidipine, -9.3 mmHg; HCTZ, -7.4 mmHg); non-inferiority of lercanidipine versus HCTZ was formally proven. Blood pressure response rates reached 69.6% on enalapril plus lercanidipine as compared with 53.6% on enalapril plus HCTZ (difference between treatments, P > 0.05). Blood pressure of 130/85 mmHg or less was achieved in 30.4% of patients on lercanidipine add-on and in 23.2% of those randomized to HCTZ add-on (P > 0.05). Both treatment regimens were well tolerated.. Lercanidipine add-on showed comparable efficacy to HCTZ add-on in diabetic patients with hypertension badly controlled on angiotensin-converting enzyme inhibitor monotherapy. The blood pressure response rates seemed to be somewhat higher following enalapril plus lercanidipine than enalapril plus HCTZ.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Single-Blind Method

Increased levels of metalloproteinase (MMP)-9 have been shown in hypertensive patients. Lercanidipine is a calcium channel blocker with antioxidant actions. We examined whether lercanidipine produces antioxidant effects and reduces MMP-9 activity in hypertensive patients in a placebo-controlled, crossover, single-blinded design study including 18 healthy volunteers (control group), and 14 hypertensive patients without (N = 7) or with (N = 7) diabetes mellitus. Hypertensive patients were randomized to treatment with placebo (15 days) or lercanidipine 20 mg/d (15 days). Arterial blood pressure was evaluated with ambulatory blood pressure monitoring. Plasma thiobarbituric acid reactive species (TBA-RS) levels were measured to assess oxidative stress, and plasma MMP-2 and MMP-9 were assayed by gel zymography before and after treatment with placebo or lercanidipine. Plasma concentrations of tissue inhibitor of metalloproteinases (TIMP)-1 were measured by ELISA. Lercanidipine reduced mean arterial pressure by 7% in hypertensive patients without diabetes (P < 0.05), but not in hypertensive patients with diabetes. It significantly decreased plasma TBA-RS levels in hypertensive patients without and with diabetes (95% confidence interval [CI], -26 to -46%, P = 0.048, and -22 to -33%, P = 0.036, respectively). In addition, lercanidipine decreased activated MMP-9 in hypertensive patients without and with diabetes (95% CI, -19 to -47%, P = 0.047, and -80 to -96%, P = 0.010, respectively). No effects were seen on MMP-2. No significant differences or changes in plasma TIMP-1 concentrations were found. Therefore, we demonstrate for the first time that lercanidipine consistently decreased MMP-9 activity and reduced oxidative stress in hypertensive patients, thus suggesting a mechanism probably involved in the pleotropic actions of lercanidipine.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Female; Humans; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Oxidative Stress; Single-Blind Method; Tissue Inhibitor of Metalloproteinase-1

Tissue Doppler Tei index is pointed to be more effective in the evaluation of global cardiac function than systolic and diastolic measurements alone in various heart diseases. This study was designed to assess the effect of cilnidipine on left ventricular function in hypertensive patients by using this index. A group of 40 hypertensives (mean age 55+/-8 years, range: 35-65) and 16 controls (mean age 52+/-9 years, range: 36-65) were included. Hypertensives were classified into non-left ventricular hypertrophy (NLVH) group (25 patients) and left ventricular hypertrophy (LVH) group (15 patients), and treated with cilnidipine for 2 months. Before and after treatment, the participants were examined by echocardiography. Tissue Doppler Tei index was calculated as diastolic time interval measured from end of late diastole to origin of early diastole (a') minus systolic Sm duration (b') divided by b', that is Tei index = (a'-b')/b'. Thirty-seven hypertensive patients finished the treatment. Tei index was significantly higher in NLVH and LVH groups than in control group, and in LVH group than in NLVH group (0.44+/-0.07 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.44+/-0.07, P < 0.05). After treatment, Tei index was significantly decreased (0.40+/-0.11 vs 0.46+/-0.10, P < 0.0001); systolic blood pressure and diastolic blood pressure were also decreased significantly. In conclusion, Tei index is impaired in hypertensives before development of ventricular hypertrophy and impairment is more prominent in hypertrophy. Cilnidipine can improve left ventricular function. Tissue Doppler Tei index is gaining importance in evaluating LV function after drug intervention in hypertensive patients.

Topics: Calcium Channel Blockers; Dihydropyridines; Echocardiography, Doppler; Female; Heart Function Tests; Humans; Hypertension; Male; Middle Aged; Ventricular Function, Left

It has been postulated that the loss of arterial compliance may precede cardiovascular diseases, and that arterial compliance is an important parameter to consider when evaluating arterial diseases such as essential hypertension (EH) and the effects of antihypertensive treatment. In all, 133 EH patients and 147 healthy subjects were enrolled in this study. Large arterial compliance (C1) and small arterial compliance (C2) were measured by the CVProfilor DO-2020 CardioVascular Profiling System. Thirty-five patients randomly received magnesium potassium supplementation (magnesium, 70.8 mg/d; potassium, 217.2 mg/d) for four weeks, and 32 patients received lacidipin (4 mg/d) as a control. Before and after the four weeks, blood pressure, C1, and C2 were measured. It was found that arterial compliance was significantly lower in EH patients compared with healthy subjects (C1: 12.53 +/- 0.33 vs. 15.63 +/- 0.30 ml/mmHg x 10, p < 0.01;C2: 3.79 +/- 0.17 vs. 5.69 +/- 0.25 ml/mmHg x 100, p < 0.01). On lacidipine, systolic and diastolic BP decreased 13.27 +/- 1.76 mm Hg and 6.33 +/- 1.55 mm Hg, and C1 and C2 compliance values increased 25.05% +/- 4.49% and 34.50% +/- 7.40%, respectively. On K+ and Mg2+ supplementation, systolic and diastolic BP decreased 7.83 +/- 1.87 mm Hg and 3.67 +/- 1.03 mm Hg, and C1 and C2 compliance values increased 12.44% +/- 4.43% and 45.25% +/- 6.67%, respectively. Decreases in systemic vascular resistance (mean arterial pressure divided by cardiac output) by 11.9% and 16.6 % (p < 0.01) were seen between the drug-induced changes, respectively. Both large arterial compliance and small arterial compliance were decreased in essential hypertension patients. In essential hypertension patients, magnesium and potassium supplementation could improve small arterial compliance, while lacidipine improved large arterial compliance significantly.

Topics: Adult; Aged; Antihypertensive Agents; Arteries; Biomarkers; Blood Pressure; Case-Control Studies; Dietary Supplements; Dihydropyridines; Female; Follow-Up Studies; Humans; Hypertension; Magnesium; Male; Middle Aged; Multivariate Analysis; Potassium, Dietary; Time Factors; Treatment Outcome; Vascular Resistance

Home blood pressure has a higher predictive power for cardiovascular events than office blood pressure, and there is a particularly close association between morning blood pressure at home and the incidence of cardiovascular events and mortality in the early morning. In this study, we evaluated the efficacy of a long-acting N-type and L-type calcium channel blocker, cilnidipine, in reducing morning blood pressure at home and in ameliorating the white-coat effect. Fifty-eight subjects diagnosed with both essential hypertension and morning hypertension (43 currently being treated, 15 new patients) were prescribed cilnidipine at a dosage of 10-20 mg per day for 8 weeks. After the addition of or a change to cilnidipine, the morning systolic blood pressure (SBP) was controlled to less than 135 mmHg in 25 (58%) out of the 43 patients currently receiving antihypertensive medication. The office SBP in 24 out of those 25 patients was also maintained under 140 mmHg. In the 15 newly treated patients, the morning SBP of 12 patients (80%) was controlled to less than 135 mmHg after administration of cilnidipine. At baseline, 17 patients showed a clear white-coat effect, in which the difference between office blood pressure and home blood pressure was 20/10 mmHg or more. The white-coat effect was depressed significantly after cilnidipine administration. These results suggest that cilnidipine may serve as a useful antihypertensive medication in the treatment of morning hypertension, and also attenuate the white-coat effect in patients with essential hypertension.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channels; Cardiovascular Diseases; Circadian Rhythm; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Middle Aged; Office Visits; Prospective Studies; Risk Factors

The effects of combination therapy of angiotensin II receptor blockers (ARBs) and a calcium antagonist, benidipine hydrochloride, on glucose and lipid metabolism and pulse pressure were studied in elderly hypertensive patients with type 2 diabetes mellitus. Twenty-five hypertensive diabetic patients aged 65 years or older, who had been receiving candesartan cilexetil, were administered benidipine hydrochloride (4 mg/day) and followed for 4 months. After 4 months, systolic and diastolic blood pressure decreased significantly from 154/91 mmHg to 139/78 mmHg (p<0.01 versus before benidipine hydrochloride administration). Body mass index (BMI) and glycosylated hemoglobin (HbA1c) were apparently reduced but the changes were not statistically significant. The serum lipid profile showed no significant changes in serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Serum lipoprotein lipase mass levels (preheparin LPL mass) increased significantly from 51 to 59 ng/dl (p<0.01 versus before benidipine hydrochloride administration), and the LDL/HDL motility ratio calculated from PAG disc electrophoresis decreased significantly (p<0.05 versus before benidipine hydrochloride administration). When patients were divided into a systolic hypertension group (systolic blood pressure > or =140 mmHg and diastolic blood pressure <90 mmHg) and non-systolic hypertension group (others), preheparin LPL mass was significantly lower in the systolic hypertension group, and the decrease in pulse pressure and increase in preheparin LPL mass were significantly greater in the systolic hypertension group. Stepwise regression analysis showed that low preheparin LPL mass at baseline was associated with a decrease in pulse pressure. Add-on benidipine hydrochloride therapy in elderly hypertensive patients with type 2 diabetes mellitus significantly decreases the LDL/HDL motility ratio and pulse pressure, and significantly increases preheparin LPL mass, in addition to improving blood pressure control. These findings suggest that combination therapy with benidipine hydrochloride and candesartan cilexetil may contribute to the suppression of arteriosclerosis and may be useful for elderly hypertensive patients with diabetes mellitus.

Topics: Aged; Aged, 80 and over; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diastole; Dihydropyridines; Drug Therapy, Combination; Female; Heparin; Humans; Hypertension; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Systole; Tetrazoles

Many patients undergoing continuous ambulatory peritoneal dialysis (CAPD) receive antihypertensive agents, including calcium antagonists, which produce reflex tachycardia through activation of the sympathetic nervous system. Azelnidipine, a newly developed calcium antagonist, has unique characteristics in that it causes less reflex stimulation of the sympathetic nervous system. In the present study, we used a crossover method to compare the effects of amlodipine (5-10 mg daily) and azelnidipine (8-16 mg daily) on drain volume and weekly creatinine clearance in 9 CAPD patients (3 women, 6 men; mean age: 64 +/- 5 years; mean duration of CAPD: 1.8 +/- 0.6 years). Each calcium antagonist was administered for 3 months and then switched for the other. As compared with amlodipine, azelnidipine increased drain volume by 13% +/- 2% (p < 0.05) and weekly creatinine clearance by 12% +/- 2% (p < 0.05). At the same time, we observed no significant differences in blood pressure and urine volume. The increases in drain volume produced by azelnidipine resulted from less activation of the sympathetic nervous system. We therefore suggest that activation of the sympathetic nervous system induced by calcium antagonists may be important in the regulation of drain volume in CAPD patients.

Topics: Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Creatinine; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Sympathetic Nervous System; Urine

Mega trials of rhythm vs rate control could not demonstrate the usefulness of available antiarrhythmic drugs, so a more effective and safer therapy for atrial fibrillation (AF) is now required. One candidate is the so-called "upstream therapy", which refers to the blockade of upstream modifying elements (renin - angiotensin system, cathecholamines, oxidative stress etc) that contribute to the arrhythmogenic substrate.. The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is a randomized comparative evaluation of an angiotensin II type 1 blocker (candesartan) and a dihydropiridine calcium blocker (amlodipine), both combined with antithrombotic therapy, as an antiarrhythmic therapy for the treatment of paroxysmal AF (PAF) associated with hypertension. To test the usefulness of this therapy, this study will reveal the recurrence rate of asymptomatic as well as symptomatic PAF during 1-year of treatment with candesartan or amlodipine, using daily transtelephonic monitoring.. The J-RHYTHM II study will follow 400 patients with PAF and hypertension who were treated at approximately 50 sites throughout Japan, and will provide clinically important information.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Atrial Fibrillation; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Secondary Prevention; Tetrazoles

Recently it has been recognized that not only blood pressure (BP) but also pulse rate (PR) assessed in the setting of the patient's home by a home BP monitoring device has higher predictive power for cardiovascular events than similar measurements made in the office setting. In this study, we compared the efficacy of azelnidipine to that of amlodipine in lowering morning BP and reducing PR in outpatients with essential hypertension. Patients were assigned to receive once daily administration of azelnidipine 8-16 mg/day (n = 54) or amlodipine 2.5-5 mg/day (n = 54) for 8 weeks. Morning BP and PR were evaluated by assessing patients' self-monitored BP and PR in the home environment. The mean reductions of morning systolic/diastolic BP (SBP/DBP) in the azelnidipine and amlodipine groups were similar (-24.1 +/- 11.8/-14.1 +/- 10.7 vs. -20.4 +/- 11.7/-12.2 +/- 7.7 mmHg). However, whereas azelnidipine decreased mean PR by -6.4 +/- 8.3 beats/min (p < 0.05 vs. baseline), amlodipine did not cause significant reduction of this parameter (-2.1 +/- 8.2 beats/min). Although neither drug changed PR in patients in whom baseline PR was < 70 beats/min, azelnidipine significantly lowered PR in patients whose baseline PR was > 70 beats/min. These results suggest that oral azelnidipine administration may be an effective therapy in the setting of chronic morning hypertension as well as for home PR control.

Topics: Aged; Amlodipine; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Physicians' Offices

The aim of this longitudinal, open-label, comparative, multicenter study was to assess cognitive function in hypertensive patients receiving mid-term treatment with lercanidipine.. Hypertensive patients aged 40 years or older were treated with lercanidipine (10 mg daily) after 7-10 days washout period. The duration of the study was 6 months. Blood pressure (BP) was measured every 4 weeks (JNC 6th report). In patients with inadequate BP control, doxazosin was added and up-titrated. At baseline and after 6 months of treatment, cognitive function was evaluated using the Spanish validated version of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT).. In the study population of 467 patients, BP decreased from 154.4/95.3 mmHg at baseline to 134.8/80.7 mmHg at 6 months. At the end of the study, 98% of patients were receiving lercanidipine, 20% an angiotensin-converting enzyme inhibitor, and 6% doxazosin. Adequate BP control was obtained in 68% of patients. The mean (standard deviation) MMSE scores improved from 32.35 (2.59) to 33.25 (2.36) (p < 0.0001). Patients with good BP control scored significantly better than those with inadequate BP control (p < 0.05), which was already observed at the first month.. The third-generation calcium channel antagonist, lercanidipine, improved cognitive function after 6 months of treatment especially in patients with good BP control, suggesting that improvements in cognitive function may be associated with a decrease in BP.

Topics: Adrenergic alpha-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cognition; Dihydropyridines; Doxazosin; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Psychiatric Status Rating Scales; Psychomotor Performance; Spain; Time Factors; Treatment Outcome

Vascular remodelling and hypertrophy represent early therapeutic targets of antihypertensive treatment. The present study was aimed at assessing the effects of 1-year administration of the highly vasoselective calcium-channel blocker lercanidipine (10 mg/day) or the diuretic compound hydrochlorothiazide (25 mg/day) on hypertension-related vascular alterations. The study was also aimed at assessing whether and to what extent: (i) pharmacological regression of vascular hypertrophy is related only to the blood pressure (BP) reduction "per se" or also to the specific ancillary properties of a given drug and (ii) treatment provides restoration of vascular function indicative of normal vascular structure.. In 26 untreated patients with mild-to-moderate essential hypertension sphygmomanometric and finger BP, heart rate, forearm and calf blood flow (venous occlusion plethysmography) and corresponding vascular resistance (forearm and calf vascular resistance: FVR and CVR) were assessed before and following 6 and 12 months of either lercanidipine or hydrochlorothiazide administration. Vascular resistance was also evaluated following a local ischaemic stimulus (FVR(min) and CVR(min)) in order to assess the effects of treatment on arteriolar structural alterations.. For superimposable BP reductions, lercanidipine caused FVR and CVR to decrease significantly more than hydrochlorothiazide. Similarly, the FVR(min) and CVR(min) reductions induced by lercanidipine were markedly and significantly greater than those caused by hydrochlorothiazide (-46.1% and -40.9% vs -22.5% and -19.9%, p < 0.01 for both). FVR(min), and CVR(min), however, remained higher than those found in 10 age-matched normotensive individuals.. These data provide evidence that, compared to hydrochlorothiazide, lercanidipine favours a greater regression of the vascular structural changes associated with hypertension, probably through its "ancillary" properties. Lercanidipine, however, does not allow restoration of a "normal" vascular structure, thereby suggesting that vascular hypertrophy is only in part a reversible phenomenon.

Topics: Blood Vessels; Calcium Channel Blockers; Case-Control Studies; Dihydropyridines; Diuretics; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy; Male; Middle Aged; Vascular Resistance

The European Lacidipine Study on Atherosclerosis (ELSA) has been planned to investigate the effect of reduction in office and ambulatory blood pressure by lacidipine versus atenolol on carotid artery wall thickness in mild to moderate essential hypertensive patients with no metabolic abnormalities. One prespecified sub-study of ELSA focused on measurements of arterial distensibility in the carotid as well as in the radial artery to determine the relationship of functional arterial properties with office versus ambulatory blood pressure (BP) values as well as the correspondence between functional and structural arterial alterations.. The sub-study was conducted on 124 patients recruited in four centres (Monza-Milan, Paris, Grenoble and Glasgow). BP was measured both by a mercury sphygmomanometer and by 24-h ambulatory monitoring. Common carotid artery wall thickness was measured by certified sonographers as described in the main study. Common carotid and radial artery distensibility were obtained by echotracking techniques, which allowed to relate changes in arterial diameter with systo-diastolic BP changes.. Carotid artery wall distensibility showed (1) a negative correlation with office and more so 24-h average systolic BP (r = -0.45 and -0.58, P < 0.008 and 0.001) but not with office or 24-h diastolic BP) and (2) a negative correlation with the corresponding wall thickness (r = -0.47, P < 0.005). In contrast, at the radial artery level distensibility and thickness showed no correlation with each other and with BP. Carotid (but not radial) artery distensibility also correlated with ambulatory systolic BP variability but the correlation was lost after adjustment for age and mean BP values.. These data suggest that stiffening of large elastic artery is reflected more by ambulatory than office BP elevations, systolic BP being much more important than diastolic. Alterations of large elastic arteries function is related to structural wall changes. Functional and structural properties of middle-size muscle arteries are independent of BP.

Topics: Antihypertensive Agents; Arteriosclerosis; Atenolol; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Carotid Artery, Common; Circadian Rhythm; Dihydropyridines; Europe; Female; Humans; Hypertension; Male; Middle Aged; Radial Artery; Ultrasonography

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypertension; Indoles; Treatment Outcome; Verapamil

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atenolol; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Nitrobenzenes; Piperazines; Platelet Aggregation

Blood pressure reduction is associated with a reduced risk for cardiovascular events and death, particularly in patients with both hypertension and type 2 diabetes mellitus.. The aim of this study was to compare the antihypertensive efficacy, tolerability, and effect on metabolic risk factors of manidipine, a new dihydropyridine calcium channel antagonist, and enalapril, a widely used angiotensin-converting enzyme inhibitor, in patients with mild to moderate essential hypertension and type 2 diabetes.. This multicenter, double-blind trial compared manidipine and enalapril in patients with type 2 diabetes and hypertension (diastolic blood pressure [DBP] 90-104 mm Hg, systolic blood pressure [SBP] < or =190 mm Hg). Following a 3-week, single-blind placebo run-in period, eligible patients were randomized to receive either manidipine 10 mg or enalapril 10 mg once daily for 24 weeks. The dose was doubled after 3 weeks in patients who had not responded to treatment (DBP > or =90 mm Hg). The primary efficacy end point was change in DBP from baseline to the end of the study. Secondary outcomes were the responder rate (DBP <90 mm Hg and/or a DBP reduction of > or =10 mm Hg) at the end of the study. Other secondary measures were changes from baseline to the end of the study in heart rate and in the following measures obtained by ambulatory blood pressure monitoring (ABPM): 24-hour, daytime, and nighttime mean DBP and SBP, and the trough:peak ratio. Blood glucose, glycosylated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine were measured at the end of the placebo run-in period and the end of treatment. The study had 80% power to detect a between-treatment difference in mean sitting DBP of >3 mm Hg.. One hundred twenty-four patients were enrolled in the study. After the placebo run-in period, 13 patients were excluded from the study: 4 for DBP values outside the specified limits, 7 at their request, and 2 for adverse events. Thus, 111 patients met the eligibility criteria and were randomized to treatment (53 manidipine, 58 enalapril). The population consisted of 61 men and 50 women with a mean (SD) age of 62 (11) years and a body mass index of 28.2 (2.4) kg/m2. Among patients who completed the study, drug doses were doubled in 67.6% (25/37) of patients in the manidipine group and 60.0% (24/40) of patients in the enalapril group (P = NS). Similar reductions in blood pressure were observed in both groups, from a mean (SD) of 164 (12)/97.5 (5) mm Hg at baseline to 141 (12)/84.5 (6) mm Hg at the end of the study in the manidipine group (P < 0.01), and from 159 (12)/98 (4) mm Hg to 139 (12)/86 (8) mm Hg in the enalapril group (P < 0.01). The proportion of responders was 66.7% (32/48) in the manidipine group and 60.0% (30/50) in the enalapril group; the difference between groups was not significant. Twenty-four-hour ABPM revealed significant (P < 0.01) and similar reductions in blood pressure in both groups, with a trough:peak ratio of approximately -50%. Neither drug affected heart rate. Among the statistically significant changes in metabolic parameters, significant reductions in HbA(1c) (from 6.7% [1.4%] to 6.2% [1.1%]) and blood glucose concentrations (from 152 [44] to 143 [44] mg/dL) were observed only in the manidipine group (P < 0.05). The incidence of adverse events was similar between groups.. In the present study, manidipine was as metabolically neutral and as effective as enalapril in reducing blood pressure in hypertensive patients with type 2 diabetes, providing a sustained 24-hour antihypertensive effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Nitrobenzenes; Piperazines

To evaluate and correlate the effects of long-term antihypertensive treatment on left ventricular (LV) mass and carotid structural changes in a large group of essential hypertensive patients, participating in the European Lacidipine Study on Atherosclerosis (ELSA).. In four (Brescia, Glasgow, Naples and Pisa) of 23 centres participating in the ELSA study, an echocardiographic examination was performed at baseline and repeated, until the end of the 4-year study, in essential hypertensive patients, followed-up for carotid quantitative ultrasound examination of intima-media thickness (IMT), after random allocation to treatment with either lacidipine or atenolol (and added hydrochlorothiazide, as required for control of blood pressure).. M-mode, two-dimensional guided echocardiography was used to measure left ventricular (LV) wall thickness and dimensions, from which LV mass was calculated, using an anatomically validated formula (Penn Convention) and indexed to body surface area (left ventricular mass index, LVMI). The echocardiographic tracings were blindly evaluated in a single reading centre (Brescia). Bilateral IMT was measured at the site of common carotid and bifurcation far walls (CBMmax).. At baseline, cardiac and carotid ultrasound scans were available in 278 patients (mean age 54 +/- 7 years, 57% males, 22% obese). A significant correlation was observed between baseline LVMI and CBMmax (r = 0.22, P < 0.001), independent of age. In multivariate analysis, CBMmax and mean 24-h pulse pressure were most strongly associated with baseline LVMI. A significant reduction in LVMI was observed both during lacidipine (n = 96) (-12.5% reduction) and atenolol (n = 78) (-13.9% reduction) treatments (up to 4 years) (P < 0.001 for both, without significant differences between treatments). Changes in LVMI were not related to changes in carotid wall thickness. In multivariate analysis, baseline LV mass and mean 24-h systolic blood pressure changes were significantly associated with changes in LV mass.. In this large, long-term controlled study, antihypertensive treatment with atenolol or lacidipine was accompanied by a similar and significant decrease in LV mass. Treatment-induced changes in LV mass were related to baseline LV mass and changes in 24-h mean systolic blood pressure, without any correlation with changes in carotid structure. In the whole ELSA population, carotid IMT changes have been shown to be unrelated to blood pressure reduction, but significantly influenced by the type of antihypertensive treatment.

Topics: Adult; Aged; Atenolol; Dihydropyridines; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Multivariate Analysis; Systole; Ventricular Function, Left

The magnitude of proteinuria is associated with a graded increase in the risk of progression to end-stage renal disease and cardiovascular events. The objective of this study was to relate baseline and early changes in proteinuria and glomerular filtration rate (GFR) to long-term progression of hypertensive nondiabetic kidney disease.. Post hoc analysis of a randomized 3 x 2 factorial trial. A total of 1094 African Americans with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were followed up for a median of 3.8 years. Participants were randomized to a mean arterial pressure goal of 102 to 107 mm Hg (usual) or 92 mm Hg or less (lower) and to initial treatment with a beta-blocker (metoprolol), an angiotensin-converting enzyme inhibitor (ramipril), or a dihydropyridine calcium channel blocker (amlodipine). Baseline proteinuria and GFR predicted the rgate of GFR decline. For each 10-mL/min per 1.73 m(2) lower baseline GFR, an associated mean +/- SE 0.38 +/- 0.08-mL/min per 1.73 m(2) per year greater mean GFR decline occurred, and for each 2-fold higher proteinuria level, a mean +/- SE 0.54 +/- 0.05-mL/min per 1.73 m(2) per year faster GFR decline was observed (P < .001 for both). In multivariate analysis, the effect of baseline proteinuria GFR decline persisted. Initial change in proteinuria from baseline to 6 months predicted subsequent progression, with this relationship extending to participants with baseline urinary protein levels less than 300 mg/d.. The change in the level of proteinuria is a predictor of subsequent progression of hypertensive kidney disease at a given GFR. A prospective trial is needed to confirm this observation.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Prognosis; Proteinuria; Ramipril; Risk Factors; Treatment Outcome; United States

In the European Lacidipine Study on Atherosclerosis (ELSA), against a similar antihypertensive effect, a significantly greater effect of lacidipine was found on carotid intima-media thickness (IMT) progression, indicating a specific anti-atherosclerotic effect of lacidipine. However, not only the extent but also the composition of an atherosclerotic plaque is a determinant of subsequent events.. Among the 2334 patients enrolled in ELSA, 420 with 4-year treatment were chosen, videodensitometric analysis of their ultrasound carotid scan was performed and the maximum wall lesion (Tmax) was classified as lipidic, fibrolipidic and fibrotic by means of software previously validated against histology. Of the 420 patients, 244 had scans suitable for videodensitometry.. Excellent reproducibility of videodensitometry analysis was found using the Bland-Altman and other methods. At baseline, ELSA hypertensive patients had predominantly fibrolipidic walls (70%), with an echoreflectivity indicating a mean collagen content of 25%. After 4 years of antihypertensive treatment, little change in the frequency distribution of carotid lesions (fibrolipidic 73%) was found, with no significant differences between patients randomized to lacidipine or atenolol.. Our study provides previously unavailable information that carotid wall composition changes to an extremely small extent during 4-year effective blood pressure lowering. With lacidipine, stable composition is associated with a lower IMT progression than with atenolol.

Topics: Adult; Aged; Antihypertensive Agents; Atenolol; Carotid Arteries; Carotid Artery Diseases; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Reproducibility of Results; Tunica Intima; Tunica Media; Ultrasonography

To estimate the influence of therapy with amlodipine (A) or lacidipine (L) on heart rate variability (HRV) time and frequency domain parameters in hypertensive patients with stable angina pectoris and isolated left ventricular diastolic dysfunction.. After a 1-week washout period, the patients were randomized to receive amlodipine 10 mg (30 patients) or lacidipine 6 mg (30 patients) once-daily for 4 weeks. HRV parameters were determined over a period of 24 h, echocardiography and exercise test were performed before and after treatment.. All HRV time domain parameters after applying amlodipine did not change significantly. A reliable decrease only of the root mean square of differences between adjacent normal-to-normal intervals (RMSSD)-32.9 +/- 13 vs. 27.5 +/- 9-was noticed after treatment with lacidipine. In the lacidipine group, the change of RMSSD negatively correlated with the extent of ST segment depression during exercise testing (R = -0.43; P < 0.05). Both drugs reduced total power (A, 2234 +/- 1270 vs. 1813 +/- 889; L, 2205 +/- 1151 vs. 1825 +/- 896; P < 0.01), very low (A, 1451 +/- 733 vs. 1143 +/- 534; L, 1413 +/- 759 vs. 1213 +/- 616; P < 0.05), and low frequency power (A, 610 +/- 459 vs. 447 +/- 321; L, 569 +/- 323 vs. 442 +/- 241; P < 0.01). After amlodipine, high frequency power remained unchanged, whereas low-high frequency ratio decreased (4.54 +/- 1.72 vs. 3.77+/-1.73; P < 0.05). After lacidipine, high frequency power decreased (178.8 +/- 153.2 vs. 132.1 +/- 79.3; P < 0.05), whereas the ratio of low frequency to high frequency did not change.. Amlodipine and lacidipine reduce the influence of humoral control and sympathetic autonomic nervous system activity. The autonomic balance becomes shifted toward the increased vagal activity only by amlodipine.

Topics: Adult; Aged; Amlodipine; Angina Pectoris; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

Impaired left ventricular (LV) diastolic and long axis functions are common in arterial hypertension and stable angina pectoris patients despite normal LV ejection fraction. Data concerning the effect of calcium channel blockers (CCB) on the LV long axis function in this context are lacking.. Fifty-nine hypertensive patients with associated coronary artery disease (stable angina pectoris) and isolated diastolic dysfunction were randomized to receive amlodipine (30 patients) or lacidipine (29 patients) for 4 weeks. Clinical investigation, exercise testing, echocardiography were performed before and after the active treatment period. LV diastolic function was analysed from transmitral flow using Doppler echocardiography. Mitral annulus motion was investigated for LV long axis function analysis using 2-D guided M-mode echocardiography (amplitudes of motion) and pulsed wave tissue Doppler (velocities). Amlodipine and lacidipine affected LV diastolic and long axis functions differently: during treatment with amlodipine isovolumic relaxation time (IVRT) and deceleration time of LV early filling (DT) decreased (IVRT--from 93 +/- 19 ms to 79 +/- 15 ms, DT--from 206 +/- 36 ms to 188 +/- 27 ms; p < 0.05), early diastolic velocity of mitral annulus motion (E') increased (from 10.0 +/- 1.9 cm/s to 10.8 +/- 1.8 cm/s after treatment; p < 0.05). Lacidipine did not significantly change these parameters (IVRT-- 88 +/- 15 ms before, 87 +/- 13 ms after treatment, DT--214 +/- 34 ms and 218 +/- 42 ms, E'-- 10.4 +/- 1.5 cm/s and 10.6 +/- 1.5 cm/s, respectively). More favourable effects of CCB on LV long axis function was found in patients with post-systolic shortening.. Amlodipine can improve diastolic and long axis functions of the left ventricle in patients with arterial hypertension and stable angina pectoris.

Topics: Aged; Amlodipine; Angina Pectoris; Calcium Channel Blockers; Coronary Angiography; Coronary Disease; Diastole; Dihydropyridines; Exercise Test; Female; Humans; Hypertension; Male; Middle Aged; Mitral Valve; Ultrasonography, Doppler; Ventricular Function, Left

The aim of this open-labelled, randomised, parallel-group study was to evaluate the effect of long-term monotherapy with manidipine or lisinopril on albumin excretion rate (AER) and left ventricular mass index (LVMI) in hypertensive patients with type-2 diabetes and microalbuminuria.. After a 4-week wash-out period, 174 patients with essential hypertension [diastolic blood pressure (DBP) >80 mmHg and <100 mmHg], type-2 diabetes and microalbuminuria were randomised to manidipine 10 mg o.d. or lisinopril 10 mg o.d.; after 8 weeks, the dose was doubled in non-responders (DBP >80 mmHg); after 3 months, treatment was discontinued in the non-responder patients and in those complaining of side effects; the remaining 121 patients continued their therapy with manidipine or lisinopril, and 99 completed the 2-year study. At the end of the wash-out period, of the titration period and after 6, 12, 18 and 24 months of treatment, BP was measured, AER, creatinine clearance, glycosylated haemoglobin (HbA1c) and body mass index (BMI) were evaluated and an echocardiographic evaluation was performed.. The 99 patients who completed the study were statistically analysed according to a per-protocol evaluation. Manidipine and lisinopril significantly reduced systolic blood pressure (SBP) and DBP levels (at 24 months, --22.3/15.5 mmHg, P<0.001 versus baseline and --21.4/15.7 mmHg, P<0.01 versus baseline, respectively). Both drugs provided a significant decrease in AER, but it was significantly more pronounced with lisinopril (at 24 weeks, --37.2 mg/24 h, P<0.001 versus baseline) than with manidipine (--29.9 mg/24 h, P<0.05 versus baseline) and became evident earlier in the lisinopril group (after 3 months versus 6 months of treatment). Manidipine produced a greater reduction of LVMI than lisinopril (--14.9 g/m(2) versus --10.8 g/m(2) at 24 months). The effect was more pronounced in patients with left ventricular hypertrophy at baseline (--19.8 g/m(2) versus --12.8 g/m(2), P<0.05).. These data suggest that, despite similar BP lowering, non-haemodynamic factors play an important role in the pharmacological reduction of AER and LVMI in diabetic hypertensive patients.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Ventricles; Humans; Hypertension; Lisinopril; Male; Middle Aged; Nitrobenzenes; Piperazines

To study the relationship between blood pressure and oxidative stress in leukocytes, the effect of benidipine on these variables was compared with that of a placebo. Hypertensive patients were randomly assigned benidipine 4 mg (n=40) or placebo (n=40), and treated for 6 months. Oxidative stress in polymorphonuclear cells (PMNs) was measured by gated flow cytometry. There was a significant relationship between systolic or diastolic arterial pressure and reactive oxygen species (ROS) formation by PMNs in the benidipine group (r=0.61, p<0.01) and in the placebo group (r=0.58, p<0.01). After administration of 4 mg benidipine, ROS formation by PMNs fell by 32 arbitrary units (n=40, p<0.01). After administration of placebo, ROS formation by PMNs decreased by 0.6 arbitrary units (n=40, p=0.31) (p<0.01 for differing treatment effects). There was a significant relationship between the decrease in systolic arterial pressure and the decrease in ROS formation by PMNs in the benidipine group (r=0.52, p<0.01), but not in the placebo group (r=-0.08, p=0.61). There was also a significant relationship between the decrease in diastolic arterial pressure and decrease in ROS formation by PMNs in the benidipine group (r=0.65, p<0.01) but not in the placebo group (r=-0.09, p=0.59). In hypertensive patients, we observed a significant relationship between systolic or diastolic blood pressure and ROS formation by PMNs, and found that benidipine decreased oxidative stress in PMNs of hypertensive patients, at least in part by decreasing blood pressure.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Flow Cytometry; Humans; Hypertension; Male; Middle Aged; Neutrophils; Oxidative Stress; Reactive Oxygen Species; Vasodilator Agents

This present study assessed the antihypertensive efficacy of the fixed combination of manidipine and delapril by ambulatory blood pressure monitoring in patients with hypertension inadequately controlled by monotherapy with either component. After a 2-week placebo period, 55 mild to moderate hypertensive patients were randomized to manidipine 20 mg o.d. or delapril 30 mg b.i.d. for 4 weeks. After this period, 30 patients, aged 30-76 years (18 males and 12 females) whose diastolic blood pressure was not adequately controlled (> or = 90 mmHg) by monotherapy were treated with the fixed combination of manidipine 10 mg plus delapril 30 mg o.d. for 8 weeks. A 24-h ambulatory blood pressure monitoring recording was performed at the end of the placebo washout, of the monotherapy and of the combination therapy. Blood pressure control over the 24 h was quantified by the trough-to-peak ratio and the smoothness index. As compared to placebo, the fixed combination of manidipine and delapril produced a statistically significant (p<0.01) decrease in sitting clinic (18 +/- 9/14 +/- 5 mmHg) and 24-h blood pressure (12 +/- 7/10 +/- 5 mmHg) without affecting heart rate. This reduction was greater than that observed with single components. At the end of the 8-week combination treatment period, the rate of normalilized patients was 73%. Treatment with the fixed combination was associated with a positively high smoothness index (1.2 +/- 0.7/13.8 +/- 0.8) and with a relatively good trough-to-peak ratio (0.46/0.60). The combination of manidipine and delapril produced significant and smooth reductions in blood pressure values, which persisted over the 24-h dosing interval. These results support the use of fixed manidipine-delapril combination in the treatment of mild to moderate hypertensive patients inadequately controlled by monotherapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Random Allocation; Time Factors

The benefits of a systolic blood pressure (BP) below 150-160 mmHg are well established; whether a systolic BP of less than 140 mmHg provides additional benefits remains controversial. This study was designed to compare the 2-year effect of a strict treatment to maintain systolic BP below 140 mmHg (group A) and that of a mild treatment to maintain systolic BP at between 140 and below 160 mmHg (group B). The study design followed the Prospective Randomized Open Blinded End-point (PROBE) study. The subjects were elderly patients (65-85 years old) who consistently had a systolic BP of 160 mmHg or higher. The baseline drug was efonidipine hydrochloride (efonidipine), a long-acting dihydropiridine calcium antagonist. The primary endpoints were stroke, cardiac disease, vascular disease, and renal failure. After a run-in period of 2 to 4 weeks, 2,165 patients were assigned to group A and 2,155 patients to group B. There were no significant differences between the groups in sex, age, baseline BP, or other cardiovascular risk factors. The systolic BP was 7.2 mmHg lower (p < 0.0001) and the diastolic BP 2.4 mmHg lower (p < 0.0001) in group A than in group B after 12 months of treatment. As of this interim analysis, primary endpoints have occurred in 87 patients (stroke in 58 patients, cardiac disease in 27 patients, occlusive arterial disease in 1 patient, and renal failure in 1 patient). Five patients have died of stroke and 2 patients of myocardial infarction. The primary-endpoint-related morbidity rate was 20.9/1,000 patient-years, and the mortality rate was 1.7/1,000 patient-years. Currently available results indicate that this study, one of the largest randomized trials of antihypertensive therapy in elderly patients in Japan, was conducted safely. The final results are expected to provide important and practical information for the management of hypertension in elderly patients.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Nitrophenols; Organophosphorus Compounds; Prospective Studies; Treatment Outcome

The objective of the present study was to determine anti-proteinuric effect of an N-type calcium channel blocker-cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (<150/90 mmHg). Calcium channel blockers in 25 patients (62+/-3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58+/-3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61+/-0.10 g/day) and control (0.86+/-0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (- 0.21+/- 0.11 g/day, - 36%, p< 0.01), whereas it did not change in control group (+ 0.01+/- 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (- 54+/-9%, n=18, p<0.01) but not in renal hypertensives (+10+/-35%, n=7, ns). Results suggest that cilnidipine has an anti-proteinuric effect especially in patients with essential hypertension.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Kidney Function Tests; Proteinuria

Hypertension is a major risk factor for atherosclerotic cardiovascular disease. Selectins, cell-surface adhesion molecules involved in leukocyte rolling and attachment to the vascular endothelium, play a role in the initiation of atherosclerosis. We investigated whether or not serum levels of soluble adhesion molecules are elevated in patients with essential hypertension (EH) and examined whether antihypertensive therapy lowers such levels. Twenty-one patients who had untreated mild to moderate EH without diabetes mellitus, hyperlipidemia, or obesity were recruited at a clinic for hypertensive patients. Blood pressure was measured, and the serum levels of soluble E-selectin, P-selectin, L-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular-cell adhesion molecule 1 (VCAM-1) were determined by enzyme-linked immunosorbent assays before and after 12, 24, and 53 weeks of antihypertensive treatment with benidipine, a long-acting calcium channel blocker, given at a dose of 6 mg/day for 53 weeks. As a control, 21 age- and sex-matched patients without hypertension were studied. Serum E- and P-selectin levels were significantly higher in the subjects with EH than in the controls (p < 0.01). There were no differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 levels between the patients with EH and the controls. Treatment with benidipine decreased the elevated blood pressure over a 53-week study period (mean blood pressure: 119.8 +/- 6.5 mmHg at baseline, 101.0 +/- 5.9 mmHg at 12 weeks, 98.6 +/- 7.3 mmHg at 24 weeks, and 93.9 +/- 5.5 mmHg at 53 weeks). Serum levels of soluble E- and P-selectin decreased after the initiation of benidipine treatment and correlated with diastolic blood pressure. Serum levels of soluble L-selectin, VCAM-1, and ICAM-1 did not change significantly during the period of benidipine treatment. Benidipine treatment reduced the content of P-selectin in the platelets from patients with EH, as determined by Western blot analysis. In conclusion, decreased blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both. Benidipine may be protective against vascular damage in people with hypertension, not only by lowering blood pressure, but also by inhibiting the expression of selectins.

Topics: Blotting, Western; Calcium Channel Blockers; Case-Control Studies; Cell Adhesion Molecules; Dihydropyridines; E-Selectin; Female; Humans; Hypertension; Male; Middle Aged; P-Selectin

Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca2+ channels were detected in the vascular endothelium. The purpose of the present study was to clarify the role of T-type Ca2+ channels in endothelial function. We studied flow-mediated vasodilation (FMD) and sublingual nitroglycerin (NTG)-induced vasodilation in the brachial artery. Forty patients with essential hypertension were randomly assigned to treatment with efonidipine, a T- and L-type Ca2+ channel blocker, or with nifedipine, an L-type Ca2+ channel blocker. Twenty healthy normotensive individuals were included as a control group. In patients with essential hypertension, FMD was attenuated and NTG was similar that of compared to healthy controls. After 12 weeks, the decrease in mean blood pressure in the efonidipine and nifedipine groups were similar. The endothelial function index, a ratio of FMD/NTG, was significantly increased by efonidipine (73 +/- 24 to 94 +/- 20%) but unchanged by nifedipine. Urinary excretion 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (LDL) were decreased by efonidipine but unchanged by nifedipine. These results suggest that a T-type Ca2+ channel blocker, but not an L-type Ca2+ channel blocker, may improve vascular endothelial dysfunction in patients with essential hypertension via a reduction in oxidative stress.

Topics: Adult; Aged; Blood Flow Velocity; Brachial Artery; Calcium Channel Blockers; Case-Control Studies; Dihydropyridines; Endothelial Cells; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Nitrophenols; Organophosphorus Compounds; Vasodilation

Pulse wave velocity (PWV) reflects arterial stiffness and is an independent predictor of cardiovascular mortality and morbidity. However, because it is closely related to blood pressure (BP), PWV is an imperfect measure for evaluating the effects of anti-hypertensive drugs on arterial wall properties. To clarify the effect of benidipine on arterial properties, we first derived the regression line between BP and PWV changes in a short-term experiment. Using this line, we evaluated the long-term effect of benidipine on PWV changes. In the short-term experiment, 29 participants were intravenously administered nicardipine for 90 min. Maximum decreases of brachial-ankle PWV (baPWV) were plotted against the corresponding decreases in BP. In the long-term experiment, 9 hypertensive patients were treated with benidipine for 1 year, during which BP and baPWV were monitored. After 1 year, benidipine was suspended for 2 weeks, and BP and baPWV were reevaluated. In the short-term experiment, PWV was dependent on BP only, and the equation of the regression line was deltaPWV (cm/s) =10.114 x deltaMBP (mmHg) (r=0.913) or deltaPWV (%) =0.719 x deltaMBP (%) (r=0.926). In the long-term therapy, benidipine treatment achieved stable BP control within 3 months; the real PWV decreases (r-PWV) were almost identical to the PWV decrease estimated (e-PWV) from BP lowering at 3 months. However, r-PWV exceeded e-PWV after 6 months. Relative BP and PWV improvements compared to the control were maintained 2 weeks after suspension of benidipine. In conclusion, long-term benidipine administration improves arterial wall properties beyond what can be accounted for by changes in BP.

Topics: Adult; Antihypertensive Agents; Arteries; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Dihydropyridines; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nicardipine; Pulse; Regression Analysis

Cilnidipine is a novel and unique 1,4-dydropyridine derivative calcium antagonist that exerts potent inhibitory actions not only on L-type but also on N-type voltage-dependent calcium channels. Blockade of the neural N-type calcium channel inhibits the secretion of norepinephrine from peripheral neural terminals and depresses sympathetic nervous system activity. The purpose of this study was to assess the effect of cilnidipine and amlodipine on ambulatory blood pressure (BP) levels. We performed 24-h ambulatory BP monitoring before and after once-daily use of cilnidipine (n=55) and amlodipine (n=55) in 110 hypertensive patients. Both drugs significantly reduced clinic and 24-h systolic BP (SBP) and diastolic BP (DBP) (p < 0.005). However, the reductions of 24-h (-1.19+/-6.78 vs. 1.55+/-6.13 bpm, p=0.03), daytime (-1.58+/-6.72 vs. 1.68+/-7.34 bpm, p=0.02) and nighttime (-1.19+/-5.72 vs. 1.89+/-6.56 bpm, p=0.01) pulse rate (PR) were significantly greater in the cilnidipine group than the amlodipine group. There was no correlation between the degree of daytime SBP change and that of daytime PR change after amlodipine treatment (r=-0.08, n.s.), but there was a significant negative correlation between the degree of daytime SBP change and that of day-time PR change after cilnidipine treatment (r=-0.27, p<0.05). N-type calcium channel blockade by cilnidipine may not cause reflex tachycardia, and may be useful for hypertensive treatment.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.

Topics: Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Cross-Over Studies; Dihydropyridines; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Sympathetic Nervous System

The aim of this double-blind, double-dummy, parallel group study was to compare the effects of delapril-manidipine combination vs a irbesartan-hydrochlorothiazide combination on plasma tissue plasminogen activator (t-PA) and plasmogen activator inhibitor type I (PAI-l) activities in hypertensive patients with type II diabetes mellitus. After a 4-week run-in placebo period, 80 patients (37 male and 43 female), aged 41-65 years, were randomly allocated to an 8-week treatment with delapril 30 mg once daily or irbesartan 150 mg once daily. Thereafter, manidipine l0 mg once daily was added to delapril treatment and hydrochlorothiazide 12.5 mg to irbesartan treatment for a further 8 weeks. Blood pressure (BP), plasma t-PA and PAI-l activities were evaluated at the end of the run-in period, after 4-week monotherapy treatments, and at the end of the combination treatment periods. Both combination treatments, delapril-manidipine and irbesartan-hydrochlorothiazide, produced a greater reduction in systolic BP/diastolic BP (SBP/DBP) values (-27.6/21.8 mmHg and -26.4/20.2 mmHg, respectively) than the respective monotherapies (-15.2/11.7 mmHg with delapril and -16.3/11.3 mmHg with irbesartan). Delapril monotherapy significantly decreased plasma PAI-l activity (-10.4 IU/mI; P<0.05). The addition of manidipine produced a significant increase in t-PA activity (+0.27 IU/mI); P<0.05). Irbesartan monotherapy did not significantly affect the fibrinolytic balance, whereas the addition of hydrochlorothiazide worsened it, producing a significant increase in PAI-l activity (+9.5 IU/ml; P<0.05). In hypertensive patients with type II diabetes mellitus, the combination delapril-manidipine may determine a greater improvement of the fibrinolytic function than the respective monotherapy, while the association irbesartan-hydrochlorothiazide may worsen it.

Topics: Adult; Aged; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Fibrinolysis; Humans; Hydrochlorothiazide; Hypertension; Indans; Irbesartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Plasminogen Activator Inhibitor 1; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome

To study the changes in macrophage inducible nitric oxide synthase (iNOS) activity, plasma levels of nitrite, lipid peroxidation (LPO) and melatonin in human essential hypertension before and 6 months after 4 mg/day lacidipine treatment.. The study was carried out in a total of 25 subjects--11 healthy subjects and 14 hypertensive patients. Blood pressure and peripheral blood samples were taken before and after 6 months of lacidipine treatment (4 mg/day).. Systolic (SBP) and diastolic blood pressure (DBP), renal function, lipid and carbohydrate metabolism, renin, aldosterone and catecholamine levels were measured by routine methods. The activity of macrophage iNOS and plasma nitrite, LPO and melatonin levels were also measured.. Besides reducing blood pressure, lacidipine treatment significantly decreased plasma LPO and macrophage iNOS activity, without changes in NO. Melatonin significantly increases in hypertensive patients, returning to control after lacidipine. Thus, lacidipine reduced blood pressure and free radicals, avoiding the oxidative damage to endothelium. It is suggested that administration of lacidipine plus melatonin may enhance the beneficial effects of each drug in essential hypertension.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Female; Humans; Hypertension; Lipid Peroxidation; Male; Malondialdehyde; Melatonin; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress

To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years.. The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up.. Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively.. Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Incidence; Linear Models; Male; Myocardial Infarction; Nitrendipine; Stroke; Survival Rate; Time Factors; Treatment Outcome

In ELSA, a randomized, double-blind trial in 2334 hypertensives, 4-year antihypertensive treatment with lacidipine slowed down progression of carotid atherosclerosis significantly more than atenolol treatment. To avoid bias, the primary outcome was measured blindly at study-end on a randomized sequence of scans, but measurements were limited to the four far walls of common carotids and bifurcations (CBMmax) and to one of each couple of duplicate scans recorded yearly.. Secondary outcomes included measurements made on all duplicate scans of both near and far walls, not only of common carotids and bifurcations, but also of internal carotids (12 walls). These measurements were made blindly during the 4-year study, shortly after recording. To avoid possible readers' drift or bias, 250 duplicate baseline scans were re-read at yearly intervals (longitudinal on-line quality control) and a correction factor calculated.. Measurements during the 4-year study showed a trend toward decreased values, with the lacidipine effect significantly greater than the atenolol one. A trend toward lower values was also observed in the longitudinal quality control of baseline scans. After applying a correction factor calculated from this longitudinal control, all measurements no longer decreased with time, but significantly increased, with progression being significantly smaller in lacidipine than in atenolol patients. Corrected values were quite similar to those calculated on measurements carried out at study-end.. The relative benefit of lacidipine over atenolol could be measured precisely by reading scans either during the study or at study-end. However, absolute treatment-related changes (progression versus regression) cannot safely be judged by readings made during a long-term study, unless a longitudinal quality control of readings is performed.

Topics: Aged; Antihypertensive Agents; Atenolol; Carotid Artery Diseases; Carotid Artery, Common; Carotid Artery, Internal; Dihydropyridines; Disease Progression; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Time Factors; Tunica Intima; Tunica Media; Ultrasonography

Since antihypertensive effects of most calcium channel blockers largely depend on their plasma concentrations, a rapid increase in blood pressure may occur as circulating levels of such blockers decrease after hemodialysis. Thus, the effects of benidipine and nifedipine CR (extended-release coated tablets, Adalat CR), which are long-acting calcium channel blockers, on post-hemodialytic blood pressures were investigated.. A randomized crossover trial was carried out with 10 hypertensive patients on chronic maintenance hemodialysis. Patients were assigned to receive benidipine (4-8 mg/day) or nifedipine CR (20-40 mg/day), and after 4 weeks, 24-hour ambulatory blood pressure monitoring was performed on the day of hemodialysis and blood samples were obtained before and after hemodialysis to measure plasma concentrations of the blockers. The calcium channel blockers were then exchanged in each patient and the same protocol was repeated.. The pattern of fluctuation of blood pressure differed markedly between the treatment with benidipine and nifedipine CR. Under treatment with nifedipine CR, rapid increase in blood pressure was observed after hemodialysis, while blood pressure remained at favorable levels with benidipine. Plasma concentrations of the blockers were significantly decreased by hemodialysis.. Benidipine exerts more sustained antihypertensive effects than expected from its disposition in plasma. The stable depressor effects of benidipine even after hemodialysis may contribute to favorable control of blood pressure in this population.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Delayed-Action Preparations; Dihydropyridines; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Nifedipine; Renal Dialysis

Calcium channel blockers (CCB) are known to be more efficacious and better tolerated in elderly patients. Lercanidipine is a highly lipophilic CCB with a specific safety profile linked to its pharmacokinetics.. To evaluate and compare the efficacy and safety of lercanidipine according to age.. Two groups of hypertensive patients (G1: aged < 65, G2: aged > or = 65) entered an open study conducted over 56 days. All received lercanidipine 10 mg/d (monotherapy or add-on), titrated to 20 mg/d if blood pressure (BP) was not controlled at D28. BP was measured using a semi-automatic device at doctor's office (three measurements at 1-min intervals) and at home by the patient himself (three measurements in the morning and in the evening at 1-min intervals over the 7 days before D0 and D56).. Seven hundred and fifty-six patients entered the study. Thirty-eight patients dropped out prematurely and 30 were excluded because they were normotensive; 691 patients (G1 n = 375, G2 n = 316) were kept for analysis. At the end of the study, 507 patients were treated with lercanidipine alone (10 mg/d n = 221, 20 mg/d n = 286) and 184 with a combination including lercanidipine (10 mg/d n = 91, 20 mg/d n = 93). Efficacy was not different between the groups excepted home pulse pressure which decreased more in G2. In the office, SBP decreased by 17 and 21 mmHg, respectively, for G1 and G2, and DBP by 9 and 10 mmHg. The prevalence of leg edema was not different between G1 and G2 and was particularly low in both groups (3%).. Lercanidipine was as efficacious and well tolerated in younger patients as in elderly patients.

Topics: Age Factors; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Edema; Female; Humans; Hypertension; Leg; Male; Middle Aged; Treatment Outcome

To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin.. Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment.. In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment.. We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.

Topics: Aged; Amlodipine; Analysis of Variance; Body Mass Index; Calcium Channel Blockers; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Delayed-Action Preparations; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome

This study investigated the significance of measuring plasma level of thiobarbituric acid reactive substance (TBARS) in patients with hypertension and compared the clinical effects of benidipine hydrochloride (CAS 91599-74-5, Coniel) and amlodipine besylate (CAS 111470-99-6) on plasma TBARS. At first, blood pressure and plasma TBARS were measured in 85 untreated patients (48 males and 37 females, 68 years old on average) with at least one risk factor of cardiovascular disease to investigate factors which had influence on plasma TBARS. As the result, plasma TBARS was significantly higher in those with hypertension, which was also true when adjusted for other factors (r = 0.359, p< 0.01). Among these patients, benidipine hydrochloride at the dose of 4 mg/day was administered to 49 patients with hypertension or angina pectoris. All patients stratified for each factor showed significantly decreased plasma TBARS after benidipine hydrochloride treatment. Second, 40 untreated patients with essential hypertension were randomly assigned to the amlodipine group (5-7.5 mg/day) or benidipine group (4-8 mg/day) to compare the plasma TBARS levels. Plasma TBARS levels were significantly decreased in both groups. The amlodipine group showed a positive correlation between the decrease in plasma TBARS level and those in both diastolic and systolic blood pressures after treatment. On the other hand, benidipine hydrochloride decreased plasma TBARS to a greater degree than both diastolic and systolic blood pressures. These findings suggest that patients with hypertension have high plasma TBARS, and benidipine hydrochloride decreases not only blood pressure but also oxidative stress in the clinical practice.

Topics: Aged; Antioxidants; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Male; Myocardial Ischemia; Oxidative Stress; Risk Factors; Thiobarbituric Acid Reactive Substances

Although calcium antagonists, derived from dihydropyridine (DHP), are important agents in achieving control in a majority of patients with high blood pressure and renal disease, there are no comparative data regarding their inhibitory effects on the progression of renal dysfunction in Japan.. Benidipine and nifedipine retard both calcium antagonists derived from DHP and were compared in terms of their inhibitory effect on the progression of renal dysfunction in hypertensive patients. The primary end-points were defined as 1.5 times the serum creatinine value at baseline, progression to end-stage renal failure (ESRF) necessitating dialysis or renal transplantation, and death.. During the study period, a significant decline in blood pressure was observed in the two groups, with no significant difference between them. The worsening of nephropathy was significantly inhibited in the benidipine group as compared with the nifedipine retard group (log-rank test: P = 0.014, Wilcoxon's test: P = 0.022). Among the subjects who reached a primary end-point, one (33%) in the benidipine group and five (50%) in the nifedipine retard group were placed on haemodialysis within 1 year.. It appears that benidipine inhibits the progression of hypertensive renal diseases more effectively than nifedipine retard.

Topics: Calcium Channel Blockers; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Nifedipine; Prospective Studies

The use of combination therapy is required to achieve blood pressure targets in 40% to 75% of patients with hypertension. There have been few studies comparing the efficacy and tolerability of the new fixed combination of the angiotensin-converting enzyme (ACE) inhibitor delapril 30 mg and the calcium channel antagonist manidipine 10 mg with those of a standard combination of another ACE inhibitor and a diuretic.. The aim of this study was to compare the antihypertensive efficacy and tolerability of delapril 30 mg given alone or with manidipine 10 mg with those of enalapril 20 mg given alone or with hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild to moderate essential hypertension.. This was a multicenter, active-controlled, parallel-group trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with diastolic blood pressure (DBP) > or =90 and < or =109 mm Hg were randomized in a 2:1 ratio to receive delapril or enalapril for 8 weeks. After the initial 8 weeks, nonresponders (DBP > or =85 mm Hg) received an additional 8 weeks of treatment with a fixed combination of delapril + manidipine or enalapril + HCTZ; patients whose DBP was normalized continued their initial monotherapy through the end of the study. The primary efficacy variable was the change in sitting DBP at the end of treatment. Secondary efficacy variables were the percentage of patients whose DBP was normalized (DBP Z:85 mm Hg) and the percentage of responders (> or =10-mm Hg reduction in DBP or DBP <85 mm Hg).. One hundred sixty patients (84 men, 76 women) were randomized to receive delapril (n = 106) or enalapril (n = 54). After 16 weeks of treatment, the mean (SD) reduction in DBP was similar with the 2 treatments (delapril, -14 [8] mm Hg; enalapril, -15 [8] mm Hg). In the delapril and enalapril groups, DBP was normalized in a respective 55 (51.9%) and 29 (53.7%) patients, and 77 (72.6%) and 38 (70.4%) were responders; there was no significant difference between groups. Tolerability was also similar in both groups--10 (9.4%) patients in the delapril group and 5 (9.3%) in the enalapril group experienced adverse events that were judged related to treatment.. The results of this study suggest that delapril alone or combined with manidipine is well tolerated and as effective as enalapril alone or combined with HCTZ in lowering blood pressure in patients with mild to moderate essential hypertension.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Single-Blind Method; Time Factors; Treatment Outcome

Microalbuminuria and hypertension are risk factors for diabetic nephropathy in Type 2 diabetic patients. Recent data suggest that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy; in contrast, the results on the renoprotective effect of calcium channel antagonists are conflicting. We evaluated the effectiveness of lercanidipine, in comparison with ramipril, on the reduction in albumin excretion rate (AER) and blood pressure in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A total of 277 patients were enrolled in a multicentric, randomized, double-blind, active-controlled, parallel-group trial; 180 were randomized to receive 10-20 mg/day of lercanidipine or 5-10 mg/day of ramipril and followed up for 9-12 months. The primary outcome was the change in AER from baseline. After 9-12 months of follow-up, a reduction in AER of -17.4+/-65 microg/min (p<0.05) and -19.7+/-52.5 (p<0.05) in the lercanidipine and ramipril group, respectively, was observed, without differences between the groups. A significant reduction in systolic and diastolic blood pressure was observed in both the lercanidipine and ramipril-based treatment groups (p<0.0001 for both). This study demonstrated that treatment with lercanidipine 10-20 mg/day does not worsen albuminuria in microalbuminuric Type 2 diabetic patients with hypertension. Indeed, both lercanidipine and ramipril treatments resulted in a significant reduction in AER without a statistically significant difference between the two groups.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Treatment Outcome

Although several lines of recent studies fail to demonstrate the beneficial action of calcium antagonists, a novel dihydropyridine efonidipine, which possesses dilatory action of both afferent and efferent arterioles and, therefore, shares the renal microvascular action with angiotensin converting enzyme (ACE) inhibitors, is reported to exhibit renal protection in experimental animals. The present study evaluated the effect of efonidipine and ACE inhibitors on blood pressure (BP) and proteinuria. Sixty-eight hypertensive patients with renal impairment (serum creatinine, >1.5 mg/dL) or chronic renal parenchymal disease were randomly assigned to efonidipine or ACE inhibitor treatment. Of the 68 patients, 23 were treated with efonidipine and 20 with ACE inhibitors; these patients were analyzed for the 48-week study. Both efonidipine and ACE inhibitors produced a similar degree of reductions in BP (efonidipine, from 161 +/- 2/93 +/- 2 to 142 +/- 5/82 +/- 2 mm Hg; ACE inhibitor, from 163 +/- 3/95 +/- 2 to 141 +/- 5/83 +/- 2 mm Hg), and maintained creatinine clearance for 48 weeks. Proteinuria tended to decrease in both groups, and a significant reduction was observed in proteinuric patients (>1 g/day) (efonidipine, from 2.7 +/- 0.3 to 2.1 +/- 0.3 g/day; ACE inhibitor, from 3.0 +/- 0.4 to 2.0 +/- 0.5 g/day). Of interest, efonidipine decreased proteinuria in proteinuric patients who failed to manifest decreases in systemic BP. Finally, the incidence of adverse effects, including hyperkalemia and cough, was less in the efonidipine-treated group. Both efonidipine and ACE inhibitors preserved renal function in hypertensive patients with renal impairment. The antiproteinuric effect was apparent in patients with greater proteinuria. The beneficial action of efonidipine, along with fewer side effects, may favor the use of this agent in the treatment of hypertension with renal impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds; Proteinuria

Antihypertensive treatment with dihydropyridines may be accompanied by sympathetic activation. Data on whether this is common to all compounds and similar in the various phases of treatment are not univocal, however. In 28 untreated essential hypertensives (age, 56.4+/-1.8 years; mean+/-SEM) finger blood pressure (BP, Finapres), heart rate (HR, ECG), plasma norepinephrine (NE, high-performance liquid chromatography), and muscle sympathetic nerve traffic (MSNA, microneurography) were measured at rest and during baroreceptor manipulation (vasoactive drugs) in the placebo run-in period and after randomization to double-blind acute and chronic (8 weeks) felodipine (10 mg/d, n=14) or lercanidipine (10 mg/d, n=14). Acute administration of both drugs induced pronounced BP reductions and marked increases in HR, NE, and MSNA. After 8 weeks of treatment, BP reductions were similar to those observed after acute administration, whereas HR, NE, and MSNA responses were markedly attenuated (-7%, -32%, and -14%, respectively; P<0.05). There was a small residual increase in sympathetic activity in the felodipine group, whereas in the lercanidipine group, all adrenergic markers returned to baseline values. Baroreflex control of HR and MSNA was markedly impaired (-42% and -48%, respectively) after acute drug administration, with a recovery and complete resetting during chronic treatment. Thus, the sympathoexcitation induced by 2 different dihydropyridines is largely limited to the acute administration. The 2 drugs have, nevertheless, a different chronic sympathetic effect, indicating that dihydropyridines do not homogeneously affect this function. The acute sympathoexcitation, but not the small between-drugs differential chronic adrenergic effect, is accounted for by baroreflex impairment.

Topics: Antihypertensive Agents; Baroreflex; Blood Pressure; Dihydropyridines; Double-Blind Method; Felodipine; Heart Rate; Humans; Hypertension; Male; Middle Aged; Muscle, Skeletal; Norepinephrine; Sympathetic Nervous System; Time Factors

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of NG-monomethyl-l-arginine (L-NMMA, 100 microg/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 microg/100 mL per minute), an Na+-K+ ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity.

Topics: Antioxidants; Ascorbic Acid; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Female; Forearm; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Regional Blood Flow; Vasodilation

We objected: 1) To compare the effects of azelnidipine and amlodipine on 24-h blood pressure; 2) To monitor the plasma concentration vs. the time profile in order to assess the association between pharmacokinetics and hypotensive activity after administration of either drug for 6 weeks. Blood pressure and pulse rate were measured by 24-h monitoring with a portable automatic monitor in a randomized double-blind study of 46 patients with essential hypertension. Azelnidipine 16 mg (23 patients) or amlodipine 5 mg (23 patients) was administered once daily for 6 weeks. Pharmacokinetics were analyzed after the last dose was taken. Both drugs showed similar effects on the office blood pressure and pulse rate. During 24-h monitoring, both drugs caused a decrease in systolic blood pressure of 13 mmHg and had a similar hypotensive profile during the daytime period (07:00-21:30). The pulse rate decreased by 2 beats/min in the azelnidipine group, whereas it significantly increased by 4 beats/min in the amlodipine group. Similar trends in the blood pressure and pulse rate were observed during the nighttime (22:00-6:30) and over 24 h. Excessive blood pressure reduction during the nighttime was not seen in either group. The pharmacokinetic results indicated that the plasma half-life (t1/2) of amlodipine was 38.5 +/- 19.8 h and that of azelnidipine was 8.68 +/- 1.33 h. Despite this difference in pharmacokinetics, the hypotensive effects of amlodipine and azelnidipine were similar throughout the 24-h administration period.

Topics: Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Physicians' Offices

Of the study was to compare the leg oedema-forming potential of two different dihydropyridine calcium channel blockers in postmenopausal women.. A total of 92 postmenopausal hypertensive patients [systolic blood pressure (SBP) 150-179 mmHg or diastolic blood pressure (DBP) 95-109 mmHg were randomized to receive a 4-week treatment with either 10 mg/day lercanidipine (n = 48) or 5 mg/day amlodipine (n = 44), with force-titration to 20 and 10 mg/day, respectively for an additional 4 weeks.. Leg volume was measured by water displacement volumetry, patients were questioned for symptoms and a physical examination was performed to detect the presence of oedema.. A total of 77 patients completed the study, without a major protocol violation and were included in the primary analysis. Leg volume increase from baseline was significantly higher in the amlodipine than in the lercanidipine group (60.4 +/- 8.6 versus 5.3 +/- 8.1 ml; P < 0.001). The percentage of patients with evidence of oedema on physical examination (33.3 versus 9.8%, P = 0.011) and with symptoms of leg swelling (63.9 versus 22%, P < 0.001) and leg heaviness (47.2 versus 12.2%, P < 0.001) was also greater with amlodipine compared with lercanidipine. A positive correlation was found between leg volume and sign or symptoms of oedema (P < 0.001). Both drugs reduced SBP and DBP, with no significant differences between treatments. No correlation was found between leg volume changes from baseline and the antihypertensive effect of either drug.. In postmenopausal females with mild to moderate hypertension the oedema formation of Lercanidipine was significantly less than that of Amlodipine, despite no significant differences in the antihypertensive effect.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Volume; Calcium Channel Blockers; Diastole; Dihydropyridines; Drug Evaluation; Edema; Female; Heart Rate; Humans; Hypertension; Leg; Middle Aged; Norway; Postmenopause; Statistics as Topic; Systole; Time Factors; Treatment Outcome; Women's Health

Topics: Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drugs, Investigational; Hypertension; Rats; Rats, Inbred SHR

The objective of this 8-week open-label study was to compare the tolerability of lercanidipine, a dihydropyridine calcium-channel antagonist (CA), with that of other CAs in the treatment of hypertension. Subjects already taking amlodipine, felodipine, nifedipine gastrointestinal therapeutic system (GITS), or nitrendipine and experiencing CA-specific adverse effects (AEs) were switched to lercanidipine for 4 weeks and then rechallenged with their initial treatment for 4 weeks. Results showed that at comparable levels of BP, lercanidipine was associated with a significantly lower incidence of ankle edema, flushing, rash, headache and dizziness compared with other CAs (p < 0.001). After 4 weeks of lercanidipine, mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) was 142.1/86.7 mmHg. After rechallenge with other CAs for 4 weeks, mean SBP/DBP was 141.1/86.7 mmHg. In this open-label study, lercanidipine compared with other CA seems to provide a significant improvement in tolerability with comparable antihypertensive effect.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Edema; Endpoint Determination; Female; Flushing; Headache; Heart Rate; Humans; Hypertension; Male; Middle Aged; Patient Dropouts

To determine the efficacy and tolerability of a long-acting dihydropyridine in the clinical settings of general practice.. 110 essential hypertensives were included (age 62.3 +/- 10.8 years, 51 men and 53 women, 38/ obese -IMC >30 kg/m2, ten diabetics). 104 patients ended the followup. Patients were treated with lercanidipine 10 mg once daily in the morning. Follow-up lasted 6 months. When blood pressure was not controlled (BP < 140/90 mmHg) in any visit, a second drug was added, excluding calcium channel blockers. Antiadrenergic drugs were recommended. If patients were not controlled ittwo consecutive visits they were excluded from follow-up.. Significant reductions in both systolic (baseline 157.4 +/- 11.7 vs 131.1 +/- 6.8 mmHg, p < 0,001) and diastolic BP (baseline 94.7 +/- 5.8 vs 80.0 +/- 5.5 mmHg, p < 0,001) were attained at six months. Mean SBP decrease was 26.7 mmHg and mean DBP reduction was 15.6 mmHg. At the study end, 84.3/ of the patients achieved a BP < 140/90 mmHg. Thirty patients needed a second drug to become controlled (26 at the study end). The overall incidence of adverse effects was 4,4/ (n=6) and just three patients withdrew the treatment due to untoward effects. Plasmatic cholesterol lowered from 225.3 +/- 41.0 to 216.7 +/- 25.3 mg/dl (p = 0,03) and urate decreased from 5.6 +/- 1.6 to 5.1 +/- 1.4 mgldl, p = 0,03).. Lercanidipine is a calcium channel blockers of high efficacy and low incidence of adverse effects in the clinical settings of general practice. It seems to have a positive metabolic effects on plasmatic levels of cholesterol and urate.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Cholesterol; Diabetes Complications; Dihydropyridines; Family Practice; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Obesity; Treatment Outcome; Uric Acid

To value the grade of anxiety and psychosomatic semiology in hypertensive patients treated with lercanidipine and to analyse their evolution. A secondary objective is to carry out a pharmacovigilance study with lercanidipine.. Prospective multicentre observational 6 month study in primary hypertensive patients with SBP between 140-180 mm Hg and/or 90-110 mm Hg DBP. After a washout period of 10 days, treatment with 10 mg (1-0-0) lercanidipine is initiated. If BP is not controlled treatment with ramipril 2.5 mg/day is instaured. Clinical check-ups are carried periodically with measurements of BP, Heart Rate, objective valuation of tolerance to the drug and observance. At the initiation and end of the study biochemical check-ups are carried out, the level of anxiety is measured using the STAI questionnaire (Trait subscale) (Evaluation in decatipes 0-4 without ansiety 4-7 moderate ansiety, 7-10 high ansiety) and the psychosomatic profile with a questionnaire designed by this group. (Scale 0-18; 0 large semiology, 18 without semiology). Clinical tolerance to the drug is valued both subjectively and objectively.. On included 538 patients. On registred 54 drop out, with side effects (3.75/). Completed the study 484 (237 M, 247 F), 429 of them with Lercanidipine in monotherapy (88.6/). Mean age 60.9 +/- 10.7. Mean BMI 29.1 +/- 5. The grade of anxiety did not alter during the study passing from 4.6 +/- 1.7 at the beginning of the study to 4.5 +/- 1.7 at the end of the study (valuation in decatypes) (ns). The psychosomatic semiology changed favourably from 10.7 +/-4.2 to 12.5 +/- 3.7 (p<0.00005). The evolution according to sex is similar. The mean SBP decreased from 165.6 +/- 12.2 mm Hg to 137.9 +/- 10.4 mm Hg (p<0.00005) and the mean DBP decreased from 96.5 +/- 8.1 mm Hg to 81.0 +/- 6.1 mm Hg (p<0.00005). Clinical tolerance was very good. Biochemical parameters were modified substantially: initial cholesterolemia 227.7 mg/dl and final cholesterolemia 213.6 mg/dl (p<0.00005); initial glucose 108.4 mg/dl and final glucose 105.7 mg/dl (p<0.00005).. The mean level of anxiety in the group studied is confirmed not to vary during the length of the study. Psychosomatic semiology is reduced being statistically significant. Lercanidipine is shown to be very effective as antihypertensive and well tolerated. 164

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Anxiety; Blood Glucose; Calcium Channel Blockers; Calcium Channels, L-Type; Cholesterol; Diabetes Complications; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Prospective Studies; Psychophysiologic Disorders; Treatment Outcome

This study aimed to compare the effects of two long-acting dihydropyridine calcium channel blockers (CCBs) with different pharmacologic properties, lercanidipine and nifedipine Gastro-Intestinal Therapeutic System (GITS), in the chronic treatment of essential hypertension. After a 4-week placebo run-in period, 60 patients of both sexes were randomly treated with lercanidipine 10 to 20 mg or nifedipine GITS 30 to 60 mg taken orally for 48 weeks, according to a double-blind, parallel group design. For the first 4 weeks of treatment, the lowest dose of each drug was used, followed by higher doses if diastolic blood pressure (BP) was >90 mm Hg. At the end of the placebo period and after 4, 8, 12, 24, and 48 weeks of active treatment BP, heart rate (HR), and plasma norepinephrine (NE) levels were assessed. Lercanidipine and nifedipine GITS similarly reduced BP values after 48 weeks (-21.7/15.9 mm Hg and -20.7/14.6 mm Hg, respectively, both P <.001 v placebo), with no change in HR. Despite the similar lack of effect on HR, the two drugs displayed different influences on plasma NE, which was significantly increased by nifedipine GITS (+56 pg/mL, P <.05 v placebo) but not by lercanidipine. These findings suggest that 1) sympathetic activation occurs during chronic therapy with nifedipine GITS but not with lercanidipine, which might be related to the different pharmacologic characteristics of the two CCBs at the doses evaluated; and 2) nifedipine GITS seems to activate peripheral but not cardiac sympathetic nerves, consistent with differing regulation of cardiac and peripheral sympathetic activity.

Topics: Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nifedipine; Norepinephrine

The effects of benidipine hydrochloride (CAS 91559-74-5, Coniel) on autonomic nervous activity in hypertensive patients with high- and low-salt diets were investigated. Six patients having a urinary sodium excretion of 80 mEq/day or less (low salt group) and 6 patients having a urinary sodium excretion of 200 mEq/day or more (high salt group) were orally given benidipine hydrochloride (4 mg). Before and four weeks after the treatment with benidipine, 24-h circadian variation in blood pressure and 24-h Holter electrocardiogram (ECG) were recorded. The low frequency power spectrum of heart rate (LF power; 0.04-0.15 Hz), high frequency power spectrum of heart rate (HF power; 0.15-0.40 Hz), and the ratio of LF to HF (LF/HF) were calculated, and these parameters were averaged every hour in every subject. HF power was significantly lower and LF/HF ratio was significantly higher in the high-salt group than in the low-salt group before the treatment. However, the benidipine treatment significantly increased the HF power in both groups, particularly in the high-salt group, and significantly decreased the LF/HF ratio in both groups. Moreover, there was no significant difference in the antihypertensive effect of benidipine between the high- and low-salt intake groups. These results suggest that benidipine favourably influences blood pressure and autonomic nervous activity in hypertensive patients with a high-salt intake. It is concluded that benidipine may be useful for improving the development of salt-induced hypertension and its accompanying haemodynamic responses.

Topics: Aged; Autonomic Nervous System; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Diet, Sodium-Restricted; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Sodium, Dietary

Our aim was to compare the effect of lacidipine and chlorthalidone on cardiovascular outcome as a primary parameter and blood pressure as a secondary in elderly patients with isolated systolic hypertension in a prospective study with an open design.. 1882 males and females outpatients > or = 60 years were randomly assigned to the administration of chlorthalidone 12.5 mg o.d. or lacidipine 4 mg o.d. Patients were recruited if sitting systolic blood pressure was > or = 160 mmHg with a diastolic blood pressure equal or lower than 95 mmHg. Primary endpoint was a composite of cardiovascular and cerebrovascular events.. At randomization mean systolic blood pressure was 178.1 mmHg in the lacidipine and 178.2 mmHg in the chlorthalidone group, the corresponding mean diastolic values being 86.9 and 86.8 mmHg. In both lacidipine and chlorthalidone groups treatment caused a significant (p < 0.001) and marked systolic blood pressure reduction which was maintained throughout the treatment period with a significant (p < 0.001) and steady although less marked reduction in diastolic blood pressure as well. At the end of treatment period (median 32 months), the reduction was 36.8/8.1 mmHg (systolic/diastolic) in the chlorthalidone and 38.4/7.9 mmHg in the lacidipine group, the final on treatment blood pressures being 142.0/79.2 and 143.2/79.5 mmHg, respectively. Treatments were similarly effective in males and females and in age groups between 60 and 69 years (n = 763), 70 and 79 years (n = 744) and > or = 80 years (n = 375). Similar reductions were obtained in a subgroup of patients (n = 209) followed in double-blind fashion for 1 year. The overall incidence of the primary endpoints was 9.3% with no significant between-group difference. Total mortality was also similar between groups.. In elderly patients with isolated systolic hypertension, administration of lacidipine or chlorthalidone markedly reduced systolic blood pressure with no difference in the incidence of cardiovascular events and total mortality.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Chlorthalidone; Dihydropyridines; Female; Humans; Hypertension; Italy; Male; Prospective Studies; Systole; Time Factors; Treatment Outcome

To clarify the effect of cilnidipine, a long-acting dihydropyridine Ca-antagonist that blocks both L- and N-type Ca(2+)-channels, on insulin sensitivity, cilnidipine at 5 to 10 mg/day was administered to ten patients with essential hypertension for 12 weeks. Mean age and body mass index (BMI) were 57.7 +/- 5.0 (SEM) years old and 27.1 +/- 1.5, respectively. Blood pressure, serum levels of catecholamines, glucose and lipid were determined before and after the treatment. Insulin sensitivity was also measured by a euglycemic hyperinsulinemic clamp method using an artificial pancreas (STG-22; Nikiso, Tokyo, Japan) before and after the treatment. Cilnidipine administration significantly lowered blood pressure from 154/96 to 137/84 mmHg (p<0.05). The glucose infusion rate was significantly increased by 20.8%, from 3.27 +/- 0.36 to 3.95 +/- 0.55 mg/kg/min (p<0.05). HbA1C and serum lipid levels such as total cholesterol and triglyceride were not altered. In addition, cilnidipine treatment did not significantly increase serum norepinephrine levels (278 +/- 25.2 vs. 332 +/- 33.6 pg/ml). Our results suggest that cilnidipine improves insulin sensitivity, possibly due to its exerting a vasodilatory action without stimulating sympathetic nervous activity.

Topics: Blood Glucose; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Catecholamines; Dihydropyridines; Female; Humans; Hypertension; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Sympathetic Nervous System

To compare the effect of amlodipine, a prototype dihydropyridine calcium-channel blocker with lercanidipine, a newer dihydropyridine compound with lipophilic properties, on dependent oedema generation and interference with skin blood flow vasomotion in hypertensive patients.. Single-blind, sequence-randomized, cross-over comparison of amlodipine and lercanidipine. Drugs were given at equipotent doses (10 mg daily and 20 mg daily, respectively) in 22 never-treated mild-to-moderate hypertensive men (age: 48 +/- 5 years). Each treatment was administered for 2 weeks with a 2-week intervening period to restore baseline values.. Dependent oedema formation was quantified through leg weight changes (water displacement method). Blood pressure (the mean of at least 10 determinations) was recorded by an automated oscillometric device and skin blood flow (laser Doppler flowmetry) measured at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, to evaluate the behaviour of cutaneous postural vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing.. Leg weight was increased by both drugs, but the increase was significantly greater during treatment with amlodipine than with lercanidipine. Blood pressure decreased to a similar extent and postural vasoconstriction was antagonized comparably during both treatments.. The oedema-forming potential of amlodipine is greater than that induced by lercanidipine, a difference which emerged in the presence of a comparable drop in blood pressure and could not be attributed to interference with postural vasoconstrictor mechanisms.

Topics: Adult; Amlodipine; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Edema; Humans; Hypertension; Laser-Doppler Flowmetry; Leg; Male; Middle Aged; Skin; Treatment Outcome; Vasoconstriction

When observed in elderly hypertensive patients, increased pulse pressure (PP) and arterial stiffness are known to be independent risk factors for cardiovascular diseases. Increased systolic blood pressure (SBP) leads to left ventricular hypertrophy, while decreased diastolic blood pressure (DBP) results in decreased coronary circulation. It is known that increased arterial stiffness is the major cause of increased PP. Thus basic morbid states of cardiac failure or ischemic heart diseases are more likely to develop in elderly hypertensive patients with increased PP and arterial stiffness, and there is need of antihypertensive drugs that decrease these effects in elderly hypertensives. In this study, we compared the effects of an angiotensin-receptor blocker (ARB: valsartan), an angiotensin-converting enzyme inhibitor (ACE-I: temocapril), and long-acting Ca antagonists (L- and N-type Ca channel blocker: cilnidipine; and L-type Ca channel blocker: nifedipine CR) on PP and arterial stiffness measured by pulse wave velocity in elderly hypertensive patients for 3 months. The ARB yielded the largest reductions in PP and brachial-ankle pulse wave velocity (baPWV), followed by the ACE-I and L- and N-type Ca channel blocker, while the L-type Ca channel blocker yielded no improvement. The effects on arterial stiffness and PP thus varied among the drug characteristics. Although ARB achieved the largest reduction in baPWV, this decrease was not associated with any reductions in PP, SBP, DBP, or mean blood pressure, as were the baPWV-decreases achieved by the other drugs, suggesting that ARB may further reduce the risk of arteriosclerosis in elderly hypertensive patients by decreasing arterial stiffness in addition to its antihypertensive effect.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Ankle; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Brachial Artery; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Nifedipine; Pulsatile Flow; Tetrazoles; Thiazepines; Treatment Outcome; Valine; Valsartan

Several studies suggest the distinctive advantages of ACE-inhibitors and calcium-channel blockers in protecting the residual renal function in hypertensive patients. Pre-clinical and clinical studies have shown rare adverse events in the treatment with manidipine, which is commonly used as antihypertensive drug. We therefore decided to compare the effects of manidipine and nifedipine, on blood pressure, and renal function. One hundred and one hypertensive patients with chronic renal failure were randomly assigned to receive either manidipine 20 mg daily or nifedipine 60 mg daily, respectively. Patients were assessed every two weeks during the active treatment period with the final follow-up after three months. The primary endpoint was the achievement of DBP < or = 90 mmHg or a 10 mmHg DBP reduction from the baseline values, whilst the secondary endpoints was the improvement of the renal function assessed through the creatinine clearance, creatinine blood levels, protein and sodium urine excretion. Significant reduction in SBP (p < 0.001) and DBP (p < 0.001), compared to the baseline values, was reached in both treatments. Creatinine blood levels (p < 0.05) and creatinine clearance (p < 0.01) significantly increased in the manidipine group. Protenuria did not significantly change in the manidipine group but increased in the nifedipine group (p < 0.05). The number of patients with severe adverse reactions differed significantly (p < 0.01) between the groups with the highest frequency for nifedipine (14.5%) compared to manidipine (8.5%). The withdrawal rate was not significantly different between the groups. Manidipine is equally safe and effective as nifedipine and it may have more activity on renal function and less severe side effects compared to nifedipine.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Nifedipine; Nitrobenzenes; Piperazines; Treatment Outcome; Urinary Tract Physiological Phenomena

This randomised, double-blind, double-dummy, parallel group, multicentre study compared the efficacy and tolerability of lercanidipine with lacidipine. Elderly patients with isolated systolic hypertension (supine blood pressure >/=160/<95 mmHg) were enrolled and underwent a placebo run-in period of 14-27 days before random allocation to lercanidipine tablets 10 mg once daily (n=111) or lacidipine tablets 2 mg once daily (n=111) for the assessment period (112-160 days). Titration to lercanidipine 20 mg once daily (two 10 mg tablets) or lacidipine 4 mg once daily (two 2 mg tablets) was allowed after 8 weeks, if required. Both treatments decreased supine and standing systolic and diastolic blood pressure between the end of the run-in period and the end of the assessment period (P<0.0001). At the end of the assessment period, the estimated mean treatment difference (95% confidence intervals) in supine systolic blood pressure was -0.81 (-4.45, 2.84) mmHg. These confidence intervals were within the limits specified for equivalence, that is, (-5, 5) mmHg. Ambulatory blood pressure monitoring showed that the antihypertensive effects of both drugs lasted for the full 24-h dosing period and followed a circadian pattern. Both treatments were well tolerated with a low incidence of adverse drug reactions and a low withdrawal rate. Significantly fewer patients withdrew from treatment with lercanidipine (P=0.015). Neither treatment had any clinically significant effect on pulse rate or cardiac conduction. In conclusion, both treatments were equally effective in controlling supine systolic blood pressure in patients with isolated systolic hypertension.

Topics: Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Supine Position; Treatment Outcome

The importance of measuring microalbuminuria is well established. However, only scanty data are available concerning the biological variability of albumin excretion in type 2 diabetic subjects. We report our experience from a large clinical trial of a new antihypertensive drug (Lercanidipine) designed to reduce albumin excretion and blood pressure in type 2 diabetic patients with hypertension and microalbuminuria. Eighty seven patients with persistent microalbuminuria were studied within 1 year of the clinical trial. The measurements were performed on blood and timed urine samples frozen at -80 degrees C and shipped to a central laboratory unit. Preliminary experiments were performed to assess albumin stability in urine under various conditions (4 degrees C, -20 degrees C and -80 degrees C), particularly with regard to the albumin/creatinine ratio. Urine samples can be stored up to 3 weeks at 4 degrees C or up to 2 months at -80 degrees C. The biological variability of the albumin excretion rate was 25.7%, while that of the albumin/creatinine ratio was 13.4%. These data are useful in defining the analytical goals of imprecision for microalbuminuria (CV = 13% for albumin, and CV = 6% for albumin/creatinine ratio). No correlation between albumin/creatinine ratio and HbA1c was found in the cohort of 61 microalbuminuric patients who completed the trial. The results of this study confirm that the albumin/ creatinine ratio is much more suitable for monitoring albumin excretion in longitudinal studies than the albumin excretion rate.

Topics: Albuminuria; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension; Protein Denaturation; Sensitivity and Specificity; Serum Albumin; Temperature

Hypertensive patients characteristically exhibit left ventricular (LV) hypertrophy and diastolic dysfunction. The effects of antihypertensive agents on LV hypertrophy and diastolic dysfunction do not always correlate with the degree of blood pressure reduction, but their effects on the sympathetic nervous system and renin-angiotensin system (RA system) are thought to be important. We investigated the effects of amlodipine and cilnidipine, N- and L-type calcium channel antagonists that suppress both blood pressure elevation and sympathetic activities, on LV hypertrophy and diastolic function. Patients with essential hypertension were randomly assigned to receive either amlodipine, cilnidipine or nifedipine CR (which does not block N-type calcium channels) for 6 months. The LV mass index was determined using M-mode echocardiography. The E/A ratio, i.e., the ratio of maximum amplitude between the early diastolic wave (E wave) and the atrial systolic wave (A wave) in the LV inflow pattern, and the deceleration time for the E wave were determined using pulse Doppler echocardiography. Systolic and diastolic blood pressures significantly decreased from the baseline values in all three groups, with no significant differences among the groups. The LV mass index had significantly decreased when it was evaluated 3 months after the initiation of treatment in the cilnidipine group and when it was evaluated 6 months after the initiation of treatment in the amlodipine group; only a slight decrease was observed in the nifedipine CR group. A significant decrease in the deceleration time and a significant increase in the E/A ratio were observed after 3 months of treatment in the cilnidipine and amlodipine groups but not in the nifedipine CR group. Thus, the effects of long-acting calcium channel antagonists on hypertensive LV hypertrophy and LV diastolic function varied from one antagonist to the other. Left ventricular hypertrophy and diastolic function improved in the cilnidipine and amlodipine groups, but not in the nifedipine CR group. These results indicate that the suppression of sympathetic nerve activity by the blockade of N-type calcium channels contributes to the improvement of LV hypertrophy and diastolic function.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diastole; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nifedipine

The aim of this study was to compare the regressive effect of clinidipine on left ventricular mass (LVM) with that of quinapril. Sixty patients with mild essential hypertension aged more than 39 years were randomly allocated to two groups to receive cilnidipine (10 mg; n = 30) or quinapril (10 mg; n = 30). The patients underwent echocardiography before and 12 months after drug treatment. Sixteen patients in each group underwent 123I-metaiodobenzylguanidine (MIBG) cardiac imaging before and 12 months after drug treatment. In both groups systolic and diastolic blood pressures significantly decreased to similar levels. In the clinidipine group, both end-diastolic and end-systolic diameters and posterior wall thickness significantly decreased, while only end-systolic diameter significantly decreased in the quinapril group. However, LVM (206 +/- 36 g to 189 +/- 40 g, p < 0.02 for the quinapril group, 195 +/- 60 g to 171 +/- 48 g, p < 0.004 for the clinidipine group) and the LVM index (127 +/- 20 g/m2, to 116 +/- 20 g/m2, p < 0.02 for the quinapril group, 121 +/- 32 g/m2 to 106 +/- 24 g/m2 p < 0.003 for the clinidipine group) significantly decreased in both groups. Regarding MIBG imaging, in the cilnidipine group, the heart-to-mediastinum ratio significantly increased (p < 0.02) and the washout rate significantly decreased (p < 0.02) after drug treatment. In contrast, there were no significant changes in MIBG parameters in the quinapril group. Clinidipine produced a greater decrease in LVM in essential hypertension than quinapril, probably due to the long-term suppression of the cardiac sympathetic nervous system. Clinidipine is useful for hypertensive patients with left ventricular hypertrophy and may improve their prognosis.

Topics: 3-Iodobenzylguanidine; Adult; Aged; Dihydropyridines; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Injections, Intravenous; Iodine Radioisotopes; Male; Middle Aged; Quinapril; Radionuclide Imaging; Tetrahydroisoquinolines; Time Factors

Rapid heart rate (HR) has been reported to be a predictor of cardiovascular morbidity and mortality in hypertensive patients. The aim of this study was to evaluate the effect of ACE inhibitors and long-acting dihydropyridine calcium antagonists on clinic and ambulatory HR in patients with essential hypertension. We selected 292 hypertensive patients treated with ACE inhibitors and 198 hypertensive patients treated with dihydropyridine calcium antagonists. Groups were balanced for age, gender, body mass index, baseline blood pressure (BP) and HR, treatment duration and occupation. Patients had been submitted to clinic evaluation and noninvasive monitoring of BP and HR at baseline and during chronic therapy. Clinic and ambulatory BP were significantly and similarly reduced in patients treated with ACE inhibitors and calcium antagonists. Globally, clinic and 24-h HR were significantly reduced in patients treated with ACE inhibitors and remained unchanged in those treated with calcium antagonists. When patients were grouped according to baseline clinic HR (< 65 beats/min, 65-74 beats/min, 75-84 beats/min, and >85 beats/min), ACE inhibitors did not significantly change HR in subjects with baseline clinic HR <74 beats/min but significantly reduced clinic, 24-h, daytime and nighttime HR in those with baseline HR >75 beats/min and particularly in those with baseline HR >85 beats/min. Calcium antagonists did not significantly change clinic, 24-h, daytime and nighttime HR in various subgroups. Our study shows that ACE inhibitors reduce both clinic and ambulatory HR in hypertensive patients with faster HR, who seem to be at higher risk, and that long-acting dihydropyridine calcium antagonists do not induce significant changes in HR during chronic treatment (neither decrease nor increase). Whether this aspect is associated with a better prognostic impact of ACE inhibitors in essential hypertension should be determined in prospective studies.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

The aim of this study was to evaluate the effects of chronic treatment with lacidipine on blood pressure, heart rate and double product during and immediately after physical effort in mild to moderate hypertensive patients. This was a single-center, randomized, double-blind, crossover, placebo-controlled clinical trial. Eighteen hypertensive patients (56% males, median age 53 years) were randomized to lacidipine 4 mg o.i.d. followed by placebo or to placebo followed by lacidipine 4 mg o.i.d. Lacidipine compared with placebo exerted a significant antihypertensive effect, lowering SBP and DBP both at baseline and either during or after exercise test. The average incremental changes of SBP and DBP between pre-exercise stage and maximal effort did not show any significant differences between treatments. HR during treatment with lacidipine was higher than during treatment with placebo both at rest and after exercise, but at maximal effort, HR was not different from placebo. The average values of DP at maximal effort, and during recovery, did not show any significant differences. Lacidipine 4 mg was effective in lowering blood pressure and in maintaining its antihypertensive effect throughout and after physical exercise, without enhancing double product value, which is an indirect index of myocardial oxygen consumption.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Exercise; Exercise Test; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Oxygen Consumption

We compared the levels of microparticles, platelet activation markers, soluble cell adhesion molecules, and soluble selectins between hypertensive patients with and without type 2 diabetes and control subjects. Binding of anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib monoclonal antibodies to platelets did not differ significantly between the hypertensive patients and controls, but platelet expression of activation markers (CD62P, CD63, PAC-1, and annexin V) was higher in the hypertensive patients. Platelet-derived microparticle (PDMP) and monocyte-derived microparticle (MDMP) levels were significantly higher in the hypertensive patients than in the controls. Soluble ICAM-1, VCAM-1, P-selectin, and E-selectin levels were also higher in the hypertensive patients, and they were significantly higher in the hypertensive patients with diabetes. After treatment with efonidipine, the levels of PDMPs, CD62P-, CD63-, PAC-1-, and annexin V-positive platelets, sICAM-1, sVCAM-1, sP-selectin, and sE-selectin all decreased significantly. The MDMP levels decreased, and the decrease was significant in the hypertensive patients with diabetes. These findings suggest that administration of efonidipine to hypertension patients with diabetes may prevent the development of cardiovascular complications caused by cell adhesion molecules or activated platelets and monocytes.

Topics: Aged; Antihypertensive Agents; Blood Cell Count; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Monocytes; Nitrophenols; Organophosphorus Compounds; Platelet Activation; Vascular Diseases

A double-blind, double-dummy, randomised, multicentre study to compare the efficacy and tolerability of lercanidipine with losartan. Patients with mild to moderate hypertension (supine diastolic blood pressure (DBP) 95-115 mm Hg) were enrolled and underwent a placebo run-in period of 14-30 days before random allocation to lercanidipine tablets 10 mg once-daily (n = 234) or losartan tablets 50 mg once-daily (n = 231) during the assessment period (approximately 16 weeks). Titration to lercanidipine 20 mg once-daily (two 10 mg tablets) or losartan 100 mg once-daily (two 50 mg tablets) was allowed after 8 weeks, if necessary. At the end of the study, 71% of patients who received lercanidipine tablets had achieved normalised DBP (ie, < or =90 mm Hg) and 81% had responded to treatment (ie, DBP < or =90 mm Hg or a decrease in DBP > or =10 mm Hg). The corresponding numbers in the losartan tablets group were 65% and 78%, respectively. In those patients who required dose titration, there was evidence of a greater response with lercanidipine tablets than with losartan tablets. Both treatments were well tolerated with a low incidence of adverse drug reactions and a low withdrawal rate. In conclusion, the antihypertensive effects of lercanidipine tablets were comparable with those of losartan tablets; both treatments gave a high response rate for an antihypertensive monotherapy and were very well tolerated.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Severity of Illness Index; Tablets

Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin-receptor blocker, losartan, on low-density lipoprotein (LDL) oxidation.. Forty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single-blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4-week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid-reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract.. Lercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P =.001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P =.04). Losartan lowered urinary albumin excretion but lercanidipine did not.. Both lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.

Topics: Adult; Aged; Analysis of Variance; Antihypertensive Agents; Antioxidants; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Lipoproteins, LDL; Losartan; Male; Middle Aged; Oxidation-Reduction; Prospective Studies; Single-Blind Method

Most cardiovascular events associated with hypertension are complications of atherosclerosis. Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering.. The European Lacidipine Study on Atherosclerosis (ELSA) was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in far walls of common carotids and bifurcations (CBM(max)). This index has been shown by epidemiological studies to be predictive of cardiovascular events. A significant (P<0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBM(max) progression of -0.0227 mm (intention-to-treat population) and -0.0281 mm (completers). The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients (completers, 40% reduction; P=0.0073). Patients with plaque progression were significantly less common, and patients with plaque regression were significantly more common in the lacidipine group. Clinic blood pressure reductions were identical with both treatments, but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol (-10/-9 mm Hg) than with lacidipine (-7/-5 mm Hg). No significant difference between treatments was found in any cardiovascular events, although the relative risk for stroke, major cardiovascular events, and mortality showed a trend favoring lacidipine.. The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient, despite a smaller ambulatory blood pressure reduction, indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Carotid Arteries; Carotid Artery Diseases; Dihydropyridines; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Time; Treatment Outcome; Tunica Intima; Tunica Media; Ultrasonography

Irrespective of their clinical relevance, side effects cannot be considered a negligible problem in antihypertensive therapy. The aim of this trial was to evaluate the tolerability profile of lercanidipine with that of two other calcium antagonists (amlodipine and lacidipine) in elderly hypertensives.. In a multicenter, double-blind, parallel study 828 elderly (aged > or =60 years) hypertensives were randomized to lercanidipine 10 mg/day (n = 420), amlodipine 5 mg/day (n = 200), or lacidipine 2 mg/day (n = 208) (ratio 2:1:1). If blood pressure (BP) control was unsatisfactory (systolic BP/diastolic BP > or =140/90 mm Hg), the dose of the double-blind medication was doubled and, as a further step, enalapril or atenolol (plus diuretic, if needed) was added. Patients were treated for an average of 12 months.. Amlodipine patients had significantly (P <.001) higher rates of edema (19%) and of early study discontinuations due to edema (8.5%) compared with lercanidipine (9% and 2.1%) and lacidipine patients (4% and 1.4%). Similarly, edema-related symptoms (lower limb swelling and heaviness) occurred significantly (P <.01) more often with amlodipine (50% and 45%, respectively) than with lercanidipine (35% and 33%) and lacidipine (34% and 31%). Most edema cases occurred in the first 6 months, a between-treatment difference being evident since beginning of treatment. Other drug-related adverse events did not differ between treatments. Blood pressure was equally and effectively reduced in the three groups.. The two lipophilic dihydropyridine calcium antagonists, lercanidipine and lacidipine, have an antihypertensive effect comparable to that of amlodipine, but a better tolerability profile.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Male; Peripheral Vascular Diseases; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia

Topics: Aged; Ambulatory Care; Calcium Channel Blockers; Dihydropyridines; Electrocardiography, Ambulatory; Female; Humans; Hypertension; Male; Middle Aged; Posture

This study was carried out to assess whether with a similar degree of blood pressure reduction, Lisinopril compares favorably or otherwise with lacidipine in respect of effects on urinary albumin excretion and renal function as assessed by creatinine clearance, plasma creatinine, urea and electrolytes. Thirty hypertensive diabetic nephropathy patients with moderate hypertension were studied. After a 2-week washout period, they were allocated into two groups matched at baseline for age, sex, weight, blood pressure, and urinary albumin excretion rate as well as creatinine clearance. There were 8 males and 7 females in each group. One group received lisinopril (with furosemide if needed to control BP) and the other group received lacidipine. Staged increases in doses of antihypertensives were used until BP was controlled or maximum dose of 40 mg/day lisinopril or 8 mg/day lacidipine was reached. Furosemide was added to lisinopril if BP was not controlled at 40 mg/day. These medications were given for 12 weeks at the end of which measurements done at baseline were repeated. Comparison of baseline and end of study values of these parameters within the groups and between the two groups were made. Lisinopril group and lacidipine group achieved similar and highly significant reduction in blood pressure levels P < 0.001. There was reduction in urinary albumin excretion rate in both groups but this only reached statistical significance in the lisinopril group [480] [269] mg/day vs. 315 [202] mg/day P < 0.05] while for the lacidipine group it was not significant [491] [257] mg/day vs. 335 [182] mg/day P > 0.05]. However, comparison of albumin excretion rate between both groups at baseline and at end of the study did not show any significant difference, P > 0.1. With both drugs there is a tendency for creatinine clearance to increase and plasma creatinine to drop while plasma potassium tended to rise more with lisinopril than lacidipine but differences within and between both groups, did not reach statistical significance P > 0.05. In conclusion, blood pressure reduction was comparable in both drugs; both drugs reduced albuminuria but lisinopril appeared superior. Treatment with both drugs tended to increase creatinine clearance but both had no significant effects on blood sugar.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged; Potassium; Prospective Studies; Treatment Outcome; Urea

Lercanidipine, a long-acting dihydropyridine with a good antihypertensive efficacy and tolerability in clinical use. With the aim to determine the efficacy and tolerability of this drug in usual clinical practice we performed the ELYPSE trial.. Grade 1 or 2 essential hypertensive patients in whom their physicians considered to prescribe a dihydropyridine were conferred to Lercanidipine 10 mg once daily with a 3-month follow-up; 9059 patients were included (age: 63 +/- 11 years; 58% women, 60% over 60 years, 56% grade 2 hypertensives and 69% previously treated with other antihypertensive drugs). A subgroup of 1267 patients (14%) who were included in the study had experienced adverse reactions with other drugs. Electronic case-report forms and a central database (Internet) were used in this trial.. At baseline, blood pressure (BP) was 160.1 +/- 10.2/95.6 +/- 6.6 mmHg; and heart rate (HR) 77.3 +/- 9.3 beats/min. Significant reductions in both systolic and diastolic BP were attained at 1 month with slight additional decreases 2 months later. At 3 months, BP was 141.4 +/- 11.3/ 83.1 +/- 6.9 mmHg, and HR 75.2 +/- 8.2 beats/min (p < 0.001 versus baseline). At the study end. 64% of the patients achieved a diastolic BP < 90 mmHg, BP control (< 140/90 mmHg) was attained in 32%. In the subgroup of diabetics (n = 1269) an adequate BP control (< 130/85) was attained in only 16.4%. The overall incidence of adverse events was 6.5%, of which the most frequent were headache (2.9%), ankle oedema (1.2%), flushing (1.1%) and palpitations (0.6%). Withdrawal rate was < 1%. The efficacy and tolerability in the subgroup of patients included in the study due to adverse events with other drugs were similar to the whole study group.. In this study Lercanidipine has shown a good efficacy and tolerability in daily clinical practice. These findings are concordant with those reported in randomized controlled trials.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Tolerance; Female; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Patient Dropouts; Prospective Studies

This study evaluates the effects of lercanidipine antihypertensive treatment on glucose homeostasis in patients with type II diabetes mellitus with mild to moderate hypertension. Forty patients were enrolled. After a 2-week wash-out period, they were randomly allocated to receive in double-blind manner either 10 mg or 20 mg in single daily administration for 8 weeks. Nonresponding patients after the initial 4 weeks, were titrated up to 20 mg and 30 mg lercanidipine, respectively. At the end of the double-blind treatment, all patients entered in single-blind 4 weeks placebo follow-up. Systolic and diastolic blood pressure significantly decreased in both groups of patients after 4 weeks of treatment, and decreased further during the following 4 weeks. In both groups, progressive and significant decrease in fasting blood glucose, glycosylated hemoglobin and area under the curve of the oral glucose tolerance test were detected during lercanidipine treatment. Similarly, a decrease in serum fructosamine values were also observed. All variables returned to towards baseline values during the placebo follow-up period. Adverse events (headache and mild asthenia) were limited to two patients and resolved spontaneously. These data indicate that lercanidipine is effective in lowering high blood pressure in hypertensive patients with type II diabetes mellitus and does not exert negative effects on glucose homeostasis.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Area Under Curve; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Single-Blind Method

Calcium channel blockers are widely used as antihypertensive drugs. However, there is some controversy as to how they should be used. Our first aim was to clarify how the dihydropyridine calcium channel blocker, benidipine, affects the quantitative relationship between blood pressure (BP) and physical activity. The second aim was to determine whether there is a relationship between systolic blood pressure (SBP) and physical activity in patients with hypertension when treating with a short-acting (nifedipine) or long-acting (benidipine) calcium channel blocker. In Study 1, ambulatory BP and physical activity were measured simultaneously in 27 patients with hypertension before and after 6 months with benidipine. In Study 2, ambulatory BP and physical activity were measured simultaneously in 16 patients with hypertension before (placebo) and after 6 weeks of crossover treatment with nifedipine and benidipine. In Study 1, there was no difference in the SBP change caused by physical activity between the pre- and posttreatment periods. In Study 2, SBP was significantly related to physical activity in the placebo (16/16) and benidipine (16/16) groups but not in the nifedipine (12/16) group. The lowest BP during day-time and nighttime in the nifedipine group were significantly lower than those in the benidipine group. Plasma renin activity (ng/mL/h) was significantly higher in the nifedipine group (1.20+/-1.05) than in the placebo (0.57+/-0.59) and benidipine (0.75+/-0.78) groups. These findings indicate that nifedipine might interfere with the adaptation mechanism of BP changed by physical activity and that the activated renin-angiotensin system might cause cardiac events.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Cross-Over Studies; Dihydropyridines; Exercise; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Systole

The purpose of the present study was to examine the mechanisms of improvement in left ventricular (LV) diastolic function in hypertensive patients treated with cilnidipine, a new and unique calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions, using pulsed Doppler echocardiography and pulsed tissue Doppler imaging. The study comprised 35 untreated patients with essential hypertension (19 men and 16 women; mean age 65+/-10 years). The peak early diastolic and atrial systolic transmitral flow velocities (E and A, respectively) and their ratio (E/A), and the peak early diastolic and atrial systolic motion velocities (Ew and Aw, respectively) of the LV posterior wall and their ratio (Ew/Aw) were determined in all patients before and after 1, 3 and 6 months on cilnidipine (10 mg/day). One month: Systolic and diastolic blood pressures were significantly decreased. E and E/A were significantly increased, whereas there were no significant changes in Ew and Ew/Aw. Three months: Ew and Ew/Aw were significantly increased compared to those before and 1 month after cilnidipine. Six months: E and E/A were significantly increased compared with before and 3 months after cilnidipine, and Ew and Ew/Aw were significantly increased compared with before cilnidipine. Moreover, the LV mass index was significantly decreased compared to that before cilnidipine. In summary, changes in LV diastolic performance in patients with essential hypertension following cilnidipine treatment were biphasic with an initial increase in early diastolic transmitral flow velocity and a later increase in early diastolic LV wall motion velocity. The initial and later changes can be related to an acute change in afterload and a later improvement in LV relaxation.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diastole; Dihydropyridines; Echocardiography, Doppler, Pulsed; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Candesartan, an AT(1) receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients.. Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor-induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups.. Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.

Topics: Adult; Aged; Antihypertensive Agents; Asthma; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bronchial Hyperreactivity; Calcium Channel Blockers; Cough; Dihydropyridines; Female; Genetic Testing; Humans; Hypertension; Incidence; Male; Methacholine Chloride; Middle Aged; Nifedipine; Nitrobenzenes; Pain Measurement; Peptidyl-Dipeptidase A; Piperazines; Polymorphism, Genetic; Respiratory Function Tests; Tetrazoles; Treatment Outcome

To investigate the beneficial effects of cilnidipine, a calcium channel blocker that shows high selectivity for N-type receptors, on the progression of chronic renal insufficiency, we compared the efficacy of cilnidipine to that of benazepril, an angiotensin-converting enzyme (ACE) inhibitor with known renal protective effects, in a one-year trial evaluating hypertensive control, serum creatinine, and albuminuria in a cohort of patients. Given the seeming importance of the etiology of chronic renal insufficiency in determining drug efficacy, we limited our study to 20 patients with a single common condition, benign nephrosclerosis. The average age of the patients was 62+/-4 years old. The changes in systolic and diastolic blood pressure over the course of the study year revealed a similar reduction with cilnidipine and benazepril. Both cilnidipine and benazepril induced similar reductions in systolic and diastolic blood pressure over the course of the study year. The baseline levels of serum creatinine were 1.40+/-0.2 mg/dl and urinary excretion of albumin was 168+/-10 mg daily. The levels of serum creatinine were not significantly changed throughout the study in either group, although the levels of urinary excretion of albumin were significantly decreased in both groups. There were no significant differences in either of these values between the two groups. In conclusion, both cilnidipine and benazepril equally and effectively reduced blood pressure and albuminuria in hypertensive patients with benign nephrosclerosis in a one-year trial.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Creatinine; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nephrosclerosis; Proteinuria

If hypertension in patients with diabetes mellitus type II is not adequately controlled by angiotensin-converting enzyme inhibitors (ACE-i), a beta-blocker is frequently added as second-line therapy. Recently, large randomized trials demonstrated the beneficial effect of second-generation dihydropyridine calcium-channel blockers in these patients. These compounds are increasingly being used to replace beta-blockers. Withdrawal of beta-blockers may influence diabetic control and may cause rebound hypertension. Any rebound hypertension from beta-blocker withdrawal may not occur if the beta-blocker is replaced with a calcium-channel blocker. A calcium-channel blocker will influence vascular resistance (VR) and blood pressure differently than a beta-blocker. Thirty-four patients with diabetes mellitus type II and a resting diastolic blood pressure above 90 mm Hg despite enalapril 10 mg daily (or equipotent dosages of other ACE-i) for at least 3 months were treated in an open label sequential comparison with the same ACE-i in combination with the beta-blocker metoprolol 100 mg for 3 months, and, subsequently for 3 more months with the same ACE-i in combination with the dihydropyridine calcium-channel blocker lercanidipine 10 mg once daily. After 6 weeks, patients with a diastolic blood pressure above 90 mm Hg were titrated up to 200 mg metoprolol or 20 mg lercanidipine once daily. Patients were examined every 6 weeks during the trial, and after 2 weeks while receiving lercanidipine. In addition to blood pressure measurements, VR was measured by iridium strain gauge plethysmography and expressed in units (1 unit = 1 mm Hg/mL blood/100 mL tissue per minute). Two of 34 patients did not complete the protocol because of non-compliance with the lercanidipine treatment in the first 2 weeks of treatment. Their data are included in the analysis. No rebound hypertension 14 days after the change-over of therapies was observed. (Mean arterial pressures [MAPs] were not significantly different from the point of withdrawal of the beta-blockers.) However, heart rate rose from 69+/-7 to 94+/-10 beats/min (p < 0.001). After 3 months on lercanidipine, MAP fell by 6+/-10 mm Hg (p = 0.002) compared to the point of withdrawal of the beta-blocker. Vascular resistance fell by 6.28+/-11.91 units (p<0.01), while glucosylated hemoglobin (HbA1c) rose by 0.4+/-0.5% (p<0.001) and body weight rose by 0.6+/-0.6 kg (p < 0.01). Multiple regression analysis revealed significant associations bet

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Metoprolol; Middle Aged; Regression Analysis; Vascular Resistance

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical-induced nitric oxide (NO) breakdown. Since calcium antagonists can improve endothelial function in hypertensive patients, we tested whether this beneficial effect could be related to restoration of NO availability by antioxidant activity.. In 10 healthy subjects and 20 essential hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (from 0.15-15 microg/100 ml per min), bradykinin (0.005-0.05 microg/100 ml per min), two endothelium-dependent vasodilators, and sodium nitroprusside (1-4 microg/100 ml forearm tissue per min), an endothelium independent vasodilator, in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) (100 microg/100 ml forearm tissue per min), an NO synthase inhibitor.. In controls, vasodilation to acetylcholine and bradykinin was inhibited by L-NMMA. In hypertensive patients, vasodilation to acetylcholine and bradykinin, but not to sodium nitroprusside, was blunted and resistant to L-NMMA. Hypertensive patients were randomized to a 12-week treatment with lacidipine (4-6 mg/daily) or atenolol (50-100 mg/daily) (n = 10 each group). Lacidipine but not atenolol increased the vasodilation to acetylcholine and bradykinin and restored the inhibiting effect of L-NMMA on endothelium-dependent vasodilation, without affecting the response to sodium nitroprusside. Moreover, lacidipine reduced circulating markers of oxidative stress including plasma and low-density lipoprotein (LDL) hydroperoxides, the susceptibility of LDL to Cu2+-induced oxidation and the reactive oxygen species generated from human umbilical vein endothelial cells after incubation with LDL derived from plasma of the patients.. Lacidipine increases endothelium-dependent vasodilation by restoring NO availability, and this effect possibly is related to antioxidant activity.

Topics: Adrenergic beta-Antagonists; Adult; Antioxidants; Atenolol; Biological Availability; Biomarkers; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Vasodilation

This double-blind, multicenter trial compared antihypertensive efficacy, tolerability, and impact on quality of life of manidipine and amlodipine in patients with mild-to-moderate essential hypertension. Patients were randomly assigned to 48 weeks of once-daily manidipine, 10-20 mg, or amlodipine, 5-10 mg. Patients who did not respond to treatment after 12 weeks were also given enalapril, 10-20 mg, for the study's duration. The main efficacy end point was equivalence in sitting systolic (SiSBP) and diastolic (SiDBP) blood pressure reduction between the two drugs after 8 weeks (per protocol analysis). An intention-to-treat (ITT) analysis was performed in all patients with at least one efficacy determination during treatment. Quality of life was assessed by the "Subjective Symptoms Assessment Profile" (SSA-P) and "General Well-being Schedule" (GWBS), after 12 weeks of treatment. SiSBP reduction after 8 weeks was equivalent for manidipine (15.2 mm Hg, n = 227) and amlodipine (17.0 mm Hg, n = 219). The corresponding figure for SiDBP was 11.3 mm Hg for manidipine and 12.3 mm Hg for amlodipine. In the larger ITT population SiDBP was similarly and significantly reduced by manidipine (from 102 +/- 5 to 88 +/- 9 mm Hg, n = 241) and amlodipine (from 101 +/- 5 to 87 +/- 8 mm Hg, n = 240). Similar results were observed for SiSBP and standing SBP and DBP. Neither drug changed sitting or standing heart rate compared with baseline. SSA-P scores improved with manidipine but not amlodipine. GWBS total and partial scores increased more with manidipine than with amlodipine. Safety profile favored manidipine, which was associated with significantly less ankle edema than was amlodipine. This study shows for the first time that long-term treatment with the long-acting calcium channel blocker manidipine is as effective as treatment with amlodipine, has a better tolerability profile, and induces greater improvement in quality of life than amlodipine.

Topics: Adult; Aged; Amlodipine; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Chi-Square Distribution; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Quality of Life; Statistics, Nonparametric

Baseline data from the European Lacidipine Study on Atherosclerosis (ELSA) have shown that carotid intima-media thickness (IMT) is not related to diastolic blood pressure (BP), but that it is related to clinic systolic (S) or pulse pressure (PP) and more so to their 24 h average values. The aim of the present study was to determine whether IMT independently relates to additional information obtained through ambulatory BP, in particular to SBP or PP variability.. In 1663 hypertensive patients, after a wash-out period from antihypertensive treatment (mean age 56.2 +/- 7.65 years), IMT was assessed from 12 different carotid sites. Ambulatory BP measurements were performed every 15 min (day) and every 20 min (night). IMT values were positively related to 24 h, day and night average SBP and PP. There was some relationship of IMT with day-night or clinic-day SBP and PP differences. The most important finding, however, was that IMT values were related with 24 h SBP or PP standard deviation (P < 0.001), a measure of overall SBP or PP variability. The relationship was seen also by multiple regression analysis, the standard deviation for SBP or PP only following age and 24 h average SBP or PP in accounting for IMT values.. This is the first demonstration from a large database that not only average 24 h PP and SBP values, but also 24 h BP fluctuations, are associated with, and possibly determinants of, the alterations of large artery structure in hypertension.

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Carotid Arteries; Cross-Sectional Studies; Dihydropyridines; Humans; Hypertension; Middle Aged; Prospective Studies; Pulse; Tunica Intima; Tunica Media; Ultrasonography

Stress elevates blood pressure (BP) by increased sympathetic nerve activity. Cilnidipine, a novel dihydropyridine calcium antagonist that has inhibitory actions on N-type as well as L-type voltage-dependent calcium channels, has been reported to attenuate the cold stress-induced increase in plasma norepinephrine and BP in rats. Because white coat effect is associated with an enhanced pressor response to mental stress, we postulated that cilnidipine would attenuate white coat effect in patients with essential hypertension. Sixty-one consecutive outpatients (50 men, 11 women) with essential hypertension were studied prospectively. Twenty-nine patients were treated with either cilnidipine (n = 15) or nifedipine, a representative L-type voltage-dependent calcium antagonist (n = 14). Gender, age, body mass index, duration of hypertension, target organ damage of hypertension, and BP and heart rate (HR) were not significantly different between cilnidipine and nifedipine groups, and both systolic (SBP) and diastolic BP (DBP) were significantly decreased after treatment in both groups. White coat effects on systolic and DBP and HR were not significantly different between groups before antihypertensive treatment. Cilnidipine, but not nifedipine, significantly reduced white coat effects on SBP and HR. Furthermore, white coat effects on systolic BP and HR were significantly lower after treatment in the cilnidipine group compared with the nifedipine group. These data suggest that cilnidipine may reduce white coat effect in hypertensive patients by N-type calcium channel antagonism.

Topics: Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Stress, Psychological; Sympathetic Nervous System; Treatment Outcome

The aim of the present study was to compare the effects of a long-acting dihydropyridine (amlodipine) and a nondihydropyridine (verapamil) on autonomic function in patients with mild to moderate hypertension. A total of 145 patients with a diastolic blood pressure (BP) between 95 and 110 mm Hg received 8 weeks of verapamil sustained release (240 mg) and amlodipine (5 mg) in a prospective randomized, double blind, cross-over study, both after 4 weeks of placebo. The 24-h autonomic balance was measured by analysis of 24-h heart rate variability and short-term autonomic control of BP by baroreflex sensitivity measurements. Plasma norepinephrine was sampled at rest. Blood pressure was equally reduced from 153/100 mm Hg to 139/91 mm Hg with verapamil and 138/91 mm Hg with amlodipine, P = .50/.59. The low- to high-frequency ratio (LF/HF), reflecting sympathovagal balance, was higher with amlodipine than with verapamil (4.66 v 4.10; P = .001). Baroreflex function was improved by both treatments; however, baroreflex sensitivity (BRS) was significantly higher with verapamil than with amlodipine (8.47 v 8.06 msec/mm Hg; P = .01). Plasma norepinephrine (NE) level was higher with amlodipine than with verapamil (1.59 v 1.32 nmol/L; P < .0001). Amlodipine induces a shift in sympathovagal balance, as measured by heart rate variability indices and plasma NE, toward sympathetic predominance compared with vagal predominance with verapamil. Short-term autonomic control of BP, as assessed by BRS, is more effectively improved by verapamil than by amlodipine. These contrasting effects on autonomic function suggest that the nondihydropyridine calcium antagonist verapamil may have additional beneficial effects beyond lowering BP compared with the dihydropyridine amlodipine.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Autonomic Nervous System; Baroreflex; Blood Pressure; Calcium Channel Blockers; Carrier Proteins; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Steroid Isomerases; Treatment Outcome; Verapamil

To evaluate the efficacy, metabolic effects and tolerability of manidipine used in the treatment of stage I and II essential hypertensive patients with overweight or android obesity.. By an open-label, non comparative protocol in 11 Brazilian clinical research centers 102 hypertensive patients of both sexes with over weight or central obesity were treated with manidipine 10 to 20mg once daily for 12 weeks. Blood pressure, heart rate and adverse events were monitored. Fasting plasma glucose, total, HDL and LDL-cholesterol and triglicerides were determined at both placebo period and end of active treatment. Also in 12 patients, insulin sensitivity index was evaluated during placebo and manidipine treatment.. Blood pressure was reduced from 159+/-15 / 102+/-5mmHg to 141+/-15 / 90+/-8mmHg with the treatment without any noticeable change in heart rate. Manidipine-efficacy rate was 71.9% with 51.1% of blood pressure normalization. No significant changes in metabolic parameters were noticed. Tolerability to manidipine was very high and at the last visit 87.1% of the treated patients were free of any adverse event.. Manidipine is an adequate, highly effective, exempt of metabolic effects and safe option for treatment of stage I and II essential hypertensive patients with overweight or android obesity.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Brazil; Dihydropyridines; Female; Humans; Hypertension; Lipid Metabolism; Lipids; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Treatment Outcome

The clinical significance of N-type calcium channel blockade has not been fully examined. We here compared the effects of the N-type calcium channel blockers cilnidipine and amlodipine on the sympathetic nervous system and platelet function in hypertension under resting and stressed conditions. Thirty-two patients with hypertension (58+/-9 years) received cilnidipine or amlodipine for 4 weeks in this crossover study. On day 28 of each treatment, plasma levels of epinephrine (EP), norepinephrine (NEP), and beta-thromboglobulin (BTG), and EC50 of ADP-induced platelet aggregation (ADPE50) were determined at rest and after a cold pressor test. On day 29, the group receiving cilnidipine was switched to amlodipine treatment, and vice versa. At rest, the blood pressure, heart rates, EP, NEP, ADPEC50, and BTG, were similar in both treatments. After the cold pressor test, increases in EP (35+/-17 to 44+/-25 pg/ml; p<0.05) and BTG (40+/-13 to 49+/-22 ng/ml; p<0.01) and a decrease in ADPEC50 (32+/-26 to 27+/-24 micromol; p<0.05) were observed in the amlodipine treatment, but not in the cilnidipine treatment. In addition, the increase in NEP was significantly greater (p<0.05) in the amlodipine (276+/-78 to 318+/-87 pg/ml; p<0.01) than in the cilnidipine treatment (273+/-88 to 291+/-100 pg/ml; p<0.05). Cilnidipine more highly attenuates the activation of platelet function in response to cold pressor stress than does amlodipine. Attenuated activation of the sympathetic nervous system via N-type calcium channel blockade may contribute to this phenomenon.

Topics: Amlodipine; beta-Thromboglobulin; Blood Pressure; Calcium Channel Blockers; Cold Temperature; Cross-Over Studies; Dihydropyridines; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Platelet Activation; Stress, Physiological; Sympathetic Nervous System

The Syst-Eur study investigated whether active antihypertensive treatment could reduce cardiovascular complications in elderly patients with isolated systolic hypertension.. Randomised, placebo-controlled, double-blind outcome trial.. Hypertension clinics or general practitioners' surgeries in 198 centres in 23 Western and Eastern European countries.. Patients aged > or = 60 years with sitting systolic blood pressure (BP) 160-219 mmHg and sitting diastolic BP < 95 mmHg during run-in phase.. Four thousand, six hundred and ninety-five patients were randomly assigned to active treatment (N = 2,398), i.e. nitrendipine, with the possible addition of enalapril and hydrochlorothiazide, or to matching placebos (N = 2,297). In the intention-to-treat analysis, the between-group difference in blood pressure (BP) amounted to 10.1/4.5 mmHg (P < 0.001). Active treatment reduced the incidence of fatal and non-fatal stroke (primary endpoint) by 42% (P = 0.003). On active treatment all cardiac endpoints decreased by 26% (P = 0.03) and all cardiovascular endpoints by 31% (P < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, P = 0.07), but all-cause mortality was not influenced (-14%, P = 0.22). For total (P = 0.009) and cardiovascular mortality (P = 0.09), the benefit of antihypertensive treatment weakened with advancing age, and for total mortality it decreased with lower systolic BP at entry (P = 0.05). The benefits of active treatment were not independently related to sex or to the presence of cardiovascular complications at entry. The antihypertensive regimen was more effective in patients with diabetes than in those without diabetes at entry. Further analyses also suggested benefit in patients who were taking nitrendipine as the sole therapy. The per-protocol analysis largely confirmed the intention-to-treat results. Active treatment reduced all strokes by 44% (P = 0.004), all cardiac endpoints by 26% (P = 0.05) and all cardiovascular endpoints by 32% (P < 0.001). Total mortality was reduced by 26% (P = 0.05), but a similar reduction in cardiovascular mortality did not reach statistical significance in this analysis. Compared with placebo, active treatment also reduced the incidence of dementia by 50%.. Stepwise antihypertensive drug treatment, starting with the dihydropiridine calcium-channel blocker nitrendipine, improves prognosis in elderly patients with isolated systolic hypertension.

Topics: Aged; Alcohol Drinking; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Double-Blind Method; Europe; Female; Humans; Hypertension; Male; Middle Aged; Nitrendipine; Prognosis; Smoking; Treatment Outcome

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines

Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor (ACE-I), delapril (Adecut) or a long-acting calcium (Ca)-antagonist, manidipine (Calslot) for 3 years. The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients. There were no significant differences in characteristics of patients between the two intervention groups, except for slightly lower blood pressure (P = .08) in the Ca-antagonist group at the initiation of the study. There were no significant differences in total death between the two groups. Cardiovascular events (both fatal and nonfatal) were noted in 34 of 699 patients (22.5/1000 patient-years) in the ACE-I group and 50 of 1049 patients (19.7/1000 patient-years) in the Ca-antagonist group, with no significant difference found between the two groups. The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure (SBP) is unnecessary and may be harmful in certain cases. Side effects were more frequent in the ACE-I group than in the Ca-antagonist group (P = .01). Cough was the major adverse event, occurring in 5.0% of patients in the ACE-I group. In conclusion, the study indicates that both ACE-I (delapril) and Ca-antagonist (manidipine) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients. However, tolerability of ACE-I was lower due to the adverse event of coughing.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Female; Humans; Hypertension; Incidence; Indans; Japan; Male; Nitrobenzenes; Piperazines; Prospective Studies; Safety; Stroke; Survival Rate

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diastole; Dihydropyridines; Double-Blind Method; Enalapril; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Systole; Treatment Outcome; Triglycerides; Uric Acid

Focal cerebral hypoperfusion is a common finding in uncomplicated hypertensives even in the absence of large vessel atherosclerosis, and neuropsychological deficits correlate with cerebral hypoperfusion in hypertensive patients with cerebral microangiopathy. We investigated the effects on cerebral perfusion of the dihydropiridine calcium antagonist lacidipine and of hydrochlorothiazide (HCTZ) in asymptomatic hypertensive patients with concomitant atherosclerosis of the carotid arteries. Fifteen essential hypertensives (including 13 males, aged 55-75 years) with at least one 30-60% stenosis of the internal carotid artery at echo-color Doppler examination were treated in a double-blind, randomized, parallel study with lacidipine (4-6 mg od) or HCTZ (25-50 mg od) for 3 months after a 4-week single-blind placebo period. Regional cerebral perfusion was assessed at baseline and at the end of the treatment period with HMPAO-SPECT. Relative perfusion of cortical and subcortical areas was calculated as the ratio between their tracer activity and that of the cerebellum. At baseline, mean relative perfusion (MRP) of the cortical and subcortical areas was similar in the stenotic and the contralateral side. Despite the fall in pressure, lacidipine increased MRP both in the cortical and in the subcortical areas, whereas HCTZ increased MRP only in the cortical areas. The mean change in local vascular resistance, adjusted for initial perfusion value, was -20 A.U. (arbitrary unit) with lacidipine and -12 A.U. with HCTZ (p < 0.001). These differential effects of antihypertensive drugs on subcortical perfusion may be of benefit in the long-term prevention of vascular dementia in hypertensive patients.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Carotid Stenosis; Cerebrovascular Circulation; Dihydropyridines; Diuretics; Double-Blind Method; Female; Humans; Hydrochlorothiazide; Hypertension; Intracranial Arteriosclerosis; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon; Vascular Resistance

With the aim of evaluating the effects on blood pressure, platelet function and insulin sensitivity of the dihydropiridines lacidipine and nifedipine GITS, a parallel double-blind study was carried out in a group of 20 patients with mild to moderate essential hypertension. They received a placebo for 4 weeks; then were divided at random into two groups of 10 patients each. Nifedipine GITS, 30 mg and lacidipine, 4 mg, were given during 16 weeks of active treatment. Blood pressure and heart rate were measured at the clinic in supine, sitting and standing positions, 24 +/- 1 h after the last dose. After the placebo and active phases were carried out, a platelet aggregation test was performed to determine platelet malondialdehyde production and a tolerance to 100 g of glucose by measuring glucaemia and plasma insulin. Both drugs reduced systolic and diastolic blood pressure at the same level, however there were observable differences in the rate of reduction. The nifedipine GITS reduced supine systolic blood pressure by 25 mm Hg in the first week, while the lacidipine did so by 11 mm Hg. At the end of the study period nifedipine reduced supine systolic blood pressure by 28 mm Hg and lacidipine by 20 mm Hg. Heart rate was increased slightly but significantly in the nifedipine GITS group only in the standing position. Both drugs reduced platelet aggregation ex vivo only marginally but they modified the malondialdehyde production, indicating an action on the arachidonic acid metabolic pathway.

Topics: Arachidonic Acid; Biomarkers; Blood Platelets; Blood Pressure; Calcium Channels; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Malondialdehyde; Middle Aged; Nifedipine; Platelet Aggregation; Posture; Single-Blind Method

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Humans; Hypertension

Endothelial function is impaired in hypertension. In the present study the effects of long-term antihypertensive therapy on endothelial production of nitric oxide (NO) were investigated. Fifteen untreated mild to moderate essential hypertensive patients and 13 normotensive subjects were enrolled in this study. Blood pressure, heart rate, lipid profiles, cyclic guanosine 3', 5'-monophosphate (cGMP) and nitrite/nitrate (NOx), which are stable metabolites of NO, were measured. The hypertensive patients were treated with a calcium antagonist, benidipine (CAS 91559-74-5) (Ca group: n = 8) or an angiotensin converting enzyme inhibitor, trandolapril (CAS 87679-37-6) (ACEI group: n = 7) and 12 weeks after the treatment the same examinations were performed. NOx and cGMP levels in hypertensive patients were significantly lower than those in normotensive subjects (32.3 +/- 4.1 versus 49.0 +/- 6.5 mumol/l and 2.16 +/- 0.39 versus 3.39 +/- 0.42 pmol/ml, respectively). Both antihypertensive agents decreased the elevated blood pressure (mean blood pressure; 120 +/- 3 to 99 +/- 3 mmHg in Ca group and 117 +/- 4 to 104 +/- 4 mmHg in ACEI group) and normalized the decreased NOx and cGMP levels (29.1 +/- 6.2 to 46.2 +/- 8.6 mumol/l and 1.96 +/- 0.37 to 3.20 +/- 0.71 pmol/ml in Ca group, 36.0 +/- 5.3 to 54.7 +/- 6.9 mumol/l and 2.45 +/- 0.52 to 2.87 +/- 0.43 pmol/ml in ACEI group, respectively). Either benidipine or trandolapril improves the endothelial function and increases the impaired basal release of NO in hypertension. This suggests the beneficial effects of the drugs on protection against the vascular complications in hypertension.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Female; Humans; Hypertension; Indoles; Kidney Function Tests; Lipids; Male; Middle Aged; Nitrates; Nitrites

The aim of this study was to evaluate the macrocirculatory and microcirculatory effects of treatment with lercanidipine, a new antihypertensive agent acting both on blood pressure and microcirculation in patients with moderate essential hypertension and without vascular disease and in patient with hypertension and vascular disease. In hypertensive subjects target-organ damage associated with high blood pressure may now be objectively documented by noninvasive tests. These alterations constitute a model to evaluate not only the pressure effects of antihypertensive treatment but also the normalization of the peripheral microcirculatory network. With color duplex scanning, flow velocity in the central retinal artery and retinal flow velocity can be measured and with use of laser-Doppler-flowmetry, it is also possible to evaluate microcirculation alterations in hypertensive subjects. These evaluation methods are completely noninvasive and may be used to assess the microcirculatory effects of antihypertensive drugs.

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Retinal Artery; Treatment Outcome; Ultrasonography; Vascular Diseases

The effects of benidipine hydrochloride (benidipine, CAS 91559-74-5), a dihydropyridine calcium antagonist, on the 24-h ambulatory blood pressure were studied by a double-blind test against placebo in 8 patients with essential hypertension. The mean resting systolic (SBP) and diastolic (DBP) blood pressures were 173 mmHg and 104 mmHg, respectively, at the time of patients enrollment. Blood pressure was measured every 30 min for 24 h after a single oral administration of either benidipine (4 mg/day) or the placebo. The mean through/peak (T/P) ratios were calculated from blood pressure measurements obtained using 2-h moving averages, and the smoothness index (SI) was calculated by subtracting the effect of the placebo from that of benidipine at each interval. The mean SBP and DBP fell to 135 and 88 mmHg, respectively, after dosing, which gave T/P ratios of 82% and 64%, respectively. The SIs for SBP and DBP were 1.82 and 0.76, respectively. These findings indicate that benidipine maintained a satisfactory and durable antihypertensive effect by once-a-day dosing.

Topics: Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Pulse

The aim of our study was to assess the effects of lacidipine, a long-acting calcium antagonist, on 24-hour average blood pressure, blood pressure variability, and baroreflex sensitivity. In 10 mildly to moderately hypertensive patients with type II diabetes mellitus (aged 18 to 65 years), 24-hour ambulatory blood pressure was continuously monitored noninvasively (Portapres device) after a 3-week pretreatment with placebo and a subsequent 4-week once daily lacidipine (4 mg) or placebo treatment (double-blind crossover design). Systolic blood pressure, diastolic blood pressure, and heart rate means were computed each hour for 24 hours (day and night) at the end of each treatment period. Similar assessments were also made for blood pressure and heart rate variability (standard deviation and variation coefficient) and for 24-hour baroreflex sensitivity, which was quantified (1) in the time domain by the slope of the spontaneous sequences characterized by progressive increases or reductions of systolic blood pressure and RR interval and (2) in the frequency domain by the squared ratio of RR interval and systolic blood pressure spectral power approximately 0.1 and 0.3 Hz over the 24 hours. Compared with placebo, lacidipine reduced the 24-hour, daytime, and nighttime systolic and diastolic blood pressure (P<0.05) with no significant change in heart rate. It also reduced 24-hour, daytime, and nighttime standard deviation (-19.6%, -14.4%, and -24.0%, respectively; P<0.05) and their variation coefficient. The 24-hour average slope of all sequences (7.7+/-1.7 ms/mm Hg) seen during placebo was significantly increased by lacidipine (8.7+/-1.8 ms/mm Hg, P<0.01), with a significant increase being obtained also for the 24-hour average alpha coefficient at 0.1 Hz (from 5.7+/-1.5 to 6.4+/-1.3 ms/mm Hg, P<0.01). Thus, in diabetic hypertensive patients, lacidipine reduced not only 24-hour blood pressure means but also blood pressure variability. This reduction was accompanied by an improvement of baroreflex sensitivity. Computer analysis of beat-to-beat 24-hour noninvasive blood pressure monitoring may offer valuable information about the effects of antihypertensive drugs on hemodynamic and autonomic parameters in daily life.

Topics: Antihypertensive Agents; Baroreflex; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Cross-Over Studies; Diabetes Complications; Dihydropyridines; Double-Blind Method; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Reproducibility of Results; Signal Processing, Computer-Assisted; Treatment Outcome

To investigate the efficacy and tolerability of lercanidipine, used as monotherapy once a day, in elderly patients with isolated systolic hypertension (ISH), 83 patients were enrolled in this multicenter, double-blind, randomized, placebo-controlled study. All patients were older than 60 years, and their mean age was 66.7 +/- 5.4 years. ISH was defined as SBP > or = 160 mmHg, and DBP < 95 mmHg. After wash-out and placebo run-in periods, patients were randomly assigned to placebo or lercanidipine (10 mg once a day) treatment for 4 weeks. Non-responding patients of the lercanidipine-treated group were later treated with 20 mg of lercanidipine once a day for 4 additional weeks. At the end of the study, the reduction in systolic blood pressure was significantly larger in the lercanidipine-treated patients (-32.4 mmHg) compared to the fall observed in the placebo group (-9.6 mmHg). Diastolic blood pressure decreased slightly but significantly in the lercanidipine-treated patients only. At the end of lercanidipine treatment, 23 of 37 patients (62%) were normalized. Changes in heart rate, occurrence of orthostatic hypotension, and clinically relevant changes in electrocardiographic and laboratory findings were not observed in either group. Lercanidipine treatment was suspended in one patient because of epigastric pain. These data indicate that lercanidipine, used as monotherapy once a day, is effective in lowering elevated systolic blood pressure in elderly patients, and is well tolerated.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Diastole; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Systole; Treatment Outcome

The aim of this study was to compare the chronic effects of four dihydropyridine calcium antagonists with different pharmacologic characteristics, amlodipine, felodipine, lacidipine and manidipine,on blood pressure (BP), heart rate (HR) and plasma norepinephrine (NE) levels in patients with mild to moderate essential hypertension.. After a 4-week placebo period, 60 patients of both sexes were randomly administered amlodipine 5-10 mg once daily (o.d.) (n = 15); felodipine 5-10 mg o.d. (n = 15); lacidipine 4-6 mg o.d. (n = 15); manidipine 10-20 mg o.d. (n = 15), for 24 weeks, according to a double blind, parallel group design. Initially, for the first 2 weeks, the lowest dose of each drug was used, then higher doses were administered if sitting diastolic blood pressure (DBP) was > 90 mmHg. BP, HR and plasma NE were evaluated at the end of the placebo and active treatment periods. NE was assessed at trough, at peak and after 12 h from drug ingestion.. Administration of all four drugs reduced clinic BP to the same level after 24 weeks, whereas HR increased only with felodipine (+ 3.1 bpm; P< 0.05). Significant increases in plasma NE levels were observed after chronic therapy with amlodipine and felodipine (+ 34.9 and + 39.4% respectively; P< 0.01 versus placebo) but not with lacidipine (+ 7.1%, NS) and manidipine (+ 2.9%, NS).. These findings suggest that sympathetic activation occurred during chronic treatment with amlodipine and felodipine, whereas manidipine and lacidipine did not increase plasma noradrenaline at the times measured. The reasons for this difference are unclear; they could be related to the different pharmacological characteristic of the two drugs, lacidipine and manidipine.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Felodipine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Norepinephrine; Piperazines; Sympathetic Nervous System

The aim of the present study was to evaluate the effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension.. Ten inpatients with mild to moderate essential hypertension (four men and six women; age: 44-64 years) underwent a drug-free period for 7 days and a treatment period with cilnidipine 10 mg orally for another 7 days, in a randomized crossover study. On the sixth day of each period, they underwent autonomic function tests including a mental arithmetic test, a cold pressor test and a Valsalva manoeuvre. After these tests, 24 h ambulatory blood pressure, heart rate, and the electrocardiogram R-R intervals were monitored every 30 min. A power spectral analysis of R-R intervals was performed to obtain the low-and high-frequency components.. Cilnidipine significantly decreased the 24 h blood pressure by 6.5 +/- 1.7 mm Hg systolic (mean +/- s.e.mean; P < 0.01) and 5.0 +/- 1.1 mmHg diastolic (P < 0.01), whereas cilnidipine did not change heart rate or any indices of power spectral components. During the cold pressor test, the maximum change in systolic blood pressure and percentage changes in both systolic and diastolic blood pressures were significantly lower during the treatment period with cilnidipine than during the drug-free period. The baroreflex sensitivity measured from the overshoot phase of the Valsalva manoeuvre did not differ significantly between the two periods.. Cilnidipine is effective as a once-daily antihypertensive agent and causes little influence on heart rate and the autonomic nervous system in patients with mild to moderate essential hypertension. Moreover, it is suggested that cilnidipine has an additional clinical benefit in the inhibition of the pressor response induced by acute cold stress.

Topics: Adult; Autonomic Nervous System; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Outcome Assessment, Health Care; Pressoreceptors

This is an open trial investigating the efficacy and metabolic effects of 3 months' treatment with lacidipine in 25 Nigerian Africans with mild to moderate hypertension. There was a significant fall in sitting diastolic blood pressure, with treatment (p = 0.01). There were no significant weight changes. The heart rate initially rose significantly with the drug but this normalised with time. All biochemical and haematological indices remained essentially unchanged during therapy. Lacidipine therefore proved an efficacious and metabolically neutral antihypertensive in mild to moderate hypertension in Africa.

Topics: Antihypertensive Agents; Black People; Consumer Product Safety; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nigeria

Previous studies have shown areas of cerebral hypoperfusion in the frontal and parietal lobes of asymptomatic hypertensives, in the absence of extracranial carotid artery stenosis. The aims of the present study were: (a) to correlate the presence of focal cortical hypoperfusion with the presence of white matter lesions (WML), lacunae and extracranial carotid artery stenosis; and (b) to compare the effects on cerebral perfusion of the dihydropyridine calcium entry blocker lacidipine and of hydrochlorothiazide (HCTZ) in hypertensive patients with carotid artery stenosis. Forty-one patients (30 males, aged 40-75) with mild to moderate essential hypertension and with negative history for cerebrovascular diseases were investigated. Twenty-four had normal extracranial carotid arteries at echo-colourDoppler examination, while 17 had at least one 50-70% stenosis of the internal carotid artery (ICA). At computed tomography (CT) scan, five patients had one or more lacunar infarctions, four WML, three lacunar infarctions and WML, and 26 a normal CT scan. Three, with old cortical infarctions, were excluded from further analysis. The prevalence of lesions was significantly higher among the patients with carotid artery stenosis (44% vs. 29%; p < 0.05). Distribution of mean relative cortical perfusion (MRCP) of regions of interest [hexamethyl-propileneamine oxime-single photon emission tomography (SPET)] was not normal, with a negative skewness in patients with lacunae. MRCP was slightly but significantly reduced in patients with lacunae in comparison with hypertensives with normal CT scan and with WML. The asymmetry index of tracer distribution was significantly greater in the patients with lacunar infarctions and WML than in the hypertensive patients with normal CT scan, irrespective of the presence of internal carotid artery stenosis. Fifteen hypertensives (13 males, aged 55-75 years) with at least one moderate stenosis of ICA at duplex scanning were treated in a double-blind, randomised, parallel study with lacidipine (4-6 mg o.d.) or HCTZ (25-50 mg o.d.) for 3 months after a 4-week single-blind placebo period. At baseline, perfusion of the cortical and basal areas was similar in the stenotic and the contralateral side. Despite the fall in pressure, both treatments increased MRCP in the stenotic side and in the contralateral side. The lower the baseline perfusion, the larger its increase with treatment. The decrease of local cerebral vascular resistance was signific

Topics: Adult; Aged; Antihypertensive Agents; Carotid Stenosis; Cerebrovascular Circulation; Dihydropyridines; Diuretics; Double-Blind Method; Echoencephalography; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Radiopharmaceuticals; Sodium Chloride Symporter Inhibitors; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

All studies suggesting a lower incidence of edema on lacidipine than on amlodipine are based on subjective scoring. Therefore, we have compared edema formation on two dihydropyridine calcium channel blockers, using an accurate method for quantitative assessment of foot volume. In a randomized study, we treated 62 patients with essential hypertension for 12 weeks starting with either lacidipine 4 mg o.d. (n = 30) or amlodipine 5 mg o.d. (n = 32). At 6 weeks, the doses were increased to that maximally allowed (lacidipine 6 mg, n = 18; amlodipine 10 mg, n = 12) if trough diastolic blood pressure response was insufficient (>90 mmHg and decrease < 10 mmHg). Edema, scored visually, occurred more frequently (p = 0.02) on amlodipine (15/32) than on lacidipine (6/30); this was confirmed by an increase of foot volume above the 95% upper limit of normal variation in 15 patients on amlodipine and in only five patients on lacidipine (p = 0.01). In the whole group of patients, both the increases of foot volume and the decreases of blood pressure just failed to be significantly different between amlodipine and ]acidipine (foot volume, +3.3+/-1.0% on amlodipine and +1.2+/-0.5% on lacidipine, p = 0.08; mean arterial pressure, -11+/-1% on amlodipine and -8+/-1% on lacidipine, p = 0.052). In patients requiring dose increase, the increase of foot volume on amlodipine was more pronounced (p < 0.05), and the antihypertensive effect was larger (p < 0.05) than on lacidipine. In conclusion, our data show a higher incidence of edema on amlodipine than on lacidipine, which has to be explained at least partly by a comparably higher dose c.q. a larger antihypertensive effect of amlodipine. Other mechanisms might have contributed to these differences and need to be explored.

Topics: Adolescent; Adult; Aged; Amlodipine; Ankle; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Edema; Female; Foot; Humans; Hypertension; Joint Diseases; Male; Middle Aged; Single-Blind Method

This study was carried out to evaluate the effect of a new long-acting calcium-channel antagonist, azelnidipine, on hemodynamic and neural responses to exercise. Ten patients (age, 36-69 years) with mild essential hypertension were enrolled in this study. A randomized, double-blind, crossover treatment of azelnidipine at a dose of 8.0 mg once daily for 4 weeks was performed. After a 4-week placebo period, the patients exercised in a submaximal test by using an ergometer with azelnidipine or placebo treatment. The changes caused by exercise in arterial blood pressure (BP), heart rate, cardiac output (CO), and systemic vascular resistance were evaluated. In addition, the plasma norepinephrine (NE), epinephrine (E), plasma renin activity, and plasma aldosterone concentration were determined at rest, at peak exercise, and at the recovery period. Both the SBP and diastolic (D) BP were decreased at rest by azelnidipine treatment (from 158 +/- 10/97 +/- 7 to 145 +/- 14/90 +/- 9 mm Hg). Azelnidipine significantly decreased both SBP and DBP during exercise (SBP, F = 6.09, p < 0.05, Fi = 0.612, NS; DBP, F = 17.78, p < 0.001, Fi = 0.298, NS). No significant changes in the resting heart rate and CO were observed, and the exercise-induced increase of these parameters was also not affected by azelnidipine. Azelnidipine produced no significant change of the resting plasma NE and E levels and an exercise-induced increase of plasma NE. In conclusion, these results indicate that azelnidipine, different from another dihydropyridine-type calcium channel antagonists, does not produce any changes in the hemodynamic and neurohumoral response to exercise, and it may be beneficial for patients with mild essential hypertension.

Topics: Adult; Aged; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Cardiac Output; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Exercise; Female; Humans; Hypertension; Male; Middle Aged; Placebos; Sympathetic Nervous System; Vascular Resistance

We compared antihypertensive efficacy and safety of a single administration of equipotent doses of lacidipine versus nifedipine in the hypertensive urgencies. Twenty-nine asymptomatic essential hypertensive patients (nine men, 20 women) with a mean age of 55.03+/-11.19 years and baseline diastolic blood pressure (DBP) of > or =120 mm Hg after resting 30 min, not taking antihypertensive drugs for the last 24 h, were randomized in a single-blind fashion to receive lacidipine, 4 mg (LCD, 15 patients) or short-acting nifedipine, 20 mg (NFD, 14 patients) in a single dose. Blood pressure (BP) and heart rate (HR) were taken every 30 min during the first 8 h and every 2 h until 24 h of follow-up. Baseline BP values were similar in the two groups (LCD, 222.5+/-32.8/124.6+/-8.4 mm Hg vs. NFD, 215.9+/-20.6/128+/-7.7 mm Hg; p = NS). Both drugs promoted a significant reduction of systolic blood pressure (SBP; 169.6+/-27.8 vs. 170.6+/-25.3 mm Hg) and diastolic blood pressure (DBP; 104.1+/-16 vs. 102.9+/-12.4 mm Hg) after 8 h. However, either SBP (165+/-27.3 vs. 190.6+/-18.2 mm Hg; p = 0.008) and DBP (99.9+/-12.3 vs. 117.2+/-11.4 mm Hg; p = 0.001) were significantly higher in the NFD group after 24-h dosing. Eleven patients in the LCD group had a decrease in BP >25% of the baseline value both 8 and 24 h after the dose. Although 10 patients showed the same response in the NFD group 8 h after the dose, only four patients maintained these values at 24 h. One patient treated with NFD had a transient cerebrovascular ischemic attack. No adverse effects were observed in the LCD group. We conclude that the long-acting calcium antagonist lacidipine was more effective than the short-acting nifedipine in both controlling BP and maintaining this BP reduction over 8 h in essential hypertensive patients with acute asymptomatic BP increase.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Diastole; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Reference Values; Single-Blind Method; Systole; Treatment Outcome

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure Determination; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Male; Nifedipine; Prognosis; Survival Rate; Treatment Outcome

The effects of a new dihydropyridine calcium antagonist, benidipine hydrochloride, on 24-hour blood pressure and blood pressure response to mental arithmetic test were investigated.. Ten elderly patients with essential hypertension (mean age: 65+/-4 years; 7 male and 3 female).. After a control period of 4 weeks, 4 mg benidipine was administered once daily in the morning for 12 weeks. Ambulatory blood pressure was monitored using a non-invasive automatic portable device with the cuff-oscillometric method at the end of both the control and treatment periods.. Benidipine administration significantly decreased 24-hour blood pressure, while little change was noted in heart rate. Daytime blood pressure decreased significantly, from 148.2+/-11.5/90.8+/-8.8 to 133.8+/-9.2/82.5+/-10.8 mmHg. However, no significant decrease in nighttime diastolic blood pressure was noted, and the decrease in nighttime systolic blood pressure was small (from 129.8+/-9.9/77.1+/-7.6 to 121.8+/-10.1/74.7+/-9.1 mmHg). No significant changes were observed in diurnal variability of blood pressure and heart rate. The decrease in systolic blood pressure by benidipine administration showed a significant positive correlation with systolic blood pressure before treatment in the 24-hour and daytime periods. Single cosinor analysis showed that benidipine administration significantly decreased MESOR of both systolic and diastolic blood pressure, without an increase in amplitude. Both systolic and diastolic blood pressure during mental arithmetic test were significantly decreased after treatment with benidipine, and the increase in systolic blood pressure induced by mental arithmetic test was also significantly attenuated.. These findings indicate that administration of benidipine once daily in the morning effectively decreases blood pressure and attenuates blood pressure response to mental stress. Neither reflex tachycardia, deterioration of diurnal blood pressure change, nor excessive lowering of nighttime blood pressure was observed after benidipine administration. It is suggested that benidipine is a potent and long-lasting calcium antagonist which may be useful for the treatment of elderly hypertensive patients with cardiovascular disease.

Topics: Administration, Oral; Aged; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Mental Processes; Middle Aged; Regression Analysis; Stress, Physiological

N-Type calcium channel antagonists may suppress sympathetic activity. The purpose of this study was to assess the effects of amlodipine and cilnidipine on the cardiac sympathetic nervous system and the neurohormonal status of essential hypertension. 123I-metaiodobenzylguanidine (MIBG) cardiac imaging was performed and blood samples were taken to determine plasma renin activity and plasma norepinephrine concentration before and 3 months after drug administration in 47 patients with mild essential hypertension. Twenty-four of the patients were treated with 5 to 10 mg/d of amlodipine; the other 23 were treated with 10 to 20 mg/d of cilnidipine. For comparison, 12 normotensive subjects were also studied. No significant differences were found in the basal characteristics between the 2 hypertensive groups. In both hypertensive groups, both the systolic and diastolic blood pressures were significantly reduced to similar levels 3 months after drug treatment. Before the drug treatment, the 2 hypertensive groups had a significantly higher washout rate and lower heart-to-mediastinum (H/M) ratio compared with the normotensive subjects. The H/M ratio significantly increased (P<0.05) in combination with a decreased washout rate (P<0.02) after drug treatment in the cilnidipine group. In the amlodipine group, a significant decrease in washout rate (P<0. 04) was noted, without an increase in the H/M ratio. However, no significant changes were found in plasma renin activity and plasma norepinephrine concentration in either group. Thus, in patients with essential hypertension, cilnidipine suppressed cardiac sympathetic overactivity and amlodipine had a little suppressive effect. Cilnidipine may provide a new strategy for treatment of cardiovascular diseases with sympathetic overactivity.

Topics: Adult; Aged; Amlodipine; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Heart; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Reference Values; Renin; Sympathetic Nervous System

To evaluate the effect of manidipine 10 mg on 24-hour ambulatory blood pressure (BP) and heart rate (HR) in very elderly hypertensive patients, 54 patients aged 76-89 years (mean age 81.8 years) with systolic blood pressure (SBP) > 160 mmHg and diastolic blood pressure (DBP) > 90 mmHg were studied. After a 4-week placebo washout period, patients were randomized to receive manidipine 10 mg or placebo, both administered once daily for 8 weeks. Patients were checked after the initial run-in placebo phase and every 4 weeks thereafter. At each visit casual BP and HR were measured. At the end of the placebo period and after 8 weeks of active treatment, noninvasive 24-hour ambulatory blood pressure measurement (ABPM) was performed. Manidipine significantly lowered casual sitting and standing SBP (P < 0.001) and DBP (P < 0.001) at the trough level. ABPM showed a significant decrease in 24-hour SBP and DBP values (P < 0.001), daytime SBP and DBP (P < 0.001), and night-time SBP (P < 0.001) and DBP (P < 0.005). In addition, ABPM confirmed a consistent antihypertensive activity throughout the 24-hour dosing interval, without effect on the circadian BP profile. The trough/peak ratio was 0.67 for SBP and 0.59 DBP. No statistically significant change in HR was observed. The treatment was well tolerated, and there were no serious side effects. In conclusion, in very elderly hypertensive patients, once-daily administration of manidipine 10 mg was well tolerated and effective in reducing casual as well ambulatory BP.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Male; Nitrobenzenes; Piperazines; Placebos

To evaluate the effects of cilnidipine (CNP), L- and N-type calcium channel blocker and nilvadipine (NVP) on 24-h urinary epinephrine (U-EP), norepinephrine (U-NE), dopamine (U-DA) and C-peptide (U-CPR) in patients associated with hypertension and non-insulin-dependent diabetes mellitus (HT-NIDDM), a randomized crossover study was performed with 35 HT-NIDDM patients. The patients were given CNP (10 mg/day) and NVP (8 mg/day), separately, for 4 weeks each. After CNP treatment, U-NE, U-DA and U-CPR levels were significantly reduced compared with pre-treatment levels: 160.4 +/- 12.7 to 111.7 +/- 8.9 microg/day (mean +/- S.E., P < 0.005); 934.8 +/- 163.4 to 590.3 +/- 33.4 microg/day (P < 0.05); 86.7 +/- 9.9 to 57.6 +/- 7.4 microg/day (P < 0.05), respectively. Although no significant differences were observed in U-EP, U-NE, U-DA and U-CPR levels by NVP treatment, U-NE, U-DA and U-CPR levels after CNP treatment were significantly lower than those after NVP treatment: 111.7 +/- 8.9 versus 155.0 +/- 13.7 microg/day (P < 0.02); 590.3 + 33.4 versus 822.2 +/- 104.3 microg/day (P < 0.05); 57.6 +/- 7.4 versus 80.6 +/- 8.1 microg/day (P < 0.05), respectively. In conclusion, it was demonstrated that CNP treatment significantly reduced U-NE, U-DA and U-CPR excretion compared with NVP treatment in HT-NIDDM patients.

Topics: Aged; C-Peptide; Calcium Channel Blockers; Catecholamines; Chromatography, High Pressure Liquid; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Dopamine; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Norepinephrine

To investigate whether the long-acting Ca channel blocker, benidipine improves insulin resistance in patients with essential hypertension, insulin sensitivity was measured using the steady state plasma glucose (SSPG) method in 11 or 14 nonobese and nondiabetic hypertensive subjects before and after treatment with benidipine or placebo, respectively, and 11 healthy control subjects. SSPG level was significantly higher in two hypertensive groups, indicating reduced insulin sensitivity than in controls. SSPG level significantly decreased after benidipine treatment, with a decrease of blood pressure. SSPG level and blood pressure did not change in the placebo group. As for oral glucose tolerance test, the area under the curve of insulin diminished significantly after benidipine treatment. SSPG level significantly correlated with intra-platelet Ca2+ concentrations in 9 hypertensive subjects. The long-acting Ca channel blocker benidipine has partially improved insulin resistance in essential hypertension, contributing to the prevention of atherosclerosis associated with insulin resistance.

Topics: Apolipoproteins; Arteriosclerosis; Blood Glucose; Blood Platelets; Blood Pressure; Calcium; Calcium Channel Blockers; Catecholamines; Dihydropyridines; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Intracellular Fluid; Male; Middle Aged; Treatment Outcome

The effect of pravastatin on renal function in hypertensive patients with mild renal dysfunction and hyperlipidemia was examined. A total of 57 subjects given dihydropyridine calcium blockers were randomly assigned to placebo (n = 25) and pravastatin groups (n = 32). The period of study was 6 months. In the placebo group, lipid metabolism did not change throughout the study period, but the serum creatinine concentration (Scr) increased from a baseline of 1.6+/-0.07 mg/dl to 2.1+/-0.2 mg/dl in the 6th month of study and blood urea nitrogen (BUN) increased from 26.2+/-1.1 mg/dl to 32.4+/-30.1 mg/dl. In the pravastatin group, the serum total cholesterol decreased from a baseline of 251.4+/-7.3 mg/dl to 218.2+/-6.5 mg/dl in the 6th month of study, while Scr (1.3+/-0.07 mg/dl vs. 1.3 +/-0.09 mg/dl) and BNU (20.5+/-1.2 mg/dl vs. 21.0+/-1.4 mg/dl) did not change. The change in Scr in the placebo group was significantly different from that in the pravastatin group (F = 3.75, p = 0.05). The slope of the change in 1/Scr was 0.02+/-0.07 dl x mg(-1) x month(-1) in placebo group and -0.01+/-0.03 dl x mg(-1) month(-1) in pravastatin group (P<0.05). The results indicate that pravastatin attenuates the deterioration of renal function in patients with mild renal dysfunction, together with an improvement of lipid metabolism.

Topics: Blood Urea Nitrogen; Calcium Channel Blockers; Cholesterol; Creatinine; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Kidney Diseases; Male; Middle Aged; Pravastatin; Treatment Outcome

Thirty four patients with mild to moderate hypertension, were put on benidipine 4 mg/day after two weeks of placebo therapy. Twenty five patients completed the trial successfully for 4 mg benidipine. The blood pressure of 20 patients was controlled with benidipine 4 mg/day (effective rate 80%). Five patients with unsatisfactory control on 4 mg/day benidipine were put on 8 mg/day. Four of them were controlled and one was considered as failure (effective rate 80%). Most of the patients tolerated the drug well. Three patients had mild side effects like headache and heaviness in the head. One of them also had puffiness of face and body (on benidipine 8 mg/day) and was withdrawn from the study. One patient had mild constipation. We conclude that benidipine is well tolerated in the dose of 4-8 mg/day and is an effective antihypertensive agent for treatment of patients with mild to moderate hypertension.

Topics: Adult; Aged; Blood Pressure Determination; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Reference Values; Severity of Illness Index; Treatment Outcome

We investigated the relationship between cardiovascular autonomic nervous system function and carotid arterial distensibility during treatment with an angiotensin converting enzyme inhibitor (derapril) or a calcium channel blocker (manidipine) for hypertension. In 37 patients with hypertension, autonomic function was assessed by heart rate variability and baroreceptor sensitivity using phenylephrine injection. Left ventricular mass index and carotid arterial distensibility were assessed by ultrasound examinations. Before the medication, both baroreceptor sensitivity and heart rate variability correlated with carotid arterial distensibility, but not with left ventricular mass index by multiple regression analysis. Subsequently, patients were randomly allocated into two groups, derapril (n = 18) and manidipine (n = 19) for 20 weeks. At the end of the study, the change in baroreceptor sensitivity correlated with change in carotid arterial distensibility (r = 0.41, P < .05), but not with change in left ventricular mass index. Although derapril and manidipine decreased blood pressure and left ventricular mass index to the same extent, the former improved heart rate variability, baroreceptor sensitivity (5.0 +/- 1.9 --> 5.6 +/- 2.0 msec/mm Hg), and carotid arterial distensibility (2.1 +/- 0.8 --> 2.5 +/- 1.0 %kPa), but the latter did not improve them at all. Thus, impairment of the autonomic balance was related to the impairment of carotid arterial distensibility in hypertension; derapril, but not manidipine, significantly improved these abnormalities.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System; Baroreflex; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Female; Heart; Heart Rate; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines

We compared the effects of cilnidipine and nifedipine retard on 24-h blood pressure (BP), heart rate (HR), and autonomic nerve activity in patients with essential hypertension. Cilnidipine is a novel and unique 1,4-dihydropyridine calcium antagonist that has the L-type and N-type voltage-dependent calcium channel-blocking action. Fourteen hypertensive outpatients (four men and 10 women; aged 64 +/- 2 years, mean +/- SEM) were enrolled in this study. Their ambulatory BP and electrocardiogram were monitored for 24 h at intervals of 30 min with a portable recorder after a 4-week drug-free period, after a 4-week treatment period with cilnidipine (5 or 10 mg once daily), and after a 4-week treatment period with nifedipine retard (10 or 20 mg twice daily). The order of the three periods was randomized. Autonomic nerve activity was evaluated by a power spectral analysis of HR variability, by using the high-frequency (HF) component as an index of parasympathetic nerve activity and the ratio of the low-frequency (LF) component to the HF component (LF/HF) as an index of sympathovagal balance. Cilnidipine and nifedipine retard significantly reduced the 24-h BP of these patients to similar extents (cilnidipine, -11 +/- 3/-6 +/- 1 mm Hg; nifedipine retard, -15 +/- 3/-6 +/- 2 mm Hg). Cilnidipine did not change the 24-h average HR, whereas nifedipine retard significantly increased it (+3.3 +/- 1.4 beats/min; p < 0.05). Nifedipine retard significantly increased the LF/HF ratio in the daytime and the nighttime. Such changes were limited to the daytime in the treatment period with cilnidipine. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and had less influence on autonomic nervous system and HR than did nifedipine retard.

Topics: Autonomic Pathways; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine

Cilnidipine is a new and unique 1,4-dihydropyridine calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions. We compared the effects of cilnidipine and another once-daily dihydropyridine calcium antagonist, nisoldipine, on 24-h blood pressure and heart rate in patients with essential hypertension. We enrolled 10 hypertensive outpatients [9 men and 1 woman; age, 55+/-3 yr (means+/-SEM)] in this study. Their ambulatory blood pressure and heart rate were monitored for 24 h at intervals of 30 min with a portable recorder (TM-2425) after 8 wk of treatment with cilnidipine (5 to 20 mg once daily) and after 8 wk of treatment with nisoldipine (5 to 20 mg once daily). The order of the two treatments was randomized. Blood pressure and heart rate measurements for a 24-h period were analyzed for four segments of the day: morning (06:00 to 11:30), afternoon (12:00 to 17:30), nighttime (18:00 to 23:30), and sleeping time (0:00 to 5:30). Blood pressure levels were similar during the two treatment periods for each 6-h segment of the day. Heart rate was significantly higher during treatment with nisoldipine than during treatment with cilnidipine in the morning segment [by 4.1+/-1.3 beats/min (p < 0.05)] and the afternoon segment [by 6.4+/-3.6 beats/min (p< 0.05)]. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and causes reflex tachycardia less than does nisoldipine.

Topics: Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nisoldipine

The possibility that calcium antagonists exert an anti-atherosclerotic action at least partly independently of the blood-pressure-lowering effect is supported by results of a large number of experimental studies and can now be investigated by quantitative B-mode ultrasound imagining of the carotid artery walls.. The European Lacidipine Study on Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multinational trial comparing effects of 4-year treatment based on the long-acting, highly lipophilic calcium antagonist lacidipine with those of treatment based on the beta-blocker atenolol on the development of carotid artery wall alterations in patients (aged 45-75 years) with mild-to-moderate hypertension (systolic blood pressure 150-210 mmHg and diastolic blood pressure 95-115 mmHg). While the intervention study is progressing, this article summarizes baseline data obtained from the whole cohort of 2259 patients randomly allocated to treatment.. Baseline ultrasound data were obtained from two replicate examinations performed shortly before random allocation to treatment by certified sonographers at 23 referral centres and read at the ultrasound coordinating centre at the Wake Forest University School of Medicine. Intima-media thickness was measured at up to 12 different sites in the carotid artery tree and expressed as the mean of the maxima at these sites (Mmax), the mean of the maxima at four sites in the distal common carotid artery and bifurcation (CBMmax) and the maximum intima-media thickness (Tmax). Baseline demographic and clinical measurements were performed by investigators in 410 peripheral clinical units and 24 h ambulatory blood pressure monitorings read and validated by members of a centralized unit at the University of Milan. The statistical analysis centre at the Technische Universität München received and analysed all baseline data, by calculating means +/- SD, medians and ranges and performing correlation (Spearman correlation coefficients) and multiple regression analyses.. Prevalence of carotid artery wall alterations among the hypertensive patients randomly allocated to treatment in the ELSA was very high: 82% had Tmax > or = 1.3 mm ('plaques' according to protocol) and 17% had Tmax > or = 1.0 and < 1.3 mm ('thickening'), with a median of two plaques per patient. We found significant correlations between ultrasound measurements and the following demographic and clinical variables: age, sex, systolic blood pressure and pulse pressure (both clinic and ambulatory), concentrations of total, high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides, smoking habit and duration of hypertension. We found no significant correlation to diastolic blood pressure and glucose concentration. A multiple regression analysis indicated significant variables in the following rank order: age, 24 h ambulatory pulse pressure, sex, low-density lipoprotein cholesterol concentration, triglyceride concentration, smoking and clinic systolic blood pressure.. Analysis of baseline data from the ELSA has shown that there is an extremely marked prevalence of carotid artery wall alterations among mild-to-moderate, middle-aged hypertensive patients. In addition to age, systolic blood pressure and pulse pressure, particularly if they are accurately measured by ambulatory monitoring, play a major role, somewhat greater than those of sex, low-density lipoprotein cholesterol concentration and smoking, in influencing intima-media thickness.

Topics: Adrenergic beta-Antagonists; Aged; Arteriosclerosis; Atenolol; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Carotid Arteries; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Ultrasonography

The aim of this study was to evaluate the spectral analysis of the heart rate in normotensive subjects and in hypertensive patients with and without left ventricular hypertrophy (LVH), under basal conditions and after a reduction in left ventricular mass.. In 12 normotensive subjects and 22 hypertensive patients (14 with and eight without LVH), we performed 24 h electrocardiogram Holter monitoring, ambulatory blood pressure monitoring and an echocardiographic study. Sequences of 512 R-R intervals, during daytime, afternoon and night-time periods, were taken for an evaluation of spectral analysis (Box-Jenkins method). We then calculated the absolute and percentage power spectral density of the peak centred at 0.10 Hz (low-frequency peak) and at 0.25 Hz (high-frequency peak).. At baseline, a daytime to night-time decrease in the low-frequency peak was detected in normotensives (P < 0.01) and in hypertensives without LVH (P < 0.01), while no change was observed in hypertensives with LVH. The power spectral density low-frequency peak during the daytime and night-time was significantly greater in hypertensives with LVH than in those without LVH (P < 0.001) and in normotensive subjects (P < 0.001). Fourteen of these patients with LVH were given effective long-term antihypertensive treatment and were studied again 20 days after the treatment had been withdrawn, when blood pressure had increased to pretreatment values. In eight patients showing a reduction in LVH, we found a significant decrease in the power spectral density low-frequency peak and an increase in the high-frequency peak during daytime and night-time in respect to basal conditions, and circadian variations in the spectral indices of heart rate variability were restored. In contrast, in six patients without reversal of LVH, the power spectral density low-frequency peak did not change in respect to basal conditions and remained significantly higher in comparison with the patients with LVH regression.. A reduction in LVH may be associated with restoration of daytime to night-time cardiac autonomic control, as evaluated by a power spectral analysis of the heart rate.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Heart Rate; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Organ Size

To evaluate the antihypertensive effect of lercanidipine once a day at three different doses (2.5, 5 and 10 mg) by clinic and ambulatory blood pressure.. After 3 weeks of a placebo run-in, 243 mild to moderate essential hypertensives (mean+/-SD age 51+/-8 years) were randomly allocated to lercanidipine at 2.5, 5 or 10 mg or a placebo for 4 weeks, in a double-blind parallel-group design. At the end of each period, supine clinic blood pressure (standard sphygmomanometry) and 24 h ambulatory blood pressure (Spacelabs 90207) were measured. The duration and homogeneity of the antihypertensive effect of the active drug compared with placebo over 24 h was evaluated by calculating the smoothness index, the ratio of the mean of the 24 hourly blood pressure changes to the corresponding SD. The higher the smoothness index, the greater and the smoother is the antihypertensive effect of a drug over the 24 h.. In 211 patients with valid clinic blood pressure data at the end of treatment, larger systolic/diastolic blood pressure reductions were found in the 5 mg (10+/-12/8+/-6 mmHg; P< 0.05 versus placebo, diastolic blood pressure only) and the 10 mg (12+/-11/9+/-7 mmHg; P < 0.05 versus placebo, both pressures) lercanidipine groups than in the placebo (5+/-11/4+/-8 mmHg) and 2.5 mg lercanidipine (7+/-12/6 +/-7 mmHg) groups. In 105 patients with complete 24 h ambulatory blood pressure recordings, there were significantly (P< 0.05 versus placebo) larger reductions in the 10 mg (9+/-7/7+/-5 mmHg) than the 2.5 mg (1+/-10/1+/-6 mmHg) and placebo (2+/-6/1+/-4 mmHg) groups. The reduction in 24 h blood pressure with 5 mg lercanidipine (6+/-7/4+/-5 mmHg) was significantly greater compared with placebo for diastolic pressure only, and when hourly average blood pressure changes were considered, this reduction did not extend to the final hours of the dosing interval. No significant changes in the clinic or 24 h heart rate were induced by placebo or lercanidipine. The smoothness index was significantly (P< 0.05) lower for 2.5 mg lercanidipine and placebo (0.2+/-0.5 and 0.3+/-0.7 for systolic and 0.1+/-0.4 and 0.2+/-0.7 for diastolic blood pressure) than for the 5 and 10 mg doses (0.7+/-1 and 1+/-0.7 for systolic and 0.7+/-1 and 1+/-0.9 for diastolic blood pressure).. At a dose of 10 mg, lercanidipine had a significant and durable antihypertensive effect over 24 h, but at 5 mg, the effect was less consistent and did not last 24 h. There was no clinically relevant reduction in clinic or ambulatory blood pressure with 2.5 mg lercanidipine, and the effect was superimposable on that of placebo.

Topics: Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Female; Humans; Hypertension; Male; Middle Aged

We compared hemodynamic and humoral responses to benidipine and nifedipine during different sodium intakes in essential hypertensives. The study had a single-blind crossover design. Doppler flowmetry and laboratory examinations were performed. During low sodium intake, both benidipine and nifedipine significantly reduced mean arterial pressure to the same extent. Benidipine increased cardiac index, superior mesenteric and renal flows, whereas nifedipine had no effect on either cardiac index or regional blood flows. In the salt-sensitive patients whose mean arterial pressure increased more than 5 mmHg during high sodium intake, sodium loading increased cardiac index and terminal aortic flow, but decreased superior mesenteric and renal flows, while plasma noradrenaline concentrations remained unchanged and plasma arginine vasopressin increased significantly. These hemodynamic responses to sodium in the salt-sensitive patients were more effectively inhibited by benidipine than by nifedipine, although neither of them had any influence on sodium-induced changes in plasma noradrenaline or arginine vasopressin concentration.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Nifedipine; Regional Blood Flow; Single-Blind Method; Sodium, Dietary

The study was designed to investigate whether a long-acting dihydropyridine calcium antagonist has additional antihypertensive effect when combined with currently used low-dose thiazide diuretic therapy. After 6 weeks with open chlorthalidone monotherapy at 25 mg daily, hypertensive patients with trough diastolic BP 90-115 mm Hg were randomly assigned to receive double-blind lacidipine, 4 mg daily or matching placebo for 4 weeks, while continuing to receive background chlorthalidone. Then patients crossed over to the alternative regimen for a second 4-week period. Clinic and 24-h ambulatory blood pressure (BP) were measured on the final day of chlorthalidone monotherapy and on the final day of each double-blind treatment. Seventeen patients completed the study [mean age, 51.0 +/- 6.9 (SD) years]. Clinic BP was lower with lacidipine versus placebo (systolic, p < 0.01; diastolic, p < 0.05). Daytime ambulatory BP was reduced with lacidipine (p < 0.05), whereas nighttime BP was unchanged. Mean 24-h ambulatory diastolic BP also was reduced on lacidipine (p < 0.05). Heart rate was increased on lacidipine during both daytime (p < 0.01) and nighttime (p < 0.05). In conclusion, when added to chlorthalidone, lacidipine produced a significant reduction in clinic and ambulatory BP during daytime but not nighttime. This was associated with increased heart rate. Modem long-acting dihydropyridines may produce small but clinically significant additive antihypertensive effects in patients uncontrolled on low-dose thiazide monotherapy.

Topics: Antihypertensive Agents; Benzothiadiazines; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Chlorthalidone; Dihydropyridines; Diuretics; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Pulse; Sodium Chloride Symporter Inhibitors

Cilnidipine (FRC-8653), a new dihydropyridine calcium antagonist, was given to 14 hospitalized patients with essential hypertension, and 24-hour ambulatory blood pressure (BP) monitoring was performed. Once-daily administration of cilnidipine (5-20 mg) for 1-3 weeks decreased the 24-hour average BP significantly from 149 +/- 4/88 +/- 2 mmHg to 141 +/- 3/82 +/- 2 mmHg without any change in the pulse rate. The decrease in ambulatory BP by cilnidipine was evident during the daytime (156 +/- 4/93 +/- 2 mmHg to 143 +/- 5/84 +/- 2 mmHg, p < 0.01 for systolic BP and p < 0.01 for diastolic BP), while it was mild during nighttime (141 +/- 4/80 +/- 2 mmHg to 133 +/- 4/76 +/- 3 mmHg, p < 0.05 for systolic and ns for diastolic BP). The decrease in the ambulatory BP over the whole day and during the nighttime was significantly correlated with the basal ambulatory BP levels. When the subjects were divided into the high ambulatory BP (n = 7) and low ambulatory BP (n = 7) groups, the BP reduction by cilnidipine was evident throughout 24 hours in the high ambulatory BP group, while it was mild and significant only during daytime in the low ambulatory BP group. In summary, once-daily cilnidipine exerts a sufficient and prolonged reduction of BP without an increase in the pulse rate in patients with hypertension. The potency of cilnidipine to decrease ambulatory BP may depend on the basal ambulatory BP level. Cilnidipine is thus a useful antihypertensive drug that may not cause an excessive decrease in BP or a reflex tachycardia.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

We studied the effects of common antihypertensive regimens on autonomic cardiovascular control. We considered calcium channel antagonists (nicardipine twice a day and isradipine once a day, respectively) and also examined, as reference treatments, once-a-day atenolol and cilazapril. A noninvasive evaluation of autonomic cardiovascular profile was obtained with spectral analysis of RR interval and systolic arterial pressure variability. We studied moderate essential hypertensives before and after 2 weeks of treatment, both at rest and during active standing and mental arithmetic. All treatments reduced arterial pressure equally well; however, marked differences in spectral profiles were observed. The low-frequency spectral component of RR interval variability [in normalized units, marker of sympathetic modulation of the sinoatrial (SA) node] tended to be greater at rest and during stimuli (p < 0.001) in subjects treated with dihydropyridines. No differences at rest, but striking increases of the low-frequency component of systolic arterial pressure variability were observed in nicardipine-treated patients during both standardized excitatory stimuli, suggesting a marked increase in sympathetic vasomotor drive. As to reference treatments, patients treated with atenolol displayed the lowest values, and patients treated with cilazapril (for 4 weeks) provided intermediate values. In conclusion, shorter acting dihydropyridine calcium channel antagonists may induce an exaggerated increase in sympathetic vasomotor drive during standardized laboratory stressors.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cilazapril; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Muscle, Smooth, Vascular; Sympathetic Nervous System

Haemodynamic and laboratory examinations were performed in 27 essential hypertensives. The participation of the sympathetic system was estimated from the percentage decrease in regional vascular resistance caused by 1 mg prazosin, during varied salt intake (50-80 mEq sodium per day for 9 weeks, followed by 220-250 mEq sodium per day for 10 days), with or without benidipine.. During low salt intake, terminal aortic and renal resistances were decreased by prazosin, but superior mesenteric resistance remained unchanged. In the saltsensitive patients, whose mean arterial pressure increased more than 5 mmHg with salt repletion, salt loading increased superior mesenteric and renal resistances but did not change terminal aortic resistance. This salt-induced vasoconstriction of renal and superior mesenteric arteries is not related to an increase in sympathetic activity, because both plasma noradrenaline concentrations and the percentage decrease in these regional vascular resistances by prazosin remained unchanged after salt loading. On the other hand, terminal aortic area demonstrated an increase in responsiveness to noradrenaline (increased response to prazosin) with salt loading in spite of unchanged terminal aortic resistance. This salt-induced increase in sympathetic responsiveness in the terminal aortic area was inhibited with the addition of benidipine, which abolished development of salt-induced hypertension and its accompanying haemodynamic responses.

Topics: Aged; Aorta; Arginine Vasopressin; Calcium Channel Blockers; Diet, Sodium-Restricted; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Prazosin; Renal Artery; Sodium Chloride, Dietary; Sympathetic Nervous System; Sympatholytics; Vascular Resistance

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Emergencies; Female; Humans; Hypertension; Male; Middle Aged

There are few studies on the use of dihydropyridine calcium antagonists in hypertensive patients with moderate renal insufficiency. We undertook an open study on the effects on renal function, albumin excretion and blood pressure of the slow-onset, long-acting dihydropyridine calcium antagonist, lacidipine, in 14 patients with stable, chronic renal insufficiency (mean assessed GFR 0.78 ml/s, range 0.50-1.17 ml/s) and moderate hypertension. Following a 2 week washout phase, lacidipine was administered for 24 weeks in a dose of 2 mg/day with the dose being titrated at 2 weekly intervals to a maximum of 6 mg/day in order to achieve adequate blood pressure control. Frusemide was introduced if blood pressure was not controlled on the maximum lacidipine dose. Blood pressure, creatinine clearance, 24 h urinary albumin excretion and plasma creatinine and albumin concentrations were measured at regular intervals throughout the study. Isotopic GFR was determined at the end of the washout period and at week 24. Lacidipine was not very effective in controlling blood pressure and had an adverse effect on renal function. In 3 patients with an incipient nephrotic syndrome this necessitated withdrawal from the study. Mean GFR of the 10 patients who completed the study decreased from 0.69 ml/s/1.73 m2 at baseline to 0.56 ml/s/1.73 m2 at week 24 (p = 0.006) with a decline in GFR being observed in 9 of these patients. The decrease in GFR was greatest in patients with poorly controlled blood pressure. An insignificant increase in mean urinary albumin excretion occurred during the study with this increase being observed only in patients with albuminuria > 1 g/24 h at baseline. These findings indicated that systemic hypertension altered glomerular hemodynamics and that the vasodilatation of pre-glomerular vessels which followed introduction of the calcium antagonist may have exacerbated this situation. The withdrawal of an angiotensin converting enzyme inhibitor during the washout period may have contributed to these changes. We suggest that renal function should be monitored closely in patients with renal insufficiency when a calcium antagonist is being used to control blood pressure, particularly in those with either marginal blood pressure control, significant albuminuria or an incipient nephrotic syndrome.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Furosemide; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Insufficiency; Serum Albumin

To compare with placebo the efficacies of once-daily administrations of lacidipine and hydrochlorothiazide separately and in combination to elderly patients with systolic hypertension.. Nineteen elderly subjects (five men and 14 women, median age 71 years, range 62-79 years) participated in the study, which had a randomized double-blind crossover design. For each subject there were four treatment phases, each of duration 4 weeks. The initial treatments in each phase were 2 mg lacidipine once a day and 25 mg hydrochlorothiazide once a day, separately and in combination, and placebo. Doses of each agent could be doubled after 2 weeks in each phase if the patient's goal systolic blood pressure had not been achieved. The numbers of subjects administered the higher dose of each treatment were 13 for placebo, 14 for lacidipine, 11 for hydrochlorothiazide and eight for lacidipine plus hydrochlorothiazide.. End-of-phase mean clinic blood pressures were 164/85 mmHg with placebo, 159/82 mmHg with lacidipine, 157/84 mmHg with hydrochlorothiazide and 152/82 mmHg with lacidipine plus hydrochlorothiazide. Systolic blood pressure was significantly reduced during all active treatment phases compared with placebo and that for the lacidipine plus hydrochlorothiazide phase was also significantly less than those for both of the other active treatment phases. There was no difference between sitting and standing blood pressure for any phase. Factorial analysis of the main effects of treatment indicated that the effects of lacidipine and hydrochlorothiazide on clinic blood pressure were additive and also that heart rate was higher when hydrochlorothiazide had been administered. Ambulatory blood pressure monitoring confirmed the pattern of the responses of blood pressure and showed that administration of hydrochlorothiazide had a significantly greater effect on systolic blood pressure and a longer duration of action than did administration of lacidipine. There was no difference in the frequency of adverse effects among any of the phases.. In treating elderly systolic hypertensives the diuretic hydrochlorothiazide is a more effective antihypertensive agent with a longer duration of action than is the calcium channel antagonist lacidipine. In combination the effects of these two drugs on blood pressure are additive.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Aorta; Blood Pressure; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Drug Combinations; Female; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Monitoring, Ambulatory; Systole

Excessive adrenergic responses have been reported in hypertensive patients treated with short-acting dihydropiridine calcium channel antagonists that might worsen cardiovascular risk. In this study we addressed whether lacidipine, a long-acting dihydropiridine, increases the sympathetic excitation produced by moderate dynamic exercise.. Because of the wide changes in autonomic drive during everyday life, the possible influence of antihypertensive regimens should be assessed not only at rest but also during spontaneous, behaviourally induced alterations of sympathovagal balance. This study was designed to test whether treatment with lacidipine might alter the autonomic response to supine moderate dynamic exercise.. We studied 16 moderate hypertensive patients (arterial pressure 151/102 mmHg) at rest and during 30% of nominal maximum recumbent bicycle exercise. The low frequency spectral component of RR interval and of systolic variability (Finapres) furnished markers of sympathetic modulation of the sinoatrial node and of the vasculature, respectively. Studies were performed during placebo and active treatment (lacidipine 4 mg per day).. Lacidipine treatment significantly reduces arterial pressure values at rest and during moderate dynamic exercise, without affecting RR interval and systolic arterial pressure variabilities, both at rest and during moderate exercise.. In conclusion, spectral analysis of RR interval and systolic arterial pressure variabilities indicate that antihypertensive treatment with lacidipine is not associated to an excessive sympathetic drive during moderate exercise.

Topics: Administration, Oral; Autonomic Nervous System; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Electrocardiography; Exercise; Exercise Test; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

The antihypertensive effects and tolerance of once-daily (od), pranidipine, a novel dihydropyridine derivative with a long duration of action, were evaluated in a double-blind, placebo-controlled, parallel-group dose-finding study. A total of 199 patients, with a diastolic blood pressure (BP) of 95-115 mmHg, were included in the trial. After 4 weeks on placebo, patients were randomly assigned to either placebo or pranidipine at 1, 2, 4, or 8 mg od for a further 4 weeks. A dose response was seen in the reduction (delta) of diastolic BP: placebo, delta 1.7 mm Hg; 1 mg, delta 6.4 mmHg; 2 mg, delta 7.5 mmHg, p < 0.01; 4 mg, delta 11.5 mmHg, p < 0.01; and 8 mg, delta 10.6 mmHg, p < 0.01. There were no meaningful changes in heart rate. The number of responders (decrease of diastolic blood pressure to < 90 mmHg and by 10 mmHg or more from baseline value) in each group also revealed a dose-response relationship: placebo = 9%; 1 mg = 25%, n.s.; 2 mg = 27%, n.s.; 4 mg = 41.5%, p < 0.01; and 8 mg = 41%, p < 0.01 (compared with placebo). Plasma concentrations of pranidipine also demonstrated linear dose-response relationships. An increase in adverse events was observed within the 8 mg group. The degree of reduction in BP and the number of responders were not greater in the 8 mg group compared with the 4 mg group, although the plasma concentration (mean values, ng/dl) of pranidine in the 8 mg group was higher (2.2 on day 42; 2.3 on day 56) compared with the 4 mg group (1.4 on day 42; 1.6 on day 56). In conclusion, pranidipine is a well-tolerated and 24-hour effective novel calcium antagonist that reduces BP in a dose-related manner up to 4 mg od.

Topics: Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged

Calcium channel blockers are increasingly used in the treatment of hypertension. Newer calcium channel blockers of the dihydropyridine group have longer elimination half-lives (t1/2) that permit once-daily dosage and are generally better tolerated than their parent compound. In this study, the efficacy and safety of lacidipine and amlodipine were compared in 65 patients with mild-to-moderate hypertension attending the hypertension outpatient clinic of a teaching hospital in a randomized double-blind cross-over trial with dose titration. Lacidipine and amlodipine both significantly reduced systolic blood pressure (SBP: by 19.2 +/- 13.5 and 22.3 +/- 15.3 mm Hg, respectively) and diastolic BP (DBP: 13.3 +/- 4.2 and 12.3 +/- 5.3 mm Hg, respectively) 24 h postdose. There were no significant differences in their antihypertensive effects. The incidence of adverse events (AE) was 3% for lacidipine and 8% for amlodipine. The incidence of withdrawal from the study due to side effects was 0% for lacidipine and 3% for amlodipine. These results suggest that lacidipine is well-tolerated, and is as effective as amlodipine as a once-daily antihypertensive agent.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Female; Half-Life; Humans; Hypertension; Male; Middle Aged; Pulse

In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid wall alterations are assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the intima-media thickness of the carotid artery wall, measured with B-mode ultrasound. About 2300 hypertensive patients have been recruited and randomized to either of the antihypertensive agents. Baseline data for 1965 patients are available, showing a high prevalence of carotid wall lesions: about 82% of the subjects have an intima-media thickness > or = 1.3 mm, defined as plaque in the ELSA protocol; 16% of the subjects have intima-media thickening (> or = 1.0 mm, < 1.3 mm) and only about 1% have normal carotid artery walls. Analysis of demographic data and risk factor prevalence in ELSA patients, and comparison of these preliminary observations with data from other intervention or observational studies indicate that high blood pressure is a very important risk factor for carotid atherosclerosis.

Topics: Antihypertensive Agents; Arteriosclerosis; Carotid Artery Diseases; Dihydropyridines; Europe; Female; Humans; Hypertension; Male; Middle Aged; Prevalence

In a double-blind, randomized, placebo-controlled, parallel-group study the ambulatory blood pressure monitoring (ABPM) and relative tolerability of different doses of manidipine hydrochloride (10, 20 and 40 mg) were compared to placebo in patients with mild to moderate essential hypertension. After an initial 2-week run-in period on placebo, 52 patients, 32 males and 20 females, aged 40 to 63 years, were randomized to receive manidipine 10 mg, 20 mg, 40 mg or placebo, all administered once daily for 4 weeks. Patients were checked after the initial placebo phase and every 2 weeks thereafter. At each visit, casual BP and HR were measured. At the end of the placebo period and after 4 weeks of active treatment, non-invasive 24-h ABPM was performed. 24-h, day-time and night-time ambulatory BP as well as the area under the curve (AUC) and casual BP were dose-dependently reduced by manidipine 10, 20 and 40 mg, without changes in the normal BP circadian profile. The trough:peak ratio for both SBP and DBP was higher than 50% for all three manidipine dosage regimens. The percentage of abnormal ambulatory SBP and DBP readings was significantly reduced in all manidipine-treated groups versus placebo. The risk/benefit ratio suggests that the intermediate manidipine dosage (20 mg) could be a suitable dose regimen for the majority of patients with mild to moderate hypertension.

Topics: Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines

The aim of this multicenter study was to evaluate the efficacy and tolerability of manidipine hydrochloride, a new calcium-antagonist of the dihydropyridine group, in the long-term treatment of mild to moderate hypertension. After a 2-week run-in period on placebo, 183 patients, 98 males and 85 females, with mean age of 53.8 years, sitting DBP > or = 95 and < or = 115 mmHg and SBP < or = 210 mmHg, were given manidipine 10 mg once daily. Two weeks later, patients whose DBP was > or = 90 mmHg or with a reduction in DBP < 10 mmHg were administered with manidipine 20 mg once daily. Follow-up visits were performed at 6, 10, 14, 26, 38 and 52 weeks after starting manidipine treatment. All BP (by mercury sphygmomanometer, Korotkoff I and V) and heart rate (HR) measures were made 24 h after dosing. Adverse events and laboratory data were recorded. Particular attention was paid to the collection of possible major cardiovascular (angina pectoris, myocardial infarction) and cerebrovascular (IRA, stroke) events, observed during the treatment period. One-hundred-and-fifty-one patients completed the study (79 on a 10 mg dose and 72 on a 20 mg dose), whereas 32 dropped out (11 lost to follow-up, 11 insufficient therapeutic response, 7 ADRs, 3 other causes). Significant reductions of BP values were achieved during the manidipine 10 mg treatment period. Analysis of covariance between doses confirmed a more potent hypotensive effect of manidipine 20 mg as compared to 10 mg on sitting DBP and mean BP and on standing SBP, especially in patients with moderate hypertension. At the end of 1 year of treatment the success rates (defined as sitting DBP > or = 90 mmHg or a reduction of > or = 10 mmHg vs baseline) were similar in the two groups (manidipine 10 mg: 96.1%; manidipine 20 mg: 94.5%). No clinically relevant change in HR was observed. Overall, 28 patients (17 in the manidipine 20 mg and 11 in the manidipine 10 mg treated group) complained of adverse events, the most common being ankle oedema (4.9%), headache (3.8%), palpitation (2.7%) and flushing (2.2%). Neither cardiovascular nor cerebrovascular events or other serious adverse event were reported. In conclusion, a significant and constant reduction of BP values was observed with long-term treatment with manidipine. The reduction in BP was dose-related especially in patients suffering from moderate hypertension. Adverse events were mild and relatively more frequent with the higher manidipine dosage.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Time Factors; Treatment Outcome

In order to evaluate the antihypertensive effects of manidipine, at the dosage of 10 or 20 mg once daily, we studied 36 patients (12 males and 24 females, mean age 54.3 years) with mild hypertension. After a wash-out period of 2 weeks and another 2 week run-in period with placebo, all the patients were assigned to a treatment with manidipine 10 mg/ day. After 2 weeks of treatment, the non-normalized (diastolic BP > 90 mmHg) and the non-responders (BP fall < 10 mmHg) received an increase in dosage to 20 mg/day. The drug effects were assessed by casual blood pressure (BP) measurement at baseline and after 4, 8, 12, 24, 36 and 52 weeks. At baseline and after 1 year of treatment a 24-h BP monitoring and a Doppler echocardiogram were performed. Routine laboratory tests were performed at baseline, after 6 months and after 1 year of treatment. At the end of the observation period, both casual systolic (p < 0.01) and diastolic (p < 0.001) BP were significantly reduced; 24-h BP monitoring showed a significant decrease in systolic (p < 0.05) and diastolic (p < 0.01) pressure, systolic and diastolic (p < 0.001) daytime and night-time measurements. The peak to through ratio was 67%. No difference was found in heart rate. Reduced interventricular septum thickness (p < 0.05), increased fractional shortening (p < 0.02), reduced end-systolic stress (p < 0.005) and systemic vascular resistances (p < 0.001), and lower values of atrial filling fraction (AFF) (p < 0.001) after 1 year of treatment have been shown at the Doppler-Echo evaluation. A multilinear regression analysis showed a relation between delta %AFF and delta %24-h systolic BP (R = 0.74; F = 7.5: p < 0.05) and with delta % daytime systolic BP (R = 0.77; F = 9.2; p < 0.02). No abnormal changes were observed in laboratory tests. Three non-responder patients and three patients with adverse effects (1 flushing and 2 ankle oedema) dropped out and were excluded from the final analysis. In conclusion, manidipine at an individualized dose of 10 or 20 mg. was effective and safe in the management of arterial hypertension. Hemodynamic evaluations after 1 year of treatment confirmed an improvement of systolic and diastolic function, with an evident reduction of afterload.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Ultrasonography, Doppler

The effects of MPC-1304, a new calcium channel blocker, on blood pressure, serum lipoproteins, and carbohydrate metabolism were compared with those of atenolol in a group of patients with mild to moderate essential hypertension. Systolic and diastolic pressures were significantly decreased by both MPC-1304 and atenolol administration. Serum levels of apolipoproteins A-I and A-II were significantly increased after 8-12 weeks of MPC-1304 treatment, but were unchanged during a similar period of atenolol treatment. Neither drug induced any significant change in other lipoprotein parameters, fasting blood sugar, immunoreactive insulin, C-peptide or HbA1c. No serious side-effects or abnormal laboratory values were observed during the course of administration of either drug. These findings indicated that MPC-1304 is as efficacious as an antihypertensive drug and is without adverse effect on lipoprotein or carbohydrate metabolism.

Topics: Adult; Aged; Antihypertensive Agents; Apolipoprotein A-II; Apolipoproteins; Atenolol; Blood Glucose; Blood Pressure; C-Peptide; Calcium Channel Blockers; Dihydropyridines; Heart Rate; Hemoglobins; Humans; Hypertension; Insulin; Lipoproteins; Middle Aged; Treatment Outcome

Pranidipine (OPC-13340), a new dihydropyridine calcium antagonist, was given to 9 elderly hypertensive inpatients aged 64-79 years. Once-daily administration of pranidipine (1-2 mg) for 1-2 weeks decreased the 24-h average BP significantly from 167/92 mmHg to 150/83 mmHg without any change in pulse rate (PR) or the variabilities of BP and PR. The reduction of BP was observed exclusively during daytime (171/95 mmHg to 153/86 mmHg, p < 0.01 for SBP, p < 0.05 for DBP), while BP reduction during nighttime was significant only for DBP (157/84 mmHg to 146/79 mmHg, p > 0.05 for SBP, p < 0.05 for DBP). The analysis of the circadian rhythm by the cosinor method revealed that the acrophases of BP and PR were not changed significantly by the treatment with pranidipine. No adverse effects such as flushing and headache developed during the treatment. These results suggest that once-daily treatment with pranidipine is safe and exerts a sufficient antihypertensive effect during daytime with mild reduction of nighttime BP in elderly hypertensives. Furthermore, it does not alter the circadian patterns or variabilities of BP and PR. Thus, pranidipine may be useful as a monotherapy for elderly hypertensives.

Topics: Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Inpatients; Male; Middle Aged

Up to the present the relationship between arterial hypertension or its treatment and cardiovascular complications has been evaluated in terms of the incidence of events, such as fatal and nonfatal myocardial infarction or stroke and cardiac deaths. However, cardiovascular events are not the direct consequence of blood pressure elevation, which, on the contrary, is responsible for atherosclerotic disease. Quantitative ultrasonography is a sensitive, specific and reproducible technique which, in comparison to arteriography, is non invasive and less expensive. The availability of this technique has allowed us to do some studies, one just published, another in the elaboration phase and others ongoing, aimed at evaluating the effects of antihypertensive agents on carotid changes in hypertensive patients. The European Lacidipine Study on Atherosclerosis (ELSA) compares the effects of lacidipine, a calcium-antagonist and of atenolol, a beta-blocker, on blood pressure, on carotid vessel modifications, and on the incidence of cardiovascular events in patients with mild to moderate hypertension with a 4-year follow-up period. Preliminary results of the study, which were concerned with the demographic characteristics of the first 1000 randomized patients enrolled, indicate that 84% of the patients had a carotid plaque, 15% had thickening of the intima-media, and 1% had a normal vessel. These results are both surprising and significant in that they admonish the physician not to neglect patients with mild to moderate hypertension even when they have neither complications nor other risk factors.

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Carotid Artery Diseases; Delayed-Action Preparations; Dihydropyridines; Double-Blind Method; Europe; Humans; Hypertension; Middle Aged

This 12-week, open-label study was conducted to gain experience with losartan potassium, an angiotensin II receptor antagonist, in patients with severe hypertension. Patients were either untreated or withdrawn from current therapy for at least 48 h before initiation of losartan 50 mg once daily. Patients were titrated to 100 mg as needed to achieve a goal of sitting diastolic blood pressure (SiDBP) 90 or 95 mm Hg. Hydrochlorothiazide (12.5 mg once daily titrated to 25 mg) was added and followed by either a dihydropyridine calcium channel blocker (CCB) and/or atenolol, if BP was not controlled. A total of 179 patients with a pretreatment mean baseline BP of 172 +/- 17/112 +/- 18 mm Hg enrolled in the trial and BP was recorded 24 h after dosing at baseline and weeks 2, 4, 8 and the final week (10-12 weeks). The mean reductions in SiDBP from baseline were 7.3, 9.3, 15.9 and 18.9 mm Hg, respectively, and these changes from baseline were statistically significant, P < 0.001. At the end of the trial, 22% of patients remained on losartan monotherapy, 30% required the addition of hydrochlorothiazide (HCTZ) and 31% required both HCTZ and a CCB; 11% required HCTZ and atenolol while 4% required HCTZ, a CCB and atenolol; 2% of patients were on regimens not specified by the protocol. SiDBP < 90 mm Hg was achieved in 68 patients by the final visit; 24% of these patients were treated with losartan monotherapy (50 or 100 mg), 41% achieved control with the addition of HCTZ (12.5 or 25 mg) and 24% required triple therapy which included losartan, HCTZ and a CCB. As assessed by the investigator, 25% of the patients in the study had drug-related clinical adverse experiences. Headache was the most frequently reported clinical adverse event (26% of patients). No clinically significant changes in laboratory parameters were observed. It is concluded that losartan potassium can be used as initial therapy for patients with severe hypertension and can be administered concurrently with hydrochlorothiazide, calcium channel blockers and atenolol.

Topics: Adolescent; Adult; Aged; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atenolol; Biphenyl Compounds; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Losartan; Male; Middle Aged; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints.. In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Topics: Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

The European Lacidipine Study on Atherosclerosis (ELSA) has been designed to compare the effects of two antihypertensive agents, the calcium antagonist lacidipine and the beta-blocker atenolol, on the development of atherosclerosis in hypertensive patients stratified according to the presence of carotid plaques, or the presence or absence of carotid artery intima-media thickening. ELSA is a multinational, multicenter, randomized, double-blind, parallel group study that is to be conducted over a 5-year period. Recruitment and treatment will take place at 23 referral centers in seven countries. A total cohort of 3,660 patients, aged between 45 and 75 years, with diastolic blood pressure 95-115 mm Hg and systolic blood pressure < or = 210 mm Hg at enrollment, will be stratified into three groups according to a B-mode ultrasound analysis of the carotid wall morphology. After a 1-month placebo run-in period, patients will be randomized to receive either lacidipine (4-6 mg once daily) or atenolol (50-100 mg once daily). Nonresponders will be treated with hydrochlorothiazide (12.5 mg, eventually titrated to 25 mg if required), on an open basis. During the course of the study, patients will be monitored by carotid ultrasound assessment and ambulatory blood pressure monitoring. The results of this study should further understanding of the pathobiology of atherosclerosis, and its development and prevention.

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Double-Blind Method; Europe; Humans; Hypertension; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Ultrasonography

Ambulatory blood pressure monitoring (ABPM) is a particularly useful method for evaluating the effects of antihypertensive drugs. ABPM allows the therapeutic effect of an agent to be assessed continually by a large number of measurements, and the greater number of readings contributes to the higher degree of reproducibility associated with ABPM compared to other methods for measuring blood pressure. ABPM also enable measurements to be taken in "real-life" situations and removes the problem of observer bias. The number of patients required for clinical studies can be significantly reduced by using ABPM. It is still essential, however, to identify "white coat" subjects, placebo responders, and patients who do not respond to the treatment. ABPM studies have demonstrated that the novel dihydropyridine calcium antagonist, lacidipine, significantly reduces both systolic and diastolic blood pressures over a 24-h period, both during the day and at night. Furthermore, although the trough-to-peak ratios of many calcium antagonists have been shown to fall below the recommended level of 50%, lacidipine has a ratio above 60%. Other ABPM studies have also shown that lacidipine can correct the 'early morning increase' in blood pressure without effecting the 24-h nycthemeral profile.

Topics: Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Humans; Hypertension; Placebo Effect

In an open, multicenter study, the calcium antagonist lacidipine was tested for efficacy and safety, particularly with respect to any influence on lipid and carbohydrate metabolism. The study was performed in 2,127 patients with essential hypertension. The patients were treated orally, with lacidipine in a dosage of 2-6 mg once daily for 48 weeks. Lacidipine significantly reduced both systolic and diastolic blood pressure by 20 +/- 17 mm Hg and 14 +/- 10 mm Hg, respectively, from baseline values (both p < 0.0001). Decreases in blood pressure were achieved without any adverse effects on lipid and carbohydrate metabolism, either in the total group or in subsets of diabetic or hyperlipidemic patients. It is concluded that lacidipine is a safe and effective drug in the long-term antihypertensive treatment of patients with essential hypertension and with concomitant metabolic disorders such as diabetes mellitus or dyslipidemia.

Topics: Calcium Channel Blockers; Cholesterol; Cholesterol, HDL; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

In a large, open, multicenter study, 2,206 outpatients with mild-to-moderate essential hypertension were recruited by 755 cardiologists throughout France. Patients received treatment with lacidipine for 12 weeks at a dose of 2-6 mg once daily. In 1,637 evaluable patients, lacidipine was shown to reduce blood pressure from a mean of 173/101 mm Hg at baseline to 147/85 mm Hg after 12 weeks, with negligible effects on heart rate. Adverse events were experienced by 29% of patients, of which only 20% were definitely or probably related to lacidipine; these adverse events were generally mild and led to premature discontinuation of treatment in only 8.7% of cases. Overall assessment of efficacy and tolerability by practitioners was very satisfactory. Acceptability and ease of use were assessed highly by the large majority of patients. Subgroup analysis of patients > or = 65 years showed no significant difference when compared to younger patients in terms of efficacy and tolerability. The current study therefore confirms, in a large study population and in general practice, that lacidipine, in a once-daily dose of 2-6 mg, has a significant antihypertensive effect and is well tolerated.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; France; Humans; Hypertension; Male; Middle Aged

Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension.

Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution

The clinical safety of lacidipine, a new dihydropyridine calcium antagonist, has been assessed in a long-term, comparative study in hypertensive patients. Slow-release (SR) nifedipine was used for comparison. The type and incidence of adverse events seen with both drugs are characteristic of the dihydropyridine class of drugs and were mainly due to pharmacologically induced vasodilation, but lacidipine caused a significantly lower incidence of ankle edema than nifedipine SR. There were no unexpected adverse events during the treatment. The addition of atenolol 50 mg once daily did not increase the frequency of adverse events. Therefore, lacidipine can be considered a safe antihypertensive drug, which can be used as a suitable agent for first-line treatment of hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Single-Blind Method

Arterial hypertension is a chronic condition regarded as one of the main risk factors for development of coronary atherosclerosis. As dyslipidemia and reduced glucose tolerance are also risk factors for coronary disease, it is considered important to use antihypertensive drugs having no negative effects on lipid and glucose metabolism when diabetic patients are treated for hypertension. Lacidipine, a new dihydropyridine-like calcium antagonist, has been shown in in vivo and in vitro preclinical studies to possess potent, long-lasting antihypertensive activity. The present study compared the efficacy and safety of once-daily treatment with lacidipine versus nifedipine SR given twice-daily in non-insulin-dependent diabetic patients. Results have shown a similar efficacy of the two treatments: 6 months later, both drugs had reduced blood pressure values [lacidipine from 184.8/105.2 mm Hg to 144.4/87.1 mm Hg; nifedipine slow-release (SR) from 182.3/106.8 mm Hg to 143.6/89.4 mmHg]. However, lacidipine exhibited a lower incidence of adverse events (particularly ankle edema and tachycardia) than nifedipine SR. Finally, both treatments showed no negative effect on metabolic parameters (total cholesterol, high-density lipoprotein cholesterol, triglycerides, and blood glucose).

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cholesterol; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Triglycerides

The aim of this study was to evaluate the effect of lacidipine and nifedipine on lower limb veins. Forty hypertensive patients, aged 30-50 years, with no deep venous thrombosis, venous insufficiency, or hypothyroidism underwent double-blind treatment with placebo (1 week), lacidipine 4 mg once daily (1 week), and slow-release nifedipine 20 mg twice daily (1 week) in randomized sequence. Echo-color Doppler examination of superficial, deep, communicating, and perforating veins of the legs was performed. The results showed venous insufficiency and hypertension after 1-week administration of lacidipine (5 and 15%, respectively) and nifedipine (10 and 25%, respectively) and only two cases (5%) of venous hypertension during placebo administration. Lower limb edema was observed in two patients (5%) during treatment with nifedipine slow-release (SR). The hemodynamic effects of lacidipine and nifedipine were reversible but may contribute to the mechanism of lower limb edema.

Topics: Adult; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Leg; Male; Middle Aged; Nifedipine; Regional Blood Flow; Ultrasonography, Doppler, Color; Veins

Diabetes mellitus is often associated with hypertension and is an additional cardiovascular risk factor. It is therefore important that antihypertensive drugs should have no negative metabolic effects. We present here the results of two distinct studies investigating the clinical efficacy and the metabolic effects of lacidipine in hypertensive patients without concomitant diabetes. Patients in the first study (group A) were hypertensive with non-insulin-dependent diabetes mellitus (NIDDM) and stable blood glucose levels in the 3 months before entering the study. Patients in the second study (group B) were hypertensive without diabetes mellitus. Before the commencement of the study, antihypertensive treatment was discontinued in all patients for a 4-week washout period, followed by 4 weeks of run-in with placebo. Patients were then treated with lacidipine (4 mg o.d.) for 6 months. After 1-2 months, the dose was doubled in patients with uncontrolled blood pressure. Every 2 months, lipid and carbohydrate metabolism were investigated by blood chemistry analyses. The results demonstrate that lacidipine 4-8 mg o.d. is efficacious and well tolerated in hypertensive patients, even in the presence of diabetes mellitus.

Topics: Adult; Aged; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Lipids; Male; Middle Aged

In the present study, we examined the circadian profile of blood pressure (BP) in 10 patients with moderate essential hypertension before and after 6 months of lacidipine therapy. Ambulatory BP was measured at 30-min intervals using SpaceLabs 90207. To account for the unequal time intervals between successive readings, BP means and variances were weighted for the time span between successive readings, and weighted linear-regression analysis was applied. The 24-h BP values were carried out using Fourier analysis, comparing the values from the baseline with those after 24 weeks of lacidipine. After 24 weeks BP values showed a significant decreased compared with baseline values (all p < 0.01). The daily BP curves obtained from Fourier analysis with four harmonics showed that the significant circadian rhythm in nine patients was not altered by lacidipine treatment. The night/day differences were statistically significant at 24 weeks vs. 0 week (all p < 0.01). The overall amplitude and acrophase of the BP curve were statistically significant at 24 weeks (all p < 0.01). After 24 weeks of lacidipine therapy, according to the nocturnal BP fall, we found three intermediate dippers, six dippers, and one non-dipper. By use of the two-step Fourier analysis method, which provides a formal and statistical method to evaluate the presence of a significant diurnal BP rhythm and parametrization of the 24-h BP recordings, we showed that lacidipine long-term therapy is effective in lowering BP and preserving the diurnal BP rhythm.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Fourier Analysis; Humans; Hypertension; Male; Middle Aged

This study estimated the efficacy of sublingual nifedipine 10 mg vs. sublingual lacidipine 4 mg in the management of hypertensive crises. We studied 40 patients with diastolic blood pressure > or = 120 mm Hg, who were divided into two groups of 20. Blood pressure and heart rate were assessed in the recumbent position before treatment and after 30, 120, and 240 min. Comparison of the effectiveness of these drugs was analyzed by Student's t test. Both drugs tested revealed a statistically significant hypotensive effect on diastolic and systolic blood pressure, and few side effects. Compared with lacidipine, nifedipine had a greater hypotensive effect on diastolic and systolic blood pressure in the first 30 min and on the diastolic blood pressure after the first 120 min. However, the hypotensive effect of lacidipine is statistically significant. After 4 h, both drugs showed a similar efficacy without significant statistical variations. We concluded that in the management of hypertensive crises the use of each of these drugs can have a particular range: nifedipine can be used when a pronounced and rapid blood pressure decrement is necessary, whereas lacidipine can be used when a more gradual effect is preferable.

Topics: Administration, Sublingual; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Emergency Medical Services; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine

Isolated systolic hypertension (ISH) is a definite risk factor for cardiovascular complications (i.e., cardiac failure, coronary artery disease, and stroke) independent of diastolic elevation. The prevalence of ISH is estimated to be approximately 15-20% in the population above the age of 60 years, and increases with advancing age. The Systolic Hypertension in the Elderly (SHELL) study is planned to evaluate the efficacy and tolerability of lacidipine, matched with the diuretic chlorthalidone, in treatment of ISH in elderly hypertensive patients (EHP). One hundred fifteen Italian centers will participate in the study. Fifty centers are associated with the Società Italiana di Geriatria Ospedaliera and 65 centers are departments of internal medicine or outpatient clinics for management of hypertension. A total of 4,800 patients will be enrolled in the trial. Two subprojects will consist of periodical echocardiographic evaluation and 24-h ambulatory blood pressure monitoring. The primary end point of the SHELL study is the incidence of cardiovascular and cerebrovascular events in EHP with ISH, treated with either lacidipine or chlorthalidone. In particular, the SHELL trial is intended to determine whether lacidipine treatment will significantly reduce fatal myocardial events and total cardiovascular mortality.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Chlorthalidone; Dihydropyridines; Double-Blind Method; Echocardiography; Female; Humans; Hypertension; Italy; Male; Middle Aged

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Middle Aged

Hypertension is well recognized to be an important cardiovascular risk factor and antihypertensive therapy has been shown to decrease cardiovascular mortality and morbidity as blood pressure control is achieved. At present, management of hypertension is obtained with effective compounds that exhibit a satisfactory safety profile. Among the antihypertensive drugs, calcium antagonists have been proven to possess this property. In the present study, our objective was to compare the antihypertensive effect of two new long-acting dihydropyridines, lacidipine and amlodipine, as once-daily monotherapies in mild-to-moderate hypertensive patients. Eighty hypertensive patients were recruited and after a 3-week washout period were randomized to receive lacidipine 4 mg once daily or amlodipine 10 mg once daily. After 4 weeks, hydrochlorothiazide 12.5 mg was added in patients not adequately controlled, and patients were treated for a total of 8 weeks. At this time, supine mean diastolic blood pressure decrease was 16 mm Hg in the lacidipine group and 10 mm Hg in the amlodipine group (p < = 0.01). Adverse events were reported in 28% of patients treated with lacidipine and in 48% of patients receiving amlodipine. Results of our pilot clinical experience show that lacidipine is a well-tolerated and effective compound, compared with amlodipine, in mild-to-moderate hypertensive patients.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

The carotid artery is one of the most important sites in the progression of atherosclerotic lesions. Atherosclerosis is known to be determined by a variety of factors, among which arterial hypertension is one of the most important. Blood pressure control by antihypertensive treatment is thus of great benefit in management of atherosclerosis, particularly in view of the direct action of some classes of antihypertensive agents on atheromatous lesions. Today, modern diagnostic technique allow a non-invasive examination of the artery wall (B-mode ultrasound and pulsed-Doppler), so that early detection of structural and functional alterations is possible. In order to evaluate the efficacy of the long term blood pressure reduction in the progression and/or in the regression of cardiovascular structural abnormalities, we studied intima-media thickness and arterial compliance during one-year antihypertensive treatment with a new calcium-antagonist, lacidipine, or a diuretic hydrochlorothiazide. In both groups we observed a comparable blood pressure reduction (lacidipine: from 166 +/- 5/100 +/- 1 to 142 +/- 4/88 +/- 2 mmHg; hydrochlorothiazide: from 154 +/- 5/102 +/- 2 to 140 +/- 4/88 +/- mmHg; both p < 0.01). On the contrary, only in patients treated with lacidipine did we obtain a significant improvement in carotid blood flow (383 +/- 16 vs 411 +/- 16 ml/min p <) and in arterial compliance (0.8 +/- 0.1 vs 1.2 +/- 0.2 cm/dyne p < 0.01). Indeed, we observed a different behaviour of the intima-media thickness in the two groups (lacidipine: 1.11 +/- 1.4 vs 1.13 +/- 1.5 mm n.s.; hydrochlorothiazide: 1.15 +/- 0.15 vs 1.21 +/- 0.17 mm p < 0.06). Our results demonstrate that an effective antihypertensive treatment with calcium antagonists may influence the progression of carotid vascular abnormalities.

Topics: Aged; Antihypertensive Agents; Blood Circulation; Blood Pressure; Calcium Channel Blockers; Carotid Arteries; Carotid Stenosis; Dihydropyridines; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Time Factors; Tunica Intima; Ultrasonography, Doppler; Vascular Resistance

The objective of this double-blind study was: 1) to evaluate and compare the effects of treatment with two dihydropyridines--isradipine and nitrendipine--on basal and circadian blood pressure and on 24-h platelet activity; and 2) to investigate the influence of low-dose aspirin on the antihypertensive, antiplatelet (antiaggregatory) efficacy of dihydropyridines. After a 4-week placebo period, 39 patients with mild-to-moderate essential hypertension were treated for 8 weeks, according to a double-blind design, with either isradipine at 2.5 mg/day (n = 20) or nitrendipine at 10 mg/day (n = 19). After this treatment period, aspirin at 100 mg/day was added to both treatments for a further 8 weeks. At week 0 (after placebo), week 8 (after dihydropyridines), and week 16 (after dihydropyridines + aspirin), blood pressure, plasma levels of beta-thromboglobulin (beta-TG) and platelet aggregation induced by serotonin (5-HT) were measured six times a day (at 5:30 AM, 9:00 AM, noon, 3:30 PM, 7:00 PM, and 11:30 PM). Both isradipine and nitrendipine significantly lowered basal and circadian blood pressure with no differences in antihypertensive efficacy between them. Low doses of aspirin did not interfere with the antihypertensive efficacy of either agent. All patients exhibited increased platelet activity after the placebo period in the form of increased beta-TG levels with circadian changes. The steepest increase in beta-TG was observed during the morning hours until midday. Treatment with the dihydropyridines inhibited platelet aggregability, shifting the beta-TG curve toward lower values. Addition of aspirin to nitrendipine produced a significant decrease and flattening of the beta-TG curve, whereas the combination of aspirin and isradipine was accompanied by a partial increase in plasma beta-TG levels. In conclusion, treatment with dihydropyridines alone or in combination with low-dose aspirin can prevent circadian increases in platelet activity in patients with essential hypertension.

Topics: Adult; Aspirin; Blood Platelets; Blood Pressure; Circadian Rhythm; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Nitrendipine

Topics: Blood Pressure; C-Peptide; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Potassium

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Humans; Hypertension; Middle Aged; Single-Blind Method; Vasodilation

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.

Topics: Adult; Antihypertensive Agents; Atenolol; Blood Pressure; Dihydropyridines; Double-Blind Method; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Exercise; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Pulse

Antihypertensive agents are routinely studied in terms of changes in the level of systolic, diastolic, and mean arterial pressure. Pulse pressure may be independently modified from these parameters as a consequence of specific changes in the mechanical properties of the large arteries and in the timing of incident and reflected pressure waves. The aim of this study was to evaluate the changes in pulse pressure produced by acute calcium blockade by the dihydropiridine derivative, lacidipine, in a double-blind design versus placebo in 18 subjects with mild to moderate hypertension. Carotid and femoral pressure waveforms were recorded noninvasively by applanation tonometry using a Millar micromanometer-tipped probe. Early (Pi) and mid-to-late (Ppk) systolic peaks of carotid pressure waveform were evaluated, enabling the effect of incident pressure wave to be quantified as the ratio of Pi to the total height of carotid pulse wave (PP) (Pi/PP) and the effect of wave reflections as the ratio (Ppk-Pi)/PP. Travel time of the reflected wave (delta tp) was timed from the foot of the pressure wave to the foot of the late systolic peak. Pulsatile changes in diameter were studied using noninvasive echo-tracking techniques. Whereas mean arterial pressure significantly decreased following lacidipine, pulse pressure measured at three different sites (brachial, carotid, and femoral arteries) was unchanged. Carotid-femoral pulse wave velocity, carotid and femoral arterial stiffness, and delta tp were not modified, whereas the (Ppk-Pi)/PP ratio and left ventricular ejection time was significantly reduced and the Pi/PP ratio was significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arteries; Blood Pressure; Calcium Channel Blockers; Carotid Arteries; Diastole; Dihydropyridines; Double-Blind Method; Elasticity; Femoral Artery; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Systole

The effects of dihydropyridine calcium antagonists on blood pressure and platelets, and the effects of aspirin on the circadian antihypertensive efficacy of dihydropyridines and on the 24-h platelet-activity profile, were the focus of a double-blind study. Patients with essential hypertension were treated for 8 weeks with either isradipine focus of double-blind study. Patients with essential hypertension were treated for 8 weeks with either isradipine (2.5 mg/day) or nitrendipine (10 mg/day). Aspirin (100 mg/day) was added to both treatment groups for a further 8 weeks. Measurements were taken after 4 weeks of placebo, after 8 weeks of dihydropyridine treatment, and after 8 weeks of treatment combined with aspirin. Plasma levels of beta-thromboglobulin (beta-TG) and platelet aggregation induced by serotonin were measured six times during 24 h. Both dihydropyridines significantly lowered systolic and diastolic blood pressure. The addition of aspirin to dihydropyridine treatment had no significant effects on systolic or diastolic blood pressure. Dihydropyridine treatment lowered the increased 24-h plasma beta-TG profile and inhibited platelet aggregability. Aspirin added to nitrendipine led to a further significant decrease in beta-TG levels whereas its addition to isradipine was accompanied by a partial increase in plasma beta-TG. It is concluded that increases in platelet activity in hypertensive patients can be prevented with either isradipine alone or nitrendipine plus aspirin. Aspirin in a daily dose of 100 mg does not affect the antihypertensive efficacy of calcium antagonists.

Topics: Adult; Aspirin; Blood Platelets; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Nitrendipine

Manidipine hydrochloride (MH) is a new calcium channel antagonist which is not yet available in Taiwan. Thus, a clinical trial was performed. The clinical effects and adverse effects of MH were compared with those of nifedipine hydrochloride retard monotherapies. Sixty-three out-patients with mild to moderate hypertension and no advanced systemic diseases were randomly divided into 2 groups. Twenty patients remained in each group after some patients withdrew from the study. Blood pressure decreased significantly after treatment in both groups (p < 0.01). In the manidipine group, systolic blood pressure (SBP) decreased from 164 +/- 14 to 140 +/- 18 mmHg and diastolic BP (DBP) decreased from 99 +/- 6 to 87 +/- 7 mmHg by the 8th week. In the nifedipine group, SBP decreased from 163 +/- 11 to 134 +/- 17 mmHg and DBP decreased from 101 +/- 10 to 88 +/- 9 mmHg by the 8th week. Pulse rates did not change significantly. Antihypertensive efficacy was 18/20 (90%) and 19/22 (86.4%) in the manidipine and nifedipine groups, respectively. There were a few adverse effects in both groups, the reaction was severe as to lead to the discontinuation of medication in two patients in the nifedipine group. No significant changes in laboratory tests were identified in either group, except for minimal decreases of lactate dehydrogenase and creatine kinase in the nifedipine group. We conclude that MH was equally safe and effective as nifedipine and it may have less severe side effects compared to nifedipine.

Topics: Adult; Aged; Blood Pressure; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Nitrobenzenes; Piperazines

Topics: Adult; Aldosterone; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Renin; Verapamil

Topics: Aged; Antihypertensive Agents; Cohort Studies; Dihydropyridines; Female; Humans; Hypertension; Male; Sweden

The effects of 5 to 20 mg/day of manidipine, a dihydropyridine-type calcium channel blocker, on blood pressure and renal function were studied in 71 hypertensive patients with renal impairment (serum creatinine levels between 1.4 and 5 mg/dl). Thirty-two patients were followed for more than 48 weeks, and 22 patients remain on the treatment after 24 to 48 weeks. The study was interrupted in 17 patients. In 32 patients who were followed for more than 48 weeks, blood pressure was well controlled in 21 (65.6%) patients. In seven of these patients alpha beta- or beta-blockers were added to manidipine to control blood pressure. Only 1 of 32 patients whose serum creatinine level was below 3.1 mg/dl showed deterioration of renal function during the 48 weeks. Two of the 17 patients in whom the study was interrupted died of cerebral bleeding or pneumonia. Two patients discontinued the study because of complications of myocardial infarction and retinal infarction, six withdrew because of deterioration in renal function, and the other seven patients withdrew because of poor compliance. From these studies, it was concluded that manidipine is well tolerated and effective in hypertensive patients with renal impairment (serum creatinine levels < or = 3 mg/dl). If blood pressure is not well controlled in these patients, combined treatment with manidipine and alpha beta- or beta-blockers is recommended.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Antihypertensive Agents; Blood Urea Nitrogen; Calcium Channel Blockers; Creatinine; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Nitrobenzenes; Piperazines; Renin; Treatment Outcome

Importance of systolic over diastolic blood pressure measurements: Systolic pressure is known to be a more important independent cardiovascular risk factor than diastolic pressure in subjects over 50 years of age; after that age, a high incidence of two types of systolic hypertension is observed, sustained essential hypertension with a disproportionate increase in systolic pressure and isolated systolic hypertension. Effects of lacidipine on blood pressure in the elderly: The effects of vasodilators on blood pressure have been studied extensively. Recently, lacidipine, nitrendipine and enalapril were compared in a multicenter, randomly allocated, double-blind trial in elderly hypertensive patients with a disproportionate increase in systolic pressure treated for 8 weeks (n = 278). In these patients, supine systolic pressure decreased to a greater extent with lacidipine and enalapril than with nitrendipine, the difference between lacidipine and nitrendipine reaching statistical significance. In another trial, lisinopril produced a greater reduction in systolic pressure than atenolol. Finally, in a study in elderly patients with systolic hypertension, long-acting isosorbide dinitrate induced a selective sustained decrease in systolic pressure. Mechanisms of action of vasodilators: A fall in systolic blood pressure may be produced by vasodilators through a reduction in peripheral resistance with or without an active change in arterial compliance. Dihydralazine-like substances do not increase arterial compliance whereas angiotensin converting enzyme inhibitors, calcium entry blockers and nitrates tend to increase arterial compliance for the same decrease in mean arterial pressure.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Nitrendipine; Time Factors; Vasodilator Agents

Topics: Blood Pressure; Calcium Channel Blockers; Chronic Disease; Dihydropyridines; Diltiazem; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Stroke Volume

The effects on cardiac structure and function of antihypertensive regimens with different effects on the renin-angiotensin system were compared. In a 1-year study, 32 patients with essential hypertension were randomized to treatment with either the converting enzyme inhibitor lisinopril or the calcium antagonist isradipine; hydrochlorothiazide could be added. Blood pressure (BP) decreased significantly (p less than 0.001) and similarly in the 2 treatment groups. Left ventricular (LV) mass was already significantly reduced after 16 weeks of treatment (p less than 0.001) and remained decreased thereafter, with no difference in the response to the 2 treatment regimens. The change in LV mass was related to the decrease in systolic BP for the total study group (p less than 0.001) and for each treatment group separately. During the 3-week run-out period on placebo, BP and LV mass increased again (p less than 0.01). Afterload decreased during active treatment (p less than 0.001), and fractional shortening of the LV internal diameter was significantly increased (p less than 0.01) to a similar extent in both groups. The ratio of peak mitral flow velocities during atrial contraction and early filling was reduced after 1 year of active treatment in the total study group (p less than 0.01); this change was similar in both groups. The data suggest that the regression of LV mass during antihypertensive therapy is mainly related to the decrease in systolic BP.

Topics: Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Echocardiography, Doppler; Enalapril; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertension; Isradipine; Lisinopril; Male; Random Allocation; Regression Analysis; Ventricular Function, Left

The effects of the calcium antagonist manidipine 20 mg/day on changes in blood pressure and renal hemodynamics in response to acute stress by the mental arithmetic test (MAT) and the cold pressor test (CPT) were investigated in 14 patients with essential hypertension (median age: 50 +/- 2, WHO stage I-II). During the drug-free period, acute stress by both MAT and CPT caused an increase in the renal vascular resistance index (RVRI) [% change in RVRI, 17% for MAT (p < 0.05) and 26% for CPT (p < 0.01)] and an increase in blood pressure [% change in mean blood pressure (MBP): 17% for MAT (p < 0.001) and 16% for CPT (p < 0.001)]. CPT stress resulted in a reduction in RAFV (% change in RAFV: -12%, p < 0.05). Oral administration of manidipine resulted in hypotensive effects at rest [MBP: from 116 to 99 mmHg, p < 0.001], no change in RAFV (31.3 to 32.9 cm/sec, p = ns), and reduced RVRI (from 3.9 to 3.2 mmHg.sec/cm, p < 0.02). Manidipine inhibited the hypertensive response to acute stress by both MAT and CPT [% change in MBP: from 17% to 11% for MAT (p < 0.02) and from 16% to 11% for CPT (p < 0.01)] and also inhibited the increase in RVRI [% change in RVRI: from 17% to -1% for MAT (p < 0.05) and from 26% to 8% for CPT (p < 0.01)]. Manidipine has beneficial effects on blood pressure and renal hemodynamics at rest in patients with essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adult; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Nitrobenzenes; Piperazines; Renal Circulation; Reproducibility of Results; Stress, Physiological; Vascular Resistance

The effect of manidipine, a new Ca2+ antagonist, on intrarenal hemodynamics was assessed in essential hypertension and compared with nicardipine, a previously studied Ca2+ antagonist. Identical 2-week studies were repeated before and during the administration of manidipine (10 mg once daily, 2 weeks) in 3 patients with essential hypertension who were given regular- and sodium-restricted diets for 1 week each. The renal function curve (pressure-natriuresis relationship) was drawn by plotting the urinary sodium excretion rate on the y-axis as a function of the systemic mean arterial pressure (MAP) on the x-axis. Assuming that the difference between MAP and the extrapolated x-intercept of the renal function curve represents the effective filtration pressure across the glomerular capillary walls, the intrarenal hemodynamics were calculated (e.g., afferent arteriolar resistance (RA), efferent arteriolar resistance (RE), and glomerular pressure (PG)). During the regular sodium diet, MAP was lowered from 100 +/- 7 to 93 +/- 5 mmHg (p < 0.04) and the effective filtration pressure was lowered from 20 +/- 2 to 10 +/- 3 mmHg (p < 0.05); the renal plasma flow rate (pre: 560 +/- 74 vs. post: 627 +/- 108 mL/min) and glomerular filtration rate (82 +/- 10 vs. 78 +/- 5 mL/min) were not altered. RA remained unchanged (3,800 +/- 700 vs. 3,400 +/- 300 dyn.sec.cm-5; % reduction: 4 +/- 16%) whereas RE was reduced from 4,300 +/- 700 to 3,300 +/- 800 dyn.sec.cm-5 (19 +/- 15%). Thus, PG was lowered from 58 +/- 2 to 50 +/- 2 mmHg (13 +/- 3%), which parallels with the reduction in MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Blood Proteins; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Hematocrit; Humans; Hypertension; Kidney; Male; Middle Aged; Nicardipine; Nitrobenzenes; Piperazines; Renal Circulation; Sodium; Sodium, Dietary

Hypertension is an important factor that accelerates deterioration in renal function. This study evaluated the antihypertensive effectiveness, tolerability, and safety of manidipine hydrochloride, a new dihydropyridine calcium channel antagonist. Sixteen patients (10 men and 6 women) with hypertension and renal disorders received 10 or 20 mg of manidipine once daily for 12 weeks. After 4 weeks of therapy, manidipine treatment produced significant reductions in both systolic and diastolic blood pressures to 146.9 +/- 3.2/87.1 +/- 2.1 mmHg from a baseline value of 174.4 +/- 3.0/98.4 +/- 3.0 mmHg. The antihypertensive effect was well tolerated and sustained during drug administration. Biochemical variables including serum creatinine were essentially unchanged during therapy despite the marked reduction in blood pressure. In addition, renal function did not deteriorate during manidipine therapy as assessed by urinary excretion of phenolsulfonphthalein (22.6 +/- 4.0% vs. 27.9 +/- 6.0%, control). No severe adverse effects were encountered during therapy. We conclude that manidipine is a safe and useful antihypertensive agent for the management of hypertensive patients with renal disorders.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Urea Nitrogen; Calcium Channel Blockers; Creatinine; Dihydropyridines; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Nitrobenzenes; Piperazines

The effects of manidipine (10 mg/day for 7 days) on the renal hemodynamics and vasoactive humoral factors were examined in 6 adults with diabetes mellitus (DM). Mean duration of DM was 9 +/- 2 years; serum creatinine concentration was 0.9 +/- 0.04 mg/dL. Plasma endothelin-1 (ET-1) concentration was 5.4 +/- 0.7 pg/mL before manidipine, compared with 1.9 +/- 0.2 pg/mL in 14 controls (p = 0.03%). Systolic and mean blood pressure decreased significantly during treatment without changes in glomerular filtration rate, renal plasma flow, or filtration fraction. Renal vascular resistance tended to decrease and fractional excretion of sodium significantly increased from 1.35 +/- 0.27% to 2.06 +/- 0.47 (p = 2.96%). ET-1 significantly decreased from 5.4 +/- 0.7 pg/mL to 3.5 +/- 0.6 (p = 2.95%), while plasma angiotensin II, atrial natriuretic factor, urinary excretion rate of ET-1, and albumin excretion rate did not change. Manidipine lowers blood pressure without adversely affecting renal function in diabetic patients. Manidipine, which lowers ET-1, may protect from progressive renal injury in diabetics.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Dihydropyridines; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Renal Circulation

Effects of manidipine, a new calcium antagonist, and delapril, an angiotensin converting enzyme inhibitor, on glucose and lipid metabolism were investigated in mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were treated with either manidipine 10 mg/day (n = 12, mean age 63 +/- 2 years) or delapril 30 mg/day (n = 8, 62 +/- 3 years) for 12 weeks. Glucose and insulin (IRI) responses to 75 g oral glucose load, glycosylated hemoglobin A1c (Hb A1c), serum levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride and apolipoproteins, and 24 h urinary excretion of C-peptide were measured before and at the end of treatment. Both manidipine and delapril showed adequate hypotensive effects. Neither manidipine nor delapril affected blood glucose and IRI responses to glucose load. Manidipine showed no effect on lipids whereas delapril increased HDL cholesterol (47 +/- 5 mg/dL to 61 +/- 7, p < 0.05), although total cholesterol and triglyceride were not altered. The ratio of TC-HDL cholesterol/HDL cholesterol was decreased by delapril (3.44 +/- 0.30 to 2.61 +/- 0.45, p < 0.05). There were no significant changes in apolipoproteins. Both manidipine and delapril have adequate antihypertensive actions without unfavorable effects on glucose and lipid metabolism in hypertensive patients with NIDDM. Delapril seems to have a beneficial effect on lipid metabolism.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Indans; Lipids; Male; Middle Aged; Nitrobenzenes; Piperazines

A multicenter open study was performed to evaluate manidipine monotherapy for 6 months on quality of life in hypertensive patients. One hundred and sixty-six patients with essential hypertension were enrolled. Of these, 2 were excluded because of violation of entry criteria, 4 withdrew from treatment because of side effects, and 12 for personal reasons. Manidipine treatment observed at a daily dose of 10 to 20 mg produced effective reduction in blood pressure during the course of the study. Adverse reactions such as palpitation or headache were experienced by 5 of 166 (3%) patients. Quality of life (QOL), assessed grossly by attending physicians, was rated as improved in 62% and unchanged in 36% of patients. Significant improvements in mean QOL scores were noted in general symptoms, physical symptoms and general well-being, work performance and satisfaction, sleep scale, emotional state, cognitive function, sexual function, and self-control. Elderly patients, age 60 years and older, achieved significant improvement in the same QOL items as in all cases; there was no difference between younger and older age groups. In conclusion, manidipine monotherapy is useful for treating patients, including the elderly, with essential hypertension, and this therapy improves their quality of life.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Middle Aged; Nitrobenzenes; Piperazines; Quality of Life

In order to investigate the effects of manidipine, a newly developed long-acting calcium antagonist, on the diurnal variation of arterial pressure and systemic hemodynamics in patients with essential hypertension, we examined 24-h arterial pressure using a direct arterial pressure monitoring method and cardiac output using the cuvette method before and during manidipine treatment. Once-a-day administration of manidipine at daily doses of 10 to 40 mg decreased systolic and diastolic arterial pressures at almost all measurement points. The arterial pressure reductions were not significantly different between daytime and nighttime. Arterial pressure variability expressed in terms of the standard deviation of values was not affected by manidipine treatment. Thus, it appears that patients treated with manidipine can avoid the excessive decrease in arterial pressure during nighttime that may occur with the use of some other calcium antagonists. Heart rate and its variability were unaffected by manidipine treatment. A hemodynamic study revealed that manidipine did not change cardiac output, but significantly decreased total peripheral vascular resistance at rest. It is concluded that once-a-day administration of manidipine at daily doses of 10 to 40 mg brings about a safe and stable antihypertensive effect over a 24-h period, without affecting the diurnal variation of arterial pressure and heart rate. Dilation of the resistance vessels underlies the antihypertensive effect of the agent.

Topics: Adult; Aged; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Diastole; Dihydropyridines; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Nitrobenzenes; Piperazines; Systole

The 24-h blood pressure (BP) response to once-daily manidipine monotherapy was examined in an open, nonrandomized study of 17 patients with untreated essential hypertension. Manidipine (10-30 mg) was administered once daily for a minimum of 2 weeks. BP and heart rate (HR) were monitored every 30 min for 48 h by an ambulatory BP monitoring device (ABPM-630, Nippon Colin) before and after therapy. Manidipine significantly (p < 0.005) decreased mean systolic and diastolic BP during the entire 24 h, day-active and night-resting periods. The reduction in both systolic and diastolic BP was consistent throughout the whole day. Manidipine also significantly reduced the fractionated pressure-time indices of both systolic and diastolic BP consistently throughout the 24-h period. The circadian amplitude of BP in hypertensive patients, which was higher than that in normal reference subjects, was reduced by manidipine into the reference range. The acrophase of BP in hypertensive patients, which was similar to the reference value, was not altered by manidipine treatment. Manidipine did not change the mean HR during 24-h, day-active or night-resting periods. Therefore, once-daily manidipine monotherapy showed a consistent antihypertensive effect over 24 h and optimized the circadian amplitude of BP without an increase in HR.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitors; Calcium Channel Blockers; Circadian Rhythm; Diastole; Dihydropyridines; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Nitrobenzenes; Piperazines; Systole

MIS is a one-year Multicentre Isradipine Study of the treatment of essential hypertension, in which participated seven centres in Czechoslovakia. The study comprised 144 patients with mild or medium severe hypertension. Isradipine belongs into the group of dihydropyridine derivatives with a high specific and low non-specific affinity to dihydropyridine binding sites of the L-type of calcium channels. After a four-week placebo period isradipine treatment (2.5 mg (1/2 tablet twice a day/was started. This dose increased to 5 mg (1 tablet twice a day) unless normalization of the diastolic pressure was achieved by a smaller dose. Monotherapy with isradipine normalized the diastolic pressure (less than 90 mmHg) in 44% of the hypertonic patients. 56% hypertonics where monotherapy with isradipine did not reduce the diastolic pressure below 90 mmHg were treated by a combination of isradipine and bopindolol. This group of patients had a significantly higher systolic and diastolic pressure, a higher number of erythrocytes and thrombocytes at the onset of the investigation. Addition of bopindolol to isradipine proved very effective. At the end of the one-year study 87% of the patients had a normal diastolic pressure. Isradipine as monotherapy and combined with bopindolol did not influence the metabolic risk factors of IHD and drug tolerance was very good.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pindolol

Calcium channel antagonists, when used to treat hypertension, may modulate baroreflex function and vascular responsiveness to endogenous vasoconstrictors. We studied regional blood flow, cardiopulmonary baroreflex function, and pressor responses in nine hypertensive patients (mean age of 44 +/- 7 years), eight males and one female, treated with isradipine (ISR), a dihydropyridine calcium channel antagonist, in a placebo-controlled, crossover trial. Each patient underwent determination of blood pressure and forearm, splanchnic, and renal blood flows (by strain gauge plethysmography and indocyanine green and p-aminohippurate clearances, respectively) at baseline and during cardiopulmonary unloading by lower body negative pressure (LBNP) at -10 and -20 mm Hg. ISR decreased the mean arterial pressure from 105 +/- 2 to 93 +/- 2 mm Hg (p less than 0.01). ISR did not change supine forearm or splanchnic vascular resistances, but renal vascular resistance fell 30% during treatment (from 0.12 +/- 0.02 to 0.09 +/- 0.01 mm Hg min/ml, p less than 0.05). Cardiopulmonary baroreceptor unloading by LBNP elicited comparable effects on forearm, splanchnic, and renal vascular resistance before and during ISR treatment. Baroreceptor unloading during placebo did not change plasma NE or PRA; during ISR, LBNP elicited a progressive rise in these hormones. The pressor response to NE was potentiated during ISR treatment (p less than 0.05); in contrast, the pressor response to angiotensin II infusion was blunted by calcium blockade (p less than 0.05). The present study, therefore, demonstrates that calcium channel blockade with ISR preserves, and may even augment, cardiopulmonary baroreflex function. These physiologic responses may contribute to the relatively low incidence of symptomatic orthostatic hypotension observed during chronic treatment with this agent.

Topics: Adult; Angiotensin II; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Isradipine; Male; Middle Aged; Norepinephrine; Pressoreceptors; Reflex; Regional Blood Flow

Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke, the reduction in coronary artery disease mortality has been less impressive. It may be that the antihypertensive drugs used in these trials induced metabolic disturbances, or produced inadequate regression of left ventricular hypertrophy, thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering. Isradipine, a dihydropyridine calcium antagonist known to be an effective antihypertensive agent, has also displayed pronounced antiatherogenic effects in animals. Thus, a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure, but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries, thereby leading to prevention of clinical sequelae of atherosclerosis. On this basis, a 3-year clinical trial is being carried out in the United States--the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)--to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients. The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries, as measured by B-mode ultrasonography.

Topics: Antihypertensive Agents; Arteriosclerosis; Dihydropyridines; Double-Blind Method; Female; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Male

The tolerability of isradipine was evaluated in an open trial of patients with mild-to-moderate essential hypertension as treated in general practice. The primary objective was to identify all adverse reactions, especially those that were newly occurring (greater than or equal to 6 reports), with a frequency greater than 1/1,000. Over 1,100 general practitioners and 5,526 patients participated in this trial. After a 2-week washout period, and a 3-week placebo run-in, patients with diastolic blood pressure (DBP) greater than or equal to 95 mm Hg were initially given isradipine at 1.25 mg twice daily. After 4 weeks, doses were doubled if DBP was greater than 90 mm Hg. If, after a further 4 weeks with doubled dosages, the DBP was still greater than 90 mm Hg, a second (nonspecified free-choice) antihypertensive agent was added to the treatment. Adverse events were recorded by open questioning. The incidence of adverse events was found to be similar to that with placebo; adverse events were generally mild or moderate in intensity and disappeared over time. No newly occurring adverse events were found. In conclusion, isradipine is safe and well tolerated at effective antihypertensive doses in patients with mild-to-moderate hypertension as treated in general practice.

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Drug Tolerance; Humans; Hypertension; Isradipine

At the end of a short-term (3-month) study of antihypertensive treatment of mild-to-moderate hypertension, 141 of the 200 study patients continued into a 2-year follow-up of isradipine as monotherapy or in combination with other antihypertensive agents. Although all 141 patients completed the first year, only 102 completed the study. Twenty-four patients dropped out: 2 with flushing; 1 each with arrhythmia, edema, angina, and headache; 12 who were noncompliant; 2 with disease unrelated to the study drug; and 4 for reasons unknown. Before the follow-up, 70% of the 141 patients were taking isradipine; after 2 years, 63% were still taking isradipine as monotherapy. During the follow-up study, the blood pressure remained stable (142.9/86.8 mm Hg after 3 months, and 142.9/86.2 mm Hg after 2 years), whereas the normalization rate was only slightly changed (73 vs. 75.2%). The incidence of reported adverse events decreased with time. At the end of the short-term study, 44.7% of patients had reported one or more adverse events; after 2 years of treatment, only 14.4% reported adverse events. Two patients had ECG signs of left ventricular hypertrophy: one showed no relevant changes while the other presented clear signs of regression. No clinically relevant laboratory abnormalities were noted during the study. In conclusion, isradipine is effective, well tolerated and safe in the long-term treatment of mild-to-moderate hypertension.

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Humans; Hypertension; Isradipine

A short-term trial of isradipine was conducted to assess its effectiveness and tolerability in the treatment of mild-to-moderate hypertension. The study was carried out by general practitioners and involved 2,702 patients, aged 18-70 years, who had diastolic blood pressures (DBP) of 95-114 mm Hg. Patients completed a pretreatment phase of up to 4 weeks for antihypertensive drug washout and placebo run-in, before entering a 12-week active-treatment phase with 1.25 mg of isradipine twice daily, which was increased after 4 weeks to 2.5 mg twice daily, depending on the blood pressure response. At the end of 12 weeks, the mean systolic blood pressure (SBP) and DBP were 148.1 and 86.7 mm Hg compared with 169.0 and 103.0 mm Hg after placebo, respectively. The majority of patients (89.6%) had a DBP reduction greater than 10 mm Hg, and 86.2% had normalized DBP (less than or equal to 90 mm Hg) at the end of treatment. Adverse events were reported by 2.8% of patients, and 90% of patients and general practitioners reported satisfaction with the treatment. Thus, our results indicate that isradipine is effective and well tolerated, and may deserve a place as first-line treatment in mild-to-moderate hypertension.

Topics: Adolescent; Adult; Aged; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged; Portugal

The clinical efficacy and tolerability of isradipine was evaluated in 63 patients with mild-to-moderate hypertension [supine systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) greater than or equal to 95 mm Hg]. Patients were divided into two groups according to age: group A (n = 41), aged 37-69 years (mean age of 54 +/- 7 years); group B (n = 22), aged 70-80 years (mean age of 72.8 +/- 2.4 years). After a 3-week washout period, group A received 2.5 mg of isradipine twice daily for 6 weeks. Group B received 1.25 mg of isradipine initially, increasing to 2.5 mg twice daily according to treatment response and tolerability. At the end of treatment (week 6), there were statistically significant decreases (p less than 0.01) in supine SBP and DBP in both groups compared with baseline values: the mean SBP in groups A and B decreased from 160.0 +/- 14.7 to 133.6 +/- 10.0 mm Hg and from 161.6 +/- 17.8 to 134.8 +/- 10.9 mm Hg, respectively; the mean DBP in groups A and B decreased from 101.3 +/- 3.0 to 83.6 +/- 5.5 mm Hg and from 101.3 +/- 8.4 to 84.2 +/- 3.6 mm Hg, respectively. Clinical and laboratory parameters did not change significantly during treatment. Side effects (headache, flushing, palpitations, and edema) were mild/moderate and disappeared after the first 2 weeks of treatment. In conclusion, 2.5 mg of isradipine twice daily is effective and well tolerated in the treatment of mild-to-moderate hypertension regardless of patient age.

Topics: Adult; Age Factors; Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Tolerance; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged

Twenty-four patients with mild-to-moderate hypertension (19 women, 5 men; mean age of 49 +/- 9.1 years) completed a 2-week washout phase followed by 1 week of single-blind placebo. Patients were then given isradipine at 2.5 mg twice daily, which was increased to up to 7.5 mg twice daily according to the blood pressure response, over a 12-month period. Thirteen patients completed the trial. The supine and sitting blood pressure decreased to normal levels within 6 weeks of starting active treatment. Heart rate remained unchanged. Plasma cholesterol and triglycerides did not change significantly. Plasma high-density lipoprotein (HDL) cholesterol increased significantly (p less than 0.05) and a decrease (NS) was observed in low-density lipoprotein (LDL) cholesterol and in the LDL/HDL cholesterol ratio. Very-low-density lipoprotein (VLDL) cholesterol did not change, nor did other biochemical laboratory tests, or electrocardiographic and echocardiographic parameters. The most notable side effects were headache (n = 1), flushing (n = 1), palpitations (n = 3), and pretibial edema (n = 1). In conclusion, our results indicate that isradipine is safe and effective in the long-term treatment of mild-to-moderate hypertension. It also appears to have beneficial effects on lipid metabolism.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Isradipine; Lipids; Male; Middle Aged

The effects of the calcium antagonist isradipine and the beta-blocker metoprolol, which are based on different antihypertensive therapeutic principles, were evaluated in 52 men with mild-to-moderate hypertension in a 6-week, double-blind, randomized study. Mental stress-testing was performed before and after active treatment. With isradipine (n = 26), the stress-induced responses of cardiac output and total peripheral resistance were not significantly changed, but the blood pressure (BP) response, specifically the diastolic response, was decreased. With metoprolol (n = 26), there was a decreased response of cardiac output and an increased response of total peripheral resistance, and the BP response was even greater than it had been before treatment. Thus, these results indicate that beta-blockade is effective in reducing cardiac responsiveness but, because of vascular counterregulatory mechanisms, BP responsiveness is not decreased. In contrast, calcium antagonism preserves the physiological hemodynamic profile while reducing BP responsiveness to stress.

Topics: Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Hemodynamics; Humans; Hypertension; Isradipine; Male; Metoprolol; Stress, Psychological

In order to investigate the efficacy of isradipine in the treatment of hypertensive crisis, we treated three groups of patients who had diastolic blood pressure (DBP) greater than 120 mm Hg, and who were without signs of acute target-organ damage. Isradipine was given sublingually in doses of 1.25 mg (group 1; n = 10), 2.5 mg (group 2; n = 10), and 5 mg (group 3; n = 7). Mean arterial pressure (MAP) was reduced in all patients [from 153.4 +/- 4.3 to 124.0 +/- 2.3 mm Hg at 60 min, and to 118.0 +/- 2.1 mm Hg at 2 h after administration (p less than 0.001)]. The heart rate (HR) did not change significantly (from 82.4 +/- 3.7 to 84.0 +/- 6 beats/min; NS). No significant differences were noted in the overall responses of the three groups; however, blood pressure reduction was more rapid in the group receiving 5 mg compared with the other two dosages. These results show that isradipine given sublingually is effective in reducing the elevated blood pressure of a hypertensive crisis and is not accompanied by limiting side effects. Isradipine's onset of action is early (approximately 30 min after dosing) and reaches its maximum blood pressure response within 2 h of administration. No dose-dependent reductions in blood pressure were observed with the dosage range employed in this study.

Topics: Administration, Sublingual; Ambulatory Care; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Isradipine

The aim of this study was to assess the effects of long-term (9-month) treatment with isradipine, alone or combined with bopindolol, on blood pressure, left ventricular hypertrophy (LVH), and diastolic function. Thirty-five hypertensive patients with LVH and supine diastolic blood pressures (DBPs) greater than or equal to 100 and less than or equal to 120 mm Hg received increasing doses of isradipine (1.25, 2.5, and 5 mg twice daily); if blood pressure was not controlled, bopindolol (0.5-2 mg once daily) was added to the treatment. Clinical and laboratory investigations were carried out after placebo for baseline values, and after 5 and 9 months of isradipine treatment alone (n = 11) or combined with bopindolol (n = 24). At the end of the study, blood pressure was significantly decreased while heart rate did not change with isradipine alone, but decreased significantly after the addition of bopindolol. Although the DBP was normalized (less than or equal to 90 mm Hg) in 28 patients (80%), complete reversal of the left ventricular mass index (LVMI) was seen in only 7 patients (20%). The ratio of early to atrial filling did not change, but the deceleration time was significantly decreased after 9 months. No laboratory abnormalities or important side effects were observed. Although isradipine alone or combined with bopindolol was effective in controlling blood pressure and significantly reduced the LVMI after 5 months, improvement in diastolic function was seen only after 9 months of active treatment.

Topics: Adolescent; Adult; Aged; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pindolol; Ventricular Function, Left

As isradipine is known to be less cardiodepressant than nifedipine, myocardial wall stress--an important determinant of cardiac oxygen demand--may also be more favorably influenced by isradipine. Therefore, the acute effects of an intravenous (i.v.) infusion of isradipine (0.4 mg) vs. nifedipine (2.0 mg) on cardiac hemodynamics and systolic wall stress were investigated in a crossover study of 12 hypertensive patients. Vasodilation-induced reflex activation was limited by pretreatment with i.v. propranolol at 0.1 mg/kg of body weight. The hemodynamic parameters measured were statistically comparable at baseline and after propranolol with both calcium antagonists, as was blood pressure reduction. However, the end-systolic volume decreased with isradipine, but not with nifedipine [before: 69 +/- 7.0 ml (mean +/- SEM); after: 61 +/- 6.1 ml; 2p less than 0.01 vs. before: 62 +/- 6.1 ml; after: 64 +/- 7.0 ml; NS, (difference between changes in response to treatments: 2p less than 0.05)]. The ejection fraction increased only with isradipine vs. nifedipine [before: 48 +/- 2.3%; after: 54 +/- 2.3%; 2p less than 0.001 vs. before: 52 +/- 2.0%; after: 52 +/- 2.3%; NS (difference between changes in response to treatments: 2p less than 0.05)]. Systolic wall stress decreased significantly more with isradipine than with nifedipine [before: 2,767 +/- 231; after: 2,153 +/- 162 relative units; 2p less than 0.001 vs. before: 2,636 +/- 212; after: 2,310 +/- 199 relative units; 2p less than 0.05 (difference between changes in response to treatments: 2p less than 0.05)]. These results suggest that isradipine, given acutely, unloads the heart more than does nifedipine.

Topics: Aged; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Humans; Hypertension; Infusions, Intravenous; Isradipine; Middle Aged; Nifedipine

The safety and efficacy of isradipine as well as its long-term effects on renal hemodynamics were evaluated in a study of 17 patients with mild-to-moderate essential hypertension and normal or slightly impaired renal function. After a 4-week placebo period, isradipine was administered according to a schedule of increasing dosages ranging from 1.25 to 5 mg twice daily. During treatment and at the latest follow-up (at 6 months), isradipine was found to lower blood pressure (diastolic and systolic) significantly. There were no significant side effects or changes in blood chemistry during treatment. Plasma renin activity and serum aldosterone were slightly raised whereas the glomerular filtration rate, renal plasma flow, and filtration fraction were significantly raised at the latest follow-up compared with the pretreatment levels.

Topics: Adult; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Isradipine; Male; Middle Aged; Renal Circulation

The long-term hemodynamic and antihypertensive effects of isradipine were investigated in 11 patients who had normal renal function and 9 who had reduced renal function. The dose regimen was 1.25-5 mg twice daily, depending on blood pressure response. After 24 weeks of active treatment, systolic/diastolic blood pressure decreased from 172/106 to 155/94 mm Hg (p less than 0.05) in the patients with normal renal function, and from 176/105 to 169/93 mm Hg (p less than 0.01) in those with impaired renal function. Contrary to the results of short-term treatment, no changes in inulin and p-aminohippuric acid (PAH) clearances were observed in either study group. There were no significant changes in plasma renin, aldosterone, glucose, or lipids, nor were these changes in protein excretion in either group; however, sodium excretion increased significantly in both groups. On the basis of our results, we conclude that isradipine has a place in the treatment of hypertensive patients with mild renal insufficiency.

Topics: Administration, Oral; Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Isradipine; Kidney; Kidney Function Tests; Middle Aged

Fourteen women with hypertension of pregnancy and who were in their last trimester were subjected to three standardized physical stress tests before and after 1-2 weeks of treatment with 5 mg of isradipine twice daily. Their blood pressure and heart rate responses to the isometric handgrip exercise, the cold pressor test, and the orthostatic tilt test were recorded. Treatment with isradipine reduced systolic and diastolic blood pressures significantly at rest. However, although the diastolic blood pressure was reduced during the stress tests, the decrease was significant only during cold pressor testing.

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Exercise Test; Female; Heart Rate; Humans; Hypertension; Isometric Contraction; Isradipine; Physical Stimulation; Pregnancy; Pregnancy Complications, Cardiovascular

Eight hundred seventy-six men and women with diastolic blood pressure (DBP) of 95-115 mm Hg during a 4-week placebo period were included in a multicenter trial; 479 patients had previously been treated for hypertension. The patients were randomized to receive isradipine or metoprolol; both groups were comparable for age, weight, height, smoking habits, and duration of hypertension. By the end of the placebo period, 79 patients did not fulfill the final entry criteria and were withdrawn. The isradipine group consisted of 398 patients (164 women and 234 men), and the metoprolol group consisted of 399 patients (173 women and 226 men). The initial dose of isradipine was 1.25 mg twice daily (b.i.d.), and the initial dose of metoprolol was 50 mg b.i.d.; the doses were doubled after 4 weeks if DBP had not decreased to less than or equal to 90 mm Hg. After 8 weeks, the isradipine group began combination therapy with metoprolol 50 mg b.i.d. and the metoprolol group began combination therapy with isradipine 1.25 mg b.i.d. if DBP was not less than or equal to 90 mm Hg. After 8 weeks monotherapy, mean BP (MBP) was reduced by 13/11 mm Hg (161/104 to 148/93) in the isradipine group and by 15/12 mm Hg (160/103 to 145/91) in the metoprolol group. Monotherapy with isradipine normalized DBP to less than or equal to 90 mm Hg in 52% with a mean dose of 4.26 mg daily, and monotherapy with metoprolol normalized DBP in 58% with a mean dose of 155 mg daily.1+

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Hypertension; Isradipine; Male; Metoprolol; Middle Aged

In a randomized trial, a calcium antagonist, isradipine (ISR) and sodium nitroprusside (SNP) were compared in the management of hypertension in the early period following coronary artery bypass grafting (CABG). Patients with a mean arterial pressure (MAP) of greater than 100 mmHg were treated with a 6 h i.v. infusion of ISR (n = 98) or SNP (n = 100). Mean MAP at baseline was 113 (ISR) and 112 mmHg (SNP). Blood pressure control (MAP less than or equal to 90 mmHg within 25 min) was achieved in 92% (ISR) and 84% (SNP), within a mean of 12 and 15 min, respectively (P less than 0.01 between groups). At 25 min, mean percentage changes from baseline for ISR and SNP were: MAP -24.3% vs. -21.4% (P less than 0.05), heart rate +4.1% vs. +8.4% (P less than 0.01), rate-pressure-product -16.9% vs. -10.6% (P less than 0.001), cardiac index +19.2% vs. +4.6% (P less than 0.001), stroke volume index +16.1% vs. -1.9% (P less than 0.001), and peripheral vascular resistance -35.4% vs. -22.0%, (P less than 0.001). Treatment was discontinued before 6 h in 24 patients in each group because of low blood pressure. Hypotension (MAP less than 70 mmHg) and tachycardia were less frequent with ISR than with SNP. In conclusion, ISR is effective and well tolerated in the treatment of hypertension following CABG, and has a haemodynamic profile which may be more favourable than that seen after treatment with SNP.

Topics: Adult; Aged; Calcium Channel Blockers; Coronary Artery Bypass; Dihydropyridines; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Nitroprusside; Postoperative Complications

In a 16 weeks open label therapeutic trial, studies were performed on isradipine (Lomir) to evaluate its haematological and biochemical safety and hypotensive capacity in the management of adult black hypertensive patients. The mean sitting diastolic blood pressure decreased from 105.5 +/- 9.66 mm hg at the end of the washout period to 92.1 +/- 7.59 mm hg at the end of the study, p less than 0.0001; while the mean standing diastolic blood pressure was 108.0 +/- 7.10 mm hg and 93.9 +/- 8.4 mm hg at the end of the washout phase and at the completion of the therapy respectively, p less than 0.0001. The corresponding mean sitting systolic blood pressures were 155.4 +/- 9.91 mm hg and 140.6 +/- 9.47 mm hg, p less than 0.001 while the corresponding mean standing systolic blood pressures were 156.6 +/- 12.50 mm hg and 142.6 +/- 9.15 mm hg, p less than 0.001. There were negligible changes in the mean heart rate; from 79.5 +/- 9.23 beats per minute (bpm) at the end of the placebo phase to 78.2 +/- 9.15 bpm at the end of the study in the sitting position, p greater than 0.1. The corresponding mean standing values of heart rate were 82.5 +/- 11.33 and 78.6 +/- 8.76, p greater than 0.5. The haematological, biochemical and electrocardiographic parameters remained within normal limits during the study. Side effects were mild, transitory, improved with therapy and consisted of dizziness, palpitations, headache, nocturia, tiredness and fainting attacks. The study achieved 96% good-to-excellent results with respect to both efficacy and tolerability. Isradipine (Lomir) is therefore an efficacious and safe antihypertensive agent in the management of black adult patients with mild to moderate primary arterial hypertension when administered in the dose of upto 2.5 mg twice daily alone or in combination with a beta-blocker.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Heart Rate; Hospitals, University; Humans; Hypertension; Isradipine; Kenya; Male; Middle Aged

To evaluate the efficacy and tolerability of isradipine, a new dihydropyridine calcium antagonist, in the treatment of mild-to-moderate hypertension.. One hundred and eighty outpatients with different races, who had supine and orthostatic diastolic blood pressure (DBP) > or = 95 mmHg and < or = 115 mmHg, with a mean age of 52.03 +/- 11.47 years, 70 men, 110 women; underwent the study. After a two-week wash-out period patients received isradipine 2.5 mg b.i.d. for 90 days. Follow-up visits were performed at the 30th, 60th and 90th days of treatment.. At the end of treatment (90 days), a statistically significant decrease (p < 0.05) in SBP and DBP in supine position was observed. A mean SBP was reduced from 159.28 +/- 16.99 to 142.51 +/- 15.12, and mean DBP declined from 101.49 +/- 6.82 to 86.63 +/- 7.40. Heart rate, weight, electrocardiograms and laboratory tests did not shows significant changes during treatment when compared to baseline evaluation. The most frequent related side effects (headache and dizziness with nausea) were transient, and at the end of the study 96.7% of the patients did not have any complaint. However, two patients were withdrawn from the trial because of important headache.. Isradipine 2.5 mg by oral route, b.i.d. has shown to be effective and well tolerated in the treatment of mild-to-moderate hypertension in patients of both sexes and several ages and races.

Topics: Administration, Oral; Adult; Aged; Brazil; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

In a randomized, double-blind, placebo-controlled, crossover study with two 4-week treatment periods, we investigated the effects of calcium channel blockade with 5 mg slow release oral isradipine on postexercise blood pressure and systemic hemodynamics (echocardiography) in ten hypertensive patients. The results show that the combination of exercise and isradipine treatment exerts additive antihypertensive effects in hypertensive patients after exercise. The antihypertensive effect of prior exercise with placebo was related to a significant fall in total peripheral resistance. After exercise during isradipine treatment, total peripheral resistance was lower than with placebo. Thus, isradipine exerts an additional antihypertensive effect during the postexercise period, which appears to be mediated by a further reduction of total peripheral resistance.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiac Output; Dihydropyridines; Double-Blind Method; Exercise; Hemodynamics; Humans; Hypertension; Isradipine; Middle Aged; Placebos; Time Factors; Vascular Resistance

Sixteen middle-aged men with primary hypertension were treated with the calcium antagonist isradipine over a 9-week period in a randomized, placebo-controlled, double-blind cross-over manner. At the end of the intervention period the urinary albumin excretion rate, systemic and renal haemodynamics, haemorheological properties of blood and plasma concentrations of atrial natriuretic peptide, noradrenaline and peripheral renin activity were determined. Treatment with isradipine resulted in a substantial reduction in blood pressure due to a reduction in peripheral resistance. The mean albumin excretion rate was not influenced by the isradipine treatment. In a multivariate analysis, changes in the urinary albumin excretion rate were only related to changes in blood pressure.

Topics: Albuminuria; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Hemodynamics; Humans; Hypertension; Isradipine; Male; Middle Aged; Multivariate Analysis; Renal Circulation; Rheology

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Diltiazem; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Isradipine; Male; Middle Aged

In a double-blind, randomized trial with 26 male white patients with essential hypertension in World Health Organization Stages I and II, we examined the impact of calcium entry blockade (5 to 10 mg/day isradipine, N = 14) and beta-blockade (100 to 200 mg/day metoprolol, N = 12) on early markers of hypertensive nephropathy before and after 7 weeks' treatment. Excretion of total protein, albumin, alpha 1-microglobuline, and N-acetyl-beta-glucosaminidase (NAG) were measured in the 24-h urine by radial immunodiffusion and fluorimetric method, respectively. Before therapy, 8 of 26 patients had microproteinuria (31%), six had microalbuminuria (22%), six had elevated urinary NAG activity (22%), and three had elevated alpha 1-microglobulin excretion (11%). In these subjects anti-hypertensive therapy led to a fall in proteinuria (296 +/- 56 v 127 +/- 116 mg/day, P less than .01), albuminuria (44 +/- 24 v 25 +/- 12 mg/day, P less than .05), and NAG excretion (45 +/- 22 v 28 +/- 5, P less than .05). The higher the pretreatment value, the greater the fall was in proteinuria (r = +0.55, P less than .01), albuminuria (r = 0.80, P less than .001), and NAG excretion (r = 0.60, P less than .01). We did not observe any significant difference in clinical characteristics, blood pressure, or urinary excretion of protein, albumin, or NAG between the two treatment groups, either before or after therapy. Thus, antihypertensive therapy reduced excretion of total protein, albumin, and NAG activity in hypertensive patients with elevated pretreatment values, potentially indicating reversal of early hypertensive nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antihypertensive Agents; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Isradipine; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Proteinuria

The efficacy and tolerability of combination therapy using Lisinopril (5-20 mg om) and Isradipine (1.25 mg-2.50 mg bd) was assessed in 29/50 Chinese subjects, whose blood pressures were not controlled on Isradipine alone. The addition of Lisinopril produced approximately two-fold reductions in blood pressure compared to Isradipine alone, increasing the responder rate of the original cohort of 50 subjects by 18% and normalization rate, by 32%. No significant changes in haematological or biochemical parameters, CXR or ECG, were observed. However, use of Lisinopril in our subjects was associated with a high incidence of cough (48%), possibly limiting its use in this population.

Topics: Adult; Aged; Antihypertensive Agents; Cough; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Lisinopril; Male; Middle Aged

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Female; Free Radicals; Humans; Hydrogen Peroxide; Hypertension; Isradipine; Male; Middle Aged; Neutrophils; Oxygen; Platelet Aggregation; Platelet Aggregation Inhibitors; Superoxides

Renal vascular resistance is increased in essential hypertension, with a consequent reduction in renal plasma flow together with a normal or slightly reduced glomerular filtration rate. Non-specific vasodilators may exacerbate this effect while loop diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium antagonists may increase these renal hemodynamic parameters. We studied the effect of lacidipine, a new long-lasting calcium antagonist, on renal hemodynamics in 11 essential hypertensives. Lacidipine (4 mg once a day) acutely increased renal plasma flow without affecting the glomerular filtration rate. A transient, but non-significant, diuresis and natriuresis occurred. After 4 weeks of lacidipine treatment, all the parameters of renal function returned to basal levels. These results suggest that the well known renal effects of calcium antagonists are, at least in part, related to the onset of the antihypertensive effect being more pronounced with compounds such as nifedipine which have a rapid-onset, blood pressure-lowering effect.

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Evaluation; Humans; Hypertension; Kidney; Renal Circulation; Vascular Resistance

The effects of calcium antagonists in reducing blood pressure at rest and during exercise were examined in patients with mild-to-moderate essential hypertension. The haemodynamic effects of calcium antagonists were evaluated at rest and during exercise. We also examined 10 patients with mild-to-moderate essential hypertension taking lacidipine, a new dihydropyridine calcium antagonist (4 mg once a day, at 0700 h). Compared with placebo, lacidipine induced significant mean reductions in 24-h blood pressure (P less than 0.001 for systolic blood pressure; P less than 0.002 for diastolic blood pressure). After 24 h, the blood pressure reductions were still significant (P less than 0.02 for systolic blood pressure; P less than 0.04 for diastolic blood pressure). The heart rate did not change. During dynamic exercise, blood pressure at maximal effort was reduced (P less than 0.01 for systolic and diastolic blood pressure) and the external workload reached at the anaerobic threshold was significantly increased (P less than 0.001), but not at maximum effort. Ventilation and tidal volume were similar at both the anaerobic threshold and peak exercise, while oxygen uptake and carbon dioxide production were increased at the anaerobic threshold (P less than 0.02 for carbon dioxide production) but were similar at peak exercise.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Anaerobic Threshold; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Diuretics; Exercise; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male

In this study of the efficacy and safety of isradipine as first-line therapy in hypertension, 1,647 patients enrolled; 1,472 completed the 4-week placebo run-in period and began treatment with isradipine at 2.5 mg twice daily for 4 weeks. During placebo, 11% (n = 175) of the 1,647 patients withdrew because of normalization of blood pressure, side effects, noncompliance, violation of the study protocol, side effects from concomitant therapy, or other reasons. During isradipine therapy (n = 1,376), blood pressure decreased from 168 +/- 18/102 +/- 8 mm Hg at the end of the placebo period to 155 +/- 17/94 +/- 9 mm Hg after 2 weeks (p less than 0.001) and 151 +/- 16/92 +/- 9 mm Hg after 4 weeks (p less than 0.001). During active treatment, 6.4% (n = 94) were withdrawn because of flushing, headache, edema, palpitations, gastrointestinal side effects, skin rashes, or other side effects, and two patients because of lack of efficacy. The side effect score in the remaining patients worsened for flushing, remained unchanged for edema, but significantly improved for palpitations, fatigue, dizziness, headache, and nervousness. After 4 weeks, 60% of patients had diastolic blood pressures of less than or equal to 90 mm Hg. Thus, isradipine is effective and safe as first-line therapy in patients with primary hypertension as seen in general practice.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Isradipine; Middle Aged; Switzerland

Hypertension is a risk factor for the development of atherosclerosis and its complications, which are among the major causes of morbidity and mortality. Although recent clinical trials indicate that antihypertensive treatment reduces morbidity and mortality associated with stroke, congestive heart failure, and renal insufficiency, questions remain as to whether such treatment also prevents coronary heart disease (CHD) mortality. The observed reduction in CHD mortality from pooled clinical trial data was 10-14% and was much less than the expected 20-25% reduction for a 5-6 mm Hg reduction in diastolic pressure. One explanation may be that subtle adverse metabolic effects of treatment may have blunted the beneficial effects. Isradipine, a dihydropyridine calcium antagonist, is a potent antihypertensive drug with antiatherogenic properties in animal models. Therefore, we hypothesized that isradipine may be appropriate for testing the efficacy of antihypertensive treatment in retarding the progression of atherosclerosis in humans. The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a clinical trial designed to compare the efficacy of isradipine (2.5 or 5 mg b.i.d.) with hydrochlorothiazide (12.5 or 25 mg b.i.d.) in retarding the progression of early carotid atherosclerosis as monitored by high-resolution B-mode ultrasonography.

Topics: Adult; Aged; Arteriosclerosis; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Double-Blind Method; Female; Humans; Hydrochlorothiazide; Hypertension; Isradipine; Male; Middle Aged; Ultrasonography

The antihypertensive effects of isradipine and captopril were studied in 231 patients with mild-to-moderate hypertension in a double-blind, randomized, between-patient trial. Treatment was started with 1.25 mg of isradipine or 12.5 mg of captopril twice daily which, if normotension was not obtained, was increased after 4 weeks to 2.5 mg or 25 mg twice daily, respectively. If the maximum dose of each drug alone did not result in normotension, captopril (12.5 mg or, if necessary, 25 mg twice daily) was added to the isradipine regimen, and isradipine (1.25 mg or, if necessary, 2.5 mg twice daily) to the captopril regimen. Following 24 weeks of active treatment, systolic blood pressure (SBP) was significantly (p less than 0.001) reduced by isradipine (170 +/- 17 vs. 153 +/- 17 mm Hg) and by captopril (170 +/- 19 vs. 155 +/- 19 mm Hg). Diastolic blood pressure (DBP) also fell significantly (p less than 0.001) in both groups (isradipine: 106 +/- 5 vs. 93 +/- 8 mm Hg; captopril: 106 +/- 5 vs. 95 +/- 10 mm Hg). After isradipine as monotherapy, DBP was normalized in 49% of patients compared with 52% after captopril monotherapy. Combination of both drugs increased the normalization rate to 84%. The results indicate that combined treatment with a calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor is effective in lowering blood pressure, and is well tolerated as long-term therapy.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Captopril; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged

Fibrinolytic activity was measured in a 14-day placebo-controlled study of propranolol and the calcium antagonist isradipine in 20 mildly hypertensive patients (diastolic blood pressure 95-115 mm Hg) compared with 24 healthy volunteers. The parameters under study included euglobulin clot-lysis time, and tissue-plasminogen activator activity and its inhibitor (PAI). The two drugs exerted equal antihypertensive effects in the patients who had raised blood pressure, but had markedly different actions on the fibrinolytic system. Propranolol substantially reduced the fibrinolytic activity in both the hypertensive and healthy control groups. Isradipine, on the other hand, had no effect on fibrinolytic activity in the controls, but augmented the activity in the hypertensive subjects. The possible mechanisms for the different actions of the two agents may be related to the vascular endothelium.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Fibrinolysis; Humans; Hypertension; Isradipine; Male; Middle Aged; Propranolol; Tissue Plasminogen Activator

The efficacy and safety of isradipine and nifedipine retard were compared in 51 patients with mild-to-moderate essential hypertension. A 4-week placebo run-in period was followed by an 8-week course of treatment. Patients were randomly allocated to either isradipine 1.25 mg twice daily (n = 24) or nifedipine 20 mg twice daily (n = 826); dosages were doubled if blood pressure was not normalized [diastolic blood pressure greater than or equal to 90 mm Hg) after 4 weeks of active treatment. Systolic/diastolic blood pressures were significantly reduced (p less than 0.01/p less than 0.01) by isradipine from 162/103 to 145/89 mm Hg, and by nifedipine from 162/104 to 143/88 mm Hg. Normalization rates were 79% with isradipine and 67% with nifedipine. It was necessary to double the dosage in seven of the patients taking isradipine and in three of those taking nifedipine; the mean final dosages were 1.63 mg and 22.4 mg twice daily, respectively. Heart rate did not change significantly with either treatment. There were drug-related adverse events in five patients (21%) taking isradipine (2 edema, 2 headache, 2 palpitations, 1 flushing) and in eight (30%) of those taking nifedipine (5 edema, 2 headache, 1 palpitations). Therapy was withdrawn in one patient in the isradipine group (1 headache) and two patients in the nifedipine group (1 edema, 1 headache). We conclude that isradipine is a highly effective and well tolerated antihypertensive agent.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged; Nifedipine; Portugal

This was a comparison of the effects of isradipine and metoprolol on sleep apnea syndrome in 12 hypertensive men who were habitual snorers. Each patient received double-blind isradipine 1.25-2.5 mg twice daily or metoprolol 50-100 mg twice daily after a 4-week placebo period. Static charge-sensitive bed examination was performed during the placebo period and 5-7 weeks after starting treatment. The number of obstructive breathing patterns was increased by metoprolol in five patients, remained the same with isradipine in four, and was decreased by metoprolol in one patient and by isradipine in two. Obstructive patterns increased in the metoprolol group from 24 +/- 26% to 32 +/- 31% and decreased in the isradipine group from 21 +/- 23% to 19 +/- 25% (p less than 0.05, Mann-Whitney U test). Neither drug had a significant effect on blood pressure values. There was no significant difference in oxygen desaturation or in the amount of quiet sleep in either treatment group. On the basis of these results, it would appear that isradipine is more suitable than metoprolol for the treatment of hypertension in patients who are habitual snorers.

Topics: Adult; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Isradipine; Male; Metoprolol; Middle Aged; Monitoring, Physiologic; Respiration; Sleep Apnea Syndromes; Snoring

The antihypertensive effect of isradipine compared with placebo was assessed in 28 male patients (aged 40-64 years) with mild-to-moderate essential hypertension. After withdrawal of all previous antihypertensive treatment, these patients were entered into a 4-week placebo period followed by randomization to receive double-blind, for 8 weeks, either placebo (n = 14) or isradipine at 1.25-2.5 mg twice daily (n = 14). Twenty-four-hour ambulatory blood pressure was measured by Accutracker at the end of the placebo period and at the end of active treatment. In the isradipine group, both systolic and diastolic blood pressures decreased significantly (p less than 0.0001) whereas blood pressure increased in those taking placebo. In addition, isradipine as monotherapy controlled blood pressure throughout the day and night, and especially during the early morning, in these patients.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Isradipine; Male; Middle Aged; Monitoring, Physiologic; Time Factors

This was a double-blind multicenter study to compare the efficacy, tolerability and effects on the quality of life with isradipine and atenolol in the treatment of essential hypertension. Of 588 patients entering the 6-week placebo run-in period, 549 were eligible for randomization to receive either isradipine or atenolol for 8 weeks. If, at the end of this period, diastolic blood pressure (DBP) remained greater than 90 mm Hg, then both agents were given in combination for a further 10 weeks. Tolerability and quality of life were assessed repeatedly during the placebo and active-treatment phases. A subgroup of 30 patients were followed by 24-h ambulatory blood pressure monitoring, and their results are now being analyzed. In another subgroup of 26 patients, maximum exercise capacity, as determined by ergometer bicycle-testing, was measured once during placebo and twice during active treatment. At the end of the 24-week study period, both isradipine and atenolol as monotherapy had produced significant decreases in blood pressure. There were no significant differences overall between the compounds in quality-of-life and side-effect profiles, although there was a relative absence of ankle edema and headache with isradipine. Furthermore, patients receiving isradipine had no change in performance on exercise testing whereas patients on atenolol had a significant decrease (p less than 0.01).

Topics: Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Isradipine; Middle Aged; Prospective Studies; Quality of Life; Safety; Sweden

Eleven centers in Tuscany, Italy, recruited 96 patients (aged 21-75 years) with mild-to-moderate essential hypertension [diastolic blood pressure (DBP) 95-115 mm Hg; systolic blood pressure (SBP) less than or equal to 200 mm Hg]. After a 4-week, single-blind, placebo run-in period, patients received lacidipine 4 mg once daily. If blood pressure was not controlled after 1 month (control = DBP less than or equal to 90 mm Hg, or less than or equal to 95 mm Hg if reduced by greater than or equal to 15 mm Hg from baseline), the dose was increased to lacidipine 8 mg once daily. Atenolol 50 mg once daily was added after 2 months' monotherapy, if required for blood pressure control. The study continued for 13 months. About 40% of patients were titrated to 8 mg lacidipine; only 7% required addition of atenolol. Lacidipine significantly reduced blood pressure, with 84% of patients showing control of pressure values 24 h after the previous dose on completion of 5 months' monotherapy (63% controlled with lacidipine 4 mg/day; 21% with lacidipine 8 mg/day). There was no clinically relevant difference in the first-dose effect between the two doses of lacidipine (4 mg and 8 mg); both smoothly reduced blood pressure, with maximum effect after 2 h. Lacidipine was well tolerated. Adverse events were those expected with dihydropyridines, were mainly mild and occurred early, disappearing without discontinuation of treatment. Results indicate that 4-8 mg of lacidipine, administered once daily, is effective and well tolerated in mildly to moderately hypertensive patients.

Topics: Adult; Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

Calcium plays an important role in endocrine reactions such as hormone biosynthesis, release, secretion, and action on target organs. The aim of this study was to evaluate the effects of a new long-lasting calcium-channel blocker, lacidipine, on basal and stimulated anterior pituitary hormone secretion. In a single-blind crossover study comparing lacidipine 4 mg p.o. once daily with placebo, variations in plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) were evaluated in 10 hypertensive patients. Basal or stimulated anterior pituitary hormone secretion was similar after lacidipine and placebo. Lacidipine treatment significantly reduced blood pressure. It can thus be concluded that lacidipine is an effective calcium antagonist that has no effect on pituitary function.

Topics: Administration, Oral; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Pituitary Gland, Anterior; Pituitary Hormones, Anterior; Single-Blind Method

Selection of the appropriate dose of a new drug for initiation of treatment and then for maintenance is a complicated task. It requires the careful assessment and weighing of benefit vs. risk. A series of studies was carried out with lacidipine to determine the optimal initial dose in a general hypertensive population as well as in special populations in whom the pharmacokinetics may be different. The conclusions of these studies are that (a) in a general adult population, the initial dose should be 4 mg once daily; (b) in the elderly and in those with impaired liver function, the starting dose should be 2 mg once daily; and (c) renal dysfunction does not alter the usual starting dose of 4 mg once daily.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged

Thirty-one centers in the U.K. recruited 637 patients (aged 21 to 75 years) with mild-to-moderate essential hypertension [diastolic blood pressure (DBP) of 95 to 115 mm Hg, and systolic blood pressure (SBP) less than or equal to 200 mm Hg on three occasions]. After a 4-week placebo run-in period, 533 patients were randomized to receive double-blind 4 mg of lacidipine once daily (n = 268) or 50 mg of atenolol once daily (n = 265). If blood pressure was not controlled after 1 month (control = DBP less than or equal to 90 mm Hg, or less than or equal to 95 mm Hg if reduced by greater than or equal to 15 mm Hg from baseline), dosages were increased to 6 mg of lacidipine once daily or 100 mg of atenolol once daily. Hydrochlorothiazide (HCTZ, 25 mg once daily) was added after 2 months of active treatment if required for blood pressure control. Both lacidipine and atenolol reduced blood pressure to a similar degree over the 5 months of double-blind active treatment. The reduction achieved was maintained for the duration of the open phase of the study (to month 14). The incidence of adverse events was also similar for both drugs, and serious adverse events were rare and thought to be unrelated to the study drug therapy. The results indicate that lacidipine once daily for mild-to-moderate hypertension has an efficacy and safety similar to that of atenolol.

Topics: Adult; Aged; Atenolol; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Safety

The aim of this study was to compare the antihypertensive efficacy and tolerability of lacidipine, a new dihydropyridine calcium antagonist, and slow-release nifedipine (SR) in patients with mild-to-moderate essential hypertension. After a 1-month placebo run-in period, 435 patients were randomized into a double-blind, parallel-group study to receive either 4 mg of lacidipine once daily (n = 220) or 20 mg of nifedipine twice daily (n = 215). After 4 weeks, the doses for "nonresponders" were increased to 6 mg of lacidipine once daily (n = 82) and to 40 mg of nifedipine SR twice daily (n = 62). After 4 weeks, 50 mg of atenolol once daily was added to the regimens of patients still uncontrolled by lacidipine (n = 32) and nifedipine SR (n = 23) as monotherapy. Sitting blood pressure and heart rate were measured at 22-24 h after lacidipine and 10-12 h after nifedipine SR. Both calcium antagonists similarly and significantly reduced the blood pressure at rest (sitting) and on exercise, while the heart rate did not change significantly. The nature and incidence of side effects and withdrawals also did not differ between the two. In conclusion, lacidipine once daily is as effective and well tolerated as nifedipine SR twice daily in patients with mild-to-moderate essential hypertension.

Topics: Adult; Aged; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Italy; Male; Middle Aged; Nifedipine

This multicenter study was designed to assess the clinical efficacy and safety of the new once-daily calcium antagonist lacidipine in the treatment of mild-to-moderate essential hypertension. Patients were randomly assigned to receive, double-blind, either lacidipine (n = 180) or hydrochlorothiazide (HCTZ, n = 182) following a 1-month placebo run-in period. Both drugs were titrated after 1 month if blood pressure was not controlled: lacidipine, from 4 to 6 mg once daily; HCTZ, from 25 to 50 mg once daily. Atenolol was added later if necessary to achieve blood pressure control. Lacidipine and HCTZ were equally effective in controlling the blood pressure levels in the majority of patients (approximately 90% after 4 months). Adverse events were those to be expected with these classes of drug and were reported in 48 (26.7%) of the patients receiving lacidipine treatment and in 34 (18.7%) of those receiving HCTZ. The diuretic produced a significantly higher incidence of hypokalemia.

Topics: Administration, Oral; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hypertension; Safety

Elderly patients are becoming a greater proportion of the hypertensive population. In addition, they may respond differently to drugs, both pharmacodynamically and pharmacokinetically. Therefore, approximately 25% of the patients treated with lacidipine in early studies were over 65 years old. In three double-blind, parallel-group comparative trials, 118 elderly hypertensive patients were treated with lacidipine or comparators, either atenolol, nifedipine SR, or hydrochlorothiazide (HCTZ). Lacidipine was at least as effective in lowering blood pressure as the comparators, as well tolerated as nifedipine SR (but with a significantly lower incidence of edema) and HCTZ, and better tolerated than atenolol. In a double-blind, placebo-controlled, parallel-group, dose-response study of 131 elderly hypertensive patients randomized to receive either lacidipine or placebo, lacidipine significantly reduced the diastolic blood pressure compared with placebo. In the long-term evaluation, more patients required titration with 2 mg of lacidipine than with 4 mg. These results suggest that 4 mg once daily is an effective and well-tolerated antihypertensive treatment in the elderly and, as with the general adult population, represents the optimal long-term maintenance dose.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Male; Safety

Ambulatory blood pressure monitoring gives a more representative blood pressure profile than office blood pressure measurements and is free of any placebo effect. It is therefore useful for studying the effect of antihypertensive agents. Although ambulatory blood pressure is less variable than office blood pressure, spontaneous fluctuations have been found in whole-day blood pressure when repeated measurements are taken. In the multicentre Triveneto Study, the mean difference between 24-h blood pressure recordings taken 3 months apart in 85 mild hypertensives was -0.1/-0.7 mmHg and the coefficient of repeatability (2 s.d.) was 17.3/12.6 mmHg. The corresponding values for office blood pressure were -8.7/-2.0 and 29.8/16.5 mmHg, respectively. This reduction in inter-measurement variability with ambulatory blood pressure monitoring makes it possible to reduce the sample size required to prove the effect of an antihypertensive agent in pharmacological trials. However, in the individual subject, the results of ambulatory blood pressure monitoring should be considered with caution, as 24-h blood pressure averages and profiles are subject to a degree of variability. This technique was used in 21 mild-to-moderate hypertensives to test the antihypertensive effect of lacidipine given once a day (4-6 mg) versus placebo. The drug proved effective throughout the day and night, showing a 24-h effect on blood pressure without reflex tachycardia or other intolerable side effects.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitors; Circadian Rhythm; Dihydropyridines; Drug Administration Schedule; Humans; Hypertension; Middle Aged; Reproducibility of Results

Recent multicenter trials have demonstrated that, in hypertensive elderly people, blood pressure control can significantly decrease the rate of cardiovascular and cerebrovascular events. Twenty-four-hour ambulatory blood pressure monitoring has proved to be superior to isolated sphygmomanometer blood pressure readings in the diagnostic evaluation of hypertension and in assessing the blood pressure response to treatment. We used 24-h ambulatory monitoring in a small, double-blind, randomly-allocated, placebo-controlled, parallel-group study of antihypertensive treatment with lacidipine given once a day at 2 or 4 mg. In our elderly subjects, the lacidipine treatment provided adequate blood pressure control both by day and by night with no effect on the heart rate profile. Furthermore, after drug therapy, we found a significant reduction in systolic blood pressure variability (standard deviation). This study shows that lacidipine can provide adequate control of arterial hypertension in the elderly.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitors; Circadian Rhythm; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Humans; Hypertension

Male patients with supine diastolic blood pressures above 95 mmHg after placebo therapy received twice daily isradipine (Dynacirc; Sandoz) 1.25, 2.5 or 5.0 mg for 12 weeks. Blood pressures were measured every 14 days. Doses of 2.5 or 5 mg isradipine twice daily significantly reduced supine and erect mean systolic, mean diastolic and mean arterial pressures. Isradipine 1.25 mg twice daily reduced supine mean diastolic and mean arterial pressures only. A dose of 5 mg twice daily was accompanied by an increase in adverse reactions. The recommended dose of isradipine is 2.5 mg twice daily.

Topics: Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Isradipine; Male

Twenty-three patients who developed intraoperative hypertension (mean arterial pressure greater than 110 mmHg) during abdominal surgery under balanced general anaesthesia were randomly assigned to two groups. The isradipine group (n = 12) received 0.5 mg of isradipine, and the placebo group (n = 11) received 10 ml of isradipine solvent over a 5-min period in a blind manner. Arterial pressure was recorded 12 min after the injection was started. If the mean arterial pressure had not decreased by at least 10% at 12 min, patients received in an open manner 0.5 mg of isradipine. None of the patients in the isradipine group received isradipine in an open manner, in contrast with nine of the 11 patients in the placebo group (P less than 0.0001, Fisher's exact test). During both the blind period and the open trial, isradipine induced a 40% decrease in systolic, diastolic, and mean arterial pressures within the first two min of infusion. Arterial pressure remained below the pre-isradipine injection values for at least 45 min. Transient hypotension (mean arterial pressure less than 70 mmHg) was noted in 6/21 patients (29%). Mean heart rate remained statistically unchanged during the decrease in arterial pressure in both groups, but a tachycardia (increase in heart rate greater than 20 beats min-1) was noted in 4/21 patients (19%). This study indicates that intravenous isradipine is an effective therapy with sustained efficacy for intraoperative hypertension during abdominal surgery. The safety of its use needs a close monitoring of arterial pressure.

Topics: Abdomen; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Tolerance; Female; Heart Rate; Humans; Hypertension; Hypotension; Injections, Intravenous; Intraoperative Complications; Isradipine; Male; Middle Aged; Placebos; Safety; Time Factors

Hemodynamic Effects of Isradipine and Nifedipine in Hypertension Myocardial wall tension is an important determinant of the oxygen demand, the function and the degree of hypertrophy of the left ventricle. Myocardial wall tension should be influenced more favourably by a non-cardiodepressive antihypertensive than by a potentially cardiodepressive one. Therefore, we investigated the effects of an intravenous infusion of the calcium antagonists isradipine (I; 0.4 mg; 3,5-pyridinecarboxylic acid, 4-[benzofurazanyl]-1,4-dihydro-2,6-dimethyl-,methyl-ethylester+ ++ [9CI]; CAS75695-93-1) and nifedipine (N; 2.0 mg) resp., on hemodynamics and myocardial wall tension in 12 hypertensives by an intraindividual comparison. The adrenergic reflex activation induced by vasodilation was limited by pre-medication with 0.1 mg propranolol/kg body weight (i.v.) before application of I and N. Baseline blood pressure of the patients and its changes in response to both calcium antagonists were statistically comparable, as were the left ventricular end-diastolic volumes. The end-systolic volumes, however, decreased significantly on I but not on N: before I: 69 +/- 7.0 (mean +/- standard error), after I: 61 +/- 6.1 ml, 2p less than 0,001; before N: 62 +/- 6.1, after N: 64 +/- 7.0 ml, n.s. (difference to I: 2 p less than 0.05). Stroke volume increased only on I (before I: 62 +/- 4.1, after I: 69 +/- 4.1 ml, 2p less than 0.001; before N: 64 +/- 3.5, after N: 65 +/- 3.8 ml, n.s. (difference to I: 2p less than 0.05)).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Cardiac Output; Dihydropyridines; Female; Heart; Heart Function Tests; Humans; Hypertension; Injections, Intravenous; Isradipine; Male; Middle Aged; Myocardial Contraction; Nifedipine; Propranolol; Stroke Volume

We evaluated the effects of lacidipine and hydrochlorothiazide on blood pressure and left ventricular mass in hypertensive patients of mild-to-moderate degree. Both antihypertensive agents significantly decreased systolic and diastolic blood pressure without relevant symptoms and signs of reflex activation of the sympathetic nervous system. Posterior wall and interventricular septal thickness and the left ventricular mass were significantly decreased by lacidipine and hydrochlorothiazide after 3 and 6 months of treatment without clinical symptoms of reduced cardiac function.

Topics: Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Double-Blind Method; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Time Factors

A short-term trial of isradipine was conducted in order to assess its effectiveness and tolerability in the treatment of mild to moderate HT. The study took place in general practice on 2702 patients, aged 18 to 70, with diastolic BP (dBP) from 95 to 114 mmHg. It included a pretreatment phase of up to four weeks out of antihypertensive drugs and on placebo and a twelve week treatment phase on isradipine 2.5 mg or 5.0 mg/day. After treatment with isradipine sBP fell from 168.0 to 148.1 and dBP from 102.7 to 86.7 mmHg. The majority of patients (89.6%) had a fall in dBP over 10 mmHg; 86.2% had normal dBP (= less than 90 mmHg) in the end. Adverse effects were referred by 2.8% of the patients. Satisfaction with the drug reached 90% among patients and physicians. Thus, isradipine proved effective and very well tolerated and may deserve a place as first line treatment for hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Patient Satisfaction; Risk Factors; Sex Factors

The efficacy of the new once-daily dihydropyridine calcium antagonist, lacidipine, in reducing ambulatory intraarterial blood pressure (BP) was examined in 12 untreated hypertensive patients. The intraarterial recording was commenced 24 hours before the first 4-mg dose and was continued for a further 24 hours thereafter. After dose titration and chronic therapy, a second 24-hour ambulatory BP recording was made. There was a steady onset of drug action, maximal at 2 hours, but with reflex tachycardia after the first dose. Chronic administration reduced BP throughout the 24-hour period, without tachycardia. Mean daytime reduction in BP was 20 mm Hg systolic (p less than 0.005) and 12 mm Hg diastolic (p less than 0.02). Mean nighttime reduction was 8-mm Hg systolic (p less than 0.05) and 6-mm Hg diastolic (difference not significant). There was no postural decrease in BP on 60 degrees head-up tilting and hypotensive action was maintained during isometric exercise (reduction at peak of 32/18 mm Hg, p less than 0.05) and throughout dynamic exercise (reduction at peak of 23/14 mm Hg, p less than 0.05). Lacidipine is an effective once-daily antihypertensive agent, with good control of stress response.

Topics: Blood Pressure; Blood Pressure Determination; Blood Pressure Monitors; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Exercise Test; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged

We conducted a randomly allocated, double-blind study in 16 essential hypertensive patients, eight of whom were treated with nifedipine and eight with lacidipine. The antihypertensive efficacy was evaluated and any modifications to peripheral haemodynamic parameters were observed in the brachial artery by a mechanographic method and B-mode scanner with a 10-MHz probe. Statistically significant reductions in blood pressure from basal values were observed after 1 and 6 months' treatment. Enhanced compliance (P less than 0.005), reduced characteristic impedance (P less than 0.001) and lower peripheral resistances (P less than 0.01) were also noted. Variations in pulse wave velocity and mean blood pressure showed a statistically significant correlation as early as the first month of treatment (P less than 0.01). Our results suggest that therapy with nifedipine and lacidipine allows an improvement in peripheral haemodynamics in hypertensive patients. This response is maintained in chronic treatment, even just before the next dose administration at the end of the longest dose interval.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nifedipine; Randomized Controlled Trials as Topic; Time Factors

Several drugs used in the treatment of hypertension have been shown to affect lipid metabolism. A few studies have examined in detail the effects of calcium antagonists on blood lipids. We investigated the effects of nifedipine and nitrendipine on blood lipids using two experimental protocols. The first study was a double-blind, randomized, placebo-controlled trial to assess the effects of acute oral administration of nifedipine 10 mg on blood lipids in 10 patients (9 males, 1 female; age range 26-50 years) with mild hypertriglyceridemia. Serum triglycerides were not significantly affected (from 310 +/- 120 to 280 +/- 110 mg/dl 2 h after nifedipine) but a slight decrease was observed in patients with higher baseline levels. In the second study, an intravenous fat tolerance test (ivFTT, Intralipid 10%, 1 ml/kg body weight, as a bolus) was performed before and after chronic oral administration of nitrendipine 10 mg b.i.d. in 10 mild to moderate hypertensive patients (7 males, 3 females; age range 40-60 years). After nitrendipine treatment, the fractional removal rate (K2) of the lipid emulsion was significantly increased from 3.1 +/- 0.9 to 3.8 +/- 0.9% min (p less than 0.05). The main findings of these studies suggest that the secretion of lipoprotein lipase might be stimulated by calcium antagonists. Alternatively, the vasodilation produced by these compounds may influence triglyceride removal by expanding the capillary bed where the enzyme exerts its activity. In conclusion, calcium antagonists do not seem to cause unwanted side effects on blood lipids and apparently enhance triglyceride removal.

Topics: Adult; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Nitrendipine; Random Allocation; Triglycerides

The combination of one of the dihydropyridine class of calcium channel antagonists with a beta-adrenoceptor blocker has particular therapeutic advantages in the management of hypertension. The beta-blocker reduces the effects of the dihydropyridine-induced reflex increases in sympathetic nervous system and renin-angiotensin system activity, while the dihydropyridine reduces the peripheral effects of beta-blockade. Numerous studies have documented additional antihypertensive effects when these two classes of agents are used as combination therapy in hypertension. This therapeutic combination is well tolerated and produces minimal alterations in clinical laboratory tests. Initial concerns that the combination may impair atrioventricular conduction and left ventricular function have not been substantiated in widespread clinical trials.

Topics: Adrenergic beta-Antagonists; Blood Pressure; Clinical Trials as Topic; Dihydropyridines; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension

Use of angiotensin II (ATII)-stimulating antihypertensive medication (AHM), including angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs), has been associated with lower dementia risk. Previous studies had relatively short follow-up periods. The aim of this study is to investigate if these effects are sustained over longer periods.. This post hoc observational analysis was based on data from a dementia prevention trial (preDIVA and its observational extension), among Dutch community-dwelling older adults without prior diagnosis of dementia. Differential associations between AHM classes and incident dementia were studied after 7.0 and 10.4 years, based on the median follow-up durations of dementia cases and all participants.. After 7 years, use of ATII-stimulating antihypertensives [hazard ratio = 0.68, 95% confidence interval (CI) = 0.47-1.00], ARBs (hazard ratio = 0.54, 95% CI = 0.31-0.94) and dihydropyridine CCBs (hazard ratio = 0.52, 95% CI = 0.30-0.91) was associated with lower dementia risk. After 10.4 years, associations for ATII-stimulating antihypertensives, ARBs and dihydropyridine CCBs attenuated (hazard ratio = 0.80, 95% CI = 0.61-1.04; hazard ratio = 0.75, 95% CI = 0.53-1.07; hazard ratio = 0.73, 95% CI = 0.51-1.04 respectively), but still suggested lower dementia risk when compared with use of other AHM classes. Results could not be explained by competing risk of mortality.. Our results suggest that use of ARBs, dihydropyridine CCBs and ATII-stimulating antihypertensives is associated with lower dementia risk over a decade, although associations attenuate over time. Apart from methodological aspects, differential effects of antihypertensive medication classes on incident dementia may in part be temporary, or decrease with ageing.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dementia; Dihydropyridines; Follow-Up Studies; Humans; Hypertension

Dihydropyridines (DHPs) may have neuroprotective effects against Parkinson's disease (PD).. This study investigated the effects of DHPs on nigrostriatal dopaminergic denervation and longitudinal motor and cognitive outcomes in PD.. We classified 476 patients with drug-naive PD who had undergone dopamine transporter imaging into three groups. They were selected according to a prior diagnosis of hypertension and use of DHPs and were matched using propensity scores: patients without hypertension (HTN-; n = 50) and patients with hypertension treated without DHP (HTN+/DHP-; n = 50) or with DHP (HTN+/DHP+; n = 50). Multiple linear regression and linear mixed model analyses were performed to determine intergroup differences in baseline dopamine transporter availability and longitudinal changes in the levodopa-equivalent dose, respectively. Using Kaplan-Meier analyses, we compared the risks of levodopa-induced dyskinesia, wearing off, and dementia-free survival during the 5.06 years of the mean follow-up period. The Cox regression model determined the independent effects of DHPs on dementia conversion.. DHPs may be associated with better long-term cognitive outcomes in hypertensive patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Topics: Antiparkinson Agents; Cognition; Dihydropyridines; Dopamine Plasma Membrane Transport Proteins; Dyskinesias; Humans; Hypertension; Levodopa; Parkinson Disease

Topics: Dihydropyridines; Drug Carriers; Drug Liberation; Humans; Hypertension

The use of calcium channel blockers (CCBs) is associated with gingival enlargement, which adversely affects oral function, hygiene and aesthetics. Although CCB-induced gingival enlargement is a known adverse effect, it is rarely or never caused by some CCBs. In this paper, we report the case of a late 80's female patient with hypertension who experienced amlodipine-induced gingival enlargement. The patient's antihypertensive medication was changed from amlodipine to another CCB of the same class, benidipine, which has not been reported to cause gingival enlargement. The patient also received periodontal therapy. A significant improvement in gingival enlargement was noted, and blood pressure control was maintained. This case indicates that it might be beneficial for patients with hypertension presenting CCB-induced gingival enlargement to switch from the CCB that caused gingival enlargement to another CCB with little to no risk.

Topics: Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Female; Gingival Hyperplasia; Gingival Overgrowth; Humans; Hypertension

Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results.. We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI).. The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus β-blockers (βBs), and α1-AB plus βBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug.. Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.

Topics: Adrenergic Antagonists; Adult; Aged; Amlodipine; Antihypertensive Agents; Apolipoprotein E4; Calcium Channel Blockers; Cognition; Cohort Studies; Dihydropyridines; Diuretics; Diuretics, Potassium Sparing; Genotype; Humans; Hypertension; Nifedipine; Thiazides; Vasodilator Agents

To analyze therapy in patients with arterial hypertension (AH) in 20102020.. Data of hypertensive patients observed in primary health care, entered into the base of hypertension registry for 20102020 years in the whole group (n=44 653) and in a separate subgroup of hypertensive patients in the absence of: ischemic heart disease, a history of myocardial infarction, chronic heart failure (n=20 569).. About 80% of hypertensive patients are patients of high and very high risks (from 2010 to 2020, the proportion of very high cardiovascular risk (CVR) increased from 18.1 to 57.3%). The number of hypertensive patients with a history of myocardial infarction increased in 5 times, in 3 times with ischemic heart disease and with chronic heart failure. The number of prescribed drugs increased: mineralocorticoid receptor antagonist (in 5.8 times), loop diuretics (in 7.2) angiotensin receptor blockers (in 3 times), b-adrenoblockers, calcium channel blockers of the dihydropyridine series, thiazide-like diuretics in 2 times. Patients at high and very high risk are more likely reached target blood pressure values. Angiotensin-converting enzyme inhibitors were prescribed in more than 70% of patients with hypertension and the absence of coronary heart disease, chronic heart failure, history of myocardial infarction; the prescription of b-adrenoblockers, angiotension receptor blockers, thiazide-like and loop diuretics increased.. The proportion of more severe and comorbid patients has increased in observed in primary health care patients with AH over a 10-year period (20102020). This was probably the main factor of increasing antihypertensive therapy and prescribing drugs with additional indications and improving the achievement of target blood pressure in patients with high and very high cardiovascular risk.. Цель. Анализ лечения больных артериальной гипертонией (АГ) в 20102020 гг. Материалы и методы. Проведен анализ медицинских данных 44 653 больных АГ, наблюдавшихся в первичном звене здравоохранения, аккумулированных в регистре АГ за период 20102020 гг. и в подгруппе, включившей 20 569 больных АГ без диагностированных сердечно-сосудистых заболеваний (ССЗ) ишемической болезни сердца, инфаркта миокарда в анамнезе, хронической сердечной недостаточности. Результаты. За 10-летний период среди больных АГ, наблюдаемых в условиях первичного звена здравоохранения, 80% больных были высокого и очень высокого сердечно-сосудистого риска (ССР); с 2010 по 2020 г. регистрируется увеличение доли больных очень высокого ССР с 18,1 до 57,3%. В 5 раз увеличилось число больных АГ, перенесших инфаркт миокарда; в 3 раза ишемическую болезнь сердца и хроническую сердечную недостаточность. Отмечено увеличение назначаемых препаратов: антагонистов минералокортикоидных рецепторов в 5,8 раза, петлевого диуретика в 7,2, блокаторов рецепторов ангиотензина в 3 раза, -адреноблокаторов, дигидропиридиновых блокаторов кальциевых каналов и тиазидоподобных диуретиков в 2 раза. У больных высокого и очень высокого риска чаще достигался целевой уровень артериального давления. У больных АГ без ССЗ (ишемическая болезнь сердца, хроническая сердечная недостаточность, перенесенный инфаркт миокарда) ингибиторы ангиотензинпревращающего фермента назначались более чем 70% больных; чаще стали назначаться -адреноблокаторы, блокаторы рецепторов ангиотензина, тиазидоподобный диуретик, петлевой диуретик. Заключение. В структуре больных АГ, наблюдаемых в первичном звене здравоохранения за 10-летний период, увеличилась доля более тяжелых больных АГ, у которых диагностированы ССЗ. Это, вероятно, явилось основным фактором усиления антигипертензивной терапии и назначения препаратов с учетом дополнительных показаний, что, по-видимому, улучшило достижение целевого артериального давления у больных высокого и очень высокого ССР.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Diuretics; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Sodium Potassium Chloride Symporter Inhibitors; Thiazides

Background Recent studies have reported that dihydropyridine calcium channel blockers (dCCBs) may increase the risk of pancreatic cancer, but these studies had methodological limitations. We thus aimed to determine whether dCCBs are associated with an increased risk of pancreatic cancer compared with thiazide diuretics, a clinically relevant comparator. Methods and Results We conducted a new user, active comparator, population-based cohort study using the UK Clinical Practice Research Datalink. We identified new users of dCCBs and new users of thiazide diuretics between 1990 and 2018, with follow-up until 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs for pancreatic cancer, comparing dCCBs with thiazide diuretics. Models were weighted using standardized morbidity ratio weights based on calendar time-specific propensity scores. We also conducted secondary analyses by cumulative duration of use, time since initiation, and individual drugs and assessed for the presence of effect modification by age, sex, smoking status, body mass index, history of chronic pancreatitis, and diabetes. The cohort included 344 480 initiators of dCCBs and 357 968 initiators of thiazide diuretics, generating 3 360 745 person-years of follow-up. After a median follow-up of 4.5 years, the weighted incidence rate per 100 000 person-years was 37.2 (95% CI, 34.1-40.4) for dCCBs and 39.4 (95% CI, 36.1-42.9) for thiazide diuretics. Overall, dCCBs were not associated with an increased risk of pancreatic cancer (weighted HR, 0.93; 95% CI, 0.80-1.09). Similar results were observed in secondary analyses. Conclusions In this large, population-based cohort study, dCCBs were not associated with an increased risk of pancreatic cancer compared with thiazide diuretics. These findings provide reassurance regarding the long-term pancreatic cancer safety of these drugs.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Humans; Hypertension; Pancreatic Neoplasms; Sodium Chloride Symporter Inhibitors

Topics: Dihydropyridines; Enalapril; Humans; Hypertension; Vasculitis, Leukocytoclastic, Cutaneous

We examined the effects of a fixed-dose single-pill combination of cilnidipine (10 mg), an L-/N-type calcium channel blocker, and valsartan (80 mg) (SPC of Cil/Val) on the day-by-day variability of morning home systolic blood pressure (MHSBP) in 616 patients with treated hypertension for 12 months as a sub-analysis of the HOPE-Combi survey, multicentral, post-marketing, and prospective observational survey. The SPC of Cil/Val was administrated once a day in the morning. The SPC of Cil/Val decreased the standard deviation (SD, from 6.3 ± 4.8 to 5.1 ± 3.8 mmHg, p < .01), coefficient of variation (from 4.3 ± 3.2 to 3.8 ± 2.9%, p < .05), average real variability (ARV, from 7.9 ± 6.6 to 6.3 ± 5.1 mmHg, p < .01), and the difference between maximum and minimum (MMD, from 11.9 ± 9.2 to 9.7 ± 7.2 mmHg, p < .01) of MHSBP. The variability of MHSBP increased with age; however, this was not increased in patients ≥70 years at the baseline. In elderly patients (≥70 years, N = 283), the SPC of Cil/Val decreased the SD (from 6.9 ± 5.6 to 5.6 ± 4.4 mmHg, p < .01), ARV (from 8.6 ± 7.7 to 6.9 ± 5.7 mmHg, p < .05), and MMD (from 13.2 ± 10.7 to 10.7 ± 8.3 mmHg, p < .01) of MHSBP at 12 months; the reduction in these MHSBP variability parameters was comparable to that in adults <70 years. These results suggest that the SPC of Cil/Val is effective in reducing day-by-day variability of MHSBP in elderly patients.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Humans; Hypertension; Tetrazoles; Valsartan

Topics: Antihypertensive Agents; Calcium Channel Blockers; Comorbidity; Correlation of Data; COVID-19; Dihydropyridines; Female; Humans; Hypertension; Hypoxia; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; SARS-CoV-2; United States; Vasoconstriction; Withholding Treatment

Topics: Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Combinations; Drug Substitution; Female; Humans; Hypertension; Imidazoles; Japan; Male; Middle Aged; Prospective Studies; Tetrazoles; Treatment Outcome

Adverse drug reaction (ADR) incidence rate was 3.77% (97 of 2572 patients). The frequency of ADRs did not differ between patients aged <75 years and those aged ≥75 years (3.70% vs. 3.93%, respectively); between patients with and without chronic liver disease (CLD; 6.44% vs. 3.54%, respectively); and between patients with and without chronic kidney disease (CKD; 5.26% vs. 3.59%, respectively). Office systolic blood pressure (BP) was reduced from 149.5 ± 19.6 mmHg to 133.5 ± 14.8 mmHg (-15.8 mmHg,

Topics: Aged; Antihypertensive Agents; Blood Pressure Determination; Dihydropyridines; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypertension; Japan; Male; Product Surveillance, Postmarketing; Valsartan

In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a β-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-β-blocker group compared to the benidipine-thiazide group.. We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients.. A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test.. Blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Japan; Outpatients

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

Topics: Administration, Intranasal; Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Disease Models, Animal; Drug Compounding; Drug Liberation; Glycerol; Hypertension; Liposomes; Male; Methylprednisolone Acetate; Nasal Absorption; Nasal Mucosa; Permeability; Phosphatidylcholines; Rats, Wistar; Solubility

The home blood pressure (BP) control by a single-pill combination of cilnidipine (an L-/N-type calcium channel blocker; CCB) and valsartan (HOPE-Combi) survey is a multicenter, post-marketing, prospective observational study of a single-pill combination of cilnidipine 10 mg and valsartan 80 mg (SPC of Cil/Val) in patients with uncontrolled hypertension. We examined the effects of the SPC of Cil/Val on morning home systolic BP (MHSBP) and morning home pulse pressure (MHPP) of 1036 patients with hypertension over 12 months. MHSBP decreased by 14.0 mm Hg (P < .01), and MHPP decreased by 6.6 mm Hg (P < .01). Moreover, morning home pulse rate (MHPR) decreased by 2.1 bpm (P < .01). A more progressive and greater decrease in MHSBP (-17.2 vs -10.3 mm Hg, P < .01) and MHPP (-7.6 vs -4.9 mm Hg, P < .01) was observed in patients with higher MHPR (≥70 bpm) than in those with lower MHPR (<70 bpm) over the treatment period. In particular, in patients with a wide MHPP (≥70 mm Hg), the difference in the MHPP reduction was greater in patients with higher MHPR than in those with lower MHPR (-17.9 vs -13.6 mm Hg, P < .01). These results suggested that the SPC of Cil/Val, which possesses the unique sympatholytic characteristics of an L-/N-type CCB, was particularly effective in patients with uncontrolled hypertension and sympathetic hyperactivity.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Humans; Hypertension; Tetrazoles; Valsartan

Hypertension and coronary events are becoming more prevalent in aging societies, and myocardial infarction usually occurs in calcium channel blocker (CCB)-treated hypertensive patients. We herein compared the effects of cilnidipine, an L/N-type CCB and amlodipine, an L-type CCB, on post-infarct left ventricular (LV) remodelling in spontaneously hypertensive rats (SHRs). Male SHRs were subjected to 30 minutes of left coronary artery occlusion followed by reperfusion (MI group). The administration of cilnidipine (10 mg/kg/d; MI + Cil group) or amlodipine (10 mg/kg/d; MI + Aml group) was initiated one week before surgery and continued for five weeks. Both CCBs decreased blood pressure. Four weeks after surgery, cilnidipine, but not amlodipine, attenuated LV dilatation, fractional shortening impairments, end-diastolic pressure elevations, and tau elongation. In the non-infarct region, myocyte hypertrophy and brain natriuretic peptide (BNP) mRNA levels were similarly attenuated by both CCBs. On the other hand, interstitial fibrosis, the mRNA expression of collagen type III and transforming growth factor (TGF) β and immunohistological TGF β protein expression in the non-infarct region were reduced more in the MI + Cil group than in the MI + Aml group. Additionally, elevated angiotensin-converting enzyme activity and interstitial noradrenaline concentrations in the non-infarct region were reduced by cilnidipine. These results suggest that cilnidipine reduced cardiac noradrenaline concentrations and inhibited the renin-angiotensin system, which attenuated post-infarct remodelling more than amlodipine in hypertensive rats.

Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hypertension; Male; Myocardial Infarction; Norepinephrine; Rats, Inbred SHR; Renin-Angiotensin System; Ventricular Function, Left; Ventricular Remodeling

From the synthesis of 43 lipophilic dihydropyridines, the aim of this study was to verify whether the new dihydropyridines have calcium channel affinity using coupling studies and to determine antihypertensive and antioxidant properties, as well as toxicology and toxicity nifedipine and three new compounds, were chosen from the previous results.. The animals were treated for 56 days, 28 days with N (ω) -nitro-L-arginine methyl ester to induce hypertension, and then treated for another 28 days with the new di- hydropyridine and the standard drug nifedipine. Throughout the treatment the animals had their blood pressure measured and their heart rate checked by pletysmography. After treatment the animals were euthanised, blood samples were collected for creatine kinase and urea analysis, and the brain, heart and liver were collected for oxidative status analysis (quantification of reactive oxygen species, total antioxidant capacity, and lipid peroxidation).. Compounds 2c, and 9a, and nifedipine significantly reduced blood pressure to control group levels. The tachycardia caused by the induction of hypertension was reversed by 2c and 9a compounds. Regarding oxidative stress analyzes, the compounds that had the best performances were also 2c and 9a. Overall the results demonstrate that two of the three new dihydropyridines tested demonstrated performance equal to or superior to the standard drug nifedipine.. In this study, for the first time, docking was applied to analyse 43 fatty dihydropyridines regarding their calcium channel binding. Afterwards, three fatty dihydropyridines were chosen and their antihypertensive and antioxidant properties.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Dihydropyridines; Heart Rate; Hypertension; Male; Nifedipine; Pyridines; Rats; Rats, Wistar

Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics.. To assess the magnitude and characteristics of the DH CCB prescribing cascade.. This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019.. Initiation of DH CCB or negative control medications.. The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs.. Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29).. This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Leg; Male; Middle Aged; Young Adult

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Practice Guidelines as Topic; Precision Medicine

Although several antihypertensive agents reduced the carotid intima-media thickness (IMT), it remains unclear whether those agents affect the interadventitial diameter (IAD). We aimed to examine whether cilnidipine, an L/N-type calcium channel blocker, reduced the common carotid IMT or IAD in post-stroke hypertensive patients.. The common carotid IMT and IAD were measured at the start of cilnidipine treatment and 12 months from that. The changes in the mean max-IMT or IAD between baseline and the 12-month follow-up were evaluated and compared between the thick group (max-IMT ≥1.1 mm) and the normal group (max-IMT ＜1.1 mm).. A total of 603 post-stroke hypertensive subjects (mean age=69.3 yr, 378 males) were included in the analysis. At baseline, IAD was increased stepwise according to the value of max-IMT (p for trend ＜0.001). Among them, 326 subjects were followed up for 12 months. The mean max-IMT from baseline to 12 months did not change in the normal group (－0.01 mm, 95% confidence interval [CI] －0.03 to 0.01, n=170), whereas a significant reduction was observed in the thick group (－0.09 mm, 95% CI －0.13 to －0.05, n=156). The mean IAD was significantly reduced during the study period in the normal group (－0.14 mm, 95% CI －0.22 to －0.05) as well as in the thick group (－0.12 mm, 95% CI －0.21 to －0.03).. Cilnidipine promoted the regression of common carotid IMT in post-stroke hypertensive patients, especially in the thick group. Cilnidipine also reduced the IAD in both normal and thick groups.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Carotid Artery Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Dihydropyridines; Female; Follow-Up Studies; Humans; Hypertension; Male; Prognosis; Stroke

Topics: Aged; Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension; Rats

Recent studies suggest that L-type calcium channel blockers (CCBs) contribute to reducing blood pressure (BP) variability. We investigated whether inhibition of the N-type calcium channel has an additional effect on BP variability by comparing the effect of L-type and L/N-type CCBs on home BP variability in elderly hypertensive patients. Twenty-six hypertensive patients (≥65 years) were subjected to repeated changes with the administration of amlodipine (L-type CCB) and cilnidipine (L/N-type CCB) every 2 months. They measured the home BP in the morning and evening, and the coefficient of variation (CV) was calculated. We measured the brachial-ankle pulse wave velocity (baPWV) and urinary catecholamine excretion as an index of the arterial stiffness and sympathetic nerve activity, respectively. There was no difference in the effect of both drugs on the CV in the morning and evening, while amlodipine was associated with a modestly higher pulse rate and lower BP than cilnidipine. By comparing individual patient data for the CV with each drug, we found that higher urinary catecholamine excretion was associated with the effectiveness of cilnidipine over amlodipine in the BP variability in the morning, which was not the case in the evening. In contrast, lower baPWV was associated with the effectiveness of amlodipine over cilnidipine on BP variability in the evening. Lower baPWV was also associated with lower BP variability in the evening. Cilnidipine has a similar capacity as amlodipine in reducing home BP variability, but the underlying mechanisms in reducing BP variability may differ.

Topics: Aged; Amlodipine; Ankle Brachial Index; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Catecholamines; Dihydropyridines; Female; Humans; Hypertension; Male; Prospective Studies; Sympathetic Nervous System; Vascular Stiffness

Hypertension is a serious component of metabolic syndrome (MetS).. This research investigates the potential protective effect of limonin against MetS-associated hypertension in comparison with azelnidipine, a common calcium channel blocker.. MetS was induced in rats by 10% fructose in water and 3% salt in diet over a 16-week period. Limonin (50 mg/kg) and azelnidipine (5 mg/kg) were administered daily in the last four weeks METHODS: Non-invasive blood pressure (BP) was recorded in conscious animals. Concentration-response curves for phenylephrine (PE) and acetylcholine (ACh) were analysed in thoracic aorta (macrovessels) and kidney microvessels. Blood glucose level, serum insulin level, advanced glycation end products (AGEs), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and transforming growth factor-β1 (TGF-β1) were determined.. Limonin alleviated elevations in systolic and diastolic BP associated with MetS similar to levels associated with azelnidipine. Limonin prevented the MetS induced exaggerated macro- and micro-vascular contractility to PE and the impaired dilatation to ACh. However, in vitro incubation with limonin partially alleviated the deteriorated vascular reactivity of aorta isolated from MetS animals or AGEs injured aorta. Limonin did not have direct relaxant effect on the isolated vessel. On the other hand, limonin reduced the elevated serum levels of AGEs, TNF-α and MDA. Limonin suppressed the vascular fibrosis through reducing the elevated serum level of TGF-β1 and excessive aortic collagen deposition. Limonin decreased the elevated HOMA-IR in MetS animals.. Limonin offsets the hypertensive and vascular impairment associated with MetS via attenuation of inflammation and fibrosis. Its impact is comparable to that of azelnidipine.

Topics: Animals; Aorta, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Dihydropyridines; Dose-Response Relationship, Drug; Fructose; Glycation End Products, Advanced; Hypertension; Insulin Resistance; Limonins; Male; Metabolic Syndrome; Rats

Cardiovascular events in hypertensives are associated with elevated average blood pressure (BP) and higher short-term BP variability (V), but little is known on treatment effects on BPV and on how to assess changes in short-term BPV. Aim of our study was to address the methodology of short-term BPV assessment and its reduction by Lercanidipine (L) or Enalapril (E) and their combination, through analysis of 24-hour ambulatory BP recordings from two studies including subjects of different age. Study-1: 64 middle-age hypertensives (52.9 ± 9.5 yrs) received L and E s.i.d. at 10 mg (L10, E10) or 20 mg doses (L20, E20) for 8 weeks. Study-2: 66 elderly hypertensives (65.5 ± 4.7 yrs) received placebo, L10, E20 and L10 + E20 s.i.d. for 4 weeks. In middle-age subjects, both L and E decreased mean BP and, at the highest dose, also short-term BPV. In elderly subjects, L10 alone or in combination with E20 reduced BPV. Treatment-induced reductions in BP levels and BPV were uncorrelated. Different methods for short-term BPV assessment did not always provide superimposable results in the elderly. Our study supports a better reduction of BPV by L in the elderly and by E + L combination at any age, suggesting BPV reduction to be independent from reduction in average BP.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class. Among the most efficient modifications of the DHP scaffold, is the introduction of biologically active N3-substituted dihydropyrimidine mimics (DHPMs). Again, some potent DHPMs showed only in vitro activity due to first pass effect through hydrolysis and removal of the N3-substitutions. Herein, the synthesis of new N3-substituted DHPMs with various functionalities linked to the DHPM core via two-carbon spacer to guard against possible metabolic inactivation is described. It was designed to keep close structural similarities to clinically efficient DHPs and the reported lead DHPMs analogues, while attempting to improve the pharmacokinetic properties through better metabolic stability. Applying whole batch clamp technique, five compounds showed promising L- and T- type calcium channel blocking activity and were identified as lead compounds. Structure requirements for selectivity against Ca

Topics: Calcium Channel Blockers; Calcium Channels, L-Type; Crystallography, X-Ray; Dihydropyridines; HEK293 Cells; Humans; Hypertension; Models, Molecular

Increased blood pressure variability has been shown to be associated with cardiovascular morbidity and mortality. Recently we reported that continuous infusion of angiotensin II not only elevated blood pressure level, but also increased blood pressure variability in a manner assumed to be independent of blood pressure elevation in rats. In the present study, the effects of the angiotensin type I receptor blocker losartan and the calcium channel blocker azelnidipine on angiotensin II-induced blood pressure variability were examined and compared with that of the vasodilator hydralazine in rats. Nine-week-old male Wistar rats were subcutaneously infused with 240 pmol/kg/min angiotensin II for two weeks without or with oral administration of losartan, azelnidipine, or hydralazine. Blood pressure variability was evaluated using a coefficient of variation of blood pressure recorded every 15min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. Treatment with losartan suppressed both blood pressure elevation and augmentation of systolic blood pressure variability in rats infused with angiotensin II at 7 and 14 days. Azelnidipine also inhibited angiotensin II-induced blood pressure elevation and augmentation of blood pressure variability; meanwhile, hydralazine attenuated the pressor effect of angiotensin II, but had no effect on blood pressure variability. In conclusion, angiotensin II augmented blood pressure variability in an angiotensin type 1 receptor-dependent manner, and azelnidipine suppressed angiotensin II-induced augmentation of blood pressure variability, an effect mediated by the mechanism independent of the blood pressure-lowering action.

Topics: Angiotensin II; Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Losartan; Male; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Time Factors

Blood pressure control is important in post-stroke hypertensive patients and antihypertensive treatment is recommended for such patients. Ca-channel blockers are recommended as the medications of choice for the treatment of post-stroke patients. Here, we report the results of a large-scale prospective post-marketing surveillance study of post-stroke hypertensive patients (n = 2667, male 60.4%, 69.0 ± 10.9 years) treated with cilnidipine, with regard to blood pressure control and adverse reactions. Cilnidipine treatment caused a decrease in both clinic and home blood pressures 2 months after the beginning of treatment, and the decreased blood pressure was maintained until the end of 12 months' observation. The proportion of patients in whom clinic blood pressure was well controlled (<140/90 mmHg) increased from 21.5% to 65.3% in cilnidipine treatment, with no differences in effectiveness among the various clinical subtypes of stroke. In total, 346 adverse events occurred, with an overall incidence of 8.9% (238 of 2667 patients). In the elderly group, specifically, a fall and a hip fracture each occurred in 1 (0.1%) patient. These results indicate that cilnidipine was effective in treating uncontrolled blood pressure and was well tolerated in Japanese post-stroke hypertensive patients in a real-world clinical setting.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Stroke

The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT.. Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (. There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373).. In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Echocardiography; Female; Heart Failure; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Radionuclide Imaging; Renin-Angiotensin System; Stroke Volume

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged

The authors sought to determine the association between the blunted morning blood pressure (BP) surge and nocturnal BP dipping of the "riser" pattern in 501 patients with hypertension enrolled in the ACHIEVE-ONE (Ambulatory Blood Pressure Control and Home Blood Pressure [Morning and Evening] Lowering by the N-Channel Blocker Cilnidipine) trial. The patients' sleep-trough morning BP surge and prewaking surge were calculated and then classified according to their nocturnal systolic BP reduction pattern as extreme dippers, dippers, nondippers, and risers. The prevalence of the riser pattern was significantly higher in both the lowest sleep-trough morning BP surge decile and the prewaking surge decile (blunted surge group) compared with the remaining deciles (56.0% vs 10.4% [P<.0001] and 59.2% vs 10.2% [P<.0001], respectively). The riser pattern was a significant determinant of both blunted sleep-trough morning BP surge (odds ratio, 73.3; P<.0001) and blunted prewaking surge (odds ratio, 14.8; P<.0001). The high prevalence of the riser pattern in patients with blunted morning BP surges may account for the cardiovascular risk previously reported in such patients.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cardiovascular Diseases; Circadian Rhythm; Dihydropyridines; Female; Humans; Hypertension; Hypotension; Japan; Male; Middle Aged; Risk Factors; Sleep

Topics: Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Electrocardiography; Female; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Tetrazoles; Ventricular Premature Complexes

Hypertension is the leading cause of cardiovascular disease worldwide. Calcium channel blockers are an effective antihypertensive treatment, but frequently hypertension remains uncontrolled for many patients, partly due to tolerability issues.. To assess the tolerability and effectiveness of barnidipine in mild to moderate hypertension patients switching treatment from other calcium channel blockers in daily practice.. BASIC-HT, a prospective real life study, enrolled 20,479 hypertensive patients initiating barnidipine treatment. The present paper focuses on a subgroup of patients in BASIC-HT for whom the previous treatment with amlodipine or lercanidipine was replaced by barnidipine. Tolerability and effectiveness of barnidipine in these patients were assessed at two visits during a 3-month follow up.. In 1710 mild to moderate hypertension patients switching treatment from amlodipine or lercanidipine to barnidipine monotherapy or in combination with other antihypertensive drug classes, mean blood pressure decreased during 3-month follow-up. The mean systolic blood pressure decreased from 153.15 mmHg [95% CI 152.35-153.95] at baseline to 139.20 mmHg [95% CI 138.58-139.82] at visit 3, after 3 months. The mean diastolic blood pressure decreased from 88.85 mmHg at baseline [95% CI 88.36-89.34], to 81.56 mmHg [95% CI 81.20-81.91] at visit 3. Among these patients, 65.4% replaced their initial calcium channel blocker treatment to barnidipine for tolerability reasons. During the follow-up, the main adverse event reported was edema (4.8%). The nature and frequency of events reported in this subgroup of switcher patients were in line with those reported by the total population in BASIC-HT.. This real-life study suggests that replacement of other calcium channel blockers with barnidipine is a valuable therapeutic option, especially when tolerability is an issue.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Substitution; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Product Surveillance, Postmarketing; Prospective Studies; Time Factors; Treatment Outcome

The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an open-label cross-over pilot study of 28 patients with type II diabetes mellitus. Patients received combination treatment with either olmesartan 20 mg plus azelnidipine 16 mg or olmesartan 20 mg plus trichlormethiazide 1 mg for more than 6 weeks each in a cross-over method. The coefficient of morning systolic BP variability in the olmesartan plus azelnidipine group was significantly lower than that in the olmesartan plus trichlormethiazide group (6.4 ± 1.9 vs. 7.5 ± 2.6, P = .004). There were no significant differences in mean morning systolic BP between the two groups. Using home BP telemonitoring for hypertensive patients with type II diabetes, this study revealed for the first time that the olmesartan with azelnidipine combination is superior to the olmesartan with trichlormethiazide combination in reducing home BP variability.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Pilot Projects; Tetrazoles; Trichlormethiazide

Calcium channel blockers (CCBs) have been proved to have beneficial effects on cardiovascular (CV) outcomes, especially in stroke. Lercanidipine, a highly lipophilic CCB, lacks data regarding long-term outcomes including: CV, stroke, renal and all-cause mortality. This retrospective cohort study aims to clarify this.. A total of 144,630 newly diagnosed hypertension (HTN) patients (age: 18-65 years) in 2005 from the Taiwan's National Health Insurance Research Database were enrolled in this observational study. A pure hypertension population was fetched by excluding all chronic diseases in the Charlson Comorbidities Index. Patients were stratified into the lercanidipine group (n = 1303) and the propensity-score-matched comparative group (nifedipine, amlodipine or felodipine, n = 15,301).. Compared to other CCBs, lercanidipine didn't have a significant difference on the study endpoints. In individual head-to-head comparisons, lercanidipine was shown to be superior to nifedipine in incident stroke with an adjusted HR with 95% CI of 0.526 (0.347-0.797) (p = .0025). The key limitations were that personal variables, such as smoking habits, alcohol intake, body mass index and physical activity and blood pressure profiles were not available in the nationwide registry database.. In newly diagnosed patients with hypertension, lercanidipine was superior to nifedipine in the six-year period when the analyzed endpoint was stroke.

Topics: Adolescent; Adult; Aged; Amlodipine; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Retrospective Studies; Stroke; Taiwan; Young Adult

Non-persistence rate (defined as not remaining on treatment) in patients taking a renin angiotensin system inhibitor plus calcium channel blocker was studied in three integrated 12-weeks surveys by matching separate drug combination therapy (CT) and fixed-dose combination (FDC). We also investigated medication adherence measured by proportion of days covered by using a claims database. The non-persistence rate was significantly lower in FDC than CT (p = 0.0074). In the database study, the medication adherence was higher in FDC than CT for 3, 6, and 12 months (all p < 0.001). In conclusion, use of single-tablet FDC antihypertensive therapy was associated with better medication-taking behavior.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Azetidinecarboxylic Acid; Cohort Studies; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Japan; Male; Medication Adherence; Middle Aged; Prospective Studies; Surveys and Questionnaires; Tablets; Tetrazoles

This study was performed to evaluate the possible protective effect of two calcium channel blocker's "lacidipine (LAC) and amlodipine (AML)" on bone metabolism in an experimental ovariectomized and inflammation-induced osteoporosis rat model (OVXinf). For the purpose of this study, the rats were divided into eight groups, each containing eight rats: sham-operated control (group 1, SH), sham + inflammation (group 2, SHinf), ovariectomy (group 3, OVX), ovariectomy + inflammation (group 4, OVXinf), ovariectomy + LAC 4 mg/kg (group 5, OVX + LAC), ovariectomy + inflammation + LAC 4 mg/kg (group 6, OVXinf + LAC), ovariectomy + AML 5 mg/kg (group 7, OVX + AML), ovariectomy + inflammation + AML 5 mg/kg (group 8, OVXinf + AML). The levels of osteocalcin and osteopontin decreased in OVXinf + LAC and OVXinf + AML groups. The serum levels of TNF-α, IL-1β, and IL-6 were increased significantly in the OVXinf rats compared with the SH group. Gene expression levels of the osteogenic factor runt-related transcription factor 2 (Runx2) and type I collagen 1A1 (Col1A1) significantly decreased in the OVXinf group, when compared with the control group. AML or LAC administrations increased the levels of Runx2 and Col1A1. These results suggest that amlodipine and lacidipine may be a novel therapeutic target for radical osteoporosis treatment in hypertensive patients.

Topics: Amlodipine; Animals; Bone Density; Calcium Channel Blockers; Collagen Type I; Collagen Type I, alpha 1 Chain; Core Binding Factor Alpha 1 Subunit; Dihydropyridines; Female; Humans; Hypertension; Inflammation; Interleukin-1beta; Interleukin-6; Osteocalcin; Osteopontin; Osteoporosis; Ovariectomy; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.

Topics: Aged; Alanine Transaminase; Amlodipine; Antihypertensive Agents; Aspartate Aminotransferases; Azetidinecarboxylic Acid; Benzimidazoles; Biphenyl Compounds; Blood Urea Nitrogen; Cohort Studies; Creatinine; Dihydropyridines; Drug Combinations; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Potassium; Propensity Score; Retrospective Studies; Sodium; Tetrazoles; Uric Acid

The study aimed to investigate the association of long-term use of different antihypertensive agents with incident breast cancer.. A total of 794 ,533 women aged at least 55 years were identified from Taiwan National Health Insurance claims database during 2001-2011. As of 31 December 2011, incident breast cancer patients were included as cases, and 1 : 4 age-matched controls were selected by risk-set sampling scheme. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer incidence associated with different durations of use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dihydropyridine calcium channel blockers (DHP CCBs). Different restriction rules were applied to reveal the potential effects of confounding by indication.. Among the 9397 incident breast cancer patients and 37 ,588 controls, a significantly elevated risk was found for relatively short-term use of DHP CCBs (<6 years) but not in those observed for more than 6 years. There was no association between either angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or β-blockers use and breast cancer. Although restricting our analyses to those with any prescription of antihypertensive medications in 2001 or those with diagnosis of hypertension, there was no longer a statistically significant association between any use of DHP CCBs and breast cancer (OR: 1.21, 95% CI: 0.88-1.67 for the former, and OR: 1.71, 95% CI: 0.99-2.95 for the latter).. The results demonstrated the potential effect of confounding by indication, and thus, did not suggest any association of the use of antihypertensive medication and breast cancer risk.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Breast Neoplasms; Calcium Channel Blockers; Case-Control Studies; Dihydropyridines; Female; Humans; Hypertension; Incidence; Logistic Models; Middle Aged; Odds Ratio; Risk Factors; Taiwan

It has been demonstrated that circulating endothelial progenitor cells (EPCs) number reflects the endogenous vascular repair ability, with the EPCs pool declining in presence of cardiovascular risk factors. Several drugs, including dihydropyridine calcium channel blockers, have been reported to elicit antioxidant and anti-inflammatory properties, as well as to improve vascular remodeling and dysfunction. However, no data are available about the effects of lercanidipine on EPCs. The aim of the present study was therefore to investigate the effects of short-term treatment with lercanidipine on circulating EPCs, as well as on indices of inflammation and oxidative stress.. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine 20 mg per day orally. Investigations were performed in basal condition, after appropriate wash out of previous treatments, and after 4 weeks of lercanidipine treatment. Inflammatory and oxidative stress markers were assessed by ELISA technique. Lin-/7AAD-/CD34+/CD133+/VEGFR-2 + and Lin-/7AAD-/CD34+/VEGFR-2 + cells were identified by flow cytometry and considered as EPCs. EPCs cells were expressed as number of cells per million Lin-mononuclear cells.. Circulating EPCs were significantly increased after lercanidipine treatment (CD34+/CD133+/VEGFR-2 + cells: 78.3 ± 64.5 vs 46.6 ± 32.8; CD34+/VEGFR-2+: 87996 ± 165116 vs 1026 ± 1559, respectively, p < 0.05). A modest reduction in circulating indices of inflammation was also observed.. In conclusion, lercanidipine is able to increase the number of circulating EPCs, possibly through a reduction of low-grade inflammation.

Topics: Antihypertensive Agents; Dihydropyridines; Endothelial Progenitor Cells; Essential Hypertension; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Risk Factors

The pupil is a suitable end organ for studying autonomic function because both sympathetic and parasympathetic nerve activity can be evaluated independently using a light stimulus. Sympathetic response elicited by physical stress is augmented in hypertensive patients compared with normotensive subjects, which increases the risk of cardiovascular events. We used pupillometry to evaluate the effects of the calcium channel blockers azelnidipine (AZ) and amlodipine (AM) on changes in autonomic nervous activity induced by isometric exercise in patients with hypertension. Twenty patients with essential hypertension who were administered AM and 21 who were administered AZ underwent a pupillary function test and blood pressure (BP) and pulse rate (PR) measurements before and after isometric handgrip exercise (IHG). Maximal velocities of pupil constriction (VC) and re-dilation (VD) obtained with light stimulation for 1 s were used as indices of parasympathetic and sympathetic nerve activity, respectively. Increases in systolic BP and PR elicited by IHG were significantly smaller in the AZ group than in the AM group. After IHG, both VC and VD significantly increased in the AM group but not in the AZ group. The low-to-high frequency ratio obtained from analysis of PR variability, another measure of sympathetic activity, also increased in only the AM group. Thus AZ inhibited autonomic activation and suppressed cardiovascular responses to IHG more effectively than AM. The sympathoinhibitory effect of AZ may therefore be beneficial for patients with essential hypertension. In addition, pupillometry was shown to be a useful tool for assessing autonomic function in hypertensive patients.

Topics: Amlodipine; Antihypertensive Agents; Autonomic Nervous System; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Essential Hypertension; Exercise; Female; Humans; Hypertension; Male; Middle Aged; Pupil

The activation of the renin-angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine.

Topics: Aged; Aldosterone; Amlodipine; Angiotensin Receptor Antagonists; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Drug Combinations; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Valsartan

The aim of the present study was to develop nanoproliposomes of lercanidipine, in order to overcome its poor biopharmaceutical properties and to improve its therapeutic efficacy in treating hypertension.. The nanoproliposomes were prepared using a modified thin-film hydration method, and the formula was optimized by varying the ratio of lipids and the types of cryoprotectants. This optimized formulation was characterized in terms of its particle size, solid-state, drug release, in-situ absorption, in-vivo pharmacokinetics, and in-vivo anti-hypertensive activity in DOCA-salt induced hypertensive rats. Finally, a PK-PD correlation was established in order to understand the clinical implications of the developed novel nanoproliposomes.. The nanoproliposomes showed a particle size of 174.7nm and an entrapment efficiency of 85.4%. The in-vitro release displayed initial rapid release (19.33%) followed by a sustained release profile, releasing 88.37% of the encapsulated drug. The in-situ studies showed a significant increase in absorption rate across the rat intestinal membrane. The pharmacokinetics of this novel form indicated a 2.75-fold increase in the absolute bioavailability as compared to pure lercanidipine. In addition, the nanoproliposomes were found to be efficient in treating hypertension in DOCA-salt induced hypertensive rats. The PK-PD correlation demonstrated no time lag between effect and exposure, indicating that a direct PK-PD relationship can be expected in the clinic.. These findings suggest that nanoproliposomes are promising carriers in improving the oral bioavailability and bioactivity of lercanidipine, and can be an effective therapy in the management of hypertension.

Topics: Animals; Antihypertensive Agents; Calorimetry, Differential Scanning; Dihydropyridines; Hypertension; In Vitro Techniques; Liposomes; Nanoparticles; Rabbits; Rats; Rats, Wistar; X-Ray Diffraction

Hypertension is one of the most common conditions seen in primary care and a major public health problem in India. It can lead to various complications if not detected early and treated appropriately. As per the latest Eighth Joint National Committee (JNC 8) the goal BP in most hypertensive patients age <60 years should be <140/90 mmHg and treatment can be started by selecting drugs from among 4 specific medication classes i.e. angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), calcium channel blocker (CCB) or diuretics. CCB is one of the first line drugs in the management of hypertension. Among CCB, Cilnidipine is a unique Ca2+ channel blocker as it has inhibitory action on the sympathetic N-type Ca2+ channels along with its effect on L-type Ca2+ channels. This article focuses on the current status of cilnidipine in the management of hypertension and co-morbidities. Cilnidipine by attenuating norepinephrine release from sympathetic nerve endings leads to vasodilatation, decreases heart rate and increases renal blood flow. Cilnidipine has an advantage of causing less reflex tachycardia, less pedal edema and better control of proteinuria in comparison to L-type CCB. By causing dilatation of efferent arteriole, it causes less damage to glomeruli and suppresses podocyte injury. Cilnidipine also increases insulin sensitivity. Therefore, cilnidipine as CCB can be a good choice in hypertensive patients with diabetes, chronic kidney disease and in patients developing pedal edema with other CCB.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Humans; Hypertension; India; Middle Aged

Hypertension is associated with alterations in the vascular structure, which in turn enhance the risk of cardiovascular events. Notably, anti-hypertensive treatment may prevent or regress the changes of arterial wall structures. Lercanidipine is a third-generation CCB with peculiar pharmaceutical properties. Enalapril is an effective drug acting on the renin-angiotensin-aldosterone axis. This commentary discusses the vascular effects of the lercanidipine/enalapril combination, and comments on their potential clinical relevance.

Topics: Antihypertensive Agents; Blood Pressure; Blood Vessels; Dihydropyridines; Drug Therapy, Combination; Enalapril; Humans; Hypertension

Evaluating the effectiveness of the various options of combination antihypertensive therapy (AHT) in women with arterial hypertension (AH) and metabolic syndrome (MS) and hypothyroidism.. The study included 163 women with hypertension, metabolic syndrome, and hypothyroidism, the median age of 53.5 (48-60) years; in 73 (44.8%) women were diagnosed with subclinical hypothyroidism (SH), 90 (55.2%) - overt hypothyroidism (OH). Patients with both SH and OH, depending on the source of the heart rate (HR) was appointed as one of the following combination of AHT. If heart rate <75 beats/min, patients (n=100) received a combination of the dihydropyridine calcium antagonist (AA) amlodipine 5 mg/day, and angiotensin receptor blockers II (ARB) losartan 50 mg/day, with heart rate >75 beats/min (n=63) - a combination of amlodipine 5 mg/day and imidazoline receptor agonist (IRA) moxonidine 200 micrograms/day. The failure to achieve target blood pressure (BP) after 4 weeks of dose drugs doubled with subsequent evaluation of the effectiveness even after 4 weeks. At baseline and after 6 months of therapy, all patients underwent daily blood pressure monitoring (DBPM).. At 8 weeks, the use of a combination of AA+ARB target BP level was registered in 26 (59%) of 44 women with SH and 34 (60.7%) of the 56 - OH. In the group of women who took the AA+IRA, after 8 weeks of the target blood pressure was observed in 24 (82.8%) of 29 patients with SH and 28 (82.4%) of 34 - to OH. Register the target blood pressure was observed significantly more frequently (p<0,05) when using a combination of AA+IRA compared with AA+ARBs as with SH and OH. As a result of the combination of DBPM AA and ARBs in patients with SH and OG provided a significant reduction in average daily, daytime and nighttime systolic and diastolic blood pressure (SBP and DBP), the time index of SBP and DBP during the day and night hours. The therapy of AA and IRA regardless of the severity of hypothyroidism, there was a significant improvement in all indicators DBPM: average daily, daytime and nighttime SBP and DBP, time index and variability in SBP and DBP during the day and at night. Furthermore, as in the SH and OH significantly more pronounced positive changes most DBPM parameters were recorded using IRA in combination with AA compared with a combination AA+ARB. Significant increase in the number of women with optimal BP daily profile "dipper" observed only when using amlodipine and moxonidine.. In women with hypertension, hypothyroidism and MS, regardless of the severity of decline of thyroid function and combination of the dihydropyridine AA IRA had an advantage over the AA combination with ARBs, since most patients provided achieving target blood pressure and clinically significant positive impact on BPM indicators. The results can be used in selecting the optimal AHT in patients with hypertension, MS, and the manifest subclinical hypothyroidism.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Hypothyroidism; Imidazoles; Losartan; Metabolic Syndrome; Middle Aged

Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood.. This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients' questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients' satisfaction with regard to combination drugs.. Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients.. Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.

Topics: Aged; Amlodipine; Angiotensin Receptor Antagonists; Azetidinecarboxylic Acid; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Drug Costs; Drug Substitution; Female; Humans; Hypertension; Imidazoles; Male; Medication Adherence; Middle Aged; Nephrology; Patient Satisfaction; Practice Patterns, Physicians'; Renal Insufficiency, Chronic; Retrospective Studies; Surveys and Questionnaires; Telmisartan; Tetrazoles; Valsartan

Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.

Topics: Amlodipine; Animals; Antihypertensive Agents; Dihydropyridines; Drug Evaluation, Preclinical; Drug Therapy, Combination; Heart; Hypertension; Hypertrophy, Left Ventricular; Male; Myocytes, Cardiac; Oxidative Stress; Rats, Inbred Dahl; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

To investigate the renal-protective effect of lercanidipine in patients undergoing renal artery intervention.. A prospective, single-center, cohort study was conducted and patients, 30-75 years of age, with atherosclerotic renal artery stenosis were consecutively enrolled between September 2011 and October 2012. Lercanidipine (10-20 mg/day) was regularly taken after the intervention. Follow up visits were performed at 3 and 6 months after the intervention. Serum creatinine, clinical blood pressure, 24 hour ambulatory blood pressure, pulse wave velocity, and 24 hour urine protein were assessed. Adverse events were recorded.. In total, 55 patients (mean age 63.5 ± 8.9 years) were enrolled and 52 completed the study. Renal function, estimated glomerular filtration rate (eGFR) and 24 hour urine protein at 3 months after the intervention were not statistically different compared with the baseline. At 6 months after the intervention eGFR significantly increased versus baseline (78 ± 23 ml/min/1.73 m(2) vs 71 ± 21 ml/min/1.73 m(2), p = 0.021); 24 hour urine protein decreased significantly (0.02 g [IQR, 0.01-0.1] vs 0.03 g [IQR, 0.01-0.28], p = 0.042). Blood pressure control improved at 3 months and 6 months after the intervention. The need for antihypertensive drugs decreased; clinical systolic blood pressure, diastolic blood pressure and 24 hour average systolic blood pressure and diastolic blood pressure decreased. The pulse wave velocity decreased after 3 and 6 months. At the end of follow-up, none of the following adverse events occurred: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred.. This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Atherosclerosis; Blood Pressure Monitoring, Ambulatory; Cohort Studies; Creatinine; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Renal Artery Obstruction; Stents; Treatment Outcome

Topics: Antihypertensive Agents; China; Dihydropyridines; Humans; Hypertension; Lebanon; Vietnam

Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk.. To investigate safety and efficacy of such combination therapies.. Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial single-pill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p = 0.0001) was used to select comparable cohorts of patients (n = 142 each).. After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six-month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p = 0.05); especially among diabetics (52.0% and 51.0%, respectively; p = 0.003). Patients receiving E/L (-19.8 ± 3.2 mmHg) and P/A (-19.9 ± 4.6 mmHg) showed greater reductions of diastolic BP (p = 0.03); whereas reductions of systolic BP were similar between treatment groups (p = 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance.. Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A.

Topics: Amlodipine; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Dihydropyridines; Dose-Response Relationship, Drug; Drug Combinations; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Middle Aged; Perindopril; Propensity Score; Ramipril; Retrospective Studies; Risk Factors; Telmisartan; Tetrazoles

Cilnidipine is an L/N-type calcium channel blocker (CCB). The effects of cilnidipine on N-type channels give it unique organ-protective properties via the suppression of hyperactivity in the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). In the present study, we compared the effects of cilnidipine and amlodipine (an L-type CCB) on cardiac and renal functions in spontaneously-hypertensive rats injected with adriamycin (ADR). After the weekly administration of ADR for 3 weeks, spontaneously-hypertensive rats were orally administered cilnidipine (20 mg/kg per day), amlodipine (3 mg/kg per day), or vehicle once daily for 4 weeks. A control group received saline rather than ADR, followed by vehicle for 4 weeks. Cilnidipine and amlodipine produced similar reductions in blood pressure after 4 weeks. Cilnidipine ameliorated ADR-induced heart and kidney damage, whereas amlodipine slightly improved cardiac echocardiographic parameters, but did not protect against ADR-induced renal damage. Cilnidipine (but not amlodipine) suppressed the reflex SNS and RAAS hyperactivity caused by their antihypertensive effects. Furthermore, cilnidipine and amlodipine treatment decreased the urinary levels of adrenocortical hormones. The protective effects of cilnidipine against ADR-induced renal and cardiac dysfunction might be associated with its blockade of N-type calcium channels, in addition to its pleiotropic actions, which include the inhibition of the RAAS.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Doxorubicin; Fibrosis; Heart Diseases; Hypertension; Kidney; Kidney Diseases; Male; Myocardium; Rats, Inbred SHR; Renin-Angiotensin System; Sympathetic Nervous System

Pupillometry was used to evaluate the effects of the calcium channel blockers cilnidipine (CL) and amlodipine (AM) on changes in autonomic nervous activity induced by isometric exercise in patients with hypertension. After handgrip exercise, the velocity of miosis increased in both the CL and AM groups. However, the velocity of mydriasis increased in only the AM group. Velocity slopes of miosis and mydriasis were smaller in the CL group than in the AM group. The low-to-high frequency ratio obtained from pulse wave analysis increased in only the AM group. Sympathetic activation elicited by isometric exercise was suppressed more effectively by CL than by AM.

Topics: Aged; Amlodipine; Autonomic Nervous System; Calcium Channel Blockers; Dihydropyridines; Exercise; Female; Hand Strength; Humans; Hypertension; Male; Middle Aged; Miosis; Mydriasis; Pupil; Reproducibility of Results

We studied effect of therapy with fixed combination of lercanidipine and enalapril on 24-hour blood pressure (BP) profile in 34 elderly patients (mean age 76.4±5.2 years, 14 men, 20 women) with degree I hypertension. After clinical examination patients were given lercanidipine/ enalapril combination (10/10 mg/day). The dose was increased to 10+20 mg/day when necessary. Assessment of efficacy was conducted on Rate of achievement of target BP [systolic (S) BP <150 mm HG, diastolic (D) BP<90 mmHg] and dynamics of parameters of 24-hour BP profile. Re-examinations were carried out on weeks 4.8 and 12 of treatment. Administration of lercanidipine/enalapril combination was associated with mean 24-hour SBP and DBP lowering (by15.3 and 8.7%, respectively). Diurnal and nocturnal SBP/DBP decreased by 15.7/ 9.2 and 14.1/8.5%, respectively. BP variability also significantly decreased: of diurnal SBP/DBP - 3.8/4.1 mm Hg (21.7/24.7%), of nocturnal SBP/DBP - 2.8/4.1 mm Hg (17.9/19.6%). There was no significant dynamics of the heart rate. Therapy with lercanidipine/enalapril combination for 12 weeks did not lead to the deterioration of carbohydrate, lipid metabolism, or renal function. Thus using lercanidipine/ enalapril combination we observed pronounced antihypertensive effect which consisted in decrease of mean BP and normalization of BP circadian rhythm of blood pressure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Treatment Outcome

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24 h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke.

Topics: Animals; Brain; Cerebral Infarction; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Signal Transduction

Calcium channel blockers (CCB) are widely used in cardiovascular medicine expressing high hopes upon decreasing cardiovascular risk, morbidity and mortality. Here, the potency of CCBs on 58 Romanian asymptomatic hypertensive patients, with no atherothrombotic cardiovascular disease, was studied by clinical and in silico methods. In our study, arterial elasticity/stiffness was assessed; anthropometric, metabolic (lipidic) parameters were quantified. We concluded that lercanidipine 10 mg once daily, during three weeks, is able to dramatically improve central aortic systolic blood pressure, aortic pulse wave velocity. Lipid profile improvement is an essential condition to improve elastic vascular properties in order to decrease the risk for further cardiovascular events. Besides, the potency of lercanidipine is expressed as the contribution of molecular descriptors (van der Waals and solvent accessible surface areas), electronic (molecular polarisability) and hydrophobic (water/octanol partition coefficient) by means of blocker effect on calcium channel, compared with cilnidipine and other 30 dihydropyridines, using molecular simulation techniques.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Vascular Stiffness

The comparative effectiveness of dihydropyridine (DHP) and non-DHP calcium channel blockers (CCBs) in maintenance dialysis patients has not been well-studied.. A retrospective cohort of hypertensive patients initiating dialysis was created. New CCB initiators, defined as individual who had no evidence of CCB use in the first 90 days of dialysis but who were initiated by day 180, were followed from their first day of medication exposure until event or censoring; events consisted of all-cause mortality (ACM) and a combined endpoint of cardiovascular morbidity or mortality (CVMM). Cox proportional hazards models were used to determine adjusted hazard ratios (AHRs) comparing the effect of DHPs vs. non-DHPs.. There were 2900 and 2704 new initiators of CCBs in the ACM and CVMM models, respectively. Adjusted for other factors, use of DHPs, compared to non-DHPs, was associated with an AHR of 0.77 (99% confidence intervals, 0.64 - 0.93, P = 0.0004) for ACM and 0.86 (0.72 - 1.02, P = 0.024) for CVMM. Results were similar when individuals who initiated therapy at any point after the cohort inception were included, with AHRs of 0.60 (0.53 - 0.69, P < 0.0001) and 0.77 (0.67 - 0.89, P < 0.0001) for ACM and CVMM, respectively. Further, elimination of individuals with chronic atrial fibrillation resulted in AHRs of 0.71 and 0.70 for ACM and CVVM, respectively.. DHPs, as compared to non-DHPs, were associated with reduced hazard of death or cardiovascular morbidity and mortality; potential mechanisms of action require further study.

Topics: Calcium Channel Blockers; Cohort Studies; Comorbidity; Dihydropyridines; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Medicaid; Medicare; Middle Aged; Renal Dialysis; Retrospective Studies; Survival Analysis; United States

Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in hypertension.

Topics: Animals; Antihypertensive Agents; Apoptosis; Carotid Artery Injuries; Caspase 3; Cell Adhesion; Cells, Cultured; Dihydropyridines; Endothelial Cells; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Male; MAP Kinase Signaling System; Mice; Mice, Nude; Receptors, CXCR; Transfection; Up-Regulation

Topics: Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Female; Gliclazide; Humans; Hypertension; Indapamide; Male; Perindopril

It has been previously demonstrated that dihydropyridine calcium channel blockers may possess antioxidant properties and might improve vascular structure. Combination treatment with an angiotensin-converting enzyme inhibitor may have additional advantages, compared with a thiazide diuretic, in this regard. The aim of the present study was, therefore, to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility.. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine 20 mg per day orally. Then they were treated for 6 months with lercanidipine + enalapril (n=10) or lercanidipine + hydrochlorothiazide (n=10) combinations. Investigations were performed in basal condition, after appropriate washout of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (W/L) and other morphological parameters of retinal arterioles using scanning laser Doppler flowmetry were performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). Capillary density was evaluated by capillaroscopy, whereas pulse wave velocity and central blood pressure were assessed by the Sphygmo-Cor device (AtCor Medical West Ryde, Australia).. A significant improvement of W/L and of other indices of retinal artery structure was observed after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, whereas after treatment with lercanidipine + hydrochlorothiazide the improvement was no longer observed. A similar behaviour was observed for central SBP and DBP. Capillary density was increased only after treatment with lercanidipine + enalapril.. Lercanidipine both in monotherapy and in combination with enalapril, was able to improve microvascular structure and to decrease central blood pressure, being thus a useful approach for both reducing blood pressure and improving vascular alterations in hypertension.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arterioles; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Enalapril; Essential Hypertension; Female; Humans; Hydrochlorothiazide; Hypertension; Kidney; Laser-Doppler Flowmetry; Male; Middle Aged; Oxidative Stress; Ultrasonography

Lercanidipine hydrochloride is a calcium channel blocker used in the treatment of hypertension. It is a poor water soluble drug with absolute bioavailability of 10%. The aim of this study was to design lercanidipine hydrochloride-loaded nanostructured lipid carriers to investigate whether the bioavailability of the same can be improved by oral delivery. Lercanidipine hydrochloride nanostructured lipid carriers were prepared by the method of solvent evaporation at a high temperature and solidification by freeze drying. The nanostructured lipid carriers were evaluated for particle size analysis, zeta potential, entrapment efficiency, in vitro drug diffusion, ex vivo permeation studies and pharmacodynamic study. The resultant nanostructured lipid carriers had a mean size of 214.97 nm and a zeta potential of -31.6 ± 1.5 mV. More than 70% lercanidipine hydrochloride was entrapped in the NLCs. The SEM studies indicated the formation of type 2 nanostructured lipid carriers. The in vitro release studies demonstrated 19.36% release in acidic buffer pH 1.2 indicating that the drug entrapped in the nanostructured lipid carriers remains entrapped at acidic pH. The ex vivo studies indicated that the drug release was enhanced from 10% to 60.54% at blood pH in 24h. The in vivo pharmacodynamic study showed that NLCs released lercanidipine hydrochloride in a controlled manner for a prolonged period of time as compared to plain drug. These results clearly indicate that nanostructured lipid carriers are a potential controlled release formulation for lercanidipine hydrochloride and may be a promising drug delivery system for the treatment of hypertension.

Topics: Administration, Oral; Animals; Blood Pressure; Calcium; Diffusion; Dihydropyridines; Drug Carriers; Drug Delivery Systems; Hypertension; Kinetics; Lipids; Male; Molecular Structure; Nanoparticles; Particle Size; Rats; Rats, Sprague-Dawley; Surface Properties

It was previously demonstrated that metabolic syndrome in humans is associated with an impairment of insulin signalling in circulating mononuclear cells. At least in animal models of hypertension, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) may correct alterations of insulin signalling in the skeletal muscle. In the first study, we investigated the effects of a 3-month treatment with an ARB with additional PPARγ agonist activity, telmisartan, or with a dihydropyridine calcium channel blocker, nifedipine, on insulin signalling in patients with mild-moderate essential hypertension. Insulin signalling was evaluated in mononuclear cells by isolating them through Ficoll-Paque density gradient centrifugation and protein analysis by Western Blot. An increased expression of mTOR and of phosphorylated (active) mTOR (p-mTOR) was observed in patients treated with telmisartan, but not in those treated with nifedipine, while both treatments increased the cellular expression of glucose transporter type 4 (GLUT-4). We also investigated the effects of antihypertensive treatment with two drug combinations on insulin signalling and oxidative stress. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine. Then they were treated for 6 months with lercanidipine + enalapril or lercanidipine + hydrochlorothiazide. An increased expression of insulin receptor, GLUT-4 and an increased activation of p70S6K1 were observed during treatment with lercanidipine + enalapril but not with lercanidipine + hydrochlorothiazide. In conclusion, telmisartan and nifedipine are both effective in improving insulin signalling in human hypertension; however, telmisartan seems to have broader effects. The combination treatment lercanidipine + enalapril seems to be more effective than lercanidipine + hydrochlorothiazide in activating insulin signalling in human lympho-monocytes.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Enalapril; Essential Hypertension; Female; Glucose Transporter Type 4; Humans; Hypertension; Insulin; Lymphocytes; Male; Middle Aged; Monocytes; Nifedipine; Pilot Projects; Signal Transduction; TOR Serine-Threonine Kinases

Fixed-dose combinations of hypertensive drugs have been advocated as a suitable option for hypertensive patients who require two or more drugs to achieve blood pressure (BP) targets.. Our objective was to assess the efficacy and safety of lercanidipine/enalapril in clinical practice.. This observational study collected data for patients with hypertension treated by 46 specialists at clinics across Portugal with lercanidipine/enalapril (10/20 mg). The primary outcome measure was the reduction from baseline in systolic BP (SBP) and diastolic BP (DBP).. The registry enrolled 315 patients (59.1 % females; mean age 64.84 ± 12.18 years). Baseline SBP and DBP were 159.11 ± 16.93 and 88.32 ± 12.35 mmHg, respectively. At a mean 2.88 ± 1.75 months after starting lercanidipine/enalapril, the mean change from baseline in SBP and DBP were -18.08 ± 15.91 and -10.10 ± 11.46 mmHg, respectively (both p < 0.001). This corresponded to reductions of 11.4 and 11.3 % in SBP and DBP, respectively. SBP was reduced independently of sex and age, and DBP was reduced independently of sex. The BP control (<140/90 mmHg) rate significantly increased from 10.2 % at baseline to 51.0 % after a mean of 2.88 months of treatment with lercanidipine/enalapril (p < 0.001). Adverse effects were seen in only one patient (0.3 %), who developed a persistent dry cough.. Treatment with the fixed-dose combination lercanidipine/enalapril was associated with significant reductions in SBP and DBP, and a significant increase in the BP control rate. This fixed-dose combination has been shown to effectively reduce BP, generally independently of age and sex, and with an excellent safety profile.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Patient Safety; Portugal

Topics: Amlodipine; Antihypertensive Agents; Azetidinecarboxylic Acid; Baroreflex; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Sympathetic Nervous System

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Cyclosporine; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Infant; Male; Neoplasms; Retrospective Studies

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

Topics: Angiotensin Receptor Antagonists; Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Combined Modality Therapy; Cytokines; Diet, Sodium-Restricted; Dihydropyridines; Drug Evaluation, Preclinical; Gene Expression; Gene Expression Regulation; Hypertension; Imidazoles; Kidney Glomerulus; Male; NADPH Oxidases; Rats, Inbred Dahl; Receptors, Mineralocorticoid; Renal Insufficiency; Tetrazoles

Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs.. This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included.. Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine.. Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children.

Topics: Adolescent; Amlodipine; Calcium Channel Blockers; Child; Child, Preschool; Cyclosporine; Dihydropyridines; Drug Interactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Immunosuppressive Agents; Infant; Male; Nicardipine; Retrospective Studies

Gingival overgrowth is, among other things, a side effect of the administration of dihydropyridine antihypertensives, generally associated with irritant factors of marginal periodontium. This case refers to a patient, female, who developed a large gingival enlargement that has a combined etiology: the systemic medication with lercanidipina and the presence of dental bridges, which are incorrectly adjusted to the dental cervix. The treatment for this case, involved a complex local treatment (antimicrobial, surgical, endodontic and prosthetic) and the collaboration with a specialist cardiologist. Maintaining the normal gingival parameters in time depends on the possibility of changing the antihypertensive medication, the accuracy of the new dental bridges and the periodic monitoring of the patient.

Topics: Calcium Channel Blockers; Dental Prophylaxis; Denture, Partial; Dihydropyridines; Female; Gingival Overgrowth; Gingivectomy; Humans; Hypertension; Middle Aged

Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.. In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated.. Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker.. In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.

Topics: Aged; Aged, 80 and over; Aldosterone; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Renin-Angiotensin System; Sympathetic Nervous System

Insulin resistance, inflammation and oxidative stress (OS), are among the mechanisms that have been implicated in pathogenesis of essential hypertension (EH). Peripheral polymorphonuclear leukocytes (PMNLs) are primed in EH patients, releasing uncontrolled superoxide anion contributing to OS in these patients. PMNL priming correlates with insulin resistance and with PMNL intracellular calcium ([Ca2+]i). Recent studies have attributed to the anti-hypertensive drug lercanidipine, a third generation calcium-channel blocker, and additional anti-ischemic and anti-oxidative characteristics. Aim of the study was to evaluate the possible non-traditional effect of two months of lercanidipine treatment on insulin resistance and on PMNL-related inflammation in EH patients.. Non-smoking EH patients with untreated mild to moderate high blood pressure (BP) were included. Low-graded inflammation was reflected by WBC and PMNL counts and by PMNL apoptosis. Systemic inflammation was measured by plasma fibrinogen, CRP and albumin levels. Fasting serum insulin levels served as a marker of insulin resistance.. Two months of lercanidipine treatment showed significant decrease in BP, in WBC and PMNL counts, in PMNL apoptosis, in CRP and serum insulin levels and significant increase in serum albumin levels. Rates of superoxide release from PMNLs, WBC and PMNL counts and insulin levels positively correlated with mean arterial blood pressure values.. We imply that use of this CCB lercanidipine can be favored in EH patients due to its combined anti-PMNL priming and anti-inflammatory effects, in addition to its anti-hypertensive characteristics.

Topics: Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Inflammation Mediators; Insulin Resistance; Male; Middle Aged; Prospective Studies; Young Adult

Morning hypertension is a risk factor for cardiovascular and cerebrovascular events. Furthermore, it is a useful measure for definitive diagnosis of hypertension, and patients who self-assess their own blood pressure (BP) in the morning tend to exhibit better compliance with antihypertensive medication than those who do not.. The objective of this analysis was to determine the BP- and pulse rate-lowering effects of azelnidipine, a long-acting dihydropyridine calcium antagonist administered once daily in the morning.. We conducted the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study by surveying patients who were taking azelnidipine. According to the study protocol, high systolic BP (SBP) was defined as ≥135 mmHg when measured at home in the morning and ≥140 mmHg when measured at the clinic during the day. A total of 5,433 hypertensive patients, who were registered at 1,011 medical institutions across Japan, were enrolled in the study. Data obtained from 4,852 of these patients (mean age, 64.8 years; female, 52.9 %; previous medication with other antihypertensive agents used concomitantly with the present study agent, 45.5 %) were used for efficacy analysis.. At baseline, the subjects' mean [± standard deviation] SBP/diastolic BP values at home in the morning, at the clinic during the day, and at home in the evening were 156.9 ± 16.4/89.7 ± 12.0, 157.5 ± 18.7/89.1 ± 13.3, and 150.2 ± 17.6/85.6 ± 12.2 mmHg, respectively. The mean pulse rates were 72.7 ± 10.7, 74.9 ± 11.2, and 72.5 ± 9.6 beats/min, respectively. Patients whose BP was defined as high accounted for 83.4 % of the study population, whereas 9.9 % had 'masked' hypertension, defined as SBP of ≥135 mmHg at home in the morning and <140 mmHg at the clinic. However, from 4 weeks after initiation of azelnidipine treatment till the end of the study at week 16, all three daily BP determinations were significantly (p < 0.0001) lowered, and pulse rates at home in the morning, at the clinic, and at home in the evening were similarly and significantly reduced (by -3.7 ± 8.0, -3.5 ± 9.5, and -3.5 ± 7.3 beats/min, respectively). Whereas achievement of home SBP of <135 mmHg in the morning was noted in only 6.6 % of patients before the start of azelnidipine treatment, this was noted in 43.3 % after 16 weeks. Meanwhile, achievement of clinic SBP of <140 mmHg was increased from 12.9 % of patients to 56.1 % of patients at the same timepoints. After azelnidipine treatment, 32.2 % of patients had well-controlled hypertension in both the home and clinic settings. Adverse drug reactions occurred in 2.92 % of patients (154/5,265). All adverse drug reactions were as expected for the calcium antagonist class of agents.. These data suggest that azelnidipine controlled morning hypertension well. Furthermore, azelnidipine reduced pulse rates significantly.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Registries; Tablets; Treatment Outcome

Morning hypertension is a risk factor for cardiovascular and cerebrovascular events, and consequently diagnosis and control of morning hypertension are considered very important. We previously reported the results of the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study, which indicated that azelnidipine effectively controlled morning hypertension.. The objective of this At-HOME subgroup analysis was to evaluate the sustained blood pressure (BP)-lowering effect of azelnidipine, using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference).. We analyzed the self-measured home BP data (measured in the morning and at bedtime) from this 16-week prospective observational study to clarify the effect of morning dosing of azelnidipine (mean [± standard deviation] maximum dose 14.3 ± 3.6 mg/day). A subgroup of patients from the At-HOME Study who had an evening home BP measurement within 28 days prior to the baseline date were used for efficacy analysis (n = 2,546; mean age, 65.1 years; female, 53.6 %).. Home systolic BP/diastolic BP levels in the morning and evening were significantly lowered (p < 0.0001) by -19.4 ± 17.1/-10.3 ± 10.6 and -16.9 ± 17.0/-9.4 ± 10.6 mmHg, respectively. Home pulse rates in the morning and evening were also significantly lowered (p < 0.0001) by -3.5 ± 7.8 and -3.5 ± 7.3 beats/min, respectively. At baseline, patients whose ME average was ≥135 mmHg and whose ME difference was ≥15 mmHg (defined as morning-predominant hypertension) accounted for 20.4 % of the study population. However, at the end of the study, the number of such patients was significantly reduced to 7.9 % (p < 0.0001). Patients whose ME average was ≥135 mmHg and whose ME difference was <15 mmHg (defined as sustained hypertension) accounted for 71.1 % of the study population at baseline. This was reduced significantly to 42.8 % at the end of the study (p < 0.0001). ME average decreased significantly from 153.8 ± 15.5 mmHg to 135.6 ± 11.9 mmHg, and ME difference also decreased significantly from 6.7 ± 13.1 mmHg to 4.7 ± 10.8 mmHg (both p < 0.0001).. These results suggest that azelnidipine improved morning hypertension with its sustained BP-lowering effect.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Young Adult

N-type voltage-dependent Ca(2+)channels (VDCCs), expressed predominantly in the nervous system, play pivotal roles in sympathetic regulation of the circulatory system. Although N-type VDCCs are also reportedly expressed in the vasculature, their pathophysiological role is obscure. We demonstrated that oxidative stress-related endothelial dysfunction induced by angiotensin (Ang) II is suppressed in mice lacking the N-type VDCC α1B subunit (Cav 2.2). Impairment of endothelium-dependent relaxation of the thoracic aorta observed following Ang II treatment in wild-type (WT) mice was significantly attenuated in the Ang II-treated Cav 2.2-deficient mice, despite the comparable increase of the blood pressure in the two groups of mice. The thoracic aorta of the Cav 2.2-deficient mice showed a smaller positive area of oxidative stress markers as compared to the WT mice. The Ang II-induced endothelial dysfunction was also suppressed by cilnidipine, an L/N-type VDCC blocker, but not by amlodipine, an L-type VDCC blocker; however, this unique effect of cilnidipine was completely abolished in the Cav 2.2-deficient mice. Furthermore, selective inhibition of N-type VDCCs by ω-conotoxin GVIA dramatically suppressed the production of reactive oxygen species (ROS) as well as agonist-induced Ca(2+) influx in the vascular endothelial cells. These results suggest that N-type VDCCs expressed in the vascular endothelial cells contribute to ROS production and endothelial dysfunction observed in Ang II-treated hypertensive mice.

Topics: Amlodipine; Angiotensin II; Animals; Aorta, Thoracic; Biomarkers; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Dihydropyridines; Dose-Response Relationship, Drug; Endothelium, Vascular; Hemodynamics; Hypertension; Macrophages; Mice; omega-Conotoxin GVIA; Oxidative Stress; Reactive Oxygen Species; Vasodilation; Vasodilator Agents

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Fibrillation; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Enalapril; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Ischemia

Endothelial progenitor cells (EPCs) play a critical role in maintaining the integrity of vascular endothelium following arterial injury. Lacidipine has a beneficial effect on endothelium of hypertensive patients, but limited data are available on EPCs-mediated endothelial protection. This study tests the hypothesis that lacidipine treatment can improve endothelial repair capacity of EPCs from hypertensive patients through increasing CXC chemokine receptor four (CXCR4) signaling.. In vivo reendothelialization capacity of EPCs from hypertensive patients with or without in vitro lacidipine treatment was examined in a nude mouse model of carotid artery injury. Expression of CXCR4 and alteration in migration and adhesion functions of EPCs were evaluated.. Basal CXCR4 expression was markedly reduced in EPCs from hypertensive patients compared with normal subjects. In parallel, the phosphorylation of Janus kinase-2 (JAK-2) of EPCs, a CXCR4 downstream signaling, was also significantly decreased. Lacidipine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs. Transplantation of EPCs pretreated with lacidipine significantly accelerated in vivo reendothelialization. The enhanced in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by shRNA-mediated knockdown of CXCR4 expression or pretreatment with JAK-2 inhibitor AG490, respectively. In hypertensive patients, lacidipine treatment for 4 weeks also resulted in an upregulation of CXCR4/JAK-2 signaling of EPCs, which was associated with augmented EPCs-mediated reendothelialization and improved endothelial function.. Deterioration of CXCR4 signaling may lead to impaired EPCs-mediated reendothelialization of hypertensive patients. Lacidipine-modified EPCs via a partially CXCR4 signaling contribute to enhanced endothelial repair capacity in hypertension.

Topics: Adult; Animals; Antihypertensive Agents; Cells, Cultured; Dihydropyridines; Endothelial Cells; Endothelium, Vascular; Essential Hypertension; Humans; Hypertension; Male; Mice; Mice, Nude; Middle Aged; Stem Cells

Lower urinary tract symptoms (LUTS) have been reported amongst the side effects of calcium antagonists (CA). CAs act on the bladder by affecting the ability of the detrusor muscle to create enough contractile force to overcome obstruction to normal voiding. We aimed to determine the relationship between CA use and LUTS in general medical inpatients.. In this cross-sectional study we recruited 278 medical inpatients (including 85 CA users) aged ≥40 (72.1±13.7) years. LUTS was assessed using the International Prostate Symptoms Score (IPSS) questionnaire. A Logistic regression model using a 'backwards-elimination' strategy was used to identify variables associated with LUTS and for calculating the adjusted odds ratios and the 95% confidence intervals (CI). After adjusting for other risk factors and drugs, patients on amlodipine/nifedipine and diltiazem/verapamil (compared to non-users) were more likely to suffer from severe LUTS [Males: 12.45(CI: 1.57-98.63) and Females: 7.75(CI: 0.94-63.94)] and moderate-to-severe LUTS [Males: 17.43(CI: 2·26-134.39) and Females: 47.8(CI: 6.22-367.37)]. Patients on felodipine/lercanidipine were less likely to suffer from either severe or moderate-to-severe LUTS. Further, 19 (22.4%) CA-users were on treatment for LUTS compared to 18 (9.3%) of the non-users group, p = 0.003. Both male and female CA-users were three times more likely to be on alpha-blockers than non-users, p<0.001. CA-users were more likely to have undergone urinary tract-related surgery (Males: two times, p = 0.07 and females: nine times, p = 0.029). The study was limited by the fact that a causal relationship could not be established between CA use and LUTS.. Our results demonstrate an association between CA use and an increasing severity of LUTS. They also demonstrate that CA-users are more likely to have medical or surgical treatment for LUTS. However, these CA's effects on LUTS vary, and the use of highly vascular selective agents does not appear to pose significant risk.

Topics: Aged; Calcium Channel Blockers; Cross-Sectional Studies; Dihydropyridines; Felodipine; Female; Humans; Hypertension; Interviews as Topic; Logistic Models; Lower Urinary Tract Symptoms; Male; Middle Aged; Odds Ratio; Severity of Illness Index; Surveys and Questionnaires

Topics: Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Comorbidity; Dihydropyridines; Dose-Response Relationship, Drug; Humans; Hypertension; Hypertrophy, Left Ventricular; Treatment Outcome

Stroke-prone spontaneously hypertensive (SHRsp) rats develop severe hypertension resulting in renal injury. We investigated apoptosis inhibitor of macrophages (AIM) expression in nephrosclerotic rats and the involvement of AIM in olmesartan (OLM)- and azelnidipine (AZN)-induced decreases in the number of macrophages infiltrating the kidney. We randomly assigned 20-week-old male SHRsp rats to receive one of the following substances every day for 12 weeks: water (vehicle), hydralazine (HYD), OLM, or AZN. Renal damage was assessed by Masson trichrome staining. Expressions of ED-1, AIM, and oxidized low-density lipoprotein (oxLDL) were immunohistochemically detected. Apoptosis was analyzed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. All treatment groups showed significantly less renal interstitial fibrosis than the vehicle group. AZN and OLM groups had significantly fewer AIM-expressing cells than the HYD and vehicle groups. The ratios AIM-positive cells/ED-1-positive macrophages and TUNEL-positive cells/ED-1-positive macrophages in the AZN and OLM groups were lower and higher, respectively, than the the HYD and vehicle groups. oxLDL expression in the renal interstitium was significantly lower in treatment groups compared to vehicle group. OLM and AZN inhibited interstitial fibrosis progression in SHRsp rats by suppressing AIM expression in macrophages, followed by reducing the number of infiltrating macrophages.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Chemokine CCL2; Dihydropyridines; Hypertension; Imidazoles; Inhibitor of Apoptosis Proteins; Kidney; Lipoproteins, LDL; Macrophages; Male; Nephrosclerosis; Olmesartan Medoxomil; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Scavenger; Tetrazoles

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Brain Ischemia; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; Stroke; Survival Analysis; Vasodilator Agents

Calcium channel blockers are increasingly used for the treatment of hypertension. Hypertension is an important risk factor for liver damage and several other circulatory abnormalities. The aim of this study was to determine the effects of lacidipine in a irradiation-induced hepatocellular damage model in Deoxyc Orticosterone Acetate (DOCA)-salt-induced hypertensive model in rats. In this study, animals were divided into five groups as follows: control (Group 1), hypertensive (Group 2), irradiated (Group 3), irradiated and hypertensive (Group 4) and irradiated, hypertensive and lacidipine-treated (Group 5). At the end of the experiment, the livers were removed and its homogenates were biochemically examined. Significant differences were found between values of all groups (p < 0.05). Group 3 and particularly Group 4 showed significant increase in lipid peroxidation and Nitric Oxide (NO) and serum tumor necrosis factor-alpha (TNF-alpha) with a significant reduction in serum level of alanine amine transferase (ALT) enzyme and in superoxide dismutase in red blood cells lysates. Lacidipine-treated group (5) showed a significant reduction in elevated systolic blood pressure together with a great protection of ALT and SOD enzymes from the destructive effects of irradiation and hypertension. Additionally, this CCB reduces hepatic NO and serum TNF-alpha levels that were increased in groups (2,3,4). The present study suggests that lacidipine has some important protective effects on liver of hypertensive irradiated albino rats.

Topics: Alanine Transaminase; Animals; Blood Pressure; Desoxycorticosterone Acetate; Dihydropyridines; Disease Models, Animal; Hypertension; Lipid Peroxidation; Liver; Liver Diseases; Nitric Oxide; Random Allocation; Rats; Salts; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Cilnidipine (Cil) is an L/N-type calcium channel blocker (CCB) that is known to provide renal protection by decreasing the activity of the sympathetic nervous system and the renin-angiotensin system (RAS). However, very few studies have evaluated the renoprotective effects of Cil in hypertension complicated by diabetes mellitus. In this study, we compared the effects of cilnidipine and the L-type CCB, amlodipine (Aml), in combination with an angiotensin II receptor blocker (ARB) on diabetic nephropathy that developed as a result of inducing diabetes in hypertensive rats.. Diabetes was induced in 9-week-old male spontaneously hypertensive rats by intraperitoneally injecting them with streptozotocin (40 mg/kg twice) and the rats (8 per group) were randomly assigned to receive valsartan (Val), Cil + Val, Aml + Val, or vehicle for 8 weeks through a gastric tube.. There were no significant differences in systolic blood pressure or plasma parameters between the two combination therapy groups. Blood pressure lowering by neither combination therapy significantly affected the glycemic variables. However, the increased glycogen levels in the kidney as a result of hyperglycemia were significantly suppressed in the groups that received combination therapy, and the increased proteinurea and glomerulosclerosis due to progression of the diabetic nephropathy were significantly suppressed in the Cil + Val group. In addition, a significant decrease in ED-1-positive cells was observed in the Cil + Val group alone.. The results of this study suggested that the L/N-type CCB, cilnidipine, had additive antihypertensive and proteinuria-lowering effects when administered in combination with an ARB, even in type-1 diabetic rats, and that the L-type CCB, amlodipine, did not. Furthermore, combination therapy with cilnidipine and valsartan significantly reduced glycogen accumulation and ED-1-positive cell infiltration, suggesting that cilnidipine suppressed the excessive increase in the activity of the sympathetic nervous system and RAS through N-type calcium channel blockade.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dihydropyridines; Disease Progression; Drug Therapy, Combination; Glomerulonephritis; Glucagon; Glucose Transporter Type 1; Glycated Hemoglobin; Glycogen; Hypertension; Kidney; Male; Norepinephrine; Proteinuria; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta1; Valine; Valsartan

To evaluate the effects of the lercanidipine on bone healing (BH) and bone density (BD) in the tibiae of spontaneously hypertensive rats (SHR), using histometric and tartrate-resistant acid phosphatase (TRAP) expression analyses.. Wistar and SHR were assigned to one of the following groups: normotensive rats (NTR) (n = 15), untreated SHR (n = 15), and lercanidipine-treated SHR (n = 15). The latter group was treated daily with lercanidipine for 6 weeks. Two weeks after the beginning of drug administration, a critical-sized surgical defect was created in the right tibia of all groups, whereas the contralateral tibia remained without defect. The animals were killed 30 days after the creation of the bone defect.. There were no significant differences among the groups for BH, trabecular BD, and the number of TRAP+ cells in the newly formed cortical bone (P > 0.05). SHR presented significantly lower cortical BD and increased cortical levels of TRAP+ cells, when compared with NTR and lercanidipine-treated SHR (P < 0.05).. SHR presented a lower cortical BD and increased levels of TRAP+ cells. In addition, the treatment of SHR with lercanidipine during 6 weeks was able to revert the deleterious effects of hypertension on cortical BD and on the number of TRAP+ cells in the tibia of SHR.

Topics: Acid Phosphatase; Animals; Antihypertensive Agents; Biomarkers; Bone Density; Bone Diseases; Bone Regeneration; Calcium Channel Blockers; Dihydropyridines; Hypertension; Image Processing, Computer-Assisted; Isoenzymes; Male; Rats; Rats, Inbred SHR; Rats, Wistar; Tartrate-Resistant Acid Phosphatase; Tibia; Wound Healing

The L/N-type calcium channel blocker cilnidipine has been shown to suppress aldosterone production induced by angiotensin II (Ang II) in vitro. In addition, cilnidipine also suppresses the reflex tachycardia induced by its antihypertensive action in vivo. We investigated the effects of cilnidipine on the reflex aldosterone production induced by its antihypertensive action, to identify the differences in the effects of cilnidipine from those of the L-type calcium channel blocker nifedipine. Male SHR/Izm rats were anesthetized by intraperitoneal injection of pentobarbital sodium, and administered an intravenous infusion of saline supplemented or not with Ang II for 30 min. Blood pressure was monitored continuously in the femoral artery. Each of the calcium channel blockers under study was administered intravenously as a bolus through the femoral vein 1 min after the start of the Ang II infusion, and blood samples were collected 30 min after the start of the Ang II infusion. Following administration at nonhypotensive doses, all calcium channel blockers tended to decrease the plasma aldosterone. In particular, cilnidipine significantly suppressed the plasma aldosterone levels. On the other hand, under the condition of Ang II-induced hypertension, administration of a hypotensive dosage of cilnidipine showed no effect on the plasma aldosterone levels, whereas a hypotensive dosage of nifedipine significantly increased the plasma aldosterone levels. Our results suggest that the L/N-type calcium channel blocker cilnidipine reduces the plasma aldosterone level by suppressing the aldosterone production induced by reflex upregulation of the renin-angiotensin-aldosterone system associated with reduction of the blood pressure.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Down-Regulation; Hypertension; Injections, Intravenous; Male; Nifedipine; Rats; Rats, Inbred SHR; Reflex; Renin-Angiotensin System

We evaluated the antialbuminuric advantage of cilnidipine, an N/L-type calcium channel blocker (CCB), compared with L-type CCBs in diabetic patients with normoalbuminuria and microalbuminuria. The study was a multicenter, non-randomized crossover trial. Participants were 90 type 2 diabetic patients exhibiting either normo- or microalbuminuria, and undergoing CCB treatment for ≥6 months prior to study entry. The CCB at the time of entry was continued for the first 6 months (Period 1). Treatment was subsequently switched from cilnidipine to an L-type CCB, or vice versa, for the second 6-month observation period (Period 2). During Period 1, the L-type CCB group showed a significant increase of urinary albumin excretion (UAE) over time, while the cilnidipine group showed no significant elevation. During Period 2, switching of the treatment from the L-type CCB to cilnidipine resulted in significant reduction of the UAE, whereas switching from cilnidipine to the L-type CCB resulted in no significant change in the UAE. This study demonstrated that the antialbuminuric effect of Cilnidipine, but not the L-type CCBs, was sustained even in patients treated for a long time. In addition, the antialbuminuric effect can be anticipated after switching from an L-type CCB to cilnidipine, but not vice versa.

Topics: Aged; Albuminuria; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Japan; Male; Treatment Outcome

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Combined Modality Therapy; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension; Physical Fitness; Stroke

A study was undertaken to test the association between dihydropyridine calcium channel blocker use and the time to important milestones of disease progression among patients with parkinsonism.. Data were obtained from Ontario's health care administrative databases. Within a cohort of hypertensive individuals older than 65 years who developed parkinsonism, we examined the effect of the length of exposure to less brain-penetrant dihydropyridines (amlodipine) and more brain-penetrant dihydropyridines (eg, nifedipine, felodipine) on parkinsonism milestones as measured by time to requiring drug treatment for parkinsonism, nursing home admission, and death.. Among 4,733 hypertensive individuals with parkinsonism, longer treatment with any dihydropyridine was associated with a decreased risk of each of the 3 outcomes. There was no difference, however, between amlodipine (adjusted hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.42-0.50 for initiation of drug treatment; HR, 0.68; 95% CI, 0.63-0.73 for application for nursing home admission; and HR, 0.75; 95% CI, 0.70-0.80 for death) and nonamlodipine dihydropyridines (adjusted HRs [95% CIs], 0.45 [0.39-0.53], 0.74 [0.67-0.81], and 0.74 [0.64-0.85] for the 3 milestones, respectively).. We found no specific beneficial effect of treatment with brain-penetrant dihydropyridines on delaying parkinsonism progression milestones. Dihydropyridine calcium channel blockers are unlikely to have a clinically significant effect on the course of parkinsonism, particularly Parkinson disease, in the doses used to treat hypertension.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Male; Parkinsonian Disorders; Retrospective Studies

It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg(-1) day(-1)), CAN/AM (4/2.5 mg kg(-1) day(-1)), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Hypertension; Imidazoles; Male; Olmesartan Medoxomil; Oxidative Stress; Rats; Rats, Inbred SHR; Tetrazoles

To determine whether the antihypertensive and vascular protective effects of short-term treatment with lercanidipine, a calcium channel blocker, are modulated by the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism.. In a self-controlled study, a total of 143 essential hypertensive patients, all permanent residents of Shanghai, were included. All of them were treated orally with lercanidipine at a single daily fixed dosage of 10mg for 28 consecutive days and the genotypes of the MTHFR C677T polymorphism were determined. Blood pressures, ankle-brachial index values (ABI), and pulse wave velocity (PWV) were measured at baseline and on the 29th day.. The 110 subjects for whom complete genotype and phenotype information were available were used for final data analysis. Patients with the TT genotype showed higher baseline diastolic blood pressure (DBP) than those with the CC and CT genotypes (P=0.018). Within each genotype group, SBP, DBP and PWV showed significant difference between baseline and after treatment (P<0.05). However, ABI showed significant difference between baseline and after treatment only within the CT and TT groups (P<0.05) but not in the CC group (P>0.05). Patients with the TT genotype presented a greater reduction in normalized PWV than those with the CC and CT genotypes (P=0.02). Patients in all genotype groups had statistically similar changes in normalized SBP, DBP and ABI (P>0.05).. The MTHFR gene polymorphism C677T might be associated with the vascular protective effects of short-term lercanidipine treatment. However, the MTHFR C677T polymorphism might not affect the antihypertensive effects of the lercanidipine treatment.

Topics: Adult; Ankle Brachial Index; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Genotype; Humans; Hypertension; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Phenotype; Polymorphism, Genetic; Time Factors

Topics: Azetidinecarboxylic Acid; Blood Pressure; Dihydropyridines; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Tetrazoles

Antihypertensive treatment may reduce prolonged QT duration in hypertension. Generally, the reductions of blood pressure and/or of cardiac mass are believed to be the responsible factors. However, drugs are not equivalent in QT modulation despite similar antihypertensive and antihypertrophic action. We investigated the effect of a calcium channel blocker, lacidipine and an angiotensin-converting enzyme inhibitor, enalapril on QT duration in rats. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with lacidipine (at the dose of 1.5 mg/kg per day for WKY and 3 mg/kg per day for SHR) or enalapril (5 mg/kg per day for WKY and 10 mg/kg per day for SHR) during 8 weeks. Tail-cuff systolic blood pressure (sBP), left ventricular weight (LVW), vascular function of isolated aorta and mesenteric artery and duration of QT (and QTc) interval on Frank electrocardiograms were evaluated. As expected, untreated SHR showed elevated sBP, impaired vascular reactivity, increased LVW and prolonged QT when compared with WKY (p < 0.05). After treatment, both agents markedly improved vascular reactivity and reduced sBP in SHR (p < 0.05). Additionally, enalapril reduced LVW in both hypertensive (by 17%; p < 0.05) and normotensive rats (by 13%; p < 0.05) and, consequently, corrected QT duration in SHR. Interestingly, lacidipine also reduced LVW in SHR (by 9%; p < 0.05), but without influence on prolonged QT. Moreover, lacidipine had no effect on LVW in WKYs but prolonged their QT interval (by 10%; p < 0.05). In conclusion, lacidipine did not reverse a progressive prolongation of QT in SHR, despite sBP lowering and LVW reduction. Thus, the lowering of blood pressure and/or reduction of LVW are not sufficient per se to normalize ventricular repolarization in hypertensive cardiac disease. More likely, modulation of QT prolongation by antihypertensive drugs is a function of their complex action on blood pressure, vascular function, cardiac mass and on reflex neurohumoral activation.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Enalapril; Heart Ventricles; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The effects of cilnidipine on the serum uric acid level and urinary NO excretion in hypertensive patients were investigated. Blood and urine samples of 16 hypertensive outpatients were collected before and 2 months after cilnidipine therapy (10 mg). The serum uric acid level decreased significantly after cilnidipine treatment, while the uric acid-creatinine clearance ratio was unaffected. The cilnidipine medication produced a significant increase in urinary NO excretion, although amlodipine did not change it significantly. Therefore, cilnidipine has a profound antihypertensive effect and may reduce the serum uric acid level and increase NO production in the kidney.

Topics: Aged; Aged, 80 and over; Amlodipine; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Nitric Oxide; Treatment Outcome; Uric Acid

Topics: Azetidinecarboxylic Acid; Blood Pressure; Dihydropyridines; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Tetrazoles

Topics: Blood Pressure; Cardiovascular Diseases; Carotid Artery Diseases; Circadian Rhythm; Dihydropyridines; Female; Humans; Hypertension; Male; Office Visits

We recently demonstrated that cilnidipine, an L/N-type calcium channel blocker, elicits protective effects against glomerular podocyte injury, in particular, in obese hypertensive rats that express the N-type calcium channel (N-CC). Since the N-CC is known to be expressed in sympathetic nerve endings, we evaluated the reno-protective effects of cilnidipine in innervated and denervated spontaneously hypertensive rats (SHR). Male SHR were uninephrectomized and fed 4% high-salt diet (HS-UNX-SHR). Animals were divided into groups, as follows, and observed from 9 to 27 weeks of age: 1) vehicle (n = 14), 2) vehicle plus renal-denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o.; n = 10), and 4) cilnidipine plus renal-denervation (n = 15). Renal denervation attenuated elevations in blood pressure, but failed to suppress urinary protein excretion and podocyte injury in HS-UNX-SHR. Cilnidipine in both innervated and denervated HS-UNX-SHR similarly induced significant antihypertensive effects, as well as suppressing the urinary protein excretion and podocyte injury, compared to vehicle-treated HS-UNX-SHR. These data indicate that renal nerves have a limited contribution to the cilnidipine-induced reno-protective effects in HS-UNX-SHR.

Topics: Angiotensin II; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line; Desmin; Dihydropyridines; Hypertension; Male; Mice; Podocytes; Protective Agents; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Imidazoles; Male; Tetrazoles

It has been proved that cilnidipine has N-type calcium channels inhibitory activity as well as L-type calcium channels and inhibits excessive release of norepinephrine from the sympathetic nerve ending. This study was undertaken to compare the efficacy of amlodipine (an inhibitor of L-type calcium channels) and cilnidipine (an inhibitor of both L-type and N-type calcium channels) in patients with hypertension and type II diabetes mellitus. Seventy-seven hypertensive patients were divided into two groups according to presence/absence of type II diabetes mellitus. In these two groups of patients, the effects of amlodipine and cilnidipine on glucose and lipid metabolism and renal function were compared. As for glucose and lipid metabolism, homeostasis model assessment insulin resistance (HOMA-R) level in the non-diabetic group and triglyceride in the diabetes group were significantly lower with cilnidipine than with amlodipine. As regards renal function in the diabetic group, estimated glomerular filtration rate (eGFR) was significantly higher and urinary albumin/creatinine ratio was significantly lower with cilnidipine than with amlodipine. Cilnidipine which inhibits N-type calcium channels is more useful for patients with hypertension and diabetes mellitus from its effects on glucose and lipid metabolism and renal function.

Topics: Adult; Aged; Amlodipine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Glucose; Humans; Hypertension; Kidney; Lipid Metabolism; Male; Middle Aged

The achievement rate of blood pressure (BP) target and the relationship between on-treatment BP and development of cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) were investigated in a total of 8,897 patients in the Japan's Benidipine Research on Antihypertensive Effects in the Elderly (J-BRAVE) study, a prospective, 3-year observational study of a calcium channel blocker-based treatment in hypertensive patients aged ≥65 years as a post-marketing surveillance. Blood pressure decreased significantly from 164.8 ± 14.1/88.2 ± 10.3 mmHg to 137.0 ± 13.5/75.6 ± 9.5 mmHg and the percentage of patients who achieved BP <140/90 mmHg was 57.2% after 3 years. The incidence of cardiovascular events was 7.54/1,000 patient-years. Subgroups of patients stratified by on-treatment systolic blood pressure (SBP) were analyzed. Baseline BP, body mass index (BMI), the dose of benidipine, the mean number of anti-hypertensive drugs, and the incidence of cardiovascular events were higher in patients with on-treatment SBP ≥160 mmHg than in those with an SBP of <130 mmHg. In patients aged 65 to 74 years (n = 5,092) and patients aged ≥75 years (n = 3,805), the percentages of patients who achieved the BP target of <140/90 mmHg were 57.5% and 56.6% after 3 years, respectively, and the incidence of cardiovascular events was higher in patients with on-treatment SBP ≥160 mmHg in both age subgroups. The results of the J-BRAVE study show that on-treatment SBP ≥160 mmHg is associated with a higher incidence of cardiovascular events in elderly hypertensive patients.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Japan; Male; Prospective Studies; Risk Factors

Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-β was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.

Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Collagen; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Sodium Chloride; Transforming Growth Factor beta; Treatment Outcome

Topics: Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Male; Middle Aged; Nocturia

Topics: Amlodipine; Azetidinecarboxylic Acid; Coronary Artery Disease; Dihydropyridines; Humans; Hypertension

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Sodium Chloride Symporter Inhibitors; Stroke

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Imidazoles; Male; Tetrazoles

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines

Topics: Blood Pressure; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Male; Metabolic Syndrome; Nitrophenols; Organophosphorus Compounds

Topics: Antihypertensive Agents; Dihydropyridines; Drug Combinations; Electrocardiography; Enalapril; Humans; Hypertension; Kidney Function Tests; Proteinuria

The study aim was to examine the effect of combination therapy comprising angiotensin receptor blocker plus calcium antagonist on post-treatment plasma adiponectin levels compared to pretreatment levels. There was a significant gender difference in the relationship between preadiponectin level and age. In the search for contributing factors for treatment-based changes in adiponectin levels, these effects of gender and age were considered in statistical analysis. The adiponectin level in the combination therapy group was further increased compared to that in each of the monotherapy groups, despite there being no significant difference in antihypertensive effect, indicating that the combined medication provided an effect beyond that of lowering blood pressure.

Topics: Adiponectin; Age Factors; Aged; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Benzimidazoles; Benzoates; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Retrospective Studies; Sex Characteristics; Telmisartan

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Data Interpretation, Statistical; Dihydropyridines; Edema; Humans; Hypertension; Meta-Analysis as Topic; Risk Assessment; Treatment Outcome

Benidipine is a dihydropyridine calcium channel blocker inhibiting not only L-type but also T-type calcium channels. To elucidate potential additive benefit of benidipine for prevention of cardiorenal injury, we compared the cardiac and renal protective effects of equihypotensive doses of benidipine and cilnidipine in stroke-prone spontaneously hypertensive rats (SHRSP).. SHRSP were divided into five groups, and were given vehicle, benidipine at 1 or 3 mg/kg per day, or cilnidipine at 1 or 3 mg/kg per day for 7 weeks, and the protective effects against cardiorenal injury were compared among each group.. Benidipine and cilnidipine at the same doses exerted comparable hypotensive effects on SHRSP throughout the treatment. Despite equihypotensive effects between both drugs, benidipine prevented cardiac hypertrophy, fibrosis, and inflammation to a greater extent than cilnidipine. Moreover, benidipine prevented glomerulosclerosis, tubulointerstitial injury, and renal inflammation more than cilnidipine. To elucidate the underlying mechanism of more beneficial effects of benidipine than cilnidipine, we compared the effects of these drugs on cardiac and renal oxidative stress, and aldosterone in SHRSP. Benidipine reduced both cardiac and renal NADPH oxidase activities in SHRSP more than cilnidipine, being associated with more attenuation of cardiac and renal superoxide by benidipine. Furthermore, serum aldosterone was significantly reduced by benidipine but not by cilnidipine.. Benidipine exerted more protective effects against cardiorenal injury of hypertensive rats than cilnidipine, through more attenuation of oxidative stress than cilnidipine, and the reduction of aldosterone. Benidipine, via blockade of T-type calcium channels, seems to elicit additive benefits for prevention of hypertensive cardiorenal injury.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Enzyme-Linked Immunosorbent Assay; Heart; Heart Rate; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Combination therapies with angiotensin II type I receptor blockers (ARBs) and calcium channel blockers (CCBs) are frequently administered to hypertensive patients, because these regimens have renoprotective and antihypertensive effects. However, few studies have focused on the renoprotective effects of individual CCBs when combined with ARBs for hypertension.. Two hundred eighty-six outpatients prescribed three different CCBs (benidipine [CAS 91599-74-5], amlodipine [CAS 111470-99-6] and controlled release nifedipine (nifedipine CR) [CAS 21829-25-4]) for hypertension in combination with ARBs during a 4-year period were registered in a retrospective comparative study. The factors that influenced the appearance of renal events defined as doubling of serum creatinine were investigated.. The renal event rate was significantly lower in the benidipine than in the amlodipine (p < 0.05) and nifedipine CR (p < 0.01) groups. Multivariate analysis revealed hazard ratios for renal events to be significantly higher with chronic kidney disease (CKD) and lower with benidipine. Moreover, among patients with CKD, the benidipine group showed a significantly lower renal event rate than the amlodipine (p < 0.05) and nifedipine groups (p < 0.05).. In hypertensive patients treated with ARB and CCB, benidipine exhibits a better renoprotective effect than other drugs of this class (amlodipine and nifedipine CR).

Topics: Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Creatinine; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Kaplan-Meier Estimate; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Nifedipine; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Treatment Outcome

This study evaluates the ligature-induced bone loss (BL) and quality of tooth-supporting alveolar bone in spontaneously hypertensive rats (SHRs) by histometric, histochemical, and immunohistochemical analyses and assesses the effects of lercanidipine on these parameters.. Wistar rats and SHRs were assigned to one of the following groups: normotensive rats (n = 15), untreated SHRs (n = 15), and treated SHRs (n = 15). The latter group was treated daily with lercanidipine for 45 days. Two weeks after the beginning of drug administration, the first right mandibular molar received a cotton ligature, whereas the contralateral tooth was left unligated. The following parameters were analyzed in the furcation area of decalcified histologic sections: BL, bone density (BD), number of positive cells for tartrate-resistant acid phosphatase (TRAP+), and expression of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG).. In ligated teeth, no significant differences among groups were found regarding BL, TRAP+ cells, and the ratio of RANKL/OPG+ cells (P >0.05), although the expression of RANKL was decreased in the treated SHR group (P <0.05). Increased BL and decreased BD were observed around unligated teeth of the untreated and treated SHR groups (P <0.05). In the furcation area of the unligated teeth, the untreated SHR group presented a higher number of TRAP+ cells and higher ratio of RANKL/OPG+ cells compared to the other groups.. SHRs present harmful alterations in the quality of tooth-supporting bone, independently of inflammation. In addition, the administration of lercanidipine for 45 days decreased the expression of bone-resorption markers.

Topics: Acid Phosphatase; Alveolar Bone Loss; Alveolar Process; Animals; Antihypertensive Agents; Biomarkers; Bone Density; Dihydropyridines; Hypertension; Immunohistochemistry; Isoenzymes; Male; Molar; Osteoprotegerin; RANK Ligand; Rats; Rats, Inbred SHR; Rats, Wistar; Tartrate-Resistant Acid Phosphatase; Tooth Root

In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC.. 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks.. Azelnidipine treatment in drug-naïve (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values.. These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

Topics: Aged; Aged, 80 and over; Aldosterone; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Renin

Accumulating evidence suggests that inflammation as well as oxidative stress play essential roles in atherogenesis, progression of atherosclerosis, and plaque instability and rupture. Recent studies on available anti-hypertensive agents have focused on their anti-atherosclerotic effects over and above their blood pressure lowering action. These studies have included investigations on several types of calcium channel blockers, with several investigations indicating that a dihydropiridine-based calcium channel blocker, azelnidipine, developed in Japan, has unique anti-oxidative properties. An anti-inflammatory effect of azelnidipine has, however, yet to be established and therefore we carried out a series of in vivo and in vitro studies to investigate this possibility. This was achieved by measuring inflammatory and oxidative stress markers in 16 high risk hypertensive patients administered 16mg/day of azelnidipine. After 4 weeks of treatment, serum levels of hsCRP, IL-6, and IL-8 and urinary 8-OHdG were decreased significantly, despite blood pressure remaining unchanged. Cultures of human mononuclear leukocytes collected from six healthy volunteers showed 100 nM of azelnidipine caused significant inhibition of formyl-methyonyl leucyl phenylalanine (fMLP)-induced production of IL-8. Taken together, these results suggest that azelnidipine has anti-inflammatory effects independent of its anti-hypertensive action. As leukocytes do not possess voltage-operated calcium channels, the effect of azelnidipine in these cells appears to occur independently of an L-type calcium channel antagonizing effect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Azetidinecarboxylic Acid; Biomarkers; C-Reactive Protein; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Female; Humans; Hypertension; In Vitro Techniques; Inflammation Mediators; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Oxidative Stress

Topics: Adult; Aldosterone; Calcium Channel Blockers; Delayed Diagnosis; Dihydropyridines; Drug Resistance; Female; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Male; Middle Aged; Potassium; Renin

Angiotensin receptor blockers (ARBs) or T- and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg(-1)), efonidipine (30 mg kg(-1)), irbesartan (60 mg kg(-1))+efonidipine (30 mg kg(-1)), amlodipine (3 mg kg(-1)), or irbesartan (60 mg kg(-1))+amlodipine (3 mg kg(-1)) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine- and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22(phox), transforming growth factor-beta, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T- and L-type CCB might produce a powerful renal protective effect.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Chemokine CCL2; Collagen Type I; Dihydropyridines; Drug Therapy, Combination; Gene Expression; Glomerulosclerosis, Focal Segmental; Hypertension; Irbesartan; Kidney Glomerulus; Male; NADPH Oxidases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred Dahl; Tetrazoles; Transforming Growth Factor beta

The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF).. Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks. Control rats were maintained on a low-salt diet. In vehicle-treated rats, left-ventricular (LV) fractional shortening was preserved but LV end-diastolic pressure was increased, indicative of DHF. Benidipine and nitrendipine had similar antihypertensive effects and reduced both LV weight and cardiomyocyte hypertrophy. Benidipine reduced LV diastolic stiffness and mortality to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight. The extent of interstitial fibrosis and the abundance of mRNAs for prohypertrophic, profibrotic, or proinflammatory genes in the left ventricle were reduced by benidipine and nitrendipine. Benidipine, but not nitrendipine, increased capillary density and restored the expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle.. Benidipine reduced LV diastolic stiffness and increased survival, effects likely attributable predominantly to promotion of coronary angiogenesis rather than to attenuation of interstitial fibrosis. Benidipine may thus be more effective than purely L-type Ca(2+) channel blockers in preventing hypertensive DHF.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Coronary Circulation; Diastole; Dihydropyridines; Heart Failure; Heart Ventricles; Hypertension; Male; Neovascularization, Physiologic; Nitrendipine; Rats; Rats, Inbred Dahl

It is unclear whether the assumed inferiority of atenolol to reduce central (aortic) blood pressure (BP) extends to other β-blockers with vasodilating properties and, within that scope, how these drugs differ from the angiotensin receptor blockers (ARBs).. In a retrospective study, we compared three groups of hypertensive patients (aged 35-65 years) chronically treated with either ARBs (n=83, group 1), carvedilol/nebivolol (n=75, 25+25 mg/day/5 mg/day, group 2) or atenolol (n=84, 50-100 mg/day, group 3), matched for age (mean 52 years), sex (61% female), brachial BP and concomitant use of diuretics (75-81%)and dihydropyridine calcium antagonists (27-33%). We measured aortic stiffness by pulse wave velocity (Complior), and central BP, central-peripheral pulse pressure amplification, wave reflection [augmentation index (AIx) corrected for heart rate] and augmentation pressure (Sphygmocor).. For similar age, sex distribution, brachial BP levels (145/85±11/10 mmHg) and pulse wave velocity (10±2 m/s), the atenolol group showed significantly (P<0.03 analysis of variance) higher central systolic BP (139±9 mmHg) versus group 2 (135±10 mmHg) and group 1 (132±11 mmHg), higher AIx (34±12%) versus group 2 (27±7%) and group 1 (23.0±9%), lower pulse pressure amplification (1.16±0.09) versus group 2 (1.22±0.10) and group 1 (1.31±0.11) and lower heart rate beats/min (61±9) versus group 2 (69±11) and group 1 (82±11). The differences on these values, between group 2 and group 1, were also significant (P<0.04). After adjustment for the heart rate, AIx became similar in groups 2 and 1, but still lower (P<0.04) than the atenolol group.. These findings suggest that, for similar brachial BP and aortic stiffness, treatment with either vasodilating β-blockers or angiotensin receptor blockers associates with lower central systolic BP and wave reflections than treatment with atenolol. These findings may suggest that the vasodilating β-blockers may exert more favourable central haemodynamic effects, compared with atenolol, which are more alike, although not completely equal, to those of the ARBs.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin Receptor Antagonists; Antihypertensive Agents; Aorta; Atenolol; Benzopyrans; Blood Flow Velocity; Blood Pressure; Brachial Artery; Calcium Channel Blockers; Carbazoles; Carvedilol; Dihydropyridines; Diuretics; Ethanolamines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nebivolol; Propanolamines; Pulsatile Flow; Retrospective Studies; Vascular Resistance; Vasodilator Agents

We performed a per-protocol analysis of the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) to evaluate the optimal target blood pressure (BP) in elderly hypertensive patients. In JATOS, conducted in elderly (65-85 years) hypertensive patients treated with efonidipine hydrochloride, there were no differences between the strict-treatment group (systolic BP maintained at <140 mm Hg) and the mild-treatment group (systolic BP maintained at ≥140 mm Hg and <160 mm Hg) in the incidence of primary end points (cardiovascular disease and renal failure) for 2 years. The present study analyzed data in subgroups of JATOS in which the average systolic BP was within the range of target values. The average BP levels achieved in the strict-target BP achieved subgroup (n=1191) and the mild-target BP achieved subgroup (n=1531) were 132.3/74.0 mm Hg and 146.6/78.3 mm Hg, respectively. The incidences of primary end points were similar between these subgroups (11.1/1000 patients per year and 13.2/1000 patients per year, respectively, P=0.502), and there were also no differences in the incidences of adverse events. The incidences of cardiovascular events in patients who failed to achieve their respective treatment goals, on the other hand, were significantly higher than in patients who achieved them. These results indicate that strict treatment for elderly hypertensive patients may have little effect in enhancing the suppression of the onset of cardiovascular events as compared with mild treatment, although patients who have difficulties in achieving treatment goals should be given more aggressive treatment as a high-risk population.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Incidence; Japan; Male; Nitrophenols; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Aged; Antihypertensive Agents; Chronic Disease; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Randomized Controlled Trials as Topic

Topics: Aging; Antihypertensive Agents; Chronic Disease; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Nitrophenols; Organophosphorus Compounds; Randomized Controlled Trials as Topic

The aims of the present study were to compare the effects of cilnidipine [L-type/N-type calcium channel blocker (CCB)] and amlodipine (L-type CCB) alone or in combination with the angiotensin II receptor blocker (ARB), valsartan, on blood pressure (BP), kidney function in Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet were divided into six groups; control (n = 13), two CCB (cilnidipine or amlodipine) groups at 1 mg/kg/day (n = 10), ARB (valsartan) at 10 mg/kg/day (n = 12), cilnidipine + valsartan (CV, n = 12), and amlodipine + valsartan (AV, n = 12). BPs were lower in the combination therapy groups than in those given either drug alone, but only CV inhibited the increase in urinary albumin excretion (UAE) and lowered the glomerular sclerosis score. In addition, AV elevated plasma renin activity and the angiotensin II concentration, and thus failed to inhibit increases in UAE and to lower glomerular sclerosis score. In conclusion, combination therapy with CCB and ARB decreases BP more effectively than either drug alone. When used in combination with valsartan, cilnidipine is more effective than amlodipine for preventing kidney injury.

Topics: Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Glomerulonephritis; Hypertension; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Tetrazoles; Time Factors; Valine; Valsartan

To examine drug synergism between angiotensin II AT1-receptor blocker and Ca(2+) channel blocker for lowering blood pressure (BP), telmisartan and lercanidipine were orally injected into to telemetered-spontaneous hypertensive rats and BP was monitored. The highest doses of both drugs (7.66 mg/kg of telmisartan and 1.92 mg/kg of lercanidipine) were clinically relevant at 80 and 20 mg human equivalent doses, respectively, and denoted as dose 1. After constructing the dose-response curve using 0 (vehicle-treated control), 1/16, 1/8, 1/4, 1/2 and 1 doses, all possible combinations of both drugs were tested. Drug synergism in combination therapy of telmisartan with lercanidipine was assessed by calculating the interaction index (γ) as evaluated by γ < 1. We found statistically significant drug synergism in the investigated (telmisartan: lercandipine) combinations of (1/8:1/4), (1/4:1) and (1/8:1). Our results suggest that the combination therapy of telmisartan and lercanidipine at lower doses are effective in lowering BP, and also reduce side effects caused by maximal doses of each drug. Therefore, drug combination of AT1-receptor blocker with Ca(2+) channel blocker is a clinically important tool for the management of hypertension and hypertension-related cardiovascular risks.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Synergism; Heart Rate; Hypertension; Kinetics; Male; Random Allocation; Rats; Rats, Inbred SHR; Statistics as Topic; Telmisartan

Calcium channel blockers are increasingly used for the treatment of hypertension. Menopause and hypertension are both important risk factors for liver damage and several other circulatory abnormalities. The aim of this study was to determine the effects of amlodipine and lacidipine in an ovariectomy-induced postmenopausal period model and a deoxycorticosterone acetate-salt-induced hypertensive model in rats.. In this study, animals were divided into six groups as follows: control (Group 1), hypertension (Group 2), ovariectomy (Group 3), ovariectomy and hypertension (Group 4), ovariectomy, hypertension and amlodipine-treated (Group 5), and ovariectomy, hypertension and lacidipine-treated (Group 6). At the end of the experiment, the livers were removed and tissue samples were histologically and stereologically examined.. The numerical densities of the hepatocytes according to group were 0.000422, 0.00329, 0.000272, 0.00259, 0.00374 and 0.000346 μm3, respectively. Significant differences were found between values of all groups (p<0.01, Mann-Whitney U test). According to histopathological investigation, Group 3 and particularly Group 4 showed some microscopic abnormalities such as dilatation in sinusoids central veins and branches of portal vein, irregularities of the hepatocyte columns, significant mononuclear cell infiltrations, and unstained vacuoles in the cytoplasm of the hepatocytes. Histological structure was protected from the destructive effects of ovariectomy and hypertension in Groups 5 and 6.. Our experimental results show that both hypertension and the postmenopausal period have negative effects on the number of hepatocytes and histological structure of the liver. Both amlodipine and lacidipine appear to ameliorate the hypertension and/or postmenopausal period-related decrease in hepatocyte number. We thus suggest that lacidipine and particularly amlodipine have important protective and recovering effects on the liver.

Topics: Amlodipine; Animals; Calcium Channel Blockers; Cytoprotection; Dihydropyridines; Female; Hepatocytes; Hypertension; Liver; Ovariectomy; Postmenopause; Rats; Rats, Inbred Strains

The response of blood pressure (BP) to L-type dihydropyridine calcium-channel blockers (dCCBs) differs among individuals.. A pharmacogenomic analysis was undertaken in 161 patients with essential hypertension who were treated with dCCBs to study whether genetic polymorphisms of the calcium channel alpha1C and alpha1D subunit genes, CACNA1C and CACNA1D, are associated with the antihypertensive effects of dCCBs. Responders were defined as those in whom systolic BP (SBP) was lowered by more than 20 mmHg or diastolic BP (DBP) was lowered by more than 10 mmHg after treatment with dCCBs. Eleven sequence-proven polymorphisms of CACNA1C and 5 common polymorphisms of CACNA1D chosen from a public database were subjected to genotypic analysis. The comparison of polymorphism prevalence between responders and nonresponders showed significant differences in CACNA1D rs312481G>A and rs3774426C>T, and in CACNA1C 527974G>A. There were significant differences in SBP or DBP between alleles in these single nucleotide polymorphisms (SNPs). A much more significant reduction in BP was observed for the combined presence of these SNPs.. Three SNPs in CACNA1D or CACNA1C are genetic polymorphisms conferring sensitivity to the antihypertensive effects of L-type dCCBs in patients with hypertension. The BP reduction by L-type dCCBs might be predicted by evaluating these polymorphisms.

Topics: Aged; Alleles; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide

Clinical studies suggest that T-type Ca(2+) channel blockade may have incremental benefits over conventional L-channel blockade, particularly in microvascular disorders. This study examined functional vasomotor differences in L- and T-channel blockade between large and small vessels and compared the abundance of the L- and T-type channels in these vessels. The inhibition of endothelin-1 and potassium-induced vascular contractile responses by L-channel blockers (verapamil and nifedipine) was compared with combined L- and T-channel blockers (mibefradil and efonidipine) in large (rat aorta) and small (rat mesenteric and human subcutaneous) vessels using wire myography. All 4 of the Ca(2+) channel blockers inhibited contractile responses to a similar extent in large rat vessels; however, in rat microvessels, the combined L- and T-channel blockers produced significantly greater inhibition of contraction than L-channel blockers alone. The significance of this differential T-channel effect in microvessels was further supported by the following: (1) a greater abundance of T-channels compared with L-channels in microvessels but not in large vessels; (2) demonstration of divergent Ca(2+) channel blocker responses in human microvessels; (3) incremental inhibition of constrictor responses with combined L- and T-Ca(2+) channel blockers despite maximal L-channel blockade; (4) the use of structurally diverse Ca(2+) channel blockers with varied affinity for L- and T-channels; (5) the use of pharmacodynamically and therapeutically appropriate Ca(2+) channel blocker concentrations; (6) confirmation of contractile agonist independent responses; and (7) exclusion of an endothelium-dependent mechanism. We propose that T-type channels play an important role in regulating contractile responses in the microvasculature and, therefore, are a potential therapeutic target.

Topics: Animals; Aorta; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Dihydropyridines; Humans; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Mibefradil; Microvessels; Nifedipine; Nitrophenols; Organophosphorus Compounds; Potassium Chloride; Rats; Rats, Sprague-Dawley; Subcutaneous Fat; Vasoconstriction; Verapamil

Topics: Animals; Aorta; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Dihydropyridines; Drug Synergism; Humans; Hypertension; Mesenteric Arteries; Mibefradil; Microvessels; Nifedipine; Nitrophenols; Rats; Vasoconstriction; Verapamil

Calcium channel blockers are well established modalities for the treatment of hypertension. However, in spite of the availability of many efficacious agents, hypertension control continues to be poor. One reason is poor tolerability due to adverse events. Racial differences also exist. Lercanidipine, a third-generation calcium channel blocker, is associated with better tolerability. However, it has not been studied in the Asian population. This study examines its efficacy and tolerability in Asian subjects of different ethnicities.. This was an eight-week open label study of adults with mild to moderate hypertension. Blood pressure (BP), pulse rate, self-administered symptom check and laboratory evaluations were done at baseline. Patients were prescribed 10 mg lercanidipine, with up-titration to 20 mg if BP was not controlled at Week 4. Baseline evaluations were repeated at Week 8. Adverse events were also enumerated.. 27 patients (mean age 53.4 +/- 12.1 years) completed the study. The baseline systolic BP (SBP), diastolic BP (DBP) and heart rate was 159 +/- 12.2, 96.6 +/- 7.7 mmHg and 71 +/- 13/min, respectively. Three racial groups were represented. SBP and DBP decreased significantly after four weeks of therapy. A further reduction to 139 +/- 14.3 and 88 +/- 9.8 (p-value is less than 0.0001) was seen in Week 8. The absolute SBP and DBP reduction was 20.5 mmHg (95 percent confidence interval [CI] 16.5-24.5, p-value is less than 0.0001) and 9.3 mmHg (95 percent CI 6.2-12.5, p-value is less than 0.0001), respectively. All adverse symptoms, except for palpitations, were reduced at the end of the study.. Lercanidipine is efficacious and well tolerated in Asians of different ethnicities. Its BP lowering effects and tolerability in Asians appear to be similar to other studies on Caucasians and other calcium channel blockers.

Topics: Antihypertensive Agents; Asia; Calcium Channel Blockers; Confidence Intervals; Diastole; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Singapore; Systole

The rostral ventrolateral medulla is an important regulation center of sympathetic nerve activity. Several clinical studies have indicated a possible association between essential hypertension and neurovascular compression of the rostral ventrolateral medulla. We have found that patients with essential hypertension and neurovascular compression of the rostral ventrolateral medulla by adjacent arteries have increased sympathetic nerve activity and that microvascular decompression of the rostral ventrolateral medulla normalizes blood pressure and sympathetic nerve activity. Although sympatholytic agents are expected to lower blood pressure in these patients, this remains to be clarified. In this study, we evaluated the effect of cilnidipine, a calcium channel blocker that blocks both vascular L-type and sympathetic N-type Ca(2+) channels in hypertensive patients with neurovascular compression. Using high-resolution magnetic resonance imaging, 46 patients with untreated essential hypertension were distributed into those with and without neurovascular compression of the rostral ventrolateral medulla. All patients were prescribed 10 mg of cilnidipine for 16 weeks. Office and home blood pressure, plasma norepinephrine and left ventricular mass index were measured by echocardiography before and after cilnidipine treatment, and changes were compared between the two groups. At baseline, plasma norepinephrine was significantly higher in patients with neurovascular compression. Decreases in office and home blood pressure, plasma norepinephrine and left ventricular mass index were significantly greater in patients with neurovascular compression. These results suggest that cilnidipine lowers blood pressure by inhibiting enhanced sympathetic nerve activity and reduces left ventricular mass in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Echocardiography; Female; Heart Rate; Humans; Hypertension; Magnetic Resonance Imaging; Male; Medulla Oblongata; Middle Aged; Nerve Compression Syndromes; Norepinephrine; Ventricular Function, Left

Baseline carotid intima-media thickness (IMT) and plaques are considered predictors of cardiovascular events, but whether they maintain predictive value in treated hypertensive patients and whether time-related (or treatment-induced) IMT changes are additional predictors are unknown.. Analyses were performed of the data from the European Lacidipine Study on Atherosclerosis (ELSA), a large, randomized, intervention trial in which 2334 hypertensive patients from 7 European countries were followed up under effective antihypertensive treatment for 3.75 years. Kaplan-Meier curves indicated progressively lower survival free of any type of outcome except stroke, with increasing baseline IMT quartiles or increasing IMT values, even after adjustment for major baseline risk factors. Incidence of any outcome except stroke also was related to baseline number of carotid plaques. However, when both baseline and on-treatment IMT values were entered in Cox proportional-hazards models, differences in IMT compared with baseline did not predict cardiovascular outcomes. Although on-treatment rather than baseline IMT values significantly entered some of the proportional-hazards models, baseline and on-treatment IMTs were highly correlated, and therefore these results are inconclusive.. ELSA shows that carotid intima-media thickening and plaques are important added risks of cardiovascular outcomes in a treated hypertensive population independently of blood pressure and traditional risk factors. However, the analysis failed to show a predictive role of treatment-dependent IMT changes. These negative conclusions should be tempered by the limitations inherent in the smallness of these changes compared with the large individual differences in baseline IMTs.

Topics: Antihypertensive Agents; Cardiovascular Diseases; Carotid Arteries; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Tunica Intima; Tunica Media

Calcium channel antagonists (calcium channel blockers [CCBs]) are often used in the treatment of patients with hypertension to achieve strict blood pressure (BP) targets. In the present study, we compared the antihypertensive effects (determined by home BP [HBP] measurements) and the effects on renal function of benidipine (hydrochloride) and amlodipine (mesylate), a commonly used CCB.. Changes in HBP and urinary albumin excretion (UAE) were investigated in 47 benidipine and 37 amlodipine recipients with essential hypertension and albuminuria between January 2007 and December 2007. Both benidipine and amlodipine significantly reduced morning and evening HBP over a 12-month period.. Both medications also significantly reduced UAE compared with pretreatment values; however, the reduction in UAE observed in the benidipine group occurred independent of the drug's antihypertensive effects, whereas a positive correlation was shown between the reduction in morning systolic BP and UAE in the amlodipine group.. These results demonstrate that benidipine favourably affects renal function in patients with essential hypertension compared with amlodipine, suggesting that the clinical benefits of benidipine as an antihypertensive drug include a renoprotective effect.

Topics: Adult; Aged; Albuminuria; Amlodipine; Blood Pressure; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Retrospective Studies

Clinical studies have suggested that pulsatile pressure is an independent risk factor for atherosclerosis. However, it is unknown whether enhanced pulsatile pressure per se directly accelerates vascular smooth muscle cell (VSMC) migration, an important process of atherosclerosis.. Using our original Pressure-loading system with a Boyden chamber, we examined the direct effects of variable pressures and pulse rates on migration of rat aortic VSMCs in vitro. High pulse pressure (180/90 mmHg, pulsatile vs. 180 mmHg, static), high mean pressure (180/90 vs. 90/0 mmHg, with the same pulse pressure), wide pulse pressure (190/110 vs. 170/130 mmHg, with the same mean pressure), and high pulse rate (120 vs. 40 per min) significantly accelerated the VSMC migration (1.35, 2.38, 1.38 and 1.27-fold, respectively). The increase in intracellular calcium levels measured by fura-2/AM fluorescence was proportional to the magnitude of pressure loaded. The pressure-promoted VSMC migration was significantly inhibited by a phospholipase-C inhibitor U-73122 or a calmodulin inhibitor W-7. Inositol 1,4,5-trisphosphate receptor blockers 2-aminoethoxydiphenyl borate or xestospongin-C significantly inhibited the VSMC migration, whereas a ryanodine receptor blocker ryanodine had no effects. Furthermore, a calcium channel blocker (CCB), azelnidipine, and an angiotensin type-1 receptor blocker, olmesartan, also significantly inhibited the VSMC migration.. These results provide direct evidence for the pro-atherogenic effects of enhanced pulsatile pressure and also suggest that the anti-atherogenic actions of CCBs and angiotensin type-1 receptor blockers are mediated in part by their direct inhibitory effects on VSMC migration in addition to their anti-hypertensive effects.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Atherosclerosis; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Calcium Signaling; Cell Movement; Cells, Cultured; Dihydropyridines; Disease Models, Animal; Equipment and Supplies; Estrenes; Hypertension; Imidazoles; Inositol 1,4,5-Trisphosphate Receptors; Macrocyclic Compounds; Muscle, Smooth, Vascular; Oxazoles; Pyrrolidinones; Rats; Rats, Wistar; Signal Transduction; Tetrazoles; Type C Phospholipases

To assess whether azelnidipine (AZN) exerts renoprotective effects, 20-week-old adult male stroke-prone spontaneously hypertensive rats (SHRsp) were treated with AZN 10 mg/kg/d (n=6), olmesartan (OLM) 3 mg/kg/d (n=4), hydralazine (HYD) 20 mg/kg/d (n=3), or water (control; n=5). Each test agent was administered by oral gavage for 12 weeks. Systolic blood pressure (SBP) was measured every 2 weeks and urinary protein excretion (UproV) every 3 weeks. At the age of 32 weeks, the rats were sacrificed and blood and kidneys collected for biochemical, histological, and immunohistochemical studies. All drug treatments significantly (p<0.05) reduced SBP, UproV, and blood biochemical parameters such as creatinine, total cholesterol, and blood urea nitrogen. Masson trichrome staining and immunohistochemical staining revealed significant (p<0.05) reductions of interstitial fibrosis, collagen type III, nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase, and p22(phox) and p47(phox) components expression in the AZN- and OLM-treated groups in comparison with rats treated with HYD and control animals. ED1, 4-hydroxy-2-nonenal (4-HNE), and heat shock protein (HSP)-47 expression was also reduced in the AZN- and OLM-treated groups versus in HYD and control animals. These results indicate that not only OLM but also AZN exerts renoprotective effects through inhibition of macrophage infiltration and antioxidant activity in SHRsp model of renal injury.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Urea Nitrogen; Calcium Channel Blockers; Collagen Type III; Data Interpretation, Statistical; Dihydropyridines; HSP47 Heat-Shock Proteins; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Macrophages; Male; NADPH Oxidases; Phosphopyruvate Hydratase; Rats; Rats, Inbred SHR

The long-acting dihydropyridine calcium channel blocker, azelnidipine, is suggested to inhibit sympathetic nerve activity. We previously demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM) activates sympathetic nerve activity. The aim of the present study was to determine whether oral administration of azelnidipine inhibits sympathetic nerve activity and if so to determine whether the effect is mediated by antioxidant effect in the RVLM. Azelnidipine, hydralazine, or vehicle was orally administered for 28 days to stroke-prone spontaneously hypertensive rats. Reductions in systolic blood pressure were similar in azelnidipine and hydralazine groups. Heart rate was significantly higher in the hydralazine group than in the control, but not altered in the azelnidipine group. Urinary norepinephrine excretion as an indicator of sympathetic nerve activity was significantly lower in the azelnidipine group, whereas it was significantly higher in the hydralazine group than in the control. Levels of thiobarbituric acid-reactive substances and nicotinamide adenine dinucleotide phosphate oxidase activity were significantly lower in the azelnidipine group than in control. Superoxide dismutase activity was significantly increased in the azelnidipine group more than in the control. These results suggest that azelnidipine decreases an indicator of sympathetic nerve activity by antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase in the RVLM of stroke-prone spontaneously hypertensive rats.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Heart Rate; Hydralazine; Hypertension; Male; Medulla Oblongata; NADPH Oxidases; Norepinephrine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Superoxide Dismutase; Sympathetic Nervous System; Thiobarbituric Acid Reactive Substances

Oxidative stress is associated with exacerbation of renal injuries in hypertension. In clinical studies benidipine hydrochloride (benidipine), a dihydropyridine calcium channel blocker with antioxidant activity, reduced oxidative stress. However, the mechanism of suppression of oxidative stress remains to be fully characterized. Reactive oxygen species production by polymorphonuclear leukocyte plays important pathological roles in hypertension. Therefore, we examined the effects of benidipine both on reactive oxygen species production of human polymorphonuclear leukocytes and oxidative stress of an animal model. Human peripheral polymorphonuclear leukocytes or polymorphonuclear leukocyte-like differentiated HL-60 cells were used to examine effects of benidipine (0.1-30 microM) on formyl-Met-Leu-Phe-induced reactive oxygen species production, calcium mobilization, NADPH oxidase activation and phosphorylation of protein kinase C substrates. High-salt (8% NaCl) loaded stroke-prone spontaneously hypertensive rats were treated with or without benidipine (1, 3, 10 mg/kg/day) for 2 weeks, and thiobarbituric acid reactive substances, a plasma oxidative stress marker, and renal expression of oxidative stress-induced genes were measured. Benidipine concentration-dependently suppressed formyl-Met-Leu-Phe-induced reactive oxygen species production in polymorphonuclear leukocytes more potently than other calcium channel blockers such as amlodipine, azelnidipine, nitrendipine and nifedipine. Benidipine partially inhibited all of intracellular Ca(2+) elevation, protein kinase C activation and NADPH oxidase activation. Salt loading in stroke-prone spontaneously hypertensive rats augmented plasma thiobarbituric acid reactive substances levels; renal dysfunction; and renal expression of transforming growth factor-beta, collagen I and collagen III mRNAs; which were attenuated by benidipine treatment. These results indicate that benidipine prevents the polymorphonuclear leukocyte-derived reactive oxygen species production, which is due at least in part to its antioxidant action and inhibition of Ca(2+)/protein kinase C/NADPH oxidase signaling. The attenuation of reactive oxygen species production might contribute to the drug's reduction of oxidative stress and renal injuries in hypertension.

Topics: Animals; Antioxidants; Calcium; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Hypertension; Male; NADP; Neutrophils; Oxidative Stress; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Sodium Chloride, Dietary; Stroke

T-type calcium channel blockers have been previously shown to protect glomeruli from hypertension by regulating renal arteriolar tone. To examine whether blockade of these channels has a role in protection against tubulointerstitial damage, we used a stereo-selective T-type calcium channel blocker R(-)-efonidipine and studied its effect on the progression of this type of renal injury in spontaneously hypertensive rats that had undergone subtotal nephrectomy. Treatment with racemic efonidipine for 7 weeks significantly reduced systolic blood pressure and proteinuria. The R(-)-enantiomer, however, had no effect on blood pressure but significantly reduced proteinuria compared to vehicle-treated rats. Both agents blunted the increase in tubulointerstitial fibrosis, renal expression of alpha-smooth muscle actin and vimentin along with transforming growth factor-beta (TGF-beta)-induced renal Rho-kinase activity seen in the control group. Subtotal nephrectomy enhanced renal T-type calcium channel alpha1G subunit expression mimicked in angiotensin II-stimulated mesangial cells or TGF-beta-stimulated proximal tubular cells. Our study shows that T-type calcium channel blockade has renal protective actions that depend not only on hemodynamic effects but also pertain to Rho-kinase activity, tubulointerstitial fibrosis, and epithelial-mesenchymal transitions.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Chronic Disease; Dihydropyridines; Hypertension; Kidney Diseases; Male; Nephrectomy; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR

Treatment regimens that require fewer dosage units and less frequent dosing to decrease the complexity and cost of care are among the strategies recommended to improve compliance with antihypertensive therapy. Simplifying therapy may be particularly important for elderly patients, who are more likely to have co-morbid conditions and to be taking multiple medications.. To determine rates of compliance with antihypertensive therapy and total costs of care among elderly Medicaid recipients treated with fixed-dose combination amlodipine besylate/benazepril versus a dihydropyridine calcium channel antagonist and ACE inhibitor prescribed as separate agents (free combination).. A longitudinal, retrospective, cohort analysis of South Carolina Medicaid claims for ambulatory services, hospital services, Medicare crossover, and prescription drug for the years 1997-2002. Follow-up was 12 months from the index date, defined as the first prescription dispensing date for a study drug.. South Carolina Medicaid beneficiaries aged >or=65 years.. Outcomes variables included compliance defined as the medication possession ratio (MPR), which was the total days' supply of drug (excluding last prescription fill) divided by the length of follow-up (with number of hospital days subtracted from the numerator and denominator). We hypothesized that elderly individuals receiving fixed-dose combination amlodipine besylate/benazepril HCl would be more compliant with therapy than those receiving a dihydropyridine calcium channel antagonist and ACE inhibitor as free combination.. There were 2336 individuals in the fixed-combination group and 3368 in the free-combination group. The mean age was 76.0 +/- 7.2 years, and 82.6% were female. Compliance rates were significantly higher with fixed-dose versus free-combination therapy (63.4% vs 49.0%; p < 0.0001). The average total cost of care for patients receiving the fixed-dose combination was $US3179 compared with $US5236 (2002 values) for the free-combination regimen. In multivariate regression analyses on the log of total cost of care, average total costs increased by 0.5% for each 1-unit increase in MPR, and for each additional co-morbidity (measured by the chronic disease score) there was an increase of 10.4%. However, average total costs were reduced by 12.5% for patients using fixed-dose versus free-combination therapy (p < 0.003).. Use of fixed-dose amlodipine besylate/benazepril HCl by elderly Medicaid recipients was associated with improved compliance and lower healthcare costs compared with a dihydropyridine calcium channel antagonist and ACE inhibitor prescribed as separate agents.

Topics: Age Factors; Aged; Aged, 80 and over; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Female; Health Care Costs; Humans; Hypertension; Longitudinal Studies; Male; Medicaid; Patient Compliance; Retrospective Studies; South Carolina; United States

We examined the effects of antihypertensive drugs, exercise training, and combinations thereof on insulin sensitivity (IS), and the association between this relation and sympathetic activity, muscle fiber composition, and capillary density in spontaneously hypertensive rats (SHR). Six-week-old male SHR were allocated to 7 groups: a control group (C), and groups treated with azelnidipine (Aze) (a calcium channel blocker), olmesartan (Olm) (an angiotensin II type 1 receptor blocker), exercise training (Exe), and combinations of drugs and exercise training (Aze+Exe, Olm+Exe, and Olm+Aze+Exe). At age 18 weeks, IS and sympathetic activity were evaluated by an euglycemic hyperinsulinemic glucose clamp technique and power spectral analysis of systolic blood pressure, respectively. After the experiments, capillary density and muscle fiber composition in soleus muscle were examined. Aze or Exe alone significantly increased IS associated with a significant reduction in sympathetic activity. Olm alone tended to increase IS with little change in sympathetic activity. Aze, Olm, or Exe significantly increased the capillary density and percentage of insulin-sensitive type I fiber. A combination of Aze and Exe or a combination of Olm and Exe tended to increase IS compared with each drug therapy alone. There were significant correlations between IS and sympathetic activity, capillary density, and the percentage of type I fiber in all the rats. We found that Aze improved IS more substantially compared with Olm in SHR. We also found that Aze, Olm, Exe, and combinations thereof improved IS, probably through the modulation of sympathetic activity or capillarity and muscle fiber type in skeletal muscles.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Combined Modality Therapy; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Heart Rate; Hypertension; Imidazoles; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Regression Analysis; Sympathetic Nervous System; Tetrazoles

Electron paramagnetic resonance (EPR) spectroscopy was used to investigate the gamma-radiation damage in the crystalline powder form of nine calcium channel blockers from the 1,4-dihydropyridine derivatives, which are in clinical use for treatment of arteria hypertension and ischemic heart disease. EPR studies have been carried out, showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals trapped. EPR spectra of isardipine and felodipine showed single EPR line. EPR spectra of nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine and nilvadipine reveal a broad anisotropic signal of hyperfine interaction. No EPR signal was observed from amlodipine.

Topics: Calcium Channel Blockers; Dihydropyridines; Electron Spin Resonance Spectroscopy; Felodipine; Gamma Rays; Humans; Hypertension; Models, Molecular; Molecular Conformation; Myocardial Ischemia; Nifedipine; Nimodipine

Despite normal indices of left-ventricular (LV) chamber function, patients with hypertension are thought to have depressed LV midwall systolic shortening. This study was designed to investigate effects of short-term therapy with cilnidipine on LV midwall fractional shortening (mFS) in Chinese patients with hypertension. Thirty-seven patients with mild to moderate essential hypertension underwent a 2 week placebo run-in period, then received 5-10 mg/day of cilnidipine orally for 8 weeks. At the end of the placebo period and treatment, patients were examined by echocardiogram, measuring and calculating LV ejection fraction (EF), LV endocardial fraction shortening (eFS), and LV mFS. Compared with the normotensive group, the hypertensive group had a significantly higher eFS (P < 0.05) and EF (P < 0.01), both at the end of the placebo period and at 8 weeks; mFS of patients with hypertension was lower at the end of the placebo period (P < 0.05), but at the end of 8 weeks mFS was not different than that of the control group (P = 0.963). After cilnidipine treatment, EF and eFS did not change (P > 0.05); however, absolute mFS and corrected mFS were increased significantly (P < 0.01). Moreover, changes of mFS showed no correlation with changes of blood pressure (P > 0.05). Midwall fractional shortening is more reliable and sensitive than conventional systolic function measures in assessment of systolic function; cilnidipine can improve left-ventricular systolic function (mFS) independently of blood pressure changes in Chinese patients who have hypertension.

Topics: Asian People; Blood Pressure; Calcium Channel Blockers; China; Dihydropyridines; Female; Heart; Humans; Hypertension; Male; Middle Aged; Ventricular Function, Left

Changes in myocardial expression of Na+/K+-ATPase alpha-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with 1 mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [3H]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with Kd approximately 25 and approximately 200 nM, ascribed to the alpha3 and alpha2 isoforms, respectively. Bmax of alpha3 was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, Bmax of alpha2 was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a Bmax reduction of 20% (P<0.05), an effect blocked by lacidipine. These effects were largely confirmed by immunoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous alpha1 isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na+/K+-ATPase alpha3 subunit, which was not found in SHRSP; the level of the alpha2 isoform was similar in untreated SHRSP and WKY; salt-loading of SHRSP promoted reduction of the alpha2 isoform, and this effect was completely hampered by lacidipine.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Heart Ventricles; Hypertension; Isoenzymes; Male; Ouabain; Protein Subunits; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Stroke

Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.

Topics: Administration, Oral; Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Cardiovascular System; Dihydropyridines; Dose-Response Relationship, Drug; Heart Rate; Homeostasis; Hypertension; Injections, Intravenous; Male; Nicardipine; Rats; Rats, Inbred SHR; Stress, Physiological; Sympathetic Nervous System; Time Factors

The study was undertaken to determine the effect of treatment with the dihydropyridine-type calcium antagonist lercanidipine on the renal vasculature in Cohen-Rosenthal diabetic hypertensive rats, a genetic model of hypertension associated with type 2 diabetes mellitus. Eight animals were given a daily oral dose of 3 mg/kg lercanidipine in drinking water for 8 weeks, and 6 control animals received no treatment. The effects on blood pressure, glucose level, and kidney microanatomy were evaluated. Lercanidipine reduced systolic blood pressure and glucose level. In the control group small arteries and glomerular arterioles exhibited wall thickening and luminal narrowing. Lercanidipine administration prevented the changes in small-sized arteries and glomerular arterioles. The glomerular changes observed in the untreated Cohen-Rosenthal diabetic hypertensive rats were not seen in the lercanidipine-treated animals. Lercanidipine also had beneficial effects on the renal vasculature, suggesting that the compound may be considered for treating hypertension associated with diabetes.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Kidney; Male; Rats; Renal Artery; Renal Circulation

To examine whether benidipine hydrochloride, one of the calcium channel blockers, up-regulate uncoupling protein 3 (UCP3) expression in two skeletal muscles (gastrocnemius and soleus) in rats. Wistar rats were treated orally with benidipine hydrochloride at 4 mg/kg for 7 days. Blood pressure was measured after 4 days. At the end of experiments, the rats were weighed, and brown adipose tissue (BAT) and skeletal muscles (gastrocnemius and soleus muscles) were removed. The mRNA levels of uncoupling protein 1 (UCP1) and UCP3 were measured using the real-time quantitative reverse transcription-polymerase chain reaction method. Benidipine reduced body weight and also had a hypotensive effect. In rats treated with benidipine, UCP1 mRNA levels were significantly increased 1.4-fold in BAT, and UCP3 mRNA levels in BAT and gastrocnemius muscle were significantly increased 1.7 and 3.0-fold, respectively, compared with the control rats. There was no difference in UCP3 mRNA levels in soleus muscle between the two groups. We concluded that benidipine up-regulates not only UCP1 gene expression in BAT but also UCP3 gene expression in BAT and gastrocnemius muscle, which may contribute to thermogenesis in rats.

Topics: Adipose Tissue, Brown; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Gene Expression; Hydrochloric Acid; Hypertension; Ion Channels; Male; Mitochondrial Proteins; Muscle, Skeletal; Rats; Rats, Inbred SHR; Rats, Wistar; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 3; Up-Regulation

Calcium channel blockers are commonly used to treat hypertension, and are known to generally act on the L-type calcium channel. Recent studies have shown, however, that some calcium channel blockers also block other calcium channel subtypes, including N- and T-type channels. Cilnidipine (CAS 132203-70-4) is an L- and N-type calcium channel blocker, and benidipine hydrochloride (benidipine, CAS 91599-74-5) is known to inhibit the T-type as well as L- and N-type calcium channels. In this study, effects of switching from cilnidipine to benidipine on blood pressure (BP) lowering and renal functions were investigated in order to clarify the physiological properties of the T-type calcium channel.. Forty hypertensive patients with diabetes and poor BP control despite receiving cilnidipine were selected, and the changes in BP and urine protein (UP) scores were investigated retrospectively after switching from cilnidipine to benidipine for more than 3 months. BP (systolic/diastolic) significantly decreased from 155.8 +/- 13.7 mmHg/76.5 +/- 13.3 mmHg to 145.9 +/- 17.0 mmHg/71.4 +/- 13.7 mmHg after benidipine treatment, and this effect was stably maintained for one year. UP also significantly decreased from 1.29 to 0.67 in the mean score. The decrease in UP may be explained by a mechanism other than BP lowering effect.. These results demonstrate that benidipine has a more potent antihypertensive effect than cilnidipine and also a renoprotective effect, indicating the high usefulness of benidipine in hypertensive patients with diabetes. T-type calcium channel blockade was suggested to be possibly involved in the enoprotective effect of benidipine.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Calcium Channels, T-Type; Diabetes Complications; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Proteinuria; Retrospective Studies

Calcium channel blockers are most commonly used in hypertensive patients in Japan. However, information on the efficacy and safety of generic calcium channel blockers is insufficient. The objective of the present study was to retrospectively evaluate the efficacy and safety of manidipine hydrochloride in 21 essential hypertensive patients (mean age; 70.6+/-10.6 years, male/female; 14/7) in Sendai Postal Services Agency Hospital who were switched (substituted) from a brand product (Calslot) to a generic product (Manidip). For this retrospective study, we used data from patient medical records and drug prescription information. Data from patients who were taking both types of manidipine hydrochloride, whose regimen were not changed for > 6 months before and after switching, and who provided informed consent were included in the analysis. Control values of blood pressure were not significantly different between before and after substitution (systolic/diastolic; from 137.9+/-9.1/78.7+/-5.4 mmHg to 137.3+/-9.1/77.8+/-6.3 mmHg, p=0.73/p=0.36). The level of patient compliance for the antihypertensive drugs was also not different between before and after substitution (from 94.0+/-8.8% to 93.1+/-9.6%, p=0.72). There were 8 cases of adverse effects before substitution and 4 after substitution. No patient stopped taking the generic drug due to an adverse effect. In conclusion, significant differences in the efficacy, safety, and patient compliance were not observed between the brand product and generic product among patients who were switched from the brand product to the generic product.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Drugs, Generic; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Patient Compliance; Piperazines; Retrospective Studies; Therapeutic Equivalency

A dihydropyridine calcium (Ca) antagonist, azelnidipine (CAS 123524-52-7, Calblock), exhibits hypotensive effects for a prolonged duration, and has been reported to have a strong antiarteriosclerotic action due to its high affinity for vascular tissues and antioxidative action. It has also been reported that azelnidipine does not cause tachycardia associated with the baroreceptor reflex due to vasodilatation. In this study, the antiarteriosclerotic and cardiac hypertrophy-inhibitory effects, and the autonomic nervous activity in essential hypertension of azelnidipine were investigated. The study was performed using the following 2 protocols: 1) Pulse wave velocity (PWV), carotid arterial intima media thickness (IMT), echocardiography, high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), adiponectin, brain natriuretic peptide (BNP), and 8-isoprostane were measured after an initial treatment with azelnidipine. 2) The treatment was switched to azelnidipine in patients who had previously been under treatment with amlodipine for essential hypertension, and 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG), measurements of plasma norepinephrine, atrial natriuretic peptide (ANP), and BNP, Holter electrocardiography, and heart rate variability analysis were performed. PWV, IMT, hs-CRP, IL-6, and TNF-alpha significantly decreased. The levels of 8-isoprostane, an antioxidative marker, were also significantly decreased, while adioponectin levels were significantly increased after the initial treatment with azelnidipine. After switching from amlodipine, azelnidipine exhibited a hypotensive effects comparable to amlodipine, and significantly decreased heart rate and the total number of extrasystoles. Noradrenaline levels and the LF/HF ratio were significantly decreased, and the washout rate was significantly reduced on 123I-MIBG myocardial scintigraphy. These findings suggest that azelnidipine inhibits the enhancement of sympathetic nervous activity and the progression of arteriosclerosis through its antioxidative effects.

Topics: 3-Iodobenzylguanidine; Adipokines; Aged; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Autonomic Nervous System; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiomegaly; Carotid Arteries; Catecholamines; Cytokines; Dihydropyridines; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Pulse; Radionuclide Imaging; Radiopharmaceuticals

Long-acting third-generation dihydropyridine calcium channel blockers (CCBs) improve endothelial dysfunction and prevent cardiovascular events in humans, but their cellular and molecular mechanisms of tissue protection are not elucidated in detail. We assessed organ (renal) protection by the highly lipophilic CCB lercanidipine in a double-transgenic rat (dTGR) model with overexpression of human renin and angiotensinogen genes. We randomly treated dTGR with lercanidipine (2.5 mg/kg/day; n=20) or vehicle (n=20) for 3 wk. Furthermore, we explored the influence of lercanidipine on protein kinase C (PKC) signaling in vivo and in vitro using endothelial and vascular smooth muscle cell cultures. Cumulative mortality was 60% in untreated dTGR, whereas none of the lercanidipine-treated animals died (P<0.001). We found significantly less albuminuria and improved renal function in lercanidipine-treated dTGR (both P<0.05). Lercanidipine treatment also significantly (P<0.05) reduced blood levels of the endogenous NOS inhibitor asymmetric dimethylarginine. On histological examination, we observed significantly less tissue inflammation and fibrosis in lercanidipine-treated animals (both P<0.05). Lercanidipine significantly inhibited angiotensin (ANG) I-mediated PKC-alpha and -delta activation in vivo and in vitro, partly due to reduced intracellular calcium flux. As a result, lercanidipine improved endothelial cell permeability in vitro. Lercanidipine prevents tissue injury and improves survival in a model of progressive organ damage. These effects may result, at least in part, from inhibition of tissue inflammation as well as improved NO bioavailability. Modulation of PKC activity may be an important underlying intracellular mechanism.

Topics: Albumins; Amidohydrolases; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arginine; Calcium Channel Blockers; Dihydropyridines; Gene Expression Regulation, Enzymologic; Hypertension; Kidney; Rats; Rats, Sprague-Dawley; Renin

The sympathetic nerve activity plays an important role on the renal function through the vasoactive system and the renin-angiotensin system. Although interest in the renal protective effects of anti-sympathetic agents has been increased, there are not enough data to clarify this efficiency. Therefore, we investigated the effects of L/N-type calcium channel antagonist, cilnidipine on progressive renal injury in Dahl salt-sensitive (Dahl S) rats. Male Dahl S rats (6 weeks of age) were fed a high salt (4% NaCl) diet. They were divided into groups with similar blood pressure at 12 weeks of age and they received vehicle (n=7) or cilnidipine (30 mg/kg/d as food admix, n=9) for 8 weeks. Cilnidipine treatment suppressed the increase in systolic blood pressure. Although urinary protein excretion was not influenced, cilnidipine inhibited the increase in blood urea nitrogen and decrease in creatinine clearance. Histological investigation revealed that progression of glomerular sclerosis was inhibited in cilnidipine treatment group. Of notes, cilnidipine reduced plasma norepinephrine level and plasma rennin activity compared with vehicle-treated Dahl S rats. These data indicated that cilnidipine has suppressive effects against progressive renal injury in Dahl S rats. This effect is not only explained by the L-type calcium channel blocking action that lowered blood pressure, but also partially explained by the N-type calcium channel blocking action that lead to suppression of the sympathetic nerve activity and renin-angiotensin system.

Topics: Angiotensin II; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Progression; Hemodynamics; Hypertension; Kidney; Kidney Cortex; Kidney Failure, Chronic; Kidney Function Tests; Male; Norepinephrine; Rats; Rats, Inbred Dahl; Renin; von Willebrand Factor

Topics: Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Felodipine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Stroke

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines; Treatment Outcome

Delapril/manidipine 30 mg/10 mg is a new oral, once-daily, fixed combination of an ACE inhibitor and a dihydropyridine calcium-channel antagonist for the treatment of essential hypertension. In a dose-finding study in 400 patients with mild to moderate hypertension, delapril/manidipine 30mg/10mg once daily produced the greatest reduction in blood pressure (BP) of the combinations tested. Delapril/manidipine 30mg/10mg once daily for 6 weeks reduced systolic BP (SBP)/diastolic BP (DBP) by 15/13mm Hg. In nonresponders to monotherapy with delapril (n = 155) or manidipine (n = 152), delapril/manidipine 30mg/10mg once daily for 12 weeks reduced mean SBP/DBP by 16/11mm Hg and 16/10mm Hg, respectively. Delapril/manidipine 30mg/10mg once daily for 12 weeks in patients with mild to moderate hypertension (n = 131) demonstrated significantly greater antihypertensive efficacy than monotherapy with manidipine 10mg once daily (n = 134) or delapril 15mg twice daily (n = 136). Mean SBP/DBP reductions from baseline were 19/14, 15/11 and 14/10mm Hg, respectively. After 50 weeks of therapy with delapril/manidipine 30mg/10mg once daily, mean SBP/DBP was reduced by 22/14mm Hg in patients with mild to moderate hypertension (n = 309). Delapril/manidipine 30mg/10mg once daily was generally well tolerated. The incidence and nature of adverse events were similar to those observed in recipients of monotherapy with the individual agents. Combination therapy was associated with less ankle oedema than manidipine monotherapy.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines; Treatment Outcome

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

To examine the mechanism and significance of tachycardia-induced cardiac damage, using azelnidipine, a relatively new dihydropyridine calcium channel blocker which does not increase heart rate.. Comparing azelnidipine and amlodipine, we examined the cardiac effects and the direct effects on a sinus node/atrial preparation in stroke-prone spontaneously hypertensive rats (spSHRs). By pacing the right atrium, we examined the effect of tachycardia per se on cardiac oxidative stress. Using apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, we investigated the role of oxidative stress in cardiac remodelling.. Azelnidipine suppressed cardiac hypertrophy, fibrosis, NADPH oxidase and superoxide in spSHRs more potently than amlodipine, and was associated with lower heart rates than amlodipine. Azelnidipine caused a greater reduction than amlodipine in the beat rate of the sinus node/atrial preparation of spSHRs. A 10 or 20% increase in heart rate, independent of blood pressure or sympathetic nerve activity, significantly enhanced cardiac NADPH oxidase activity, superoxide and activated mitogen-activated protein kinases. Reduction of cardiac oxidative stress by apocynin led to the suppression of cardiac hypertrophy, inflammation and fibrosis in spSHRs, beyond its hypotensive effect.. Our work provided evidence that the increase in heart rate per se, independent of sympathetic nerve activity, enhances cardiac oxidative stress and activates mitogen-activated protein kinases, which seem to be responsible for cardiac remodelling. Azelnidipine, without causing an increase in heart rate, has the potential to be useful for the treatment of cardiac remodelling.

Topics: Amlodipine; Animals; Azetidinecarboxylic Acid; Cardiomegaly; Dihydropyridines; Endomyocardial Fibrosis; Hydralazine; Hypertension; Male; Mitogen-Activated Protein Kinases; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tachycardia; Ventricular Remodeling

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Atenolol; Dihydropyridines; Diuretics; Drug Therapy, Combination; Eplerenone; Humans; Hypertension; Spironolactone; Treatment Outcome

Effects of a new lipophilic L-type calcium channel blocker, azelnidipine, on the expression of molecular components of the renin-angiotensin-aldosterone system (RAAS) were assessed. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of diabetes with hypertension, and their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats, were treated with azelnidipine for 2 weeks. The renal cortical mineralocorticoid receptor mRNA in OLETF was higher than in LETO, but was suppressed (P<0.05) by azelnidipine. Renal cortical angiotensin-converting enzyme mRNA of OLETF was lower than that of LETO rats, and it was further suppressed by azelnidipine (P<0.05). Azelnidipine can down-regulate the gene expression of molecular components of RAAS.

Topics: Animals; Aorta, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Down-Regulation; Heart; Hypertension; Kidney Cortex; Male; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Receptors, Mineralocorticoid; Renin-Angiotensin System; RNA, Messenger

To determine whether the antihypertensive effectiveness of lercanidipine was independent of the different cardiovascular risk levels. Patients with treated or untreated mild-to-moderate essential hypertension were included in a multicentre, prospective, non-comparative, open-label study. Patients received lercanidipine (10 mg/day, uptitrated to 20 mg/day) during 6 months. A total of 3175 patients, age 63 +/- 10 years, 51% women, were included. The cardiovascular risk was low in 237 patients, medium in 1396, high in 722, and very high in 820. At baseline, blood pressure (BP) was 159.5 +/- 11.7/95.2 +/- 7.4 mmHg. BP was progressively higher according to increase in cardiovascular risk. After 6 months of treatment, BP was 136.0 +/- 9.7/79.7 +/- 6.8 mmHg. The decrease in systolic BP and diastolic BP at each follow-up visit compared with baseline was statistically significant both in the intergroup and intragroup comparisons (p < 0.001). Mean decreases of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were -18.5/-13.8 mmHg in the low risk group, -23/-15.2 mmHg in the medium risk group, -24.4/-16.1 mmHg in the high risk group, and -27.4/-17.4 mmHg in the very high risk group. Most frequent side effects were oedema (5.1%), headache (3.3%), flushes (2.5%), and asthenia (1%). Only 1.7% of patients discontinued antihypertensive medication because of adverse events. Tolerability of lercanidipine was independent of the cardiovascular risk group. Lercanidipine was effective and well-tolerated in patients with mild-to-moderate hypertension in the daily practice. The effectiveness and safety of the drug were independent of the degree of cardiovascular risk.

Topics: Aged; Analysis of Variance; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Treatment Outcome

Chronic hypertension shifts cerebral blood flow (CBF) autoregulation towards higher blood pressure. We examined whether or not benidipine, a long-lasting dihydropyridine calcium channel blocker (CCB), improves the CBF autoregulation in spontaneously hypertensive rats (SHRs). CBF was analyzed by laser-Doppler flowmetry during stepwise hypotension by controlled bleeding. The lower limit of CBF autoregulation was calculated as the mean arterial blood pressure at which CBF decreased by 10% of the baseline. Mean arterial blood pressure and cerebral vascular resistance in SHRs were higher than those in normotensive Wistar rats. Oral administration of benidipine (3 mg/kg) for 8 d lowered the mean arterial blood pressure and cerebral vascular resistance, which were equivalent to the effects of amlodipine (3 mg/kg), another CCB, or candesartan (1 mg/kg), an Angiotensin II type-1 receptor blocker. The lower limit of CBF autoregulation in SHRs (142+/-4 mmHg) was significantly shifted to a higher-pressure level compared with Wistar rats (59+/-2 mmHg). The lower limit of CBF autoregulation was significantly lower in the benidipine-treated group (91+/-4 mmHg) than that in the control SHRs, and similar to that of the amlodipine group (97+/-6 mmHg). Benidipine reduced the lower limit of CBF autoregulation more effectively than candesartan (109+/-4 mmHg). In conclusion, benidipine shifted the limit of CBF autoregulation towards lower blood pressure in SHRs under hypotensive conditions by hemorrhage. These results suggest that benidipine may be useful for the treatment of hypertensive patients with the elderly or cerebrovascular disorders, in whom autoregulation of CBF is impaired.

Topics: Administration, Oral; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Flow Velocity; Blood Gas Analysis; Blood Pressure; Calcium Channel Blockers; Carbon Dioxide; Cerebral Cortex; Dihydropyridines; Hypertension; Male; Oxygen; Rats; Rats, Inbred SHR; Rats, Wistar; Species Specificity; Tetrazoles; Ultrasonography, Doppler, Pulsed; Vascular Resistance

Oxidative stress (OS), inflammation and insulin resistance are among the mechanisms that have been recently implicated in pathogenesis of essential hypertension (EH). Peripheral polymorphonuclear leukocytes (PMNLs) are primed in EH patients, releasing uncontrolled superoxide anion contributing to OS and chronic low-grade inflammation in these patients. PMNL priming correlates with insulin resistance and with PMNL intracellular calcium ([Ca2+]i). Recent studies have attributed additional anti-oxidative characteristics to the anti-hypertensive drug Lercanidipine (Vasodip), a third generation calcium-channel blocker.. To evaluate possible novel effects of two months of Lercanidipine treatment on systemic and PMNL-related inflammation and on insulin resistance in EH patients.. Fifteen non-smoking EH patients with untreated mild to moderate high blood pressure (BP) and age- and gender-matched healthy controls (HC) were included in the study. Low-grade inflammation was expressed by PMNL counts and apoptosis, by plasma fibrinogen, CRP and albumin (as a negative acute phase reactant) levels. Fasting serum insulin levels served as a marker of insulin resistance.. Inflammation parameters and insulin levels were higher in EH compared to HC. PMNL counts, fibrinogen and insulin levels positively correlated with mean arterial blood pressure values. Two months of Lercanidipine treatment showed a significant decrease in BP, PMNL counts and apoptosis, CRP and serum insulin levels and a significant increase in serum albumin levels.. The authors imply that the low-grade systemic inflammation and insulin resistance detected in EH patients may be attenuated by the use of Lercanidipine, adding new unknown anti-inflammatory properties to this calcium channel blocker.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Inflammation; Middle Aged; Neutrophils

The object of this study was to examine blood pressure (BP) variability due to postural change in elderly hypertensive patients. The subjects studied were 154 elderly inpatients in a hospital for the elderly (48 male and 106 female; median age: 82 years), consisting of age- and sex-matched bedridden (n=39) and non-bedridden (n=39) normotensive controls and bedridden (n=38) and non-bedridden (n=38) hypertensive patients. BP and pulse rate (PR) were measured in the supine position, then again after a 2-min, 45 deg head-up tilt with the legs horizontal. The decrease in systolic BP (SBP) on tilting in the bedridden hypertensive group (median: -10 mmHg; range: -32 to 9 mmHg) was significantly (p<0.008) greater than those in the other three groups. Monotherapy with azeinidipine, a long-acting calcium channel blocker, for 3 months not only significantly reduced the basal BP and PR of hypertensive patients in the two groups, but also significantly (p<0.05) attenuated the tilt-induced decrease in the SBP to -3 mmHg (-19 to 25 mmHg) and enhanced the change in PR from -1 bpm (-10 to 7 bpm) to 1 bpm (-4 to 23 bpm) in the bedridden hypertensive group. Our findings indicate that tilt-induced decrease in SBP is a rather common phenomenon in bedridden elderly hypertensive patients, and that treatment with azelnidipine attenuates tilt-induced decrease in SBP, probably through an improvement of baroreceptor sensitivity.

Topics: Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Inpatients; Male; Posture; Systole

The purpose of this study was to assess the clinical utility of the smoothness index (SI) and normalized SI (SIn), measures of duration and homogeneity of blood pressure (BP) reduction, during an observation period without antihypertensive therapy followed by a treatment period using dihydropyridines (DHP) in 54 newly diagnosed and previously untreated subjects (age 46.9 +/- 9.1 years) with essential hypertension. In addition, we aimed to describe the reduction-duration-homogeneity (RDH) index for statistical assessment of the BP reduction in the individual patient. Twenty-four-hour BP was lowered during treatment (139.2 +/- 13.9/ 91.0 +/- 7.6 mmHg vs 130.9 +/- 11.3/85.2 +/- 5.2 mmHg, p < 0.001/p = 0.001). SI showed great interindividual variation, and increased from zero to 0.9 +/- 0.8 (systolic BP) and 0.8 +/- 0.7 (diastolic BP) after treatment (p < 0.001 for both), similar results were obtained for SI(n). The RDH index revealed BP reduction in agreement with the change in individual 24-h, daytime and night-time BP. Although SI and SI(n) may add important information regarding the homogeneity of the antihypertensive effect in a group of patients, and the RDH index for the individual patient, conclusions regarding antihypertensive efficacy can be obtained from assessment of the 24-h, daytime and night-time BP changes and ambulatory BP profiles. Based on our findings, we do not recommend the use of SI or RDH index in the clinical practice.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diastole; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Models, Statistical; Systole

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Diltiazem; Drug Therapy, Combination; Female; Humans; Hypertension; Lisinopril; Male; Middle Aged; Nifedipine; Verapamil

Topics: Antihypertensive Agents; Calcium Channel Blockers; Contraindications; Dihydropyridines; Drug Interactions; Humans; Hypertension

The objective was primary to evaluate the safe use of a new calcium channel blocker, lercanidipine, in patients with chronic renal failure (CRF). The secondary objective was to study the protective effect of calcium channel blocker on renal function in CRF patients previously treated with ACE inhibitors or angiotensin receptor blockers.. The study recruited 203 CRF patients (creatinine >1.4 mg/dL for males, creatinine > 1.2 mg/dL for females, or creatinine clearance <70 mL/min). All patients were receiving ACE inhibitors (63.4%) or angiotensin II antagonist (36.6%) therapy, but they had higher blood pressure than recommended for CRF (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3, and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to the treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection.. 175 patients rendered valuable for the study (age 63.9+/-11.9 years, 52.9% males and 47.1% females). Blood pressure (BP) significantly decreased from 162+/-17/93+/-8.3 mmHg to 132+/-12/78+/-6 mmHg. 89.2% of patients showed a significant BP reduction, and 58.1% achieved optimal BP control (<130/85 mmHg). Seven patients (3.4%) showed untoward effects. Not one case of edema was detected, and the prevalence of adverse effects related to vasodilatation was extremely low (three patients, 1.48%). Plasmatic creatinine did not change (1.9+/-0.5 baseline versus 1.9+/-0.6 mg/dL), but creatinine clearance increased at the end visit (41.8+/-16.0 baseline versus 45.8+/-18.0 mL/min, p=0.019). Plasmatic cholesterol also decreased from 221+/-46 to 211+/-35 mg/dL (p=0.001).. Lercanidipine showed a high antihypertensive effect in CRF patients. It has a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, measured through creatine clearance, was detected.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Treatment Outcome

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Administration Schedule; Endothelium, Vascular; Humans; Hypertension; Patient Compliance; Treatment Outcome

Topics: Antihypertensive Agents; Arteriosclerosis; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Treatment Outcome

We investigated the effects of long-term benidipine treatment on levels of monocyte and endothelial cell activation markers in hypertensive patients with (n = 28) and without (n = 10) type 2 diabetes mellitus. Benidipine, 4 mg/day, was administered for 6 months; there were no other changes in any of the patients pharmacologic regimens during benidipine treatment. Clinical and biochemical data obtained before and after benidipine administration were compared; all markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, and PAC-1), microparticles (monocyte-derived microparticles: MDMPs, and endothelial cell-derived microparticles: EDMPs), chemokines (monocyte chemotactic peptide 1: MCP-1, regulated on activation normally T-cell expressed and secreted: RANTES) and soluble adhesion markers (soluble E-selectin and soluble ICAM-1) differed in the control and hypertension groups. In addition, levels of platelet, monocyte, and endothelial cell activation markers, microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients than in those without type 2 diabetes. Furthermore, benidipine administration decreased the concentrations of all these markers. The effect of this drug was significant in diabetes patients with high levels of antioxidized low-density lipoprotein (LDL) antibody. These results suggest that benidipine is effective for the treatment of oxLDL-dependent vascular disorders in hypertensive patients with type 2 diabetes.

Topics: Aged; Autoantibodies; Biomarkers; Diabetes Mellitus, Type 2; Dihydropyridines; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hypertension; Lipoproteins, LDL; Male; Middle Aged; Monocytes; Oxidation-Reduction; Retrospective Studies; Time Factors; Vasodilator Agents

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic synd

Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Azetidinecarboxylic Acid; Biomarkers; Calcium; Cardiovascular Diseases; Cells, Cultured; Chemokine CCL2; Diabetes Mellitus; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Insulin Resistance; Interleukin-8; Models, Biological; Reactive Oxygen Species; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Umbilical Veins

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.

Topics: Aged; Analysis of Variance; Animals; Atrial Fibrillation; Bradycardia; Calcium Channel Blockers; Dihydropyridines; Dogs; Electrocardiography; Female; Humans; Hypertension; Nicardipine

Calcium antagonists have evolved as useful drugs in the treatment of hypertension and angina. Dihydropyridines are the largest subgroup and various products have been marketed. Safety concerns have largely been allayed by comparative outcome trials but concern remains over short-acting products. In New Zealand, many patients requiring fully subsidised dihydropyridines have had several changes of product imposed due to successive reference pricing and sole-supply arrangements, along with deregistering and reregistering of generic felodipine. Some narrowly avoided a complete loss of access to a suitable low dose of any dihydropyridine. Generic substitution and sole-supply arrangements may make useful savings but can leave the supply of key pharmaceuticals vulnerable and impose significant loss in quality of healthcare from multiple changes in pharmaceutical preparation.

Topics: Angina Pectoris; Calcium Channel Blockers; Dihydropyridines; Drug Approval; Drug Industry; Felodipine; Humans; Hypertension; National Health Programs; New Zealand; Therapeutic Equivalency

Intravenous and oral labedipinedilol-C showed a dose-dependent long-lasting hypotension and a decrease of heart rate in normotensive and conscious spontaneously hypertensive rats (SHR). In isolated Wistar rat and guinea pig tissues, labedipinedilol-C competitively antagonized (-)isoproterenol-induced cardiac stimulation, tracheal relaxation, and phenylephrine-, CaCl2-, and high-K-induced aorta contractions in a concentration-dependent manner. The estimated pA2 and pKCa values were 8.22+/-0.04 and 7.11+/-0.52, respectively. [H]CGP-12177 binding to ventricle and lung tissues as well as [H]prazosin and [H]nitrendipine binding to brain membranes were inhibited by labedipinedilol-C with Ki values of 2.86, 9.03, 0.39, and 0.05 muM, respectively. The vasorelaxant effects of labedipinedilol-C on phenylephrine (10 microM)-induced contractions were attenuated by removing endothelium, by pretreatment with soluble guanylyl cyclase (sGC) inhibitors ODQ (10 microM) and methylene blue (10 microM), a NOS inhibitor L-NAME (100 microM), a K channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 microM), and Ca-dependent K channel blockers apamin (1 microM) and charybdotoxin (0.1 microM). In human umbilical vein endothelial cells (HUVECs), labedipinedilol-C increased NO release, which was significantly inhibited by L-NAME. The Western blot analysis on HUVECs indicated that labedipinedilol-C increased the expression of eNOS. These results indicate that hypotension effects of labedipinedilol-C result from alpha-adrenoceptor and Ca entry-blocking activities and release of NO or NO-related substance from vascular endothelium. The endothelium-independent relaxation of vascular smooth muscle is probably linked to K channel opening and alpha-adrenoceptor-blocking activities.

Topics: Adrenergic Antagonists; Animals; Aorta; Binding, Competitive; Blood Pressure; Calcium Channel Blockers; Cell Line; Dihydropyridines; Guinea Pigs; Heart Rate; Humans; Hypertension; In Vitro Techniques; Ion Channel Gating; Nitric Oxide; Piperazines; Potassium Channels; Radioligand Assay; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Trachea; Vasoconstrictor Agents; Vasodilation

The pathophysiological role of endothelial cells is important in the mechanism of progression of atherosclerosis and improvement of endothelial function may be important for cardiovascular morbidity. Calcium antagonists are reported to have protective effects on the endothelium in vitro and in vivo. In this clinical study, we investigated the effect of calcium antagonist, benidipine, on endothelial function in the patients with essential hypertension, which causes endothelial dysfunction. Twenty-five patients with hypertension without other risk factors for atherosclerosis were treated with monotherapy (8 mg benidipine, n=25) for 8 weeks. Blood pressure was reduced significantly. Endothelial function was evaluated using forearm blood flow by strain-gauge plethysmography after 8 weeks of treatment. Changes in vasodilator response to reactive hyperemia were significantly improved (p<0.01), while the response to nitroglycerin was not changed, suggesting the improvement of endothelial function. Moreover, we focused on hepatocyte growth factor (HGF), which is a novel angiogenic growth factor with an anti-apoptotic action on endothelial cells, and evaluated involvement of HGF in improvement of endothelial function. Serum HGF concentration in subjects treated with benidipine was significantly elevated at 8 weeks (p<0.05). Overall, these results demonstrated that benidipine improved endothelial dysfunction in patients with hypertension. Interestingly, an increase in serum HGF concentration by benidipine might contribute to the improvement of endothelial dysfunction.

Topics: Aged; Blood Flow Velocity; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Forearm; Hepatocyte Growth Factor; Humans; Hyperemia; Hypertension; Middle Aged; Nitroglycerin; Time Factors; Vasodilator Agents

Topics: Antihypertensive Agents; Chylous Ascites; Dihydropyridines; Humans; Hypertension; Male; Middle Aged

The aim of this study was to determine the correlation of changes in left ventricular mass, with changes in office blood pressure (BP) and in 24-h ambulatory (ABP), with the trough-to-peak (T/P) ratio and with the smoothness index (SI), as induced by antihypertensive treatment with lercanidipine.. This was done through an observational, prospective, open, non-comparative, single centre, pilot study in patients naïve to antihypertensive therapy. All patients were treated with lercanidipine 10-20 mg/day plus hydrochlorothiazide 12.5-25 mg/day if treated BP exceeded an arbitrarily defined safety level (>160/100 mmHg) after 1 month on monotherapy. ABP monitoring was repeated after 1 month and after 6 months. Two-dimensional mode echocardiography was performed twice, at the beginning and end of the study. Seventeen patients were included in the final analysis (aged 45.8 +/- 10.7 years, 35% women).. Treatment-induced changes in left ventricular mass index (LVMI) were not found to correlate neither with changes in office BP, with changes in ABP values, nor with T/P. However, a significant correlation was found between LVMI changes and SI at 6 months (r=0.50, P=0.039).. The results of this study suggest that the SI has a higher predictive value, compared to other BP-derived parameters, for treatment-induced LVMI changes, in hypertensive patients treated with lercanidipine.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Pilot Projects; Prospective Studies

Calcium channel blockers (CCBs) are widely used in clinical practice, and have been reported to be effective in preventing the progression of atherosclerosis. We examined whether various types of calcium channel blockers affected the expression of ATP binding cassette transporter A1 (ABCA1), a factor contributing to anti-atherogenesis. Undifferentiated monocytic cell line, THP-1 cells were maintained in RPMI 1640 medium and treated with different kinds of calcium channel blockers. Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression. H89, a protein kinase A inhibitor inhibited the aranidipine-induced ABCA1 protein expression, whereas genistein (a tyrosine kinase inhibitor), or AG490 (a JAK-2 inhibitor) had no effects. Neither of these inhibitors suppressed the efonidipine-induced ABCA1 protein expression. Intracellular cAMP levels were elevated only by aranidipine, but not by efonidipine. In conclusion, aranidipine and efonidipine have the ability to induce ABCA1 protein by distinct mechanisms; protein kinase A is involved in the aranidipine-induced ABCA1 upregulation. This non-class effect of calcium channel blockers may potentially offer beneficial action in the treatment of hypertensive subjects with atherosclerosis.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcium Channel Blockers; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dihydropyridines; Humans; Hypertension; Janus Kinase 2; Nitrophenols; Organophosphorus Compounds; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; RNA, Messenger

Long-acting dihydropyridine calcium channel blockades have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events in humans and animals. To investigate the vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (20 mg/kg/ day) and manidipine (10 mg/kg/day) were administered by gavage to N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats for 2 weeks. L-NAME treatment (0.7 mg/ml in drinking water) significantly decreased the gene and protein expression of endothelial nitric oxide synthase (eNOS) and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in the aorta, as determined by Western blotting and reverse transcription (RT)-polymerase chain reaction (PCR). Amlodipine and manidipine normalized the decreased expression of eNOS gene and protein, and attenuated the overexpression of NADPH oxidase, VCAM-1, and MCP-1 mRNA. Furthermore, amlodipine and manidipine prevented the L-NAME-induced increase in the angiotensin converting enzyme (ACE) mRNA content, thereby restoring control levels in the aorta. On the other hand, hydralazine treatment had no such effect in L-NAME treated rats. Furthermore, the increased expression of manganese superoxide dismutase (Mn-SOD) by L-NAME treatment was not affected by amlodipine, manidipine, or hydralazine. We concluded that the direct anti-inflammatory and antioxidative effects of calcium channel blockades in the aorta of rats with L-NAME-induced hypertension were not likely to have been mediated by the blood pressure-lowering action of these agents, but instead these beneficial effects appear to have been mediated by an augmentation of eNOS expression and by the inhibition of the expression of ACE.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Aorta; Blood Pressure; Body Weight; Calcium Channel Blockers; Chemokine CCL2; Dihydropyridines; Enzyme Inhibitors; Gene Expression Regulation; Heart Rate; Hypertension; Inflammation; Male; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Nitrobenzenes; Oxidative Stress; Peptidyl-Dipeptidase A; Piperazines; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Vascular Cell Adhesion Molecule-1

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Nitrobenzenes; Piperazines; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Europe; Follow-Up Studies; Humans; Hypertension; Randomized Controlled Trials as Topic; Stroke; Survival Rate

Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors.. The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors.. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration.. Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups.. Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.

Topics: Administration, Sublingual; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Case-Control Studies; Cyclooxygenase Inhibitors; Dihydropyridines; Enalapril; Endothelium, Vascular; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Nitrobenzenes; Nitroglycerin; Piperazines; Platelet Aggregation Inhibitors; Regional Blood Flow; Vasodilator Agents

Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers.

Topics: Adult; Aged; Animals; Biological Availability; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Male; Maximum Tolerated Dose; Middle Aged; Nitrobenzenes; Piperazines; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome

To explore the effect of benidipine, a calcium channel blocker on the plasma levels of calcitonin gene-related peptide (CGRP) in patients with essential hypertension.. 58 outpatients with essential hypertension were treated with benidipine 4-8 mg/day for 8 weeks. 38 matched healthy people were taken as controls. The plasma levels of CGRP were measured in all patients before and after treatment and in controls.. The plasma levels of CGRP in hypertensive patients were significantly lower than those in controls (minimal value: 1.28 vs 39.95 ng/L; maximal value: 43.72 vs 155.59 ng/L; P <0.001). In hypertensive patients, treatment with benidipine for 2 weeks markedly decreased systolic pressure and diastolic pressure and its depressor effect was maintained during the study (P <0.05). At 8 week after treatment, the plasma levels of CGRP in hypertensive patients were significantly increased compared with those before treatment (minimal value: 2.84 vs 1.28 ng/L; maximal value: 123.99 vs 43.72 ng/L; P <0.001).. Benidipine, a calcium channel blocker significantly decreases blood pressure concomitantly with an increase in the plasma levels of CGRP in the patients with essential hypertension.

Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiac Output, Low; Creatinine; Dihydropyridines; Drug Combinations; Echocardiography; Gene Expression; Hypertension; Imidazoles; Myocardium; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred Dahl; Survival Analysis; Tetrazoles; Thiazepines

Dihydropyridine Ca antagonists cause reflex tachycardia related to their hypotensive effects. Efonidipine hydrochloride has inhibitory effects on T-type Ca channels, even as it inhibits reflex tachycardia. In the present study, the influence of efonidipine hydrochloride on heart rate and autonomic nervous function was investigated. Using an electrocardiogram and a tonometric blood pressure measurement, autonomic nervous activity was evaluated using spectral analysis of heart rate/systolic blood pressure variability. Three protocols were used: (1) a single dose of efonidipine hydrochloride was administered orally to healthy subjects with resting heart rate values of 75 beats/min or more (high-HR group) and to healthy subjects with resting heart rate values less than 75 beats/min (low-HR group); (2) efonidipine hydrochloride was newly administered to untreated patients with essential hypertension, and autonomic nervous activity was investigated after a 4-week treatment period; and (3) patients with high heart rate values (>/=75 beats/min) who had been treated with a dihydropyridine L-type Ca channel inhibitor for 1 month or more were switched to efonidipine hydrochloride and any changes in autonomic nervous activity were investigated. In all protocols, administration of efonidipine hydrochloride decreased the heart rate in patients with a high heart rate, reduced sympathetic nervous activity, and enhanced parasympathetic nervous activity. In addition, myocardial scintigraphy with (123)I-metaiodobenzylguanidine showed significant improvement in the washout rate and H/M ratio of patients who were switched from other dihydropyridine Ca antagonists to efonidipine hydrochloride. Efonidipine hydrochloride inhibits increases in heart rate and has effects on the autonomic nervous system. It may be useful for treating hypertension and angina pectoris, and may also have a cardiac protective function.

Topics: 3-Iodobenzylguanidine; Adult; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Electrocardiography; Female; Heart; Heart Rate; Hemodynamics; Humans; Hypertension; Iodine Radioisotopes; Male; Nitrophenols; Organophosphorus Compounds; Radionuclide Imaging; Spectrum Analysis; Sympathetic Nervous System; Tachycardia; Treatment Outcome

Topics: Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Delayed-Action Preparations; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension

Effects of treatment with equi-hypotensive doses of first-, second-, and third-generation dihydropyridine-type Ca2+ channel blockers on hypertension-dependent left ventricle hypertrophy and coronary vascular changes were assessed in spontaneously hypertensive rats (SHRs) by quantitative microanatomic techniques. Male SHRs were treated for 12 weeks with equi-hypotensive doses of nifedipine, isradipine, manidipine, amlodipine, and lercanidipine. Untreated age-matched normotensive Wistar-Kyoto rats were used as a reference group. Compounds investigated decreased to a similar extent systolic pressure in SHRs. Increased cardiocyte size (hypertrophy), development of necrosis and fibrosis areas, and increased thickness of coronary arteries with luminal narrowing were observed in control SHRs. Pharmacologic treatment countered hypertension-dependent left ventricle and coronary artery changes in SHRs. Manidipine, amlodipine, and lercanidipine displayed a similar activity, whereas nifedipine and isradipine were less potent. These findings support observations that antihypertensive treatment counters hypertension-related left ventricle and coronary changes. The observation of a different effect of Ca2+ antagonists tested suggests the possibility of a more favorable cardiac profile exerted by some dihydropyridines. The evaluation of specific properties of dihydropyridines on hypertensive end-organ damage may contribute to better choices depending on clinical situations.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Hypertension; Hypertrophy, Left Ventricular; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The influence of treatment with the dihydropyridine-type Ca2+ antagonist lercanidipine on heart and coronary microanatomic changes was investigated in spontaneously hypertensive rats, Cohen-diabetic rats, and Cohen-Rosenthal diabetic hypertensive rats. At 12 weeks of age, animals were left untreated (control groups) or were treated for 8 weeks with an oral dose of 3 mg/kg per day of lercanidipine. Wistar-Kyoto rats were used as a normotensive reference group. In spontaneously hypertensive rats and diabetic hypertensive rats, systolic blood pressure was higher in comparison with Wistar-Kyoto rats. Augmented pressure values were decreased by lercanidipine treatment. Systolic blood pressure was slightly higher in Cohen-diabetic rats than in Wistar-Kyoto rats, and this increase was countered by treatment with lercanidipine. In spontaneously hypertensive rats, diabetic rats, and diabetic hypertensive rats, the thickness of left ventricle and cardiocyte area were increased. Focal connective tissue areas and diffuse accumulation of connective tissue were observed in the left ventricle of spontaneously hypertensive and Cohen-diabetic rats, respectively. Pharmacological treatment countered left ventricle thickening and restored cardiocyte area values in subendocardium. An increased thickness of tunica media accompanied by luminal narrowing was found in coronary artery branches of control spontaneously hypertensive and diabetic hypertensive rats. Treatment with lercanidipine countered vascular changes primarily in small-sized coronary arteries. These results indicate that hypertensive, diabetic, and diabetic hypertensive rats undergo cardiac hypertrophy and vascular changes affecting small-sized coronary arteries. Treatment with lercanidipine countered hypertension-related cardiac and coronary changes, suggesting that this dihydropyridine-type Ca2+ antagonist may improve heart and coronary structure in diabetes associated with hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Coronary Vessels; Diabetes Mellitus, Type 2; Dihydropyridines; Heart; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

A 73-year-old hypertensive, non-diabetic woman without obvious renal dysfunction had frequently been hyperkalemic over four years after receiving antihypertensive drugs including the calcium channel blocker (CCB) benidipine. One week after all medications were accidentally discontinued, the serum potassium level returned to normal. After we obtained the informed consent of the patient, benidipine alone was administered again for over two weeks and hyperkalemia developed once more. This previously uncommon side effect of hyperkalemia induced by benidipine is not very serious but it is apt to be overlooked. Since CCBs are now widely prescribed, the development of hyperkalemia should be considered.

Topics: Aged; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hyperkalemia; Hypertension; Risk Assessment; Severity of Illness Index

Topics: Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension

We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine, the angiotensin II type 1 receptor blocker (ARB) candesartan, and the combination of these drugs on blood pressure and kidney and vascular function in rats with salt-induced hypertension. Dahl salt-sensitive (DS) rats were fed with a high-salt (8% NaCl) diet from 7 weeks of age. Benidipine (1, 3 mg/kg), candesartan (1, 3 mg/kg), benidipine (3 mg/kg) combined with candesartan (3 mg/kg), or vehicle was administered orally after the start of the feeding. Relaxant responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) were measured to examine the vascular function. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by glomerular sclerosis and an increase in urinary albumin excretion. Relaxant responses to acetylcholine and sodium nitroprusside were impaired in superior mesenteric arterial rings from the hypertensive DS rats. SBP was significantly lower in all of the drug-treated groups than in the vehicle-treated group. The antihypertensive effect of benidipine at 3 mg/kg was more potent than that of candesartan at 3 mg/kg. The albuminuria was significantly decreased in the benidipine and benidipine plus candesartan groups, but not in the candesartan group. The level of SBP in the benidipine plus candesartan group was lower than that by either drug alone. In addition, benidipine alone and benidipine plus candesartan inhibited the glomerular sclerosis and the impairment of relaxant responses in the arteries. These results demonstrate that benidipine is more effective than candesartan in lowering blood pressure and preventing the impairment of kidney and vascular function in salt-sensitive hypertensive rats. In addition, the results suggest that combination therapy with benidipine and an ARB decreases blood pressure more effectively than either drug alone and may be useful for the treatment of hypertension.

Topics: Albuminuria; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Hypertension; Kidney; Male; Mesenteric Artery, Superior; Rats; Rats, Inbred Dahl; Tetrazoles; Vasodilation; Vasodilator Agents

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Nitrendipine

The treatment of hypertension in dialysis patients is prevalent and poorly characterized. beta-Blockers and calcium channel blockers (CCBs) have been associated with reduced all-cause and cardiovascular mortality. This study describes the treatment of hypertension and assesses the association between mortality and class of antihypertensive medication among a cohort of dialysis patients.. The US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study Wave II cohort was analyzed. A total of 2,877 patients initiating hemodialysis or peritoneal dialysis in 1996 or 1997 and treated with antihypertensives were included in this analysis. Vital status was followed until November 2000.. Calcium channel blockers were prescribed to 70.3% of patients. Only 31.5% and 27.0% of patients with cardiovascular disease were prescribed angiotensin-converting enzyme inhibitors and beta-blockers, respectively. Mono-, double-, triple-, and more than triple-therapy were reported in 48.0%, 36.1%, 13.2%, and 2.7% of the cohort, respectively. In multivariable, fully adjusted models, no individual class of antihypertensives was associated with changes in all-cause mortality. In all patients, nondihydropyridine CCBs (non-DHP CCBs) were associated with a reduced risk of cardiovascular death (hazard ratio, 0.78; 95% confidence interval, 0.62 to 0.97) and among end-stage renal disease patients with preexisting cardiovascular disease, dihydropyridine CCBs (DHP CCBs) and non-DHP CCBs were associated with reduced risk of all-cause and cardiovascular mortality.. Calcium channel blocker use is widespread among hypertensive dialysis patients. Antihypertensive prescription patterns suggest a lack of consensus regarding treatment of hypertension. Multivariable analysis of associations between antihypertensive class and mortality reveals results of uncertain clinical significance. Hypertension treatment trials in dialysis patients should be performed to appropriately inform treatment decisions.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Cause of Death; Cohort Studies; Comorbidity; Diabetes Mellitus; Dihydropyridines; Drug Prescriptions; Drug Utilization; Female; Humans; Hypertension; Kidney Failure, Chronic; Logistic Models; Lung Diseases; Male; Middle Aged; Peritoneal Dialysis; Prospective Studies; Renal Dialysis

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and calcium antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone or in combination with azelnidipine (AZN) in a spontaneously hypertensive rat (SHR) remnant kidney model of chronic renal failure. Male 5/6-nephrectomized SHR/Izumo rats were randomly assigned to receive vehicle (control group), TMP (TMP group; 10 mg x kg(-1) x day(-1)), AZN (AZN group; 3 mg x kg(-1) x day(-1)), or both (TMP+AZN group) orally for 12 weeks. Systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) were measured every 2 weeks. At the end of the experiment, serum creatinine (Scr), heart weight (HW), and blood urea nitrogen (BUN) levels were measured and the remnant kidneys were examined to determine the index of glomerular sclerosis (IGS). SBP and UalbV in the control group increased progressively throughout the experimental period. TMP, AZN, and TMP+AZN blocked the development of hypertension. TMP+AZN did not enhance the antihypertensive effects of either TMP or AZN used singly. TMP, AZN, and TMP+AZN all significantly decreased the UalbV, Scr, BUN, and HW/body weight (BW) ratio. The level of UalbV and the HW/BW ratio in the TMP+AZN group were significantly lower than those in the TMP and AZN groups, and the level of Scr in the TMP+AZN group was significantly lower than that in the TMP group. TMP, AZN, and TMP+AZN all significantly protected against an increase in the IGS. The IGS in the TMP+AZN group was significantly lower than that in the TMP and AZN groups. These results indicate that both TMP and AZN have antihypertensive and renoprotective effects in this model. They also suggest that simultaneous administration of TMP and AZN provides greater renoprotective effects than TMP alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Hypertension; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Protective Agents; Rats; Rats, Inbred SHR; Thiazepines

The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Cilazapril; Dihydropyridines; Drug Therapy, Combination; Heart Failure; Hypertension; Kidney; Natriuretic Peptide, Brain; Organ Size; Rats; Receptor, Angiotensin, Type 1; RNA, Messenger; Survival Rate; Systole; Transforming Growth Factor beta

Topics: Adolescent; Adult; Amlodipine; Calcium Channel Blockers; Child; Child, Preschool; Cyclosporine; Dihydropyridines; Edema; Female; Flushing; Humans; Hypertension; Infant; Male

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Atenolol; Blood Pressure; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Treatment Outcome

Topics: Animals; Ankle; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney

It is well known that severe gingival overgrowth (GO) is induced in patients taking certain calcium channel blockers (CCB) for the treatment of hypertension, angina pectoris, and other diseases. No case has been reported to date of severe GO induced by manidipine hydrochloride (manidipine), a second generation CCB. This case report describes severe GO induced by manidipine in a female patient (43 years old) with hypertension and Sjögren syndrome (SS). The patient was administered manidipine and carteolol hydrochloride (carteolol) as antihypertensive drugs, together with bromhexine hydrochloride for the treatment of SS.. At the initial periodontal examination, probing depth (PD, average 4.83 mm), plaque control record (PCR, 84.3%), bleeding on probing (BOP, 100%), and gingival overgrowth index (GOI, 2.42) were assessed. The patient received periodontal treatment without cessation or replacement of the causative drug. Initial treatment included oral hygiene and scaling and root planing (SRP) under local anesthesia. As corrective therapy, remaining pockets were surgically removed and fixed bridges placed to establish proper occlusion.. Obvious reductions in PCR (10.0%), PD (1.93 mm), GOI (0.02), and BOP (4.7%), together with a disappearance of GO, were obtained. Salivary secretion was increased after the periodontal and prosthetic treatments. Histological features were similar to those of nifedipine-induced GO.. This case indicated that manidipine may act as a potent inducer of severe GO, and that conventional periodontal treatments without a major change of the causative drugs can yield satisfactory clinical responses.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Dental Plaque Index; Dental Scaling; Denture, Partial, Fixed; Dihydropyridines; Female; Gingival Overgrowth; Gingivectomy; Humans; Hypertension; Nitrobenzenes; Oral Hygiene; Periodontal Index; Periodontal Pocket; Piperazines; Root Planing; Saliva; Sjogren's Syndrome

Topics: Arteriosclerosis; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Randomized Controlled Trials as Topic; Tunica Intima; Tunica Media

Microalbuminuria (30-300 mg 24 h-1) is recognized to be independently associated with renal and cardiovascular risk. Antihypertensives may lower microalbuminuria. We questioned whether the use of different antihypertensive drug classes in general practice influences microalbuminuria as related to blood pressure in nondiabetic subjects.. To study this, we used the data from 6836 subjects of an on-going population based study, focused on the meaning of microalbuminuria (PREVEND). Odds ratios, adjusted for age, sex, blood pressure, cholesterol level, smoking and the use of other antihypertensive or cardiovascular drugs, were calculated to determine the association of drug groups with microalbuminuria. Influence of antihypertensives on the relation between blood pressure and (log) urinary albumin excretion was determined by comparing linear regression lines.. Microalbuminuria was significantly associated with the use of dihydropyridine calcium channel blockers (odds ratio: 1.76 [1.22-2.54]), but not with other antihypertensive drug groups. The linear regression line of the relation between blood pressure and (log) urinary albumin excretion was significantly steeper (P = 0.0047) for users of calcium channel blockers, but not for other antihypertensives, compared with subjects using no antihypertensive. Users of a combination of renin-angiotensin system inhibitors and diuretics however, had a less steep regression line (P = 0.037).. This study suggests a disadvantageous effect of dihydropyridine calcium channel blockers on microalbuminuria compared with other antihypertensive drug groups. Thus, if microalbuminuria is causally related to an increased risk for cardiovascular morbidity and mortality, dihydropyridines do not seem to be agents of choice to lower blood pressure. Furthermore, the combination of renin-angiotensin system inhibition and diuretics seems to act synergistically.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Cohort Studies; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Prevalence

We tested the hypothesis that long-term application of a Ca2+ channel blocker would ameliorate the functional and morphological deterioration of the cerebral arteries during hypertension. Male spontaneously hypertensive rats (SHR) were fed a standard rat chow, containing a low (3 mg/kg/day) or high dose (6 mg/kg/day) of benidipine, a Ca2+ channel blocker, for 2 months. Using a cranial window, we examined responses of the basilar artery to acetylcholine, sodium nitroprusside, (-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (Y-26763; an opener of ATP-sensitive K+ channels), and (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632; an inhibitor of Rho-associated kinase). Mean arterial pressure of the control group was 193+/-5 mm Hg (mean+/-S.E.M.), while that of the low-dose benidipine group was 183+/-5 mm Hg and that of the high-dose group was 159+/-4 mm Hg. Dilator responses of the basilar artery to acetylcholine and Y-26763 were impaired in SHR compared with those of normotensive Wistar-Kyoto (WKY) rats and treatment with benidipine enhanced the vasodilator responses to acetylcholine and Y-26763 in SHR. Y-27632-induced dilatation of the basilar artery was enhanced in SHR compared to that in WKY rats and the vasodilatation was reduced by benidipine in SHR. Sodium nitroprusside caused similar dilatation of the basilar artery, in both WKY rats and the SHR control group, and benidipine did not affect nitroprusside-induced dilatation of the artery in SHR. The wall of the basilar artery was significantly thicker in SHR than in WKY rats and benidipine treatment reduced the wall thickness of the artery in SHR. These findings suggest that chronic treatment with a Ca2+ channel blocker may enhance the dilator capacity and reduce contractility of the basilar artery during hypertension. Benidipine may also ameliorate the morphological changes of the basilar artery in hypertension.

Topics: Acetylcholine; Amides; Animals; Basilar Artery; Body Weight; Calcium Channel Blockers; Cerebral Arteries; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Male; Muscle Relaxants, Central; Nitric Oxide Donors; Nitroprusside; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Vasodilation; Vasodilator Agents

The long-term effects of benidipine on left ventricular hypertrophy (LVH) and collagen metabolism were examined in patients with essential hypertension.. Forty patients with untreated essential hypertension were given benidipine at a dose of 6 mg a day. Routine echocardiographic parameters, serum concentrations of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed before and 12 months after treatment with benidipine. Patients were classified according to left ventricular mass index (LVMI) into three groups: severe LVH (LVMI > or = 159), mild LVH (159 > LVMI > or = 125) and no LVH (LVMI < 125).. Serum levels of free TIMP-1 to MMP-1 ratio were significantly higher in patients with severe LVH than in the other two groups before treatment. There was a significant positive correlation between the free TIMP-1 to MMP-1 ratio and LVMI in all study subjects (r = 0.51, p < 0.01). Twelve months after treatment, percentage changes of the LVMI and free TIMP-1 to MMP-1 ratio were significantly larger in the patients with severe LVH (-27% and -54%) than with mild LVH (-12% and -23%) or no LVH (-4% and -11%), respectively. Changes in the systolic blood pressure but not changes in the free TIMP-1 to MMP-1 ratio correlated with changes in the LVMI in patients with mild LVH (r = 0.78, p < 0.01). Changes in the free TIMP-1 to MMP-1 ratio but not changes in the systolic blood pressure correlated with changes in the LVMI in patients with severe LVH (r = 0.69, p < 0.01).. Long-term administration of benidipine reduced left ventricular mass and normalized systemic collagen type I degradation abnormalities in essential hypertensive patients with severe but not mild LVH.

Topics: Administration, Oral; Aged; Calcium Channel Blockers; Collagen; Dihydropyridines; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Matrix Metalloproteinase 1; Middle Aged; Tissue Inhibitor of Metalloproteinase-1

The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.

Topics: Albuminuria; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Genetic Predisposition to Disease; Hypertension; Kidney Glomerulus; Male; Phosphorylation; Proteinuria; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Platelet-Derived Growth Factor beta; Stroke; Tyrosine

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta. Stroke-prone rats were exposed to a salt-rich diet (1% NaCl in drinking water) with or without lacidipine (1 mg. kg(-1). d(-1)) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (P<0.05); (2) markedly reduced nitric oxide (NO)-mediated, endothelium-dependent relaxation of aortic rings to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-N-acetylpenicillamine, an NO donor (P<0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (P<0.01) without affecting endothelial NO synthase mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproendothelin-1 gene, and increased endothelial NO synthase mRNA levels in aortic tissue (P<0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke.

Topics: Animals; Antihypertensive Agents; Aorta; Calcium Channel Blockers; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Gene Expression; Hypertension; Nitric Oxide Synthase; Rats; Rats, Inbred SHR; Sodium, Dietary; Vasodilation

Hypertension is the main cause of stroke that represents the second most common cause of death in the industrialized world and a leading cause of inability of the elderly. Lowering blood pressure reduces cerebrovascular morbidity and mortality, but it is still controversial if blood pressure should be lowered in elderly individuals with concomitant cerebrovascular disease. The present study has analyzed comparatively the effect of treatment with the dihydropyridine-type Ca(2+) channel blockers lercanidipine, manidipine and nimodipine and with the non dihydropyridine-type vasodilator hydralazine on hypertension-dependent cerebrovascular changes in spontaneously hypertensive rats (SHR). Analysis included medium and small sized pial arteries and intracerebral arteries of frontal cortex, hippocampus, striatum, and cerebellum. In control SHR, systolic pressure (SBP) values were significantly higher in comparison with WKY rats. Pharmacological treatment significantly decreased SBP values, with nimodipine reducing only moderately SBP. In control SHR, thickening of arterial wall accompanied by luminal narrowing with consequent increase of the wall-to-lumen ratio occurred both in pial and intracerebral arteries. Dihydropyridine-type Ca(2+) antagonists and to a lesser extent hydralazine countered these morphological alterations. Lercanidipine displayed a particular activity on small sized intraparenchymal brain arteries, where it was more effective than other compounds tested. This activity of lercanidipine on small-sized intracerebral arteries might represent an interesting property for the treatment of hypertensive brain damage with concomitant ischemia.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Hydralazine; Hypertension; Male; Nimodipine; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Wistar

Endothelin and growth factors such as transforming growth factor (TGF)-beta1 are important regulators of the cardiovascular system. Although increased production of endothelin-1 (ET-1) and TGF-beta1 have been reported in left ventricular hypertrophy, the detailed roles of these substances in hypertrophy remain to be determined. To elucidate the cardioprotective effects of calcium antagonists in left ventricular hypertrophy, we evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on preproET-1, ET(A) receptor (ETAR) and TGF-beta1 expression in the left ventricle and evaluated the relations between these effects and myocardial remodeling in Dahl salt-sensitive hypertensive (DS) rats fed a high-salt diet. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e., at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy (DSLVH) was noted. Benidipine (DSLVH-B group, n= 8; 1 mg/kg/day, subdepressor dose) or vehicle (DSLVH-V group, n=8) was administered to 6-week-old DS rats for 5 weeks, or until the onset of DSLVH stage, and age-matched (11-week-old) Dahl salt-resistant rats fed the same diet served as a control group (DR-C, n=8). Blood pressure was similar between the DSLVH-B and DSLVH-V groups, but was significantly lower in DR-C rats. The preproET-1, ETAR and TGF-beta1 expressions in the left ventricle were significantly higher in DSLVH-V than in DR-C rats, and significantly lower in DSLVH-B than in DSLVH-V. Benidipine administration resulted in significant improvements in the wall-to-lumen ratio and perivascular fibrosis in the coronary arterioles, and in myocardial fibrosis. We therefore concluded that myocardial remodeling and left ventricular hypertrophy in DS hypertensive rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of benidipine, and that this amelioration was partly due to decreases in the expression of ET-1 and TGF-beta1 in the left ventricle.

Topics: Animals; Blood Pressure; Blotting, Western; Calcium Channel Blockers; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression; Heart Ventricles; Hypertension; Male; Myocardium; Organ Size; Protein Precursors; Rats; Rats, Inbred Dahl; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

We evaluated the effects of cilnidipine, a long-acting Ca(2+) channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ETA receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ETA receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ETA receptor expression in the left ventricle.

Topics: Animals; Blotting, Western; Body Weight; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Organ Size; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Humans; Hypertension

Topics: Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Treatment Outcome

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Humans; Hypertension; Randomized Controlled Trials as Topic

The main objective of this study was to evaluate well-being and physical activity of 248 hypertensive patients, including 177 females, who had previously been included in the Latin-American Study on Lacidipine in Hypertension (LASTLHY).. This open study was carried out in 12 clinical centers in Argentina, Brazil, Colombia, Mexico and Venezuela, to compare, over a period of 16 weeks, the antihypertensive action of a fixed-dose, once daily of 4 mg lacidipine administered orally to 120 patients and 30 mg nifedipine GITS (Gastro-Intestinal Therapeutic System) administered to 128 patients, aged between 40 and 65 years. All patients had mild to moderate hypertension and treatment was begun at the end of a one-week placebo run-in period (end of week -1). Well-being and physical activity were assessed by means of single questionnaire, which reflected the physical and cultural diversities amongst the clinical centers and patients. The questionnaire included 13 multiple-choice and 8 contingent open questions. The score of each question was multiplied by a coefficient related to the importance of each question to the patient (semipersonalization); the coefficient was obtained from cultural and socioeconomic data collected at the time of enrollment. The semipersonalization was carried out by a blind psychological study with respect to the medication and had a high repeatability in the assignment of personalized coefficients to the score of each question. The scores of each question were added to obtain an overall well-being and activity scoring. The possible theoretical range for the overall scoring in this study was 10 - 124.. See Table 1.. The study revealed that the administration of calcium channel blockers such as lacidipine and nifedipine GITS, and lacidipine in particular, produced low incidence of side effects, and lacidipine in particular induced significant improvement in the quality of life.

Topics: Activities of Daily Living; Administration, Oral; Adult; Aged; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Exercise; Female; Health Surveys; Humans; Hypertension; Male; Middle Aged; Nifedipine; Psychometrics; Quality of Life

The relationship between oxidative stress, lipoproteins, cardiovascular risk factors and vascular disease progression has recently attracted fresh attention due to the possibility of measuring free radicals (FRs). The aim of this study was to evaluate blood plasma variations in oxygen FRs in hypertensive patients treated with lercanidipine, a drug acting on blood pressure and microcirculation.. Twenty-two patients with moderate hypertension (M:F=12:10; age=52) and no vascular disease (evaluated by high-resolution ultrasound) were treated for 24 weeks with Lercanidipine (10 mg/day or 20 mg/day if BP values did not decrease at least 15 percent after four weeks of treatment). BP was measured at inclusion and after 4, 8, 12 and 24 weeks of treatment. FRs measurements (using the D-Roms test) were made at inclusion, at the 8th, 12th and 24th week.. All patients completed the treatment which was well tolerated and without side effects. Systolic and diastolic BP decreased after 8, 12 (p<0.05) and 24 weeks (at 24 weeks systolic pressure was decreased by 21.1 percent, and diastolic by 11.1 percent; p<0.02). FRs levels progressively decreased from 541 Carr Units (SD 54) at inclusion to 411 (SD 56) at eight weeks (p<0.05), to 401 (SD 35) (p<0.05) at 12 weeks and finally to 398 (SD 33), (p<0.02) at 24 weeks of treatment (72.2 percent of the initial value).. The possibility of measuring FRs in vivo with a simple, inexpensive test allows the identification of subjects with a high level of oxidative stress, and the monitoring of the effects of treatments. Lercanidipine, acting on blood pressure, on the microcirculation and decreasing oxidative stress and Frs plasma levels may effectively decrease the rate of progression of cardiovascular diseases offering the advantage of an increased level of protection in patients with high levels of oxidative stress.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Electrocardiography; Female; Free Radicals; Heart Rate; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Oxygen; Time Factors

Hypertension is the main risk factor for cerebrovascular disease including vascular dementia and control of blood pressure might protect from lesions causing cognitive impairment. The influence of anti-hypertensive treatment on hypertensive brain damage was assessed in spontaneously hypertensive rats (SHR). SHR and age-matched normotensive Wistar Kyoto (WKY) rats were treated from the 14-26th week of age with the dihydropyridine-type Ca2+ channel blockers lercanidipine, manidipine and nimodipine and as a reference with the non-dihydropyridine-type vasodilator hydralazine. Volume of brain areas, number of nerve cells and glial fibrillary-acidic protein (GFAP)-immunoreactive astrocytes and neurofilament 200 kDa immunoreactivity were investigated in frontal and occipital cortex and in hippocampus. In control SHR, systolic blood pressure (SBP) was significantly higher in comparison with WKY rats. Compounds tested decreased to a similar extent SBP values in SHR, with the exception of nimodipine that caused a smaller reduction of SBP compared with other compounds. Decreased volume and number of nerve cells and loss of neurofilament protein immunoreactivity were observed in SHR. GFAP-immunoreactive astrocytes increased in number (hyperplasia) and in size (hypertrophy) in the frontal and occipital cortex of control SHR, and only in number in the hippocampus. Anti-hypertensive treatment countered in part microanatomical changes occurring in SHR. Drugs investigated with the exception of nimodipine exerted an equi-hypotensive effect. In spite of this the best protection was exerted by lercanidipine and, to a lesser extent, by nimodipine. Compared with nimodipine, lercanidipine induced a more effective decrease of SBP. This may represent an advantage in the treatment of hypertension with risk of brain damage.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain; Brain Injuries; Calcium Channel Blockers; Dihydropyridines; Frontal Lobe; Hippocampus; Hypertension; Male; Nimodipine; Nitrobenzenes; Occipital Lobe; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Calcium Channel Blockers; Dihydropyridines; Edema; Erythema; Exanthema; Humans; Hyperpigmentation; Hypertension; Male; Middle Aged; Nifedipine

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Approval; Germany; Humans; Hypertension

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure. 3. The lowest dosages of both drugs had non-significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt-loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor-beta1. 4. The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine. 5. Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. 6. We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

Topics: Actins; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Collagen Type I; Dihydropyridines; Dose-Response Relationship, Drug; Fibrosis; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypertrophy; Kidney; Male; Muscle, Skeletal; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

The release of endothelial relaxing factors has been suggested to be important in modulating the inhibition of the contractile activity caused by the increase in extracellular Ca(2+) concentration in arterial tissue. Since the hypertensive process in spontaneously hypertensive rats (SHR) could be associated with the release of endothelial vasoconstrictor factors (mainly cyclooxygenase-dependent endoperoxides and endothelin-1), we studied the contractile responses to KCl, methoxamine and phenylephrine in different aorta ring preparations (intact, de-endothelized, 10(-5) M indomethacin-treated, 10(-6) M CGS-27830 [meso-1,4-dihydro-5-methoxycarbonyl-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid anhydride]-treated, and treated simultaneously with 10(-5) M indomethacin and 10(-6) M CGS-27830) from SHR and normotensive Wistar Kyoto rats (WKY), at various Ca(2+) concentrations (1.25, 2.5, 5 and 10 mM) in the organ bath. In endothelium-intact preparations from WKY rats we observed a decrease in KCl, methoxamine and phenylephrine contractions with high Ca(2+) concentrations (5 and 10 mM), but in the endothelium-intact preparations from SHR, the increase in extracellular Ca(2+) concentration potentiated methoxamine contractions and caused no change in KCl and phenylephrine contractions. When the endothelium was disrupted in preparations from both WKY rats and SHR, we observed a decrease in KCl and methoxamine contractions with high Ca(2+) concentrations. The decrease in phenylephrine contractions caused by high Ca(2+) concentrations was clear in de-endothelized preparations from WKY rats but slight in de-endothelized preparations from SHR. In all indomethacin- and CGS-27830-treated preparations, and also in the preparations from WKY rats and SHR treated with both drugs, we observed a decrease in all the contractile responses with increased Ca(2+) concentration. Besides, there was a clear reduction in the responses of the alpha(1)-adrenoceptor agonists in the WKY and SHR preparations treated with both drugs. The results indicate that, in the hypertensive arteries, endothelium-derived contractile factors can counteract the relaxing effect of high extracellular Ca(2+) concentrations.

Topics: Animals; Aorta, Thoracic; Calcium; Dihydropyridines; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypertension; In Vitro Techniques; Indomethacin; Male; Methoxamine; Phenylephrine; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction; Vasoconstrictor Agents

Topics: Aged; Antihypertensive Agents; Arteriosclerosis; Atenolol; Calcium Channel Blockers; Carotid Stenosis; Dihydropyridines; Double-Blind Method; Humans; Hypertension; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors; Ultrasonography, Doppler, Color

In the present study, in order to elucidate the role of dihydropyridine (DHP)-sensitive calcium (Ca) channels in the regulation of neurotransmitter release in hypertension, we examined the effects of the DHP-sensitive Ca channel blocker nicardipine on norepinephrine (NE) release in blood vessels of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The stimulation-evoked pressor responses and NE release were significantly greater in the mesenteric arteries of SHR than in the mesenteric arteries of WKY rats. Nicardipine significantly inhibited the stimulation-evoked NE release as well as vasoconstrictor responses in the mesenteric arteries to a greater extent in SHR than in WKY rats. These results demonstrated that nicardipine markedly reduced the stimulation-evoked NE release in blood vessels of SHR, which might suggest that the DHP-sensitive Ca channels could be involved, at least in part, in the regulation of NE release in hypertension.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Male; Mesenteric Arteries; Nicardipine; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Sixteen adult hypertensive patients of both sexes, classified as having 'medium' (total lipid profile 240-300 mg dl(-1)), and 'high' (total lipid profile >300 mg dl(-1)) baseline values, underwent serum lipids, lipoproteins and plasma fibrinolytic parameters evaluations after 3 months of cilnidipine treatment. Patients with 'medium baseline values' did not have any change in lipids, lipoproteins and fibrinolytic parameters while patients with 'high baseline values' had beneficial lipid and lipoprotein changes [decreases in total cholesterol (TC), triglycerides (TG), very low density lipoprotein-cholesterol (VLDLC) and increases in high density lipoprotein-cholesterol (HDLC), and HDLC/TC ratio] after cilnidipine treatment. Changes in lipids were negatively associated with fibrinolysis for the patients with 'medium baseline values' and positively associated in patients with 'high baseline values' after cilnidipine treatment. Reduction in blood pressure was related to fibrinolysis and reduced risk of coronary heart disease in the patients with 'high baseline values' after cilnidipine therapy. These results show that during cilnidipine treatment, the baseline lipid profile levels of the patients may influence the lipid altering actions as well as the interaction between lipids and fibrinolysis.

Topics: Aged; Calcium Channel Blockers; Dihydropyridines; Female; Fibrinolysis; Humans; Hypertension; Lipids; Lipoproteins; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator

Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. Calcium antagonists have been shown to improve endothelial function in hypertensive patients. Here we report that pranidipine, one of the latest long-acting calcium antagonists in the dihydropyridine group, enhances the actions of NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP accumulation in vascular smooth muscle cells cocultured with ECs, whereas amlodipine and nifedipine had no significant effects. In addition, pranidipine also suppressed basal and thrombin-stimulated endothelin-1 production from ECs. Pranidipine also enhanced cGMP accumulation in rat aortic segments with endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had no effect in the presence of N(G)-monomethyl-L-arginine, an inhibitor of NO synthesis. Pranidipine did not affect the basal expression of endothelial NO synthase in ECs. However, pranidipine upregulated the activity of superoxide dismutase in ECs. These findings suggest that pranidipine enhances NO action through inhibition of superoxide-induced NO decomposition in the vessel wall. Thus, pranidipine may be useful in the treatment of impaired endothelial function in patients with hypertension.

Topics: Amlodipine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Cells, Cultured; Coculture Techniques; Cyclic GMP; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Male; Muscle, Smooth, Vascular; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Superoxide Dismutase

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

Recently, there have been some reports indicating that calcium antagonists induce a reflex increase in sympathetic activity, triggering cardiac events, especially in coronary artery disease (CAD) patients. In this study, we assessed heart rate (HR) variability (HRV) using power spectral analysis of the 24-h RR interval in 25 hypertensive outpatients with CAD treated with nifedipine. We compared blood pressure (BP), HR, and HRV variation in the same patients substituting benidipine (long-acting) for nifedipine (intermediate-acting). There were no significant differences in 24-h, daytime, nighttime, and morning BP between the nifedipine phase and the benidipine phase. HRV parameters (LF: low frequency power, HF: high frequency power, LF/HF ratio) also showed no significant differences in 24-h, daytime, nighttime, and morning LF, HF, and LF/HF ratio between the nifedipine phase and the benidipine phase. Blood pressure, HR, and HRV parameters, except the LF component from 2 to 4 h after nifedipine administration (the most effective duration), showed no differences compared to before administration. The LF component after the nifedipine administration was lower than before administration. In conclusion, in hypertensive patients with CAD, whose BP levels were well-controlled by twice-daily use of intermediate-acting nifedipine, switching from nifedipine to a long-acting calcium antagonist, benidipine, maintained well-controlled BP levels to a similar degree, but it may not have additional benefit in sympatho-vagal balance.

Topics: Autonomic Nervous System; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Coronary Disease; Delayed-Action Preparations; Dihydropyridines; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Treatment Outcome

Topics: Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension

Topics: Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension

We previously reported a highly sensitive chemiluminescence high-performance liquid chromatographic method to determine catecholamines in plasma. In this study, we employed this method to measure the cardiac function and plasma norepinephrine (NE) concentration in conscious rats. Benidipine, 1,4-dihydropyridine calcium antagonist (4 mg/kg), and beta-blocker (propranolol, 30 mg/kg) were administered orally to conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats, and blood pressure, heart rate and plasma NE levels were measured. Plasma NE concentration was used as an index of sympathetic nervous system activity in conscious rats. The basal plasma NE levels were significantly higher in SHRs than in WKY rats (P<0.05), indicating the activity of the basal sympathetic nervous system in SHRs was elevated. The sensitivity of the baroreflex-mediated sympathetic nervous response was reduced in SHRs as compared to that in WKY rats. The concomitant administration of benidipine and a beta-blocker decreased heart rate without affecting the baroreflex-mediated sympathetic nervous response, indicating that propranolol might suppress mainly the cardiac beta-adrenoceptor. The present study suggested the high activity of the basal sympathetic nervous system and the reduced response of the baroreflex-mediated sympathetic nervous system in SHRs compared to WKY rats in the conscious condition.

Topics: Animals; Blood Pressure; Dihydropyridines; Heart Rate; Hypertension; Male; Norepinephrine; Propranolol; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System

Benidipine hydrochloride has been developed as an antagonist for the L-type calcium channel and is used as an anti-hypertensive drug. But recent studies have reported that benidipine exerts not only antihypertensive actions but also anti-hypertrophic actions on cardiac muscles. Endothelin-1 (ET-1), one of the endogenous pathological humoral factors of cardiovascular diseases such as hypertension and heart failure, has a strong vasoconstrictive action and could induce hypertension and cardiac hypertrophy. So, it is a matter of great interest whether or not calcium antagonists can decrease cardiac hypertrophy induced by the pathological vasoactive substances such as ET-1. Thus, the present study was designed to elucidate the effects of benidipine on cardiac hypertrophy, and particularly on the interaction with ET-1, using neonatal rat cardiac myocytes (MCs) and cardiac non-myocytes (NMCs) culture systems. Cells were cultured with or without ET-1, benidipine, and nifedipine and the effects of calcium antagonists on cardiac hypertrophy were evaluated by incorporations of [3H]-leucine and [3H]-thymidine into MCs and/or NMCs. Benidipine significantly decreased the ET-1-induced increase of [3H]-leucine and [3H]-thymidine uptake into cardiac MCs and NMCs, whereas no significant effects of nifedipine were observed. Furthermore, benidipine (10(-8)M) attenuated ET-1 secretions from NMCs. In summary, benidipine at least partially decreased the cardiac hypertrophy induced by paracrine mechanisms through its attenuation of ET-1 secretions from NMCs. Benidipine could thus be a useful tool for preventing cardiac hypertrophy due to hypertension.

Topics: Animals; Animals, Newborn; Calcium Channel Blockers; Cardiomegaly; Cells, Cultured; Dihydropyridines; Endothelin-1; Hypertension; Leucine; Muscle Fibers, Skeletal; Myocardium; Nifedipine; Rats; Rats, Wistar; Thymidine; Tritium

Sixteen Japanese patients of both sexes aged 46-78 years with essential hypertension were studied at the cardiac clinic of the Department of Cardiology, Shizuoka General Hospital, Shizuoka, Japan. Serum lipids, lipoproteins, plasma fibrinolytic parameters, renin and noradrenaline were determined before and after 3 months of cilnidipine treatment. Systolic and diastolic blood pressures and heart rate were reduced while renin and noradrenaline levels remained unchanged after cilnidipine treatment. Total cholesterol and tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complex were reduced. Changes in the other lipids, lipoproteins and fibrinolytic parameters were not significant after cilnidipine treatment. A negative correlation was found between low-density lipoprotein cholesterol and t-PA antigen levels after cilnidipine treatment. In conclusion, cilnidipine was effective for the treatment of hypertension and did not cause reflex tachycardia in Japanese patients. Cilnidipine treatment produced a beneficial lipid profile (decrease in total cholesterol), but did not show a consistent effect on fibrinolytic parameters in hypertensive patients. The metabolic interaction between beneficial lipid changes and fibrinolysis will be of value to better our understanding of the antiatherogenic effects of cilnidipine treatment in hypertensive patients.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Lipids; Lipoproteins; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator

The effect of long-term treatment with dihydropyridine calcium antagonists (amlodipine, pranidipine, nicardipine) on the periarterial nerve function was investigated in the perfused mesenteric vascular bed isolated from spontaneously hypertensive rat (SHR). Male 8-week-old SHR received amlodipine (0.01% and 0.02%) and nicardipine (0.1%) in drinking water and pranidipine (0.0035% and 0.035%) in rat chow for 7 weeks. Mean blood pressure in SHR was significantly lowered by long-term treatment with each calcium antagonist. In mesenteric vascular preparations treated with each calcium antagonist, vasoconstriction induced by periarterial nerve stimulation (PNS; 4, 8 and 12 Hz) was significantly smaller than that in non-treated SHR. The PNS (8 Hz)-evoked norepinephrine (NE) overflow in the perfusate was significantly decreased by amlodipine and pranidipine treatment, whereas nicardipine-treatment significantly enhanced the overflow of NE. In preparations with active tone produced by methoxamine and guanethidine, the PNS-induced vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves was not affected by these drugs. These results suggest that long-term treatment of SHR with long-acting drugs, amlodipine and pranidipine, reduces sympathetic adrenergic nerve function but calcium antagonists have no effect on CGRPergic nerve function.

Topics: Amlodipine; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Interactions; Hypertension; Male; Mesenteric Arteries; Nervous System; Nicardipine; Norepinephrine; Rats; Rats, Inbred SHR; Vasoconstrictor Agents; Vasodilator Agents

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Collagen; Creatinine; Dietary Carbohydrates; Dihydropyridines; Dose-Response Relationship, Drug; Fibronectins; Fructose; Heart Diseases; Hypertension; Insulin; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Myocardium; Nitric Oxide; Organ Size; Rats; Rats, Inbred WKY; Triglycerides

Topics: Adult; Calcium Channel Blockers; Chylous Ascites; Dihydropyridines; Female; Humans; Hypertension; Lupus Erythematosus, Systemic; Nitrobenzenes; Piperazines

We investigated the protective effect of chronic treatment with AE0047, a dihydropyridine-type calcium channel blocker, on vascular endothelial abnormalities in stroke-prone spontaneously hypertensive rats (SHRSP). Ten-week repeated antihypertensive treatment with AE0047 inhibited blood pressure elevation and improved endothelium-dependent relaxation in response to acetylcholine in aorta isolated from SHRSP. Furthermore, the abnormal production of prostaglandin I2 and thromboxane A2 in the aorta was normalized to a level equivalent to that in Wistar-Kyoto rats. These results suggest that chronic treatment with AE0047 exerts protective effects against endothelial abnormalities associated with the development of hypertension.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Endothelium, Vascular; Heart Rate; Hypertension; Male; Prostaglandins; Protective Agents; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction; Vasodilation

The stroke-prone spontaneously hypertensive rat (SHRSP) is a strain with high incidence of cerebrovascular accidents increased by salt-rich diet and decreased by calcium-antagonist treatment. In the SHRSP rat basilar artery the authors have previously shown reduced contractility and altered structure including regions of smooth muscle cell (SMC) disorganization. The aims of this study have been to analyze (1) the morphology of these abnormal regions, (2) the structural modifications responsible for the reduced function, and (3) the effect of salt and calcium-antagonist treatment on vascular structure and function. Wistar Kyoto and SHRSP rats, untreated or treated from week 8 through 14 with 1% NaCl or 1% NaCl + 1 mg x kg(-1) x d(-1) lacidipine, were used. Function was studied with wire myography. Structure was analyzed in fixed intact arteries with confocal microscopy. Basilar arteries from SHRSP rat showed (1) reduced contractility, (2) discrete foci of SMC disarray with altered proportion of adventitia to SMC, and (3) decreased SMC and increased adventitial cell number. Arteries from salt-loaded SHRSP rats showed a higher degree of SMC disarray and further reduction in contractility. Lacidipine treatment of salt-loaded rats significantly improved structure and function. These data suggest that vascular remodeling can provide an explanation for the observed reduction in vascular contractility of SHRSP rat basilar arteries and might show light on the effects of salt load and calcium-channel blockers in life span and the incidence of cerebrovascular accidents in SHRSP rats.

Topics: Animals; Antihypertensive Agents; Basilar Artery; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Genetic Predisposition to Disease; Hypertension; Microscopy, Confocal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary

Normotensive rats fed a high fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine could be effective not only in preventing, but also in inducing the regression of hypertension, and renal and cardiac damage in rats fed HFD.. Thirty male Wistar-Kyoto (WKY) rats received HFD for 1 month; thereafter, five rats were sacrificed (Group 1) and the other 25 rats were divided into three groups: Group 2 (five rats) received HFD plus placebo, Group 3 (10 rats) HFD plus lacidipine 3 mg/kg per day, and Group 4 (10 rats) HFD plus hydralazine 10 mg/kg per day. At the end of the second month all animals were sacrificed. Kidneys and hearts were immediately removed. Renal deposits of collagen I, collagen IV, fibronectin and cardiac deposits of collagen III were assessed by means of immunohistochemistry.. In the rats receiving HFD plus placebo, blood pressure was increased after the first and the second month of diet. This increase was reversed by lacidipine and hydralazine but, although both drugs normalized blood pressure, only lacidipine was effective in reducing renal and cardiac damage.. These data suggest that lacidipine is effective in reversing hypertension and reducing target organ damage induced by HFD. Moreover, this protective effect on target organs appears to be not simply a consequence of blood pressure reduction, but seems to be connected to the type of hypotensive drug administered.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Collagen; Diet; Dihydropyridines; Fibronectins; Fructose; Hypertension; Kidney Glomerulus; Male; Myocardium; Rats; Rats, Inbred WKY

The effects of a novel calcium antagonist, benidipine hydrochloride, on responses of platelets to mental stress were evaluated in nine patients with essential hypertension. Before and 12 weeks after the monotherapy with benidipine (2-4 mg/day), platelet aggregability and plasma beta-thromboglobulin were determined during rest and after a 10-min arithmetic stress. Before the treatment, arithmetic stress significantly increased platelet aggregability in response to adenosine diphosphate (ADP) and plasma beta-thromboglobulin level. Blood pressure, pulse rate, and plasma catecholamines also increased during arithmetic stress. The treatment with benidipine did not affect resting values of platelet functions, but attenuated significantly stress-induced alterations in primary aggregation to 1.0 microM ADP (34 +/- 4% to 40 +/- 3% before treatment vs. 32 +/- 2% to 34 +/- 3% after benidipine), ADP threshold for biphasic aggregation (2.2 +/- 0.4 to 1.8 +/- 0.3 microM before treatment vs. 2.2 +/- 0.3 to 2.2 +/- 0.4 microM after benidipine) and plasma beta-thromboglobulin level (74 +/- 16 to 104 +/- 15 ng/ml before treatment vs. 60 +/- 10 to 52 +/- 8 ng/ml after benidipine; p < 0.05 for Stress x Treatment interactions in all values). The pretreatment elevations in blood pressure and sympathetic activity with stress were not modified by benidipine treatment. In conclusion, the monotherapy with benidipine did not affect platelet function during the resting condition, but significantly suppressed the platelet activation induced by arithmetic stress in patients with essential hypertension.

Topics: Adult; Aged; beta-Thromboglobulin; Blood Platelets; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Stress, Psychological

The aim of this study was to investigate the therapeutic effectiveness of lacidipine in stroke-prone spontaneously hypertensive rat (SHRSP) with cerebrovascular lesions in comparison with nicardipine. SHRSP were fed 1% saline as drinking water. After the onset of stroke, saline was replaced with water and each drug was administered orally once a day for 3 weeks. In the drug-untreated group, recurrence of stroke was repeated, deterioration and amelioration of neurological deficits (ND) were repeated, and histological examination and measurement of regional blood flow (rBF) using nonradioactive colored microspheres performed at the end of treatment revealed severe damages and significantly decreased rBF in brain and kidney, respectively. In kidney, not only lacidipine (1 mg/kg) but also nicardipine (30 mg/kg) decreased vascular lesions and ameliorated low-rBF significantly. Both drugs also inhibited the recurrence of stroke completely even at a low dose that did not ameliorate severe hypertension. Neuronal damages and ND in each lacidipine-treated group were ameliorated significantly, whereas those in each nicardipine-treated group were slightly improved. Lacidipine at 1 mg/kg alone ameliorated the cerebral low-rBF significantly even at 24 hr after administration. These results suggest that a long-lasting improvement of low-rBF after stroke may be useful in the treatment of SHRSP with cerebrovascular lesions.

Topics: Animals; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Cerebellum; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Kidney; Male; Nicardipine; Rats; Rats, Inbred SHR; Recurrence; Regional Blood Flow; Renal Artery; Systole

We investigated the effects of benidipine hydrochloride (benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.

Topics: Amlodipine; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Heart Rate; Hypertension; Male; Nifedipine; Norepinephrine; Rats; Rats, Inbred SHR

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Lercanidipine (Zanidip) is a new calcium antagonist belonging to the dihydropyridine family suitable for the first-line treatment of hypertension. This molecule displays a high specificity and selectivity for vascular smooth muscle cells and has, in spite of a short plasma half-life, a long duration of action due to its liposolubility. The usual and once a day dose to treat high blood pressure of any grade is 10 mg, which if needed could be increased to 20 mg once a day. It has a gradual onset of effect on blood pressure, thus leading to a good tolerability and hopefully a better compliance in the treatment of hypertension. No adaptation of the dose is needed in older patients or in patients with moderate renal or liver impairment.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Half-Life; Humans; Hypertension

Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship

The purpose of this study was to investigate the renal effects of aranidipine, a novel calcium channel blocker of the dihydropyridine type, and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats (SHRs). When infused into the renal artery in anesthetized dogs, aranidipine (0.03 microg/kg/min) induced sustained increases in urine volume and urinary excretion of sodium and of potassium. This effect was greater than that elicited by nifedipine (0.1 microg/kg/min). The aranidipine metabolite, M-1 (0.1 microg/kg/min), also caused diuresis and natriuresis almost equal to those of nifedipine. The stop-flow experiment using the anesthetized dog showed that intrarenal infusion of aranidipine (0.03 microg/kg/min), as well as nifedipine (0.1 microg/kg/min), produced natriuresis at the distal tubular site rather than at the proximal site. Aranidipine (0.3, 1, and 3 mg/kg), when administered orally, dose-dependently increased urine volume and urinary excretion of electrolytes in conscious saline-loaded SHRs. M-1 (10 mg/kg, p.o.) also showed diuretic and natriuretic effects comparable to those of nifedipine (10 mg/kg) in SHRs. In addition, after repeated oral administration of aranidipine for 7 days, short-term tolerance was not found for its diuretic and natriuretic effects in SHRs. These results suggest that, apart from antihypertensive efficiency, aranidipine may offer a therapeutic advantage by producing diuresis and natriuresis in hypertensive patients. The metabolite of aranidipine may contribute, in part, to the diuretic, natriuretic, and antihypertensive effects of aranidipine.

Topics: Administration, Oral; Animals; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Diuretics; Dogs; Dose-Response Relationship, Drug; Drug Tolerance; Glomerular Filtration Rate; Hemodynamics; Hypertension; Infusions, Intra-Arterial; Kidney; Male; Nifedipine; Organ Size; p-Aminohippuric Acid; Potassium; Rats; Rats, Inbred SHR; Renal Circulation; Sodium; Time Factors; Trichlormethiazide; Urine

1. We investigated the renal protective effect of efonidipine hydrochloride (efonidipine, NZ-105) in STZ-induced spontaneously hypertensive rats (SHRs, 8 weeks of age). Diabetic SHRs were treated with 15 mg/kg/day of efonidipine for 12 weeks. 2. The dosage of efonidipine was chosen after preliminary studies demonstrated that it showed mild antihypertensive action (within 20% decrease of systemic blood pressure). 3. In the diabetic SHRs, the excretion of urinary albumin was increased (1.78 +/- 0.09 mg/day) at 4 weeks and reached 4.41 +/- 0.12 mg/day at 12 weeks. The levels of urinary albumin in the diabetic SHRs after treatment with efonidipine were significantly less than those in the diabetic SHRs at 8 and 12 weeks (P < 0.01). 4. Levels of creatinine clearance were decreased in the diabetic SHRs after treatment with efonidipine. 5. In light microscopy, the ratio of glomerular tuft to Bowman's areas was significantly decreased compared with those in the diabetic SHRs (P < 0.05). 6. These findings suggest that efonidipine inhibits the development of albuminuria and glomerular enlargement in the streptozotocin-induced diabetic SHRs and may become a useful antihypertensive drug with a renal protective effect.

Topics: Albuminuria; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Streptozocin

We investigated the effects of a calcium antagonist, efonidipine, which was reported to dilate not only afferent arterioles but also efferent alterioles, on progression of renal failure in salt-loaded partially nephrectomized spontaneously hypertensive rats (SHR). Forty-four SHR's with 5 of 6 nephrectomy were divided into four groups: group 1 as control (n=20); group 2, efonidipine-treated (n=8); group 3, enalapril-treated (n=8); and group 4, nifedipine-treated (n=8). The rats were given these drugs and a high-salt diet (5% NaCl) for 8 weeks. During the experiment, systolic blood pressure (SBP) and daily urinary protein excretion were measured every 2 weeks. At the end of the study, serum creatinine was determined, and renal tissues were obtained for light microscopic examination. SBP was markedly reduced by 8-week antihypertensive treatment. (control, 267+/-7 mmHg; efonidipine, 181+/-7 mmHg; enalapril, 200+/-12 mmHg; nifedipine, 184+/-6 mmHg). Glomerular sclerosis developed markedly in the control group, but was partially prevented in all treated groups. Similarly, urinary protein excretion (UPE) was suppressed by efonidipine (180+/-16 mg/day) and enalapril (186+/-16 mg/day vs. 301+/-28 mg/day for control). In contrast, nifedipine failed to prevent the increase in urinary protein excretion (258+/-22 mg/day). In conclusion, efonidipine attenuates SBP increase and ameliorates glomerular injury as well as nifedipine and enalapril. Furthermore, beneficial effects of efonidipine, but not nifedipine, on proteinuria suggest that different mechanisms mediate the improvement of proteinuria; one possible mechanism could be efferent arteriolar dilation, not reported in nifedipine.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Hypertension; Kidney; Male; Nephrectomy; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Systole

Calcium antagonists (CaAs) of the dihydropyridine type are widely used in the treatment of hypertension and other cardiovascular disorders. They are markedly effective in lowering elevated arterial pressure, and are well tolerated. Data from long-term intervention trials are emerging, which also show a beneficial effect on cardiovascular morbidity with the use of CaAs in the treatment of hypertension. The first such evidence was from the Shanghai Trial of Nifedipine in the Elderly (STONE), and, in February 1997, the Systolic Hypertension in Europe (Syst-Eur) trial was stopped prematurely because the active treatment, based on a CaA, was found to be significantly better than placebo in preventing cardiovascular disease. In addition, ongoing trials with dihydropyridine CaAs (e.g. the Hypertension Optimal Treatment [HOT] Study and the Swedish Trial in Old Patients with Hypertension-2 [STOP-2]) are close to termination. Final results are not yet available, but cardiovascular morbidity appears to be lower than expected in the HOT Study, suggesting a positive effect of the CaA-based therapeutic regimen. Claims of increased morbidity and mortality from the use of CaAs have been clearly refuted by the thorough scrutiny of all available data by a committee formed by the World Health Organization and the International Society of Hypertension. It can therefore be concluded that the available evidence on the use of dihydropyridine CaAs shows that these agents have a beneficial effect on morbidity. Whether this effect of CaAs is greater than that obtained with conventional therapies, such as diuretics and/or beta-blockers, will be shown by the STOP-2 Study, which is expected to be completed in 1998.

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans; Hypertension; Morbidity

Topics: Dihydropyridines; Humans; Hypertension

In malignant SHRSP (M-SHRSP), a strain of stroke-prone spontaneously hypertensive rat (SHRSP), blood pressure rapidly increases during early development (5 weeks of age). Changes in the gastric vascular architecture of WKY and M-SHRSP were investigated using scanning electron microscope images of vascular casts focusing on the morphological differences in the three-dimensional arrangement of the capillaries. In WKY, the density, tortuosity and regular honeycomb formation of the gastric vessels were studied. The casts of gastric capillaries were 5.9 +/- 0.6 microns in diameter with a regular smooth surface. In M-SHRSP, the overall vascular pattern was not regularly organized at 6.3 +/- 1.9 microns in capillary diameter. Administration of the Ca antagonist, manidipine, to 11-week-old M-SHRSP with hypertensive vascular lesions decreased blood pressure and prolonged the rats' survival. With the administration of manidipine, vascular morphological patterns became similar to that of normotensive WKY, and the mean capillary diameter was 8.4 +/- 1.2 microns. It seems that manidipine plays a role in the recovery of normal vascular structure, as well as decreasing blood pressure.

Topics: Animals; Antihypertensive Agents; Arteries; Blood Pressure; Calcium Channel Blockers; Capillaries; Dihydropyridines; Hypertension; Male; Microscopy, Electron, Scanning; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stomach

The study was designed to investigate whether the acute antihypertensive effects of calcium channel blockers are affected by calcium supplementation in patients with essential hypertension. The antihypertensive effects of calcium channel blockers (oral manidipine or intravenous nicardipine) were studied before and during calcium supplementation (1200 mg/day for 8 weeks) in 30 hospitalized patients with essential hypertension. The averages of systolic and diastolic blood pressure during a 24-hour period were not decreased by calcium supplementation. The acute antihypertensive effects of the calcium channel blockers nicardipine (0.25, 0.5, 1.5, 2.0 micrograms/kg/min, intravenous infusion) or manidipine (20 mg, once a day, orally) were not enhanced by calcium supplementation. Thus, calcium channel blockers can be safely combined with calcium supplementation in terms of blood pressure.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium, Dietary; Dihydropyridines; Drug Evaluation; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Nicardipine; Nitrobenzenes; Piperazines

To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension.. We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP).. SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis.. Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene.. Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Dihydropyridines; Follow-Up Studies; Gene Expression; Hypertension; Male; Myosin Heavy Chains; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride; Ventricular Remodeling

Effects of benidipine hydrochloride or triple therapy (hydralazine, reserpine, and hydrochlorothiazide) on renal cortical and medullary intrinsic antioxidant enzyme (AOE) activity were evaluated in stroke-prone spontaneously hypertensive rats (SHR-SP) as an animal model for human essential hypertension with cerebral stroke. This study showed a significant decrease of renal intrinsic glutathione peroxidase (GSH-Px) activity in untreated SHR-SP. Renal GSH-Px activity in untreated SHR-SP was significantly lower than that in Wister Kyoto rats (WKY) as a normotensive reference strain. GSH-Px activity in SHR-SP was significantly improved after benidipine hydrochloride therapy. Levels of urinary albumin excretion or creatinine clearance (Ccr) in SHR-SP were also improved after the therapy. Glomerular sclerosis index was slightly improved in SHR-SP treated with benidipine hydrochloride according to light microscopic analysis. It appears that hypertension may influence the renal intrinsic GSH-Px activity, albuminuria, and Ccr in SHR-SP. Thus it is indicated that control of blood pressure may improve the GSH-Px activity in SHR-SP.

Topics: Animals; Antioxidants; Blood Pressure; Calcium Channel Blockers; Catalase; Cerebrovascular Disorders; Creatine; Dihydropyridines; Drug Therapy, Combination; Glutathione Peroxidase; Hydralazine; Hydrochlorothiazide; Hypertension; Kidney; Male; Organ Size; Oxidoreductases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reserpine; Superoxide Dismutase

The regulation of cardiac L-type Ca2- current (Ica) and contraction by dihydropyridine antagonists and beta-adrenergic receptor agonists has been the subject of numerous studies over the last decade. However, little is known on the crosstalk between these two regulatory pathways. For instance, a fundamental question that remains unanswered is: does activation of the beta-adrenergic receptors modify the sensitivity of the myocardium to dihydropyridine agonists? To answer this question, we examined in the present study how activation of the beta-adrenergic receptors modifies the effects of nifedipine on the mechanical and energetic parameters of the isolated perfused rat heart. Activation of the beta-adrenergic receptors was achieved by perfusing the hearts with isoprenaline, a non-selective beta-adrenergic receptor agonist, and could be reduced by atenolol, a beta-adrenergic receptor antagonist. To examine possible alterations during hypertension in the sensitivity of the hearts to the drug, tested, the study was performed in both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive animals (SHR). While 0.1 microM nifedipine reduced left ventricular pressure (LVP) by 36% and 34% in WKY and SHR rats, respectively, under basal conditions, its effects became negligible in both groups of rats after stimulation of the hearts with 0.1 microM isoprenaline. Addition of 1 microM atenolol in the presence of isoprenaline restored the inhibitory effect of nifedipine to control values in both WKY and SHR rats. Additional experiments were performed in isolated ventricular myocytes from WKY rats using the whole-cell patch-clamp technique. The inhibitory effects of 0.1 to 1 microM nifedipine were significantly larger on basal Ica than after the current had been previously elevated by 0.1 microM isoprenaline. Addition of 1 microM atenolol in the presence of isoprenaline partially restored the inhibitory effect of nifedipine on Ica. Our results demonstrate a reduced sensitivity of the heart muscle to nifedipine during activation of beta 1-adrenergic receptors. This effect is partly explained by a reduced inhibitory effect of nifedipine on Ic during activation of cAMP-dependent phosphorylation.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Atenolol; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Dihydropyridines; Heart Ventricles; Hypertension; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Myocardial Reperfusion; Nifedipine; Patch-Clamp Techniques; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta; Sympatholytics; Sympathomimetics; Ventricular Function

To evaluate the modifications of the morphology of mesenteric small resistance vessels in spontaneously hypertensive rats (SHR) induced by lacidipine treatment.. Lacidipine was administered at three different dosages, 20, 10, and 0.3 mg/kg per day. Fifty rats were studied. Nine SHR and 11 Wistar-Kyoto (WKY) rats were not treated. Each lacidipine dose was administered to 10 SHR. The drug and the placebo were administered by gavage from age 4 to age 12 weeks. The blood pressure was measured noninvasively every week. The animals were killed when they were aged 13 weeks, and the relative left ventricular mass (left ventricular weight plus septum weight/body weight) was calculated. Small mesenteric resistance vessels were dissected and mounted on a micromyograph (Mulvany's technique), and morphological parameters of the vessels were studied (media thickness and media: lumen ratio).. The systolic blood pressure of SHR administered 20 and 10 mg/kg lacidipine per day was reduced significantly during the treatment period, whereas that of rats treated with 0.3 mg/kg lacidipine per day did not change. A significant reduction in media: lumen ratio was observed for all three groups of treated rats, including those to which 0.3 mg/kg lacidipine per day had been administered, and no reduction in systolic blood pressure could be detected. The relative left ventricular mass was reduced significantly only in rats to which 20 and 10 mg/kg lacidipine per day had been administered.. A significant reduction in magnitude of vascular structural alternations was observed even in SHR treated with a low, nonhypotensive dose of lacidipine.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Heart Ventricles; Hypertension; Mesenteric Arteries; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Cardiovascular hypertrophy is a common feature of hypertension, but it is not known if this is related only to increased blood pressure or also to non-hemodynamic factors. Indeed, drug treatment of hypertension with hydralazine does reduce blood pressure but not cardiovascular hypertrophy. We used Stroke-prone rats (SHRSP) who are sensitive to salt load in order to better characterize the action of an antihypertensive agent on salt-dependent vascular hypertrophy and change in reactivity of calcium channels. SHRSP were submitted to salt load from 8 to 14 weeks of age with or without lacidipine, a long acting dihydropyridine. We observed that the cardiovascular hypertrophy was attenuated by lacidipine 0.3 mgkg-1 day-1 which did not change high blood pressure. The action of 1 mgkg-1 day-1 was higher on hypertrophy but, in addition, it reduced blood pressure. The salt-related increase in vascular responsiveness to the calcium channel activator Bay K 8644 was blunted by lacidipine treatment in both basilar and mesenteric arteries. By contrast with basilar artery, in mesenteric artery, this increased responsiveness was insensitive to bosentan, an endothelin antagonist but could be related to smooth muscle cell depolarization inhibited by lacidipine treatment. The present results confirm that lacidipine has blood pressure-independent effect on tissue remodeling in hypertension. They show that vascular response to salt is heterogeneous among vessels but is equally sensitive to lacidipine.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hypertension; Rats; Rats, Inbred SHR; Sodium Chloride

The antihypertensive effects of oral or intravenous administration of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj), one kidney-one clip renal hypertensive rats (RHR), deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DHR) and two kidney-one clip renal hypertensive dogs (RHD). AE0047 (1, 3, 10 mg/kg, p.o.) caused a dose-related reduction of systolic blood pressure (SBP) with low reflex tachycardia in SHR/crj and RHR. The effect reached its maximum at 2-4 hr after administration and was sustained for a long time. In DHR, AE0047 (0.3, 1, 3 mg/kg, p.o.) similarly showed the antihypertensive effects at 2-7 hr with no significant changes in heart rates (HR). The doses (ED30) of AE0047 required to decrease SBP by 30% were 2.6, 3.4 and 0.68 mg/kg in SHR/crj, RHR and DHR, respectively. In RHD, and AE0047 capsule (GJ-0956: 4, 8, 16, 32 mg/body, p.o.) produced dose-dependent and long lasting effects with a transient and slight increase in HR. Furthermore, the intravenous administration of AE0047 (10, 30, 100 micrograms/kg) produced the antihypertensive action slowly, reached a plateau 10 min later and then maintained for many hours. In contrast, nitrendipine (3-100 mg/kg, p.o., 3-30 micrograms/kg, i.v.) and nicardipine (1-30 mg/kg, p.o., 3-30 micrograms/kg, i.v.) exhibited a similar potency to AE0047, but these maximal effects were produced at 1-2 hr and 0.5-1 min in the case of oral and intravenous administration, respectively, with a rapid recovery in the above hypertensive rats. These results indicate that AE0047 exhibits an antihypertensive effect with a slow onset and long-lasting profile.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Hypertension, Renal; Injections, Intravenous; Nicardipine; Nitrendipine; Rats; Rats, Inbred SHR

The antihypertensive effects of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long-term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, and AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR

Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.. To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.. Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.. In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Calcium-Transporting ATPases; Captopril; Cardiomyopathy, Hypertrophic; Diastole; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Mice; Mice, Transgenic; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Tetrazoles

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Cyclic GMP; Dihydropyridines; Hemodynamics; Hormones; Hypertension; Kidney; Rats; Rats, Inbred SHR; Renin; Tetrazoles

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of nitrendipine in stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the preventative study, drug administration was started before the appearance of renal injury, such as proteinuria. Treatment for 6 weeks with AE0047 (1 and 3 mg/kg, p.o.) led to a dose-related reduction in systolic blood pressure (SBP). Nitrendipine, at doses of 10 and 30 mg/kg, also lowered SBP to a similar degree to that seen with AE0047 at 1 and 3 mg/kg, respectively. 3. In the vehicle-administered SHRSP group, urinary excretion of protein (Uprotein V) increased progressively from 14 weeks of age for another 6 weeks. AE0047 at both doses maintained Uprotein V within normal levels throughout the experimental period. However, the elevation of Uprotein V was only inhibited in the 30 mg/kg nitrendipine-treated group. Urinary N-acetyl-beta-D-glucosaminide (NAG) activity in the vehicle-treated SHRSP group was elevated. Urinary NAG activity remained at a low level only in AE0047-treated groups. 4. Histopathological examination revealed severe lesions (i.e. fibrinoid necrosis, proliferative vasculitis and glomerular lesions) of the kidney in SHRSP. AE0047 treatment at each dose attenuated the development of renal lesions in SHRSP. In contrast, nitrendipine, at 10 mg/kg, was ineffective against the development of renal lesions. Although nitrendipine at 30 mg/kg suppressed the development of renal lesions, this effect was still weaker than that seen with AE0047 at 1 mg/kg. 5. In the therapeutic study, drugs were administered to 17-week-old SHRSP with moderate renal damage for 10 days. Treatment with AE0047 (1 and 3 mg/kg) produced dose-dependent decreases in Uprotein V. In the nitrendipine-treated group, Uprotein V tended to decrease but the changes were not significant. 6. Histopathological studies revealed that 3 mg/kg AE0047 improved renal lesions, such as fibrinoid necrosis, proliferative vasculitis and glomerular lesions, whereas 30 mg/kg nitrendipine did not. 7. Taken together, the results indicate that AE0047 is capable of preventing proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore, AE0047 improves proteinuria and renal lesions in proteinuria-established SHRSP. Thus, AE0047 may have therapeutic potential in suppressing either the development or the progression of renal diseas

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Chronic hypertension is associated with structural and functional changes in the cerebrovascular bed, which influence cerebral circulation and its autoregulation. We examined whether or not long-term treatment of spontaneously hypertensive rats (SHRs) with the new calcium antagonist AE0047 would reverse structural changes in the cerebral vasculature and normalize the elevated lower blood pressure (BP) limit of the cerebral blood flow (CBF) autoregulation. Treating 6-month-old SHRs with a diet containing either 0.013 or 0.04% AE0047 for 8 weeks reduced BP and, at the higher dose, maintained BP at a level similar to that of age-matched Wistar-Kyoto (WKY) rats. At the end of the treatment period, CBF was measured by using the hydrogen-clearance method, and the lower limit of the autoregulation curve was estimated by repeated CBF measurement with stepwise reduction of BP through bleeding. This limit was significantly higher in untreated SHRs than in WKY rats (111 +/- 8 vs. 60 +/- 8 mm Hg). AE0047 caused a significant and dose-dependent shift in the elevated lower BP limit, which decreased to 83 +/- 9 and 75 +/- 6 mm Hg at the low and high dose, respectively. In perfusion-fixed proximal, intermediate, and distal portions of the middle cerebral artery, media thickness/external diameter (M/ED) ratios were significantly greater in untreated SHRs than in WKY rats. In AE0047-treated animals, M/ED ratios in all portions tended to be reduced halfway between those for untreated SHRs and those for WKY rats, but with no statistical significance. These results suggest that long-term treatment of patients with hypertension with AE0047 will normalize the autoregulatory threshold while preserving CBF and thereby improve tolerance to BP reduction, but the potential to ameliorate structural alterations may be small.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebral Arteries; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Homeostasis; Hypertension; Hypertrophy; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To evaluate the effects of calcium antagonists on sympathetic activity in hypertensive patients, a MEDLINE search for English language articles published between 1975 and May 1996 using the terms calcium antagonists, sympathetic nervous system, and catecholamines was conducted. Clinical studies only reporting the effects of calcium antagonists on blood pressure, heart rate, and plasma norepinephrine (NE) levels in patients with hypertension were included. Data were combined and analyzed according to class of calcium antagonist (dihydropyridine vs nondihydropyridine), their duration of action (short-acting [SA] vs long-acting [LA]), and treatment duration. We identified 63 studies involving 1,252 patients. Acutely after single dosing, SA calcium antagonists decreased mean arterial pressure by 13.7 +/- 1.1% and increased heart rate by 13.7 +/- 1.4% and NE levels by 28.6 +/- 2.5%. Change in NE levels correlated with change in heart rate (r = 0.59, p <0.01) and inversely with change in arterial pressure (r = 0.46, p <0.05) in patients taking dihydropyridine calcium antagonists acutely. With sustained therapy, both classes of SA calcium antagonists increased NE levels. Whereas NE levels remained slightly elevated and heart rate unchanged with LA dihydropyridine calcium antagonists, both heart rate and NE levels decreased with LA nondihydropyridine calcium antagonists. SA calcium antagonists stimulate sympathetic activity when given acutely and over the long term, irrespective of their molecular structure. Sympathetic activation is less pronounced with LA dihydropyridine calcium antagonists and decreases with LA nondihydropyridine calcium antagonists. These data offer a possible pathophysiologic explanation for the increase in morbidity and mortality observed in some studies using SA calcium antagonists.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Diltiazem; Dose-Response Relationship, Drug; Drug Administration Routes; Follow-Up Studies; Heart Rate; Humans; Hypertension; MEDLINE; Middle Aged; Norepinephrine; Retrospective Studies; Time Factors; Verapamil

Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to test whether antihypertensive treatment with the calcium antagonist lacidipine can improve endothelium-dependent vasodilation in essential hypertensive patients. In 12 normotensive subjects (mean age, 47.8+/-8.6 years; blood pressure, 118.6+/-4.2/76.7+/-3.9 mm Hg) and 19 hypertensive patients (mean age, 49.4+/-10.2 years; blood pressure; 153.5+/-13.3/101.3+/-6.4 mm Hg), we studied forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute) and bradykinin (5, 15, and 50 ng/100 mL per minute), two endothelium-dependent vasodilators that act through different receptors and signal transduction pathways, and sodium nitroprusside (1, 2, and 4 microg/100 mL per minute), an endothelium-independent vasodilator. In essential hypertensive patients, vascular reactivity was repeated during prolonged (8 weeks of oral treatment at 6 mg/d) lacidipine administration and 2 weeks after withdrawal of chronic (32-week) treatment. Hypertensive patients showed significantly (P<.01) blunted vasodilation in response to acetylcholine (vascular resistance, 31.5+/-4.9 to 7.6+/-2.4 SU) and bradykinin (vascular resistance, 32.3+/-5.8 to 8.5+/-3.0 SU) compared with control subjects (vascular resistance: acetylcholine, 24.3+/-3.9 to 3.7+/-1.2 SU; bradykinin, 24.7+/-0.4 to 4.1+/-1.3 SU), whereas the response to sodium nitroprusside was similar. After either 8 or 32 weeks of lacidipine treatment, the vasodilation in response to acetylcholine (30.6+/-7.7 to 5.7+/-1.5 and 34.3+/-6.6 to 5.9+/-1.9 SU, respectively) and bradykinin (31.3+/-7.2 to 6.4+/-1.6 and 33.7+/-5.4 to 6.1+/-1.5 SU, respectively), but not to sodium nitroprusside, proved to be significantly (P<.05) increased compared with baseline. In essential hypertensive patients, oral treatment with lacidipine increased forearm vasodilation in response to acetylcholine and bradykinin, suggesting that this drug can improve endothelial function in patients with essential hypertension.

Topics: Acetylcholine; Blood Pressure; Bradykinin; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Female; Forearm; Humans; Hypertension; Male; Middle Aged; Nitroprusside; Reference Values; Regional Blood Flow; Vascular Resistance; Vasodilation

Although benidipine hydrochloride, a hydrophobic and weakly cationic dihydropyridine calcium antagonist, has slow onset but long-lasting anti-hypertensive effect in experimental animals and man, after administration it rapidly disappears from the plasma. Correlation of the plasma concentration with reduction in blood pressure has been investigated in spontaneously hypertensive rats, and concentrations in the mesenteric artery were compared with those in plasma after oral and intravenous administration of benidipine to rats. After oral administration of benidipine to spontaneously hypertensive rats, the fall in blood pressure showed an anti-clock hysteresis phenomenon. Using concomitant analysis, plasma concentrations and anti-hypertensive activity could both be closely fitted to a one-compartment open model and the effect compartment for the pharmacological activity of benidipine could be described by a Hill equation. Concentrations in the mesenteric artery increased rapidly and then declined more slowly than in plasma. The mean residence time of benidipine in the mesenteric artery corresponded closely to the reciprocal of the rate constant for elimination of benidipine from the effect compartment. From these results it seems that benidipine is retained longer in the plasma membrane, an effective site, because of its physicochemical properties, and thus shows a more sustained anti-hypertensive effect than would be predicted from its disposition in plasma.

Topics: Administration, Oral; Animals; Area Under Curve; Calcium Channel Blockers; Dihydropyridines; Half-Life; Hypertension; Injections, Intravenous; Male; Molecular Structure; Rats; Rats, Inbred SHR; Rats, Wistar; Species Specificity; Splanchnic Circulation

Thirty patients with mild to moderate essential hypertension had received four weeks treatment with Lacidipine and serum lipid peroxide (LPO), superoxide dismutase (SOD) and insulin levels were measured before and after treatment. The results showed: (1) there were decreased in SOD activity and increased Lpo content the patients group (P < 0.01); (2) after treated with Lacidipine, the SOD acitvity increased and Lpo content decreased (P < 0.01); (3) Lacidipine had obvious antihypertensive effect with no significant changes in heart rate; (4) Lacidipine had no significant effects on insulin, blood glucose and lipids. The results suggest that lacidipine is a safe and effective antihypertensive agent and can improve the metabolic balances in free radical system.

Topics: Aged; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Insulin; Lipid Peroxides; Male; Middle Aged; Superoxide Dismutase

Biological actions of natriuretic peptide (NP) are determined by the condition of the receptor as well as that of the hormone. Although we previously demonstrated in hypertensive rats the up-regulation of NP-A receptor that mediates various biological actions of NPs, the pathophysiologic significance of NP-C receptor, another subtype thought to be related to clearance of NPs and possibly to biological actions, remains unknown. In the present study, we determined NP-C receptor messenger RNA (mRNA) level in the aortic tissue of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and in cultured aortic smooth muscle cells by ribonuclease protection assay. The aortic NP-C receptor mRNA level in SHR-SP/Izm was significantly lower than that in the control WKY/Izm. Oral administration of an angiotensin (Ang) II receptor (AT1) antagonist, TCV-116, but not a calcium channel blocker, manidipine, reversed the down-regulated NP-C receptor mRNA in SHR-SP/Izm to the level in WKY/Izm, whereas the latter was more potent in decreasing the blood pressure. In cultured aortic smooth muscle cells, the NP-C receptor was the predominant subtype. Ang II decreased the NP-C receptor mRNA level in a dose-dependent manner, but this effect was reversed by an AT1 antagonist, CV-11974. Neither the NP-A nor NP-B receptor mRNA level was altered by Ang II. These findings indicate that vascular NP-C receptor is down- regulated via Ang-II-mediated mechanism in SHR-SP/Izm. The phenomenon, together with the up-regulation of the NP-A receptor, may play an important role in counteracting hypertension by enhancing the action of NPs.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Cells, Cultured; Dihydropyridines; Down-Regulation; Guanylate Cyclase; Hypertension; Male; Muscle, Smooth, Vascular; Natriuretic Peptide, C-Type; Nitrobenzenes; Piperazines; Proteins; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles

The purpose of this study was to compare the regional vascular effect of a novel dihydropyridine derivative, MPC-1304 [(+/-)- methyl-2-oxopropyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylate], with that of nifedipine and manidipine in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The radioactive microsphere technique was used to measure systemic and regional hemodynamic parameters before and 1 hr after p.o. administration of drugs. In SHR, MPC-1304 at a dose of 1 mg/kg reduced the mean blood pressure and systemic vascular resistance and increased cardiac output, as did nifedipine (10 mg/kg) and manidipine (3 mg/kg). MPC-1304, as well as nifedipine, significantly increased the blood flow in pulmonary, gastric, small intestinal and skeletal muscular beds and reduced their vascular resistance. Manidipine increased regional blood flow only in small intestinal and skeletal muscular beds. Only MPC-1304 increased the renal blood flow. In WKY, MPC-1304 and nifedipine reduced the mean blood pressure and systemic vascular resistance to lesser degrees than in SHR. Both drugs significantly increased coronary and skeletal muscular blood flow. MPC-1304 significantly reduced the renal blood flow without altering renal vascular resistance, in striking contrast to its renal effect in SHR. These findings suggest that MPC-1304 possesses a genetic hypertension-dependent renal vasodilating action, unlike nifedipine and manidipine. One possible mechanism for this difference in the effect on renal circulation between SHR and WKY may involve the potent antagonizing effects of MPC-1304 on alpha-2 adrenoceptor-mediated vasoconstriction.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Heart Rate; Hypertension; Male; Nifedipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We studied the effects of long-term antihypertensive treatment on endothelial function in renal resistance arteries from spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) were used as a normotensive reference. Adult SHR were treated with benidipine (a calcium antagonist) or ecarazine (a vasodilator) for 10 weeks; the drugs caused similar reductions in blood pressure. Changes in isometric tension of rings prepared from the third-order branches of the renal arteries were recorded. Endothelium-dependent relaxations induced by acetylcholine in rings contracted with norepinephrine were smaller in SHR than in WKY. The impaired relaxation was improved by benidipine treatment, but ecarazine had no significant effect. In vitro treatment with meclofenamic acid, a cyclooxygenase inhibitor, did not alter the differences in the relaxations. In the presence of meclofenamic acid, N omega-nitro-L-arginine methyl ester slightly reduced the relaxations; the relaxation was smaller in SHR than in WKY and was not affected by benidipine treatment. In rings contracted with 40 mmol/L. KCI, the relaxations induced by acetylcholine in the presence of meclofenamic acid were smaller than those in rings contracted with norepinephrine. The relaxation was smaller in SHR than in WKY but was normalized by benidipine treatment. Thus, acetylcholine relaxes rat renal resistance arteries by releasing nitric oxide and endothelium-derived hyperpolarizing factor from the endothelium, which is impaired in SHR. Long-term benidipine treatment improves the impaired relaxation in SHR by enhancing nitric oxide-mediated relaxation.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Heart Rate; Hypertension; In Vitro Techniques; Male; Muscle Relaxation; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery; Time Factors; Todralazine; Vascular Resistance

The antihypertensive action of lercanidipine (CAS 132866-11-6, Rec 15/2375), a new 1,4-dihydropyridine (1,4-DHP) calcium entry blocker (CEB), was examined in spontaneously hypertensive rats (SHR) and renal hypertensive dogs after acute and repeated administration, in comparison to several reference 1,4-DHPs. In acute experiments in SHR, lercanidipine reduced diastolic blood pressure showing a potency similar to felodipine and 2-3 fold higher than those of nicardipine and nitrendipine, after both intravenous and oral administration. Analysis of the area under the curves of percent reduction of diastolic blood pressure exerted for 3 and 8 h after intravenous and oral administrations, respectively, showed that the duration of the antihypertensive effect of lercanidipine was longer than that of the reference dihydropyridines. After repeated administrations to SHR no tachyphylaxis was observed, as indicated by the marked and persistent decrease in systolic blood pressure elicited by lercanidipine, given orally once a day for 21 days. Moreover, starting from the first week of treatment, the daily basal values of systolic blood pressure of the rats treated with lercanidipine were significantly lower than those of the placebo-treated group. In renal hypertensive dogs, after acute oral administration, lercanidipine was as potent as nitrendipine. After repeated administration, the action of lercanidipine was longer lasting than that of nicardipine and no decrease in the antihypertensive effects was observed. The in vivo studies show that lercanidipine has a potent and long-lasting antihypertensive profile, suggesting that this compound may be used for once-a-day treatment.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Catheterization; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Injections, Intravenous; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Effect of cilnidipine (CIL) on renal function in SHR were evaluated in comparison with that of nifedipine (NIF) and nicardipine (NIC). In conscious SHR, CIL (3 and 10 mg/kg, p.o.) increased the urine volume, urinary Na+ excretion and urinary Na+/K+ ratio. NIF (3 and 10 mg/kg, p.o.) and NIC (10 mg/kg, p.o.) also increased the urine volume and urinary Na+ excretion, but not the urinary Na+/K+ ratio. In anesthetized SHR, CIL (3 and 10 micrograms/kg, i.v.) and NIF (10 micrograms/kg, i.v.) elevated the renal blood flow (RBF), but NIC did not. CIL (10 micrograms/kg, i.v.) also increased the glomerular filtration rate (GFR), whereas NIF did not. Furthermore, we investigated the effect of these three drugs on endothelin (ET)-induced renal dysfunction in anesthetized SHR. ET (2 micrograms/kg, i.v. +30 ng/kg/min) prolongly reduced RBF, GFR and urine volume by 47, 60 and 48%, respectively. CIL (1-10 micrograms/kg, i.v.) improved the decrease in RBF and urine volume induced by ET as well as NIF and NIC. When blood pressure was lowered to the similar extent among the three drugs in ET-treated SHR, CIL increased the RBF and urine volume compared with the others. NIF and NIC did not affect the reduction in GFR by ET, but CIL (0.3-3 micrograms/kg, i.v.) significantly increased GFR. These results suggest that CIL, NIF and NIC all have natriuretic action and no suppressive action on renal function in SHR. In addition, CIL has an ameliorative effect on renal dysfunction in ET-treated SHR, suggesting that CIL might improve renal dysfunction not only in hypertensive patients but also in those with acute renal failure.

Topics: Acute Kidney Injury; Animals; Calcium Channel Blockers; Dihydropyridines; Diuresis; Endothelins; Hypertension; Male; Natriuresis; Nicardipine; Nifedipine; Rats; Rats, Inbred SHR; Renal Circulation

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Dihydropyridines; Humans; Hypertension

Previous studies have shown that antihypertensive drugs attenuate the progression of proteinuria by their treatments from young age, but few have examined their effects on impaired renal function in older age. In the present study the calcium antagonists efonidipine ((+/-)-2-[benzyl (phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3, 2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxyla te hydrochloride ethanol, CAS 111011-76-8, NZ-105) and nicardipine, and an angiotensin-converting enzyme inhibitor, captopril, were examined for their effects on heavy proteinuria in aged spontaneously hypertensive rats (SHR). Efonidipine (20 mg/kg), nicardipine (20 mg/kg) and captopril (30 mg/kg) were orally administered once a day for 4 weeks. The urinary protein excretion (UproE) increased with age (54.9 mg/kg/day at 24 weeks of age to 170.8 mg/kg/day at 36 weeks). The increased UproE was significantly suppressed by daily administration of efonidipine or captopril as compared to that in the non drug treated control group. The UproE in the nicardipine group was maintained at a slightly lower level than in the control. The histological examination showed that the damages of the kidneys were slightly suppressed by efonidipine and captopril. These findings indicate that efonidipine as well as captopril reduce proteinuria in aged SHR and the effect was stronger than that of nicardipine. This beneficial effect of efonidipine on proteinuria suggests its usefulness in antihypertensive therapy.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Captopril; Creatinine; Dihydropyridines; Heart Rate; Hypertension; Kidney; Male; Nicardipine; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Topics: Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Piperazines

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Capillary Permeability; Cardiomegaly; Coloring Agents; Coronary Vessels; Diabetes Mellitus, Experimental; Dihydropyridines; Evans Blue; Hypertension; Hypertrophy; Kidney; Male; Mesenteric Arteries; Ramipril; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Serum Albumin; Tetrazoles; Valine; Valsartan

Fast-absorbed and short-acting dihydropyridines (e.g., nifedipine capsules) cause intermittent hemodynamic effects associated with sympathetic hyperactivity. In contrast, long-acting dihydropyridines, such as nifedipine GITS and amlodipine, provide, during chronic treatment, stable hemodynamic effects with little or no activation of the sympathetic nervous system. This markedly different pattern of hemodynamic changes may explain why the short-acting drugs cause little to no regression of left ventricular hypertrophy, may make angina worse, and may negatively affect cardiac outcome, whereas the long-acting drugs decrease LV mass as anticipated from the fall in blood pressure and, at least in stable coronary artery disease, produce an outcome comparable with beta-blockers. In hypertension, beta-blocker treatment appears to be associated with a short fall in positive outcome, perhaps in part related to increased rates of sudden death. Such an adverse outcome may also be due to sympathetic hyperactivity, possibly during treatment via cardiac alpha-receptors, but also during the common short periods of noncompliance due to actual increased sympathetic responses. For both drug classes, we suggest that long-acting agents be considered, providing therapeutic coverage well beyond the normal dosing interval.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nifedipine; Sympathetic Nervous System

We reviewed the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer. Although a number of prospective, randomly allocated trials under way at present are investigating the effects of treatment with calcium antagonists on cardiovascular morbidity and mortality, these results are not yet available. Therefore, the present approach may be useful. A fuller account of this work has been published in Blood Pressure.. Since 1985,50 phase III-IV trials have been performed to investigate antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment. Only data from trials completed before 1 January 1995 are presented here.. In all, 16590 patients were treated with lacidipine; 13419 in open studies and 3171 in double-blind comparative trials. A total of 1810 patients were given active comparative treatment and 451 were given placebo. Altogether, 5124 person-years of data were obtained.. Numbers of both fatal and non-fatal cardiovascular events were estimated. Efficacy (change in blood pressure and heart rate), adverse event rates and drop-out rates were compared for the different treatment regimens.. In all trials, 2-6 mg lacidipine was effective in lowering blood pressure. In the controlled trials, systolic/diastolic blood pressure fell from 166/102 to 144/85 mmHg and the heart rate fell from 75.6 to 74.1 beats/min. The estimated event rate for a possible myocardial infarction in all studies was 5.46/1000 person-years; the fatal (all-cause) event rate was 5.27/1000 person-years and the estimated fatal cardiovascular event rate was 2.93/1000 person-years. There were 21 malignant events during treatment with lacidipine, for all studies yielding a crude incidence of 4.10/1000 person-years. In patients treated with lacidipine, the age-standardized (according to the world population) incidences were 1.49 (men) and 0.79/1000 person-years (women) compared with 2.74 (men) and 2.09/1000 person-years (women) in the European Community in 1990. The overall incidence in the comparative studies of one or more adverse events included 30.3% for lacidipine, 43.8% for other calcium antagonists, 18.7% for diuretics, 48.7% for beta-receptor blockers, 10.4% for angiotensin converting enzyme inhibitors and 15.7% for placebo. The adverse effects of lacidipine were, as expected, headaches, flushing, pedal oedema and palpitations.. Lacidipine proved to be an effective and well tolerated drug in almost 19000 hypertensive patients. It displayed a reasonable adverse profile that was typical of a calcium antagonist of the dihydropyridine group. This analysis has two obvious limitations: (1) it is a retrospective analysis; and (2) the data were obtained from a large cohort of patients, but most were treated with lacidipine for a relatively short period of time. Although we found a lower fatal event rate than that reported by Collins et al., their meta-analysis included 10 times more person-years than our analysis, and therefore our event rate may be less accurate. Further prospective studies are under way at present to determine whether these drugs can produce reductions in atherosclerosis or in the incidence of cardiovascular disease.

Topics: Adolescent; Adult; Aged; Calcium Channel Blockers; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Dihydropyridines; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.

Topics: Aged; Aged, 80 and over; Antibiotics, Antitubercular; Blood Pressure; Calcium Channel Blockers; Cytochrome P-450 CYP2E1; Dihydropyridines; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Female; Humans; Hypertension; Male; Rifampin; Tuberculosis

To evaluate the relationship between the mechanical properties of the carotid artery wall and baroreflex function after acute reduction of blood pressure with lacidipine in essential hypertension.. After 15 days of placebo washout, the hypertensive patients underwent a single-blind haemodynamic study before and 90 min after administration of 4 mg lacidipine (a dihydropyridine calcium antagonist).. Brachial intra-arterial blood pressure was recorded in eight mild-to-moderate essential hypertensive patients aged 40-53 years (mean +/- SEM 46.8 +/- 4.7 years). The carotid pulse diameter was recorded simultaneously by an echo-tracking technique. The mechanical properties of the carotid artery wall were evaluated by calculating Peterson's incremental elastic modulus (Ep) both as an averaged value of 10 heart cycles with stable blood pressure and was the dynamic correlation, on a beat-to-beat basis, of Ep and the systolic blood pressure during a 20 mmHg increase in blood pressure following a bolus injection of phenylephrine. The elastic properties of the carotid artery were investigated further by determining the correlation between the systolic pressure and systolic diameter, beat by beat, during a ramped increase of blood pressure after phenylephrine administration. The baroreceptor reflex sensitivity was measured simultaneously by the Oxford method and by correlating Ep and the electrocardiographic R-R' interval on a beat-to-beat basis during phenylephrine injections.. After lacidipine administration Peterson's elastic modulus, measured under resting steady-state conditions, was reduced (18.7 +/- 7.4 versus 16.4 +/- 6 x 10(5) dyne/cm2), whereas the baroreflex sensitivity was unchanged (6.6 +/- 3.3 versus 6.3 +/- 0.2 ms/mmHg) and resetting of the baroreflex had occurred. At the same time, the correlations between the systolic blood pressure and Ep and between the systolic blood pressure and carotid systolic diameter over a 20 mmHg increase in blood pressure were unchanged. Moreover, the correlations between the systolic blood pressure and the R-R' interval and between Ep and R-R' interval during the phenylephrine-induced blood pressure increase did not differ statistically.. The results suggest that the resetting of the baroreflex after the acute reduction in blood pressure caused by lacidipine is dissociated from mechanical changes in the carotid artery wall.

Topics: Adult; Carotid Arteries; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Pressoreceptors; Reflex

m-Nifedipine(m-Nif 20 mg.kg-1.d-1 ig) was administered orally to male deoxycorticosterone-acetate-salt(DOCA) hypertensive rats for 9 or 12 wk, the affinity and density of dihydropyridines (DHP) binding sites in the membranes of left ventricle (LV) were investigated. Treatment with m-Nif, whether for prevention (6 wk postoperation) or regression (9 wk postoperation) lowered systolic blood pressure, decreased the weight of left ventricle and the Ca2+ concentration in mitochondria in hypertrophied LV. The density (Bmax) and the total number of DHP binding sites in hypertrophied LV were also markedly decreased (450 +/- 25, 462 +/- 36 fmol.mg-1 vs 836 +/- 47 fmol.mg-1 protein, P < 0.001). There was no difference between groups in constant (KD) values of DHP binding sites. These results indicate that m-Nif prevented and regressed cardiac mass in DOCA hypertensive rats through mechanisms that may be associated with their density of DHP binding sites and control of blood pressure.

Topics: Animals; Binding Sites; Calcium; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Hypertension; Hypertrophy, Left Ventricular; Male; Mitochondria, Heart; Nifedipine; Rats; Rats, Sprague-Dawley

Novel 2-amino-1,4-dihydropyridine derivatives, which contain nitroxy-alkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their pharmaceutical effect was evaluated in spontaneously hypertensive rats. The structure-activity relationships are discussed in terms of potency, onset-rapidity, and duration of antihypertensive activity. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced on either side of an ester chain.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hypertension; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred SHR; Structure-Activity Relationship

Novel 2-amino-1,4-dihydropyridine derivatives I, which contain N,N,-dialkylaminoalkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their antihypertensive effects were evaluated in spontaneously hypertensive rats. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced into either the 3- and/or 5-ester side-chain of the 1,4-dihydropyridine ring. In particular, the compounds containing cyclic amino moieties at the 3-position showed greater potency than those with acyclic amino moieties. Chemical modification studies indicated that the two ester side-chains of 1,4-dihydropyridine at the 3- and 5-position might function in a different manner in relation to the antihypertensive activities. 3-(1-Benzhydrylazetidinited potent and long-lasting antihypertensive effects with gradual onset of action, and is a promising candidate as an antihypertensive drug.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hypertension; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred SHR; Structure-Activity Relationship

The effect of regression of left ventricular hypertrophy was studied in deoxycorticosterone-acetate-salt hypertensive rats (DOCA-salt hypertensive rats) treated with tetrandrine. Treatment with tetrandrine (by gastric intubation, 50 mg/kg per day for 9 weeks) lowered systolic blood pressure, left ventricular weight, Ca2+ of mitochondria, and markedly decreased the density (Bmax) and total number of dihydropyridine binding sites in hypertrophic left ventricle (P < 0.001). There was no difference between groups in dissociation constant (Kd) values of dihydropyridine binding sites. These facts indicate that tetrandrine decreased cardiac mass in DOCA-salt hypertensive rats through mechanisms that may be associated with the density and the total number of dihydropyridine binding sites, Ca2+ and blood pressure control.

Topics: Alkaloids; Animals; Antihypertensive Agents; Benzylisoquinolines; Binding, Competitive; Blood Pressure; Body Weight; Calcium; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Male; Mitochondria, Heart; Organ Size; Radioligand Assay; Random Allocation; Rats; Rats, Sprague-Dawley

Topics: Calcium Channel Blockers; Coronary Disease; Delayed-Action Preparations; Dihydropyridines; Drug Approval; Germany; Humans; Hypertension; Structure-Activity Relationship

The aim of this study was to compare the renal effects of angiotensin converting enzyme (ACE) inhibition with calcium channel blockade in a model combining genetic hypertension with diabetes. Streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). The animals were then randomized to receive no treatment, the ACE inhibitor, perindopril, or the dihydropyridine calcium antagonist lacidipine. Body weight, systolic blood pressure, glycemic control, renal function, and albumin excretion rate (AER) were assessed serially over the 32-week study period. At week 32 the animals were killed and glomerular volume was measured. Both antihypertensive regimens significantly reduced systolic blood pressure in diabetic SHR. There was no significant difference in glycemic control, serum creatinine, or glomerular filtration rate among the three groups at week 32. The ACE inhibitor perindopril significantly reduced AER and glomerular hypertrophy over the 32 weeks, whereas the calcium antagonist lacidipine failed to reduce AER or glomerular hypertrophy. Thus, in contrast to the effects of ACE inhibition, calcium channel blockade with lacidipine, despite significantly reducing blood pressure, failed to reduce renal injury in this model. These results support the hypothesis that antihypertensive regimens may differ in their capacity to protect the diabetic kidney, despite similar effects on systemic blood pressure.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Indoles; Kidney Diseases; Male; Perindopril; Random Allocation; Rats; Rats, Inbred SHR; Renin

The present study was conducted to determine the effects of a calcium antagonist, manidipine, on the outcome of a remnant kidney model of chronic renal failure in Fisher 344 rats. After sham operation or five-sixths nephrectomy (Nx), the rats were assigned to one of the following groups according to the administered amount of drug and were provided a specified diet for 12 weeks: group 1 (sham), diet without manidipine; group 2 (Nx), diet without manidipine; group 3 (Nx), diet with 0.0004% manidipine; group 4 (Nx), diet with 0.002% manidipine; group 5 (Nx), diet with 0.01% manidipine; group 6 (Nx), diet with 0.05% manidipine. All diet contained the same amount of calories (3.44 kcal/gm) and protein (25% casein). Systolic blood pressure and urinary protein excretion in group 2 began to increase at 8 and 4 weeks after ablation, respectively. Manidipine attenuated the increase in blood pressure in groups 4 through 6 but not in group 3. Manidipine-treated groups 3 to 5 had significantly less proteinuria than group 2. Group 6 had significantly more proteinuria than group 2. At 12 weeks after ablation, the kidneys from group 2 showed severe parenchymal damage, which is characteristic of end-stage renal pathology. These changes were ameliorated in groups 3 through 5, while group 6 had significantly more injured renal pathology than group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Kidney; Male; Nephrectomy; Nitrobenzenes; Piperazines; Rats; Rats, Inbred F344

In an attempt to clarify whether glomerular capillary pressure (Pgc) in hypertension can be reduced by a calcium channel blocker (CaB), renal clearance and micropuncture experiments were carried out on male heminephrectomized spontaneously hypertensive rats (SHR; n = 15). Renal circulatory parameters (RBF and GFR) and proximal tubular stop flow pressure (Psf) were measured during the control period, during manual aortic clamping, and after administration of manidipine hydrochloride (MDP, 10 micrograms/kg body weight in bolus). Because Psf only represents Pgc during zero tubular flow, the responsiveness of tubulo-glomerular feedback (TG feedback) was also assessed to obtain the "steady state Pgc", an operating point in each experimental period. Administration of MDP decreased systemic blood pressure (SBP) and renal vascular resistance (RVR), but increased renal blood flow (RBF) significantly. Psf decreased following the administration of MDP (33.65 +/- 1.45 mmHg), reaching a lower level than during aortic clamping (39.93 +/- 2.37 mmHg) or in the control period (50.78 +/- 2.73 mmHg). TG feedback responsiveness was attenuated during clamping, and was incompletely inhibited by MDP, whereas the operating point (29.3 mmHg) was lower than during clamping (32.9 mmHg) or in the control period (41.0 mmHg). The stability of RBF during the alteration of renal perfusion pressure (RPP) was not abolished by MDP. From these results, we suggest that MDP significantly decreases Pgc in the steady state not only by the reduction of RPP, but also by the amelioration of renal microcirculation.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Capillaries; Dihydropyridines; Feedback; Hypertension; Kidney Glomerulus; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation

To test for evidence of stroke-preventive action, we initially examined the effect on salt-loaded stroke-prone spontaneously hypertensive rats of chronic treatment with 4-(4-benzhy-drylpiperazino)phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride (AE0047), a novel calcium antagonist with slow onset and long-lasting hypotensive effect, and compared its efficacy with that of the calcium antagonist nicardipine and the vasodilator hydralazine. We then used radioactive microspheres to study the effects of these three agents on hemodynamic impairment to clarify the mechanism of the test drug's putative preventive action. In a 12-week repeated-administration study using animals of initial age 9 weeks; all vehicle-treated subjects died within 37 days as a result of severe hypertension and stroke, whereas those treated with AE0047, at doses of 1 or 3 mg/kg/day, remained free of stroke and showed no signs of hemorrhage, brain softening or the cerebrovascular lesions typical in this animal model. Significant suppression of the development of hypertension was not noted at the lower of these doses nor at a nicardipine dose of 10 mg/kg/day, which failed to prevent stroke in most cases. A 10-mg/kg/day dose of hydralazine did suppress the development of hypertension but failed to prevent death in half of all cases. In the hemodynamic study, 4-week treatment with AE0047 averted the marked decreases in cardiac output and blood flow in the brain, heart, kidneys and adrenal glands observed in the control group, as well as the accompanying rise in total peripheral resistance before and after stroke.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hemodynamics; Hypertension; Male; Rats; Rats, Inbred SHR

We investigated the effect of cilnidipine on cardiovascular and neuroendocrine responses to acute cold stress in conscious and unrestrained or moderately restrained spontaneously hypertensive rats (SHRs). Acute cold stress significantly increased mean blood pressure without marked change in heart rate. The acute cold stress-induced elevation in blood pressure was almost abolished by 1 mg/kg, p.o. of prazosin. The cold stress also elevated plasma norepinephrine and epinephrine levels. Cilnidipine at 3 mg/kg, p.o. significantly inhibited the pressor response to acute cold stress. Although 3 mg/kg, p.o. of nifedipine, nicardipine or manidipine lowered mean blood pressure to a similar extent as cilnidipine, none of these three drugs affected the pressor response. Cilnidipine also reduced the cold stress-induced increment in plasma norepinephrine but not the epinephrine level. These findings suggest that acute cold stress may induce the elevation in blood pressure due to an enhanced activation of the sympathoadrenal system in SHRs and that cilnidipine may suppress the pressor response by inhibiting the sympathetic nerve activity.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Catecholamines; Cold Temperature; Dihydropyridines; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Nifedipine; Rats; Rats, Inbred SHR; Time Factors

In the present study, we investigated the change in renal hemodynamics induced by a calcium antagonist in young (6 week-old) spontaneously hypertensive rats (SHR), a salt-sensitive hypertensive model. In acute experiments, SHR were fed either a 0.66% or 8.0% NaCl diet for 4 weeks. In acute experiments, manidipine, a calcium antagonist, was administered in a bolus dose of 10 microg/kg. In chronic experiments, SHR were fed a 0.66% NaCl, 0.66% NaCl plus 0.05% manidipine, 8.0% NaCl or 8.0% NaCl plus 0.05% manidipine diet for 4 weeks. Mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal blood flow (RBF) were measured. Salt loading increased MAP in young SHR. Acute administration of manidipine decreased MAP more in salt-loaded SHR compared to non-salt-loaded SHR (-43.3 +/- 3.1 vs. -18.6 +/- 2.1 mmHg: p < 0.01). Moreover, chronic administration of manidipine attenuated the rise in MAP in salt-loaded SHR (155 +/- 3 mmHg vs. 196 +/- 5 mmHg; p < 0.01) and less so in non-salt-loaded SHR (150 +/-2 mmHg vs. 160 +/- 3 mmHg; p < 0.01). Salt loading elevated renal vascular resistance (RVR) but changed neither RBF nor GFR. The acute- and chronic-administration of manidipine increased RBF (Acute; +0.77 +/- 0.22 ml/min/g kidney: p < 0.05, Chronic; 4.32 +/- 0.29 vs. 5.50 +/- 0.90 ml/min/g kidney: p < 0.01) in non-salt-loaded SHR, which was greater in salt-loaded SHR (Acute; +2.19 +/- 0.52 ml/min/g kidney: p 0.05 vs. non-salt-loaded SHR, Chronic; 4.29 +/- 0.53 vs. 6.09 +/- 1.41 ml/min/g kidney: p < 0.01) Manidipine also decreased RVR (Acute; -10.2 +/- 2.2 mmHg/ml/min/g kidney: p < 0.01, Chronic; 35.3 +/- 1.6 vs. 27.3 +/- 4.1 mmHg/ml/min/g kidney: p < 0.01) in non-salt-loaded SHR, which was greater in salt-loaded SHR (Acute; -21.1 +/- 3.1 mmHg/ml/min/g kidney: p < 0.01 vs. non-salt-loaded SHR, Chronic; 44.9 +/- 2.6 vs. 27.6 +/- 4.1 mmHg/ml/min/g kidney: p < 0.01). GFR did not change significantly following manidipine. It is suggested that the antihypertensive effect of the calcium antagonist, manidipine, was greater in salt-loaded SHR and was accompanied by profound amelioration of the abnormal renal hemodynamics.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Hypertension; Kidney; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation; Sodium Chloride, Dietary; Vascular Resistance

MPC-1304, (+/-)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarbonate , is a novel 1,4-dihydropyridine Ca2+ channel antagonist with potent and long-lasting antihypertensive effects. We characterized the ex vivo and in vivo binding properties of MPC-1304 to Ca2+ channel antagonist receptors in myocardial, aortic and brain tissues of spontaneously hypertensive rats (SHR) by radioreceptor assay using [3H](+)-PN 200-110 ([5-methyl-3H](+)-PN 200-110 (4-(2,1,3-benzoxadiazol-4-yl)-1,4,-dihydro-5-methoxycarbonyl-2,6-d imethyl-1,4-dihydro-3-isopropylcarbonylpyridine-5-carboxylic acid methyl ester)). At 1 and 6 h after oral administration of MPC-1304 (10 mg/kg) in SHR, there was significant decrease (48%) in the number of [3H](+)-PN 200-110 binding sites (Bmax) in myocardial membranes compared to control values. The plasma concentration of MPC-1304 in SHR correlated significantly with the occupation by this drug of myocardial Ca2+ channel antagonist receptors. The in vivo specific binding of [3H](+)-PN 200-110 in particulate fractions of aorta of SHR was significantly reduced (74.8 and 37.9%, respectively) at 1 and 6 after oral administration of MPC-1304 (3 mg/kg), while the myocardial [3H](+)-PN 200-110 binding was decreased only at 1 h later. In these rats, there was little change in cerebral cortical [3H](+)-PN 200-110 binding. In conclusion, MPC-1304 exerted more selective and sustained occupation in vivo of Ca2+ channel antagonist receptors in vascular tissues of SHR than in those of myocardial and brain tissues.

Topics: Administration, Oral; Animals; Aorta; Binding, Competitive; Calcium Channel Blockers; Cerebral Cortex; Dihydropyridines; Heart; Hypertension; Male; Nifedipine; Rats; Rats, Inbred SHR; Time Factors

1. Malignant or precocious stroke-prone spontaneously hypertensive rats (M-SHRSP) showed hypertensive ocular fundus changes with severe hypertension, but various anti-hypertensive drugs given over a proper period improved funduscopic findings. 2. We treated a M-SHRSP with SQ29,852 (an angiotensin converting enzyme inhibitor, ACEI) or manidipine (a calcium antagonist) and observed hypertensive vascular changes in the fundus. 3. The M-SHRSP treated with anti-hypertensive drugs lived longer and the hypertensive fundic changes improved in both groups. But there were some differences of histochemical staining reaction on the endothelial cell-surface and mucopolysaccharides accumulations between the treated group of ACEI and the group treated with the calcium antagonist. 4. In the treated group with calcium antagonist, the anionic ion functions of the endothelial cell-surface were impaired and organic retinal or choroidal damages appeared to have deteriorated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Fundus Oculi; Histocytochemistry; Hypertension; Male; Nitrobenzenes; Organophosphorus Compounds; Piperazines; Proline; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. The effects of benidipine hydrochloride (benidipine), a long-acting dihydropyridine calcium antagonist, on the development of hypertension and renal lesions were examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were fed with 8% NaCl diet for 3 weeks from 13 weeks of age, and benidipine (1 or 3 mg/kg per day) was orally administered during the same period. 3. The high salt diet accelerated an increase in urinary excretions of total protein and albumin, and caused marked arteriole, glomerular and tubular lesions in the kidney. 4. Benidipine significantly inhibited these changes, and also suppressed the elevation of blood pressure in salt-loaded SHRSP. 5. These results reveal that benidipine has protective effects against the development of hypertension and the progression of renal lesions induced by the high salt diet in SHRSP.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Kidney; Male; Organ Size; Rats; Rats, Inbred SHR

1. We evaluated the protective effects of manidipine on spermatogenic damage induced by the hypertensive vascular changes in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Blood pressure reached more than 250 mmHg in SHRSP at 15 weeks of age, and thereafter the hypertensive changes in testicular arterioles developed. Manidipine reduced both the blood pressure and the hypertensive vascular changes. 3. Although immature and mature spermatids greatly diminished in SHRSP at 23 weeks of age, manidipine could preserve almost normal spermatogenesis even at 23 weeks of age. Transferrin concentration in testicular cytosol, which was considered to be indicative of the Sertoli cell function, in SHRSP with manidipine administration was significantly higher than that in SHRSP with no treatment at 23 weeks of age. 4. In conclusion, manidipine could prevent the development of the hypertensive changes in intratesticular arterioles and maintain normal Sertoli cell function. As a result, manidipine protected spermatogenic damage in SHRSP.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Cytosol; Dihydropyridines; Hypertension; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Spermatogenesis; Testis

Interest in the cardiovascular protective effects of calcium channel antagonists has increased in the past decade. We investigated prevention of vascular wall remodeling by the long-acting calcium channel antagonist pranidipine in 12-week-old Dahl salt-sensitive (SS) rats with high-salt-induced (4% NaCl) hypertension. Six-week pranidipine treatment (60 mg/kg chow) decreased systolic blood pressure (SBP) by 22% in SS rats. This BP reduction was associated with decreases in cardiac mass and weight of the aortic wall. Glomerular filtration rate (GFR) was increased by 33%, but this did not lead to a decrease in urinary protein or NAG excretion. Morphologic investigation demonstrated striking resolution of arterial injury (medial necrosis and/or hyperplasia, inflammatory cell infiltration, and thrombus formation) by 87% after pranidipine treatment. Glomerular sclerosis was also attenuated by 61%, whereas tubular injury was improved by only 28%. These morphologic changes were reflected in the findings that the capacity of kidney homogenate for generating lipid peroxides was significantly decreased and that collagen levels and pattern type became similar to those of normotensive salt-resistant (SR) rats. Pranidipine also attenuated hypertensive vasculopathy in small arteries of the middle cerebral arteries. Thus, the calcium channel antagonist pranidipine can attenuate the vascular injury that occurs in salt-induced hypertension, a promising property that implicates its clinical usage, particularly in essential hypertension with cardiovascular complications.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Hypertension; Kidney; Kidney Diseases; Models, Biological; Potassium; Rats; Rats, Inbred Strains; Sodium; Sodium, Dietary

Lacidipine is a second-generation 1,4-dihydropyridine calcium antagonist, whose potent and long-lasting antihypertensive properties prompted us to investigate whether its chronic administration to Dahl-S rats prevented salt-induced hypertension, vasculopathy, and accelerated mortality. These studies revealed that lacidipine proved vasoprotective when administered both prophylactically and therapeutically at doses of 0.1 and 0.3 mg/kg p.o. once a day, largely equivalent to the therapeutic doses. A generalized dose-related protection against necrotizing vasculopathy and brain damage was detected, although only the highest dose used (10 mg/kg) controlled the development of hypertension. These protective properties were further confirmed in stroke-prone spontaneously hypertensive rats, which develop accelerated mortality as a result of salt-induced cerebral apoplexy and renal lesions. All untreated controls died within 12 weeks of salt-rich diet, whereas all animals survived during the same period when treated prophylactically with lacidipine at 0.3 and 1 mg/kg p.o. once a day, although a slight reduction in systolic blood pressure was measured only with the highest dose. No cerebral lesions and a clear protection against renal damage were detected in lacidipine-treated animals. In conclusion, these findings reinforce the concept that the beneficial effects of calcium antagonists are not simply restricted to a reduction in blood pressure.

Topics: Animals; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Hypertension; Kidney; Proteinuria; Rats; Rats, Inbred Strains

1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We have recently found that vascular natriuretic peptide (NP)-A receptor mRNA is upregulated in genetically hypertensive (SHR-SP/Izm) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In the present study, we examined the effects of antihypertensive treatments on aortic NP-A receptor mRNA expression in these hypertensive rats using ribonuclease protection assay. Oral administration of an angiotensin converting enzyme inhibitor, derapril, but not a calcium channel blocker, manidipine, produced a significant decrease of the NP-A receptor mRNA level after 4 weeks, while both antihypertensive agents showed similar hypotensive effects. Plasma renin was high in SHR-SP/Izm and low in DOCA-salt rats. These results suggest that the vascular renin-angiotensin system rather than the blood pressure has an important role in the regulation of the vascular NP-A receptor.

Topics: Animals; Aorta; Blood Pressure; Dihydropyridines; Down-Regulation; Hypertension; Indans; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; RNA, Messenger

Effects of benidipine on urine volume, excretion of electrolytes and renal hemodynamics were investigated in anesthetized spontaneously hypertensive rats (SHR). Benidipine at 3 and 10 micrograms/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretion with no change of creatinine clearance (CCRE). The increase in K excretion was relatively slight when compared with that in Na excretion. In another series of experiments, the tubular sites of action of benidipine were determined by the lithium clearance (CLi) technique and the stop-flow method. Benidipine at 3 micrograms/kg (i.v.) increased CLi, decreased creatinine concentration and increased Na concentration in the stop-flow urine from the distal nephron. These results suggest that benidipine produces diuresis and natriuresis by the inhibition of water and Na reabsorption at both the proximal tubule and the distal nephron. Benidipine increased p-aminohippuric acid clearance, but not CCRE, at doses of 3 and 10 micrograms/kg (i.v.), suggesting that benidipine dilates the glomerular efferent arteriole as well as the afferent arteriole. It is, therefore, expected that benidipine does not cause intraglomerular hypertension and has a beneficial effect in progressive renal disease.

Topics: Anesthesia; Animals; Calcium Channel Blockers; Dihydropyridines; Electrolytes; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Function Tests; Kidney Tubules; Lithium; Male; Rats; Rats, Inbred SHR; Renal Plasma Flow; Urodynamics

The hypertensive effect on the development of the prostatic abnormality in spontaneously hypertensive rats (SHRs) was examined using Efonidipine hydrochloride, a calcium antagonist. The control SHRs were given a high sodium and potassium diet (SP-diet) alone, and the treated SHRs were given a SP-diet with 0.15% Efonidipine hydrochloride from 8 to 28 weeks of age. The systolic blood pressure (SBP) in the control SHRs increased with age, while the elevation of SBP was significantly prevented in the treated SHRs. Light-microscopically, the prostatic lesion was observed both in the control and treated SHRs. The glandular lumen was narrowed with papillary protrusions, and the epithelium was composed of tall columnar epithelial cells. However, hypertension-induced complications in kidneys and hearts were not observed in the treated SHRs. These results suggested that the prostatic abnormality of SHRs might not be the consequent lesions upon hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Epithelium; Hypertension; Male; Nitrophenols; Organophosphorus Compounds; Prostate; Rats; Rats, Inbred SHR

The objective of this study was to investigate the effects of a dihydropyridine calcium antagonist, manidipine HCl, and an angiotensin II receptor antagonist, CV-11974, on renal microvasculature in hypertensive rats. Hydronephrosis was induced by ligation of the left ureter in 8-week-old stroke-prone spontaneously hypertensive rats. Two months after the operation, the hydronephrotic kidney was split longitudinally and spread out as a thin sheet, and the renal microvasculature was observed directly under a light microscope. Administration of manidipine HCl (20 micrograms/kg) caused a gradual fall in blood pressure (-34 mmHg). The afferent arterioles were dilated, and maintained the same level of dilatation until 30 min (+20%). The efferent arterioles were also dilated (+8%). Glomerular blood flow was significantly increased (+38%). Administration of CV-11974 (100 micrograms/kg) caused a sharp fall in blood pressure at 2 min (-24 mmHg), with a continuous fall in blood pressure until 60 min (-46 mmHg). The afferent arterioles were gradually dilated (+15%). The efferent arteriole was also dilated until 60 min, but to a lesser extent than the afferent arteriole. Glomerular blood flow was immediately increased (+35%). We conclude that both manidipine HCl and CV-11974 dilated both the afferent and efferent arterioles and increased glomerular blood flow.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Arterioles; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Hydronephrosis; Hypertension; Kidney; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Artery; Tetrazoles

Renal hemodynamic responses were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto Rats (WKY) to two acute stresses: environmental stress (foot shock (FS) and air jet (AS)). The effects of calcium channel blocker (benidipine) and alpha 1 blocker (urapidil) on these responses were studied using an ultrasonic pulsed Doppler flowmeter. The increments in mean arterial pressure (MAP) and renal vascular resistance (RVR) were greater in SHR during both stresses. On the other hand, the decrease in the renal blood flow (RBF) with these stresses almost disappeared with renal denervation. These renal hemodynamic responses in SHR disappeared with alpha 1 blocker (urapidil), but not with calcium channel blocker (benidipine). The sympathetic nervous system became hyperactive in SHR under environmental stress, Which induced specific renal hemodynamic change. These results suggest that investigations on essential hypertension should focus on clarifying not only systemic hypertensive reaction, but also changes in renal hemodynamics. Furthermore, it is necessary for antihypertensive therapy to take these hemodynamic changes into consideration.

Topics: Acute Disease; Adrenergic alpha-Antagonists; Animals; Calcium Channel Blockers; Dihydropyridines; Female; Hypertension; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Stress, Physiological; Vascular Resistance

An animal model having both hypertension and reduced renal function was produced by intraperitoneal injection of puromycin aminonucleoside (PAN) in spontaneously hypertensive rat (SHR). Using this model, two different dihydropyridine Ca blockers, CS-905 and nicardipine, were compared with regard to the relationship between hypotensive effects and changes in renal function in a conscious state. A single oral administration of CS-905 or nicardipine at doses of 3 or 10 mg/kg produced a dose-dependent decrease in blood pressure and an increase in heart rate. Glomerular filtration rate (GFR) was decreased only at 10 mg/kg. However, there was a substantial difference between the two drugs with respect to the relationship between blood pressure and GFR. The decrease of GFR by nicardipine was observed when blood pressure was at the lowest level, while GFR decreased by CS-905 returned to the initial level when blood pressure reached a nadir. Percent decrease of GFR by CS-905 was significantly less than that by nicardipine although both agents produced almost the same degree of peak hypotension. These results suggest the decrease in GFR by Ca blockers depends not only on the degree of hypotension but other factors as well, such as the rate of blood pressure lowering. Despite the hypotension, both agents produced a marked natriuresis. Since the natriuresis was not accompanied by an increase in GFR, it was assumed that the natriuretic effect of Ca blockers stemmed from their tubular effects rather than glomerular ones.

Topics: Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Heart Rate; Hypertension; Kidney Function Tests; Male; Nephrosis; Nicardipine; Puromycin Aminonucleoside; Rats; Rats, Inbred SHR; Sodium

To study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats.. Vehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks.. Systolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out.. NKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta.. NKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.

Topics: Animals; Aorta, Thoracic; Arteries; Blood Pressure; Calcium Channel Blockers; Cerebral Arteries; Dihydropyridines; Epoprostenol; Hypertension; Kidney; Male; Nicardipine; Rats; Renal Artery; Thromboxane A2

Conditions under which patients with hypertension controlled by combined therapy may be able to be switched to monotherapy were investigated. Eleven patients with benign phase accelerated malignant hypertension had their long-term combination antihypertensive treatment withdrawn for 1 day in an attempt to determine factors contributing to individual variability in the extent of BP increase. Patients were divided into two groups according to BP on day 1: patients with DBP above 130 mmHg formed group A, and those with DBP below 130 mmHg formed group B. Group A patients were not controlled by monotherapy with manidipine, even at the maximal dose of 60 mg/day, while group B patients were satisfactorily controlled by manidipine 20 mg/day. Group A patients had renal dysfunction whereas those in group B did not. Thus, renal dysfunction appears to be the most important single factor in predicting whether long-term combination therapy may be reduced in patients with a history of accelerated malignant hypertension.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Nitrobenzenes; Piperazines

We investigated the effect on cardiac hypertrophy of a once-daily treatment with lacidipine, at doses that do not reduce systolic blood pressure. Spontaneously hypertensive stroke-prone rats (SHR-SP) were fed a 1% NaCl enriched diet and treated daily by gastric gavage with lacidipine at doses of 0.3, 1, or 3 mg/kg/die or vehicle. At 15 weeks of age the rats were sacrificed. The heart was removed, weighed and processed for transmission electron microscopy, scanning electron microscopy and ultrastructural morphometry. Though the treatment did not reduce systolic blood pressure, heart weight and heart weight/body weight ratio were lower in the lacidipine-treated rats than in those treated with vehicle alone. Medial and subendothelial lesions were visible in coronaries of vehicle-treated SHR-SP but not in animals treated with lacidipine. In the cardiocytes of the lacidipine-treated rats, the myofibrils had a more regular arrangement and the intercalated discs did not show the irregular course and infoldings seen in the vehicle-treated rats. Morphometry showed a significantly higher density of mitochondria in the cardiocytes of lacidipine-treated SHR-SP. Scanning electron microscopy identified a decrease in the width of cardiocytes and in the number and length of lateral branches following lacidipine-treatment. The cardio-protective action of this calcium-antagonist at doses that do not reduce systolic blood pressure is attributable both to its vascular activity and to improvement in cytoplasmic organization of cardiocytes.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Myocardium; Rats; Rats, Inbred SHR

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Antiparkinson Agents; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Neurologic Examination; Nitrobenzenes; Parkinson Disease; Parkinson Disease, Secondary; Piperazines

The calcium antagonists currently available exert significantly different in vitro and in vivo electrophysiologic, hemodynamic, and contractile effects on cardiovascular function, mediated through differential cardiac and vascular smooth muscle responses to calcium channel blockade. These differences have important implications regarding choice of agent in specific clinical conditions, such as sinus or atrioventricular nodal disease, depressed left ventricular function, or congestive heart failure--conditions that may coexist with angina or hypertension. Recognizing and utilizing the properties of the different calcium antagonists is important to ensure maximally effective clinical outcomes. For example, in patients with hypertrophic cardiomyopathy and supraventricular arrhythmias, verapamil is singularly effective, whereas in post-myocardial infarction patients with pulmonary congestion, diltiazem may produce an added risk. Calcium antagonists of the dihydropyridine class, such as nifedipine and amlodipine, have the greatest peripheral vasoselective effects and thus the greatest potential to reduce afterload, minimizing direct left ventricular depression of contractility. Despite favorable effects of calcium antagonists, most of the agents currently available are not clearly safe in congestive heart failure and may adversely affect left ventricular function. However, newer calcium antagonists such as amlodipine are being investigated with regard to their safety in congestive heart failure.

Topics: Amlodipine; Calcium Channel Blockers; Cardiac Output; Dihydropyridines; Electrophysiology; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Myocardial Contraction; Myocardial Ischemia; Ventricular Function, Left

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Nitrobenzenes; Piperazines

A new calcium antagonist, NZ-105 ((+/-)-2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2-yl)-4- (3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol) (10 mg kg-1, p.o.), showed slow-onset hypotensive effect in spontaneously hypertensive rats (SHRs). The tachycardia evoked by NZ-105 was completely prevented when combined with a beta-adrenoceptor blocker, propranolol (20 mg kg-1), which did not affect the hypotensive response to NZ-105. In long-term administration experiments for 12 weeks with SHRs, the systolic blood pressure in the control group increased with age and the heart rate was stable throughout the period. NZ-105 (10 mg kg-1 day-1) alone and its combined treatment with propranolol (20 mg kg-1 day-1) maintained the systolic blood pressure and heart rate at a low level compared with the control group. The hypotensive action of NZ-105 were reproducible after repeated dosing for 12 weeks. Long-term administration of propranolol affected neither the elevation of the systolic blood pressure nor the heart rate substantially. The heart weight per body weight was significantly reduced after the chronic combination of both drugs, suggesting that the cardiac hypertrophy accompanying hypertension was prevented.

Topics: Administration, Oral; Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Heart; Heart Rate; Hypertension; Kidney; Liver; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Propranolol; Rats; Rats, Inbred SHR; Renin; Time Factors

Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Desoxycorticosterone; Dihydropyridines; Dogs; Female; Heart Rate; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Renin

The prophylactic and therapeutic effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) were compared with those of nimodipine or nicardipine using male stroke-prone spontaneously hypertensive rats (SHRSP). The survival rate of SHRSP was dose-dependently increased by once a day oral administration of S-312-d (0.3, 1, and 3 mg/kg) or nimodipine (10 mg/kg), while all non-treated SHRSP fed with high Na+ diet died within 40 days after the start of the experiment. All SHRSP treated with 3 mg/kg S-312-d survived during the 60-day experiment periods. Marked decreases of body weights and various neurological symptoms were also inhibited with S-312-d or nimodipine. Moderate diuretic effects were observed with S-312-d at doses of 1 and 3 mg/kg. The appearance of urinary occult blood in control SHRSP was markedly inhibited with S-312-d at 1 mg/kg and nimodipine at 10 mg/kg. Histological examination of the brain of SHRSP showed that cerebral stroke lesion including edema, hemorrhage, and/or softening was dose-dependently inhibited with S-312-d. Once a day oral administration of S-312-d (1, 3, or 10 mg/kg) dose-dependently increased the body weights and improved the neurological symptoms of diseased SHRSP. The appearance of proteinuria and of occult blood in the urine of SHRSP were also markedly inhibited with S-312-d or nicardipine. Histological examination of the brain of SHRSP showed that the arbitrary neurotoxic index (ANI) for stroke lesion dose-dependently decreased with S-312-d at 1, 3, and 10 mg/kg as follows: 4.8, 3.0, 2.3. The ANI for non-treated SHRSP was 7.6. The therapeutic effects of nicardipine (ANI 3.9) at 10 mg/kg corresponded to those of S-312-d at 3 mg/kg. Thus, S-312-d can be recommended for the treatment of cerebral insufficiency or vasospasm following stroke as well as in essential hypertension.

Topics: Animals; Behavior, Animal; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Drinking; Eating; Heart Rate; Hypertension; Life Expectancy; Male; Nicardipine; Nimodipine; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary

To evaluate the effects of antihypertensive therapy with lacidipine on the increase in radial artery compliance observed in mild essential hypertensive patients.. The study was performed in eight mild to moderate essential hypertensive patients in whom clinic blood pressure, radial artery diameter and radial artery compliance were evaluated before and after 3 months' administration of lacidipine, at a single daily dose of 4 mg. Radial artery diameter and compliance were evaluated by means of a high precision echo-tracking device able to assess arterial compliance over the blood pressure oscillations that characterize the cardiac cycle.. Lacidipine treatment caused a significant reduction in clinic systolic and diastolic blood pressure, while the heart rate was not modified by the drug. Radial artery diameter and compliance were both reduced by lacidipine over the entire systolodiastolic blood pressure range.. Chronic administration of lacidipine seems to reverse the increase in compliance observed in essential hypertension at the radial artery level. We suggest that lacidipine treatment can reverse an increase in the smooth muscle component in the arterial wall induced by hypertension.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Radial Artery; Vascular Resistance

The acute antihypertensive effects of 3-pyridine carboxylic acid 5-[(cyclo-propylamino)carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitroph eny l) octyl ester (NP-252, CAS 132031-81-3) administered orally to conscious spontaneously hypertensive rats (SHRs) and renal hypertensive rats (RHRs) were evaluated using the impedance plethysmographical technique as a modified tail cuff method, and compared with those of nifedipine (NF). In the fitness test of this indirect method, the average value of blood pressure (BP) measured in 7 conscious SHRs was 201 +/- 6.9 mmHg. This value showed good correlation with that (201 +/- 8.8 mmHg) of systolic BP measured by the direct method in the same animals. In the comparative study of antihypertensive activities of the compounds on both models of hypertension using this method, NP-252 and NF dose-dependently lowered BP having a different peak time and restoration after dosing. Therefore, the antihypertensive activities were compared using a 20% effective dose (ED20) for producing hypotension, and the ED20 values of NP-252 and NF were 2.55 and 2.00 mg/kg in SHRs, and 1.25 and 0.67 mg/kg in RHRs, respectively. Moreover, the duration of actions of the compounds were evaluated by the simulated duration time (SDT) which was calculated from the peak time of BP-fall and the pharmacological half life time for the maximum BP-fall and the SDT values of NP-252 and NF were 1.85-4.70 and 0.90-0.75 h in SHRs, and 3.30-12.80 and 0.57-6.90 h in RHRs, respectively. Also, the BP-falls by the compounds were accompanied by an increase in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Half-Life; Heart Rate; Hypertension; Hypertension, Renal; Male; Nifedipine; Rats; Rats, Inbred SHR; Rats, Wistar

MPC-1304 ((+-)-methyl 2-oxopropyl 1,4-dihydro 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 86780-90-7), a new calcium antagonist, was orally administered to 10 outpatients with mild essential hypertension. It was observed that MPC-1304 inhibited elevations of blood pressure both at rest and under exercise loading without any adverse hemodynamic effects. The findings obtained indicated that MPC-1304 would be clinically useful in the treatment of hypertensive patients undergoing therapy while continuing normal everyday activities including physical exertion.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Exercise; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Myocardial Contraction; Pulse; Rest; Vascular Resistance

The renal effects of manidipine hydrochloride were investigated in ten hospitalised patients with mild-to-moderate essential hypertension. After a one-week placebo period, manidipine was given for 1 week in a dose rising from 5 mg to 10 mg or 20 mg daily to normalise the mean blood pressure measured after 2 h. Blood pressure had decreased from 171/101 to 147/86 mm Hg at the end of manidipine treatment. The pulse rate was unaltered. Renal vascular resistance decreased from 1.90 to 1.33 dyn.s.cm-5/1.48 m2 x 10(4), and renal blood flow and glomerular filtration rate increased from 522 to 662 ml.min-1 x 1.48 m-2 and from 81 to 93 ml.min-1 x 1.48 m-2, respectively, in spite of a fall in renal perfusion pressure. Manidipine reduced the filtration fraction from 0.260 to 0.243, suggesting a preferential reduction in efferent arteriolar resistance. The fractional excretion of sodium and potassium did not change. Manidipine did not produce any significant alteration in plasma renin activity or in the plasma aldosterone concentration. The results indicate that manidipine has favourable renal effects and a concomitant hypotensive action in patients with mild-to-moderate essential hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Nitrobenzenes; Piperazines; Renal Circulation; Renal Plasma Flow; Vascular Resistance

To examine the molecular basis for the unique pharmacokinetics of lacidipine by defining interactions between lacidipine and biological membranes, which may explain the long clinical half-life of this calcium channel antagonist.. Radiotracer analysis was used to determine the membrane partition coefficient and washout kinetics of lacidipine with membranes of different composition. Small-angle X-ray diffraction with angstrom resolution was used to determine the location of lacidipine in membranes.. Lacidipine had a high membrane partition coefficient, which decreased as cholesterol in the membrane increased, and a slow rate of membrane washout. The drug was found deep within the membrane's hydrocarbon core, which was consistent with the other membrane drug parameters.. Lacidipine's location and interaction within membranes may provide a longer duration of therapeutic action and can explain the unique pharmacokinetics of this drug.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Cattle; Cell Division; Cell Membrane; Cholesterol; Dihydropyridines; Half-Life; Humans; Hypertension; In Vitro Techniques; Lipid Bilayers; Membrane Lipids; Radioligand Assay; X-Ray Diffraction

Calcium-dependent processes involved in atherosclerotic lesion formation include platelet aggregation, monocyte adhesion, release of growth factors, cell proliferation and migration, protein and collagen secretion and synthesis, and endothelial necrosis. In addition, the calcium (Ca2+) component of smooth muscle cell contraction contributes to one of the main risk factors, hypertension. The ability of the calcium channel blockers (CCBs) to interrupt the sequence of events that culminates in the formation of atherosclerotic lesions has been demonstrated in animal models and clinical trials. These studies have involved the short-acting CCBs. The results of this animal study show that manidipine, a new long-acting CCB, produces a dose-dependent reduction in atherosclerotic lesion formation without reducing plasma cholesterol.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cholesterol; Cholesterol, Dietary; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Male; Nitrobenzenes; Piperazines; Rabbits

Clinical studies were performed on patients with mild-to-moderate essential hypertension to elucidate the efficacy and mode of action of manidipine. Augmentation of diuresis and natriuresis during the short- and long-term phases of manidipine treatment was found in essential hypertensive patients. Manidipine partly inhibited sympathetic nerve activity and suppressed the mean arterial pressure response to infused norepinephrine. This drug also inhibited aldosterone secretion. Natriuresis and suppression of pressor responses may contribute to the depressor mechanisms of this drug. After manidipine administration, increases in both urinary calcium and uric acid were observed. Both parameters were positively correlated with urinary excretion of sodium, and the inhibition of tubular reabsorption may contribute to this mechanism. The increase in plasma parathyroid hormone may also be involved in the calciuresis produced by manidipine. Patients with lower plasma renin activity or lower plasma ionized calcium levels showed a greater reduction in blood pressure after manidipine administration. Thus the hypotensive action of manidipine was more pronounced in low renin essential hypertension.

Topics: Adult; Aldosterone; Calcium; Calcium Channel Blockers; Dihydropyridines; Diuresis; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuresis; Nitrobenzenes; Norepinephrine; Piperazines; Renin; Treatment Outcome

The Ca2+ entry blocking effects of MPC-1304, a new Ca2+ entry blocker of the 1,4-dihydropyridine type, and of its (S) and (R) enantiomers and metabolites were examined on Ca(2+)-induced contractions in isolated rabbit arteries. The Ca2+ entry blocking activity of the (S) enantiomer of MPC-1304 was approximately 150 times greater than that of its (R) enantiomer. Likewise, the antihypertensive effect of the (S) enantiomer was twice as great as that of MPC-1304 (racemate) in conscious spontaneously hypertensive rats, while the (R) enantiomer was ineffective. Thus, most of the pharmacological activity of MPC-1304 resides in its (S) configuration. The main metabolic products of MPC-1304 also inhibited the Ca(2+)-induced contraction in the isolated vascular smooth muscles. These active metabolites showed a stereoselectivity similar to that of MPC-1304 for Ca2+ entry blocking activity, and may contribute to the potent antihypertensive action of MPC-1304.

Topics: Animals; Blood Pressure; Calcium; Calcium Channel Blockers; Dihydropyridines; Hypertension; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rabbits; Rats; Rats, Inbred SHR; Stereoisomerism

Antihypertensive effects of a novel calcium antagonist, MPC-1304, (+-)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5- pyridine-dicarboxylate and its active metabolites were investigated in experimental hypertensive rats and dogs and compared with those of other dihydropyridine derivatives (nifedipine, nisoldipine, nicardipine, and nitrendipine). MPC-1304 had a dose-related antihypertensive effect with a slight increase in heart rate (HR) in rats. The antihypertensive effects of MPC-1304 were more potent than those of other dihydropyridines, and its active metabolites had antihypertensive effects comparable to those of other dihydropyridines. The hypotensive effects of MPC-1304 were stronger in hypertensive rats than in normotensive rats. During repeated oral administration of MPC-1304 to spontaneously hypertensive rats (SHR, once daily for 4 weeks, 0.3-3 mg/kg), dose-response curves of the antihypertensive effect did not change and body weight gain was equal to that of the vehicle-treated group. When given orally to conscious renal hypertensive dogs, MPC-1304 0.1-0.3 mg/kg had a potency and duration of antihypertensive action comparable to that of nitrendipine (1-3 mg/kg). MPC-1304 increased coronary blood flow (CBF) and aortic blood flow (ABF) in conscious normotensive dogs. In conclusion, MPC-1304 and its active metabolites have potent antihypertensive effects and cause slight tachycardia, and they may be useful in treating hypertension.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Coronary Circulation; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Nicardipine; Nifedipine; Nisoldipine; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Wistar

We wished to clarify the effects of a newly developed calcium antagonist, manidipine hydrochloride (HCl), on renal microcirculation in hypertensive rats by using the micropuncture technique. Oral administration of manidipine HCl for 2 months reduced systemic blood pressure (BP), did not change the single-nephron glomerular filtration rate (SNGFR), but increased the SNG plasma flow (SNGPF). Moreover, the glomerular transcapillary hydraulic pressure difference (delta P), which is assumed to be the parameter most related to development of glomerulosclerosis, was significantly reduced. Both afferent and efferent arteriolar resistance (RA and RE) were reduced. Intravenous (i.v.) infusion of manidipine HCl (20 micrograms/kg) decreased systemic BP but did not change SNGFR, SNGPF, or delta P. Both RA and RE were also significantly decreased. These results indicate that chronic administration of manidipine HCl increases renal blood flow (RBF) by dilating the afferent arterioles and improves glomerular hypertension by dilating the efferent arterioles. Thus, manidipine HCl might be a beneficial antihypertensive agent for patients with renal diseases. Because acute i.v. infusion of manidipine HCl did not change delta P, apparently time must elapse before glomerular hypertension is corrected.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney Glomerulus; Male; Microcirculation; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vascular Resistance

The occupancy in vivo of cardiovascular and cortical Ca++ antagonist receptors by mepirodipine in spontaneously hypertensive rats (SHR) was investigated. At 0.5, 3 and 6 hr after an oral administration of mepirodipine (3 mg/kg) in SHR, there was a significant (69, 51 and 41%, respectively) decrease in the number of cardiac (+)-[3H]PN 200-110 binding sites (Bmax) compared to control values. At 12 hr later, the Bmax value returned to the control value. On the other hand, the mepirodipine administration had little effect on the dissociation constant (Kd) for cardiac (+)-[3H]PN 200-110 binding except at 0.5 hr, when there was a significant increase in the value, suggesting a change in the density rather than affinity of Ca++ antagonist receptors. In the cerebral cortex of these rats, there was a significant (34%) decrease in Bmax values for (+)-[3H]PN 200-110 binding only at 0.5 hr after mepirodipine administration. In contrast, nifedipine administration had a significant increase in Kd values for cardiac (+)-[3H]PN 200-110 binding without a change in Bmax values. The occupancy of cardiac Ca++ antagonist receptors by mepirodipine correlated significantly with its hypotensive effect in SHR. There was approximately a 39 mm Hg reduction of blood pressure by occupying 50% of these receptors. After an i.v. injection of (+)-[3H]PN 200-110 (15 microCi) to SHR, there was specific binding of the ligand in particulate fractions of heart, aorta, ileum and cerebral cortex, but not liver and kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding Sites; Blood Pressure; Brain; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Hypertension; Isradipine; Male; Myocardium; Nifedipine; Rats; Rats, Inbred SHR; Receptors, Nicotinic

Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.

Topics: Adrenal Glands; Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Dihydropyridines; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Myocardium; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; RNA, Messenger

Mesangial cells play an important role in physiological and pathophysiological regulation of glomerular functions. To explore the involvement of deranged mesangial cell functions in the pathogenesis of hypertension, the growth activity of mesangial cells was compared in stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY). Upon exposure to fetal calf serum, the growth rate was significantly higher in mesangial cells cultured from glomeruli of 4-week old SHRSP than in those of age-matched WKY. This abnormally high growth of SHRSP mesangial cells was significantly inhibited by dihydropyridine calcium antagonists. Of the three antagonists tested, manidipine was the most potent inhibitor. Significant growth inhibition occurred at a concentration as low as 10(-12) M; inhibition as high as 65% was found at 10(-6) M. Calcium antagonists, particularly manidipine, may prevent or delay the development of hypertension not only through vasodilation but also through inhibition of mesangial cell growth. By slowing mesangial cell proliferation, calcium antagonists also may slow the progression of hypertension-induced glomerular sclerosis.

Topics: Animals; Calcium Channel Blockers; Cell Division; Cells, Cultured; Dihydropyridines; Dose-Response Relationship, Drug; Glomerular Mesangium; Hypertension; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thymidine; Tritium

This study was designed to investigate the effects of antihypertensive drugs on vascular hypertrophy and vascular angiotensin II in vivo in spontaneously hypertensive rats (SHR). Hydralazine (10 mg/kg/day), delapril (angiotensin converting enzyme inhibitor; 20 mg/kg/day), manidipine (calcium channel blocker; 10 mg/kg/day), and vehicle were given by gavage to four groups of SHR between 4 and 5 months of age. The aortic angiotensin II level was measured by highly sensitive radioimmunoassay coupled with high pressure liquid chromatography; aortic morphologic studies were performed. Each drug treatment effectively lowered blood pressure to the same level. However, the aortic wall thickness, medial-intimal areas, and wall to lumen ratio of abdominal aorta decreased significantly (p < 0.05, p < 0.01, p < 0.01, respectively) with delapril and manidipine but not hydralazine. Delapril significantly decreased aortic angiotensin II levels (p < 0.05), whereas manidipine treatment significantly increased them (p < 0.05). The aortic angiotensin II level was not changed by hydralazine. These results show that delapril and manidipine caused regression of hypertension-induced vascular hypertrophy in SHR. The probable mechanism of regression of aortic hypertrophy by delapril was inhibition of vascular angiotensin II formation, but the mechanism for manidipine was unclear.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Abdominal; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hydralazine; Hypertension; Hypertrophy; Indans; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renin-Angiotensin System

The effect of manidipine on cardiac hypertrophy, coronary circulation, left ventricular weight and maximal coronary flow in hypertension was measured in DOCA/salt treated systolic hypertensive rats with and without manidipine treatment. Normotensive rats were used as controls. After feeding with 0.05% manidipine-containing food, blood pressure was reduced only in DOCA/salt hypertensive rats, but not in control rats. After 3 weeks of treatment, sodium excretion was significantly increased in DOCA/salt-treated rats with or without manidipine treatment. Hearts were removed and perfused with modified Krebs-Henseleit solution with adenosine (5 x 10(-5) M) in a Langendorff apparatus. Maximal coronary flow (MCF) was significantly decreased only in DOCA/salt hypertensive rats without treatment, while manidipine treatment restored MCF. Left ventricular weight/body weight was also markedly greater in DOCA/salt-treated rats not given manidipine. Left ventricular weight in DOCA/salt-treated rats given manidipine was significantly reduced compared with DOCA/salt hypertensive rats without treatment, although it was heavier than in the control animals. Morphological examination showed that the increased wall/lumen ratio in DOCA/salt hypertensive rats was reduced by manidipine treatment. These findings suggest that treatment with manidipine in DOCA/salt hypertensive rats lowered high blood pressure and improved impaired coronary circulation with a reduction in left ventricular and vascular hypertrophy.

Topics: Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Coronary Circulation; Coronary Vessels; Desoxycorticosterone; Dihydropyridines; Electrolytes; Heart Rate; Hypertension; Male; Nitrobenzenes; Piperazines; Rats; Rats, Wistar; Renin; Sodium Chloride

Topics: Animals; Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Kidney; Kidney Diseases; Nitrobenzenes; Piperazines

To examine acute effects of manidipine hydrochloride, a new calcium antagonist, on renal blood flow (RBF) in spontaneously hypertensive rats, we recorded changes in RBF as the Doppler shift and a neurogram of renal sympathetic nerve activity (RSNA) simultaneously in a conscious and unrestrained state. An intravenous infusion of manidipine did not decrease RBF until mean arterial pressure (MAP) fell by 20 +/- 1 mmHg and RSNA increased by 98 +/- 18%. At the nadir of RBF (-25 +/- 2%, MAP: -31 +/- 2 mmHg, RSNA: +154 +/- 25%), percent increase in RSNA significantly correlated with percent decrease in RBF (r = -0.802, p < 0.02). On the other hand, the infusion of sodium nitroprusside did not decrease RBF significantly even at a nadir of MAP (-35 +/- 2 mmHg). Air jet stress increased both MAP and RSNA associated with a decrease in RBF. Responses of MAP and RBF were blunted after manidipine infusion while the stress evoked a similar degree of enhancement of RSNA to that of the control trial. Although manidipine may be less effective than nitroprusside in maintaining RBF during abrupt reductions of MAP, the results of this study suggest that antihypertensive treatment with manidipine may be clinically beneficial in maintaining RBF both at rest and during psychologically stressful conditions.

Topics: Air Pressure; Animals; Blood Pressure; Consciousness; Dihydropyridines; Heart Rate; Hypertension; Kidney; Male; Nitrobenzenes; Nitroprusside; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation; Stress, Physiological; Sympathetic Nervous System

To study the effect of antihypertensive therapy on the regulation of renin gene expression, the levels of tissue renin messenger RNA (mRNA) were measured after treatment with a calcium channel blocker (manidipine hydrochloride 3 mg/kg/day) or an angiotensin-converting enzyme inhibitor (delapril hydrochloride 30 mg/kg/day), administered orally for 1 week, in spontaneously hypertensive rats (SHR). Male SHR, aged 15 weeks old, were used in this study (n = 5 per group). Control rats were administered the vehicle alone. Tissue total RNA was isolated from kidney, adrenal gland, heart, and brain tissue, and tissue RNA was reverse-transcribed to complementary DNA (cDNA), which was specifically amplified by polymerase chain reaction with labeled-primers for the rat renin gene. The radioactivity of the cDNA products was measured directly. Although delapril increased plasma renin activity (PRA) about 5-fold compared with the control group, manidipine did not change PRA. The kidney renin mRNA content was increased about 6-fold by treatment with delapril. Manidipine and delapril significantly decreased the renin mRNA content in the heart (p < 0.01 and p < 0.05, respectively). The level of renin mRNA in the adrenal gland and brain tissues was not significantly changed by treatment with either drug. These results suggest that tissue renin gene expression in SHR is regulated by a tissue-specific process independent of the circulating renin-angiotensin system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Gene Expression; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Renin; RNA, Messenger

An enhanced renal vasoconstrictive response to emotional stress may be related to the pathogenesis of essential hypertension. We examined the effects of chronic manidipine treatment on renal blood flow (RBF) responses to air jet stress, angiotensin II (ANG II), and endothelin-3 (ET-3) in the conscious unrestrained spontaneously hypertensive rat (SHR). Male SHRs were placed on a control diet or one containing 0.05% of manidipine for 4 weeks. Age-matched Wistar-Kyoto (WKY) rats placed on a control diet served as normotensive controls. In comparison with control SHRs, manidipine reduced blood pressure (p < 0.01), increased urinary sodium excretion (p < 0.01), and reduced body weight (p < 0.01). Air jet stress elevated arterial pressure and increased RBF. The pressor response was enhanced more in the control SHRs than in the WKY rats (p < 0.01) and was not altered by manidipine. The percent fall in RBF in the manidipine-treated SHRs (-16%) was less than that in the control SHRs (-30%, p < 0.05) and similar to that in the WKY rats (-18%). In contrast, the pressor effect and the percent fall in RBF caused by ANG II (0.1 nmol/kg/min) were similar in the three groups. Intravenous ET-3 (1 nmol/kg) caused a transient fall, followed by a sustained increase in systemic blood pressure, both of which were associated with a decrease in RBF. The RBF response to ET-3 was blunted in SHRs compared to WKYs and was not altered by manidipine treatment. These results suggest that antihypertensive therapy with manidipine may be beneficial in maintaining RBF during emotional stress.

Topics: Air Pressure; Angiotensin II; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Endothelins; Heart Rate; Hypertension; Infusions, Intravenous; Injections, Intraventricular; Kidney; Male; Natriuresis; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Sodium; Stress, Physiological; Stress, Psychological; Time Factors

The purpose of this study was to investigate the effects of 4-week oral administration of manidipine (40 mg daily), a newly developed calcium channel blocker, on blood pressure and renal function in salt-loaded (8% NaCl) spontaneously hypertensive rats. Systolic blood pressure of spontaneously hypertensive rats increased from 167 +/- 4 to 221 +/- 7 mmHg with salt loading for 4 weeks; manidipine completely prevented this elevation in blood pressure. Urinary excretion of sodium in salt-loaded spontaneously hypertensive rats was twelve-fold compared with those receiving a normal diet (0.38% NaCl). The pressure-natriuresis relationship was obtained during week 4 of the metabolic study. At similar renal perfusion pressures, sodium excretion was significantly higher in salt-loaded rats than in rats fed a normal diet. Glomerular filtration rate and renal plasma flow were similar between the two groups. In salt-loaded spontaneously hypertensive rats, treatment with manidipine improved the pressure-natriuresis relationship toward lower pressures. Further, manidipine attenuated the autoregulation of glomerular filtration rate and renal plasma flow. These results indicate that manidipine normalizes the relation between sodium excretion and renal perfusion pressure in salt-loaded spontaneously hypertensive rats by resetting pressure natriuresis.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Hypertension; Kidney; Natriuresis; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation; Sodium; Sodium Chloride

The effect of a calcium antagonist, manidipine, on blood pressure and proteinuria induced by the inhibition of endothelial-derived relaxation factor (EDRF) formation was examined. Manidipine attenuated the increase in blood pressure and prevented proteinuria caused by renal damage associated with the inhibition of EDRF formation in stroke-prone spontaneously hypertensive rat (SHRSP) and Wistar Kyoto (WKY) rats.

Topics: Animals; Arginine; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Male; Nitric Oxide; Nitroarginine; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Radioligand binding studies were undertaken in renal membranes of normotensive and hypertensive rats in order to test the hypothesis that there are alterations in renal alpha 1-adrenergic subtypes of genetic hypertensive animals. The highly selective competitive compound, (+)-niguldipine, was used to distinguish high-affinity (alpha 1a) from low-affinity (alpha 1b) sites, after initial studies demonstrated that this compound had greater selectivity than 5-methylurapidil in distinguishing alpha 1a and alpha 1b sites in rat renal membranes. In contrast to the significant difference in the blood pressure of the spontaneously hypertensive rats (delta BP = 74 mm Hg), there was no difference in the renal alpha 1-adrenergic receptor density. Membranes from the whole kidneys of spontaneously hypertensive rats (SHRs) possessed 31% alpha 1a and 69% alpha 1b sites with -log(Ki) values of 10.0 +/- 0.3 and 7.1 +/- 0.1, respectively, for (+)-niguldipine. However, these values were not different from those obtained from renal membranes of the normotensive Wistar-Kyoto (WKY) rats. These results indicate that in spite of the elevated blood pressure during the established phase of hypertension, the number, the affinity, and the ratio of the alpha 1a and alpha 1b appear not to be responsible for the manifestation of hypertension during this phase.

Topics: Animals; Dihydropyridines; Hypertension; In Vitro Techniques; Kidney; Kidney Medulla; Male; Membranes; Piperazines; Prazosin; Radioligand Assay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Adrenergic, alpha

The effects of isradipine on ambulatory blood pressure, platelet aggregation, and oxygen free radicals were assessed in 30 patients with hypertension in a non-comparative 16-week study. After 4 weeks of placebo run-in, patients received isradipine at 2.5 mg twice daily for 12 weeks. The average supine systolic/diastolic blood pressure (155 +/- 17/101 +/- 11 mm Hg) was significantly reduced at the end of treatment (144 +/- 13/95 +/- 9 mm Hg; p less than 0.01). The heart rate was not significantly altered. Isradipine had no adverse effects on red or white blood cells or on plasma viscosity. The thromboxane B2 level and epinephrine-induced platelet aggregation were significantly (p less than 0.05) reduced. High-density lipoprotein cholesterol was significantly (p less than 0.01) increased after vs. before treatment; total cholesterol was significantly (p less than 0.05) increased at midstudy, but this was not significant at the end of the study. Other biochemical parameters were unchanged. Studies of neutrophil oxygen free radicals by serum opsonized zymosan and phorbol myristate acetate were not affected by isradipine. In conclusion, isradipine is an effective antihypertensive agent that also has beneficial effects on platelet aggregation and lipids while having no effects on neutrophil oxygen free radicals or most of the biochemical variables tested, making it an ideal agent for hypertension.

Topics: Aged; Blood Pressure; Blood Pressure Monitors; Calcium Channel Blockers; Dihydropyridines; Female; Free Radicals; Humans; Hypertension; Isradipine; Male; Middle Aged; Neutrophils; Oxygen; Platelet Aggregation; Platelet Aggregation Inhibitors

1. The effects of endothelin-1 (ET-1) on the vasorelaxant properties of structurally different potassium channel openers (PCOs), BRL-38227, Ro 31-6930, SDZ PCO 400, EMD-52692, RP-49356 and pinacidil, were studied. 2. All PCOs evoked concentration-related relaxations of ET-1 (10 nM) or KCl (20 mM) contracted rat isolated aortic rings denuded of endothelium. BRL-38227, EMD 52692, SDZ PCO 400 and Ro 31-6930 were 11-42 times less potent in relaxing contractions to ET-1 than KCl. In contrast, this differential potency was not observed with RP-49356 or pinacidil. 3. BRL-38227 (0.06-3.0 microM), RP-49356 (0.3-3.0 microM) and pinacidil (0.3-3.0 microM) displaced KCl concentration-response curves to the right of controls, without modifying the maximum response. A subcontractile concentration of ET-1 (0.1 nM) prevented the inhibitory effects of low concentrations of BRL-38227 (0.06-0.1 microM) on KCl responses, but failed to modify those to RP-49356, pinacidil or high concentrations of BRL-38227 (0.3-3.0 microM). The inhibitory effects of BRL-38227 (0.1 microM) were also not changed by ET-3 (1.0 nM) or angiotensin II (0.1 nM). 4. In anaesthetized spontaneously hypertensive rats (SHR), cumulative bolus intravenous administrations of BRL-38227 (1-1000 micrograms kg-1, i.v.), Ro 31-6930 (1-1000 micrograms kg-1, i.v.), RP-49356 (10-1000 micrograms kg-1, i.v.) or nitrendipine (0.1-30 micrograms kg-1, i.v.) produced dose-dependent falls in diastolic blood pressure (DBP).ET-1 (i.v.) evoked a transient fall in DBP (1 pg kg- = 58 + 1 mmHg) which returnedto pre-administration levels within 4 min.5. Pretreatment of anaesthetized SHR with ET-l (1 pg kg-', i.v.) significantly increased the ED,5 (dose to evoke a 15% fall in DBP) values for BRL-38227 and Ro 31-6930. However, ET-l failed to modify the ED,5 values for RP-49356 or nitrendipine. The ED50 values for all of the vasodilators studied were not modified by ET-1.6. Infusion of BRL-38227 (2 pgkg-'min-', i.v.) or RP-49356 (4 pgkg-'min', i.v.) to anaesthetized SHR evoked dose-related falls in DBP, with a corresponding increase in descending aortic blood flow (DABF) and a decrease in total lower body vascular resistance (TLBVR). Pretreatment with ET-1 (1 ptg kg-', i.v.) significantly attenuated the decreases in DBP and TLBVR observed with low doses of BRL-38227, but not RP-49356 or high doses of BRL-38227. In contrast, ET-3 (3 pig kg-, i.v.) failed to modify the effects of BRL-38227 on DBP or TLBVR.7. In conscious SHR, the fall

Topics: Animals; Aorta; Benzopyrans; Cromakalim; Cyclopentanes; Dihydropyridines; Dose-Response Relationship, Drug; Endothelins; Guanidines; Hypertension; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Pinacidil; Potassium Channels; Pyridines; Pyrroles; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

The effect of treatment for eight weeks with isradipine 1.25 mg twice daily for 4 weeks and thereafter 2.5 mg twice daily for 4 weeks on ex vivo platelet function was investigated in 10 male hypertensive patients, aged 51 (6.1) y. Systolic and diastolic blood pressure, platelet aggregation in response to ADP, serum thromboxane B2 and beta-thromboglobulin levels were significantly decreased at rest before exercise ergometry, during exercise and at rest after exercise. The platelet count, platelet sensitivity and the plasma levels of 6-oxo-prostaglandin F1 alpha were not affected by isradipine. It is concluded that a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit in the routine treatment of hypertension.

Topics: Analysis of Variance; Antihypertensive Agents; Blood Platelets; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Epoprostenol; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged; Platelet Aggregation; Prostaglandin D2

The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl-methyl-4-(2-f luoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride), a new calcium antagonist, was investigated in normotensive and hypertensive rats. By oral administration, the antihypertensive activity of TC-81 (ED20% in spontaneous hypertensive rats (SHR), DOCA-salt hypertensive rats and renal hypertensive rats were 0.37, 0.32, and 0.38 mg/kg p.o., respectively) was 7-14 times more potent in conscious hypertensive rats in comparison with nicardipine. Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at an equipotent dose. Similar results were observed by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized rats. Tolerance of the antihypertensive effect of TC-81 in long-term daily dosing and the rebound phenomenon after discontinuance of the treatment were not observed in hypertensive rats. TC-81, at a concentration of 10(-10)-3 x 10(-9) mol/l, inhibited the KCl-induced contraction of isolated rat vascular preparations. Moreover, TC-81 inhibited the norepinephrine-induced contraction of isolated SHR aorta preparation, but in isolated normotensive rat aorta, TC-81 inhibited the norepinephrine-induced contraction very little. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Heart Rate; Hypertension; Hypertension, Renovascular; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred Strains

The influence of renal function on the antihypertensive effect and pharmacokinetics of NZ-105 were studied in 7 patients with essential hypertension (EH) and 6 patients with hypertension having impaired renal function (RH). 1. As for the hypertensive effect, both in EH and RH, the maximum antihypertensive effect was attained 3 to 5 hr after drug administration and there was not significant difference between EH and RH. 2. There was not significant difference in transition of plasma concentration of NZ-105 between EH and RH. 3. Concerning pharmacokinetic parameters of NZ-105, there was significant difference between EH and RH in Tmax. at 20 mg of NZ-105 administration. However, in regard to Tmax. at 30 mg of NZ-105 administration and Cmax., AUC and t1/2 at 20 mg, 30 mg of NZ-105 administration, there were not significant differences between EH and RH. 4. There was no correlation between t1/2 and serum creatinine levels. 5. All cases showed good tolerance without any adverse effect.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds

Antihypertensive effects of FRC-8653, a new 1,4-dihydropyridine derivative, and its combined effects with an angiotensin converting enzyme (ACE) inhibitor, a diuretic, and a beta-adrenergic blocking agent were examined in conscious spontaneously hypertensive rats (SHR). When administered intravenously to SHR (10, 30 micrograms/kg), FRC-8653 lowered blood pressure more slowly and sustained it longer than nifedipine and nicardipine. Consecutive once-daily administrations of FRC-8653 to SHR (3 mg/kg, p.o.) produced a stable reduction of blood pressure throughout the experimental period of 29 d. When blood pressure was continuously measured for 24 h in conscious unrestricted SHR, orally administered FRC-8653 produced a long-lasting reduction in blood pressure. When concomitantly used with atenolol (30 mg/kg, p.o.), the antihypertensive effect of FRC-8653 was augmented in both potency and duration. However, simultaneous administration of captopril (30 mg/kg, p.o.) or hydrochlorothiazide (2.5 mg/kg, p.o.) did not modify the antihypertensive effect of FRC-8653.

Topics: Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Captopril; Dihydropyridines; Heart Rate; Hydrochlorothiazide; Hypertension; Male; Rats; Rats, Inbred SHR

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Creatinine; Dihydropyridines; Hypertension; Isradipine; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Sodium, Dietary

We describe the effects of Bay K 8644, a dihydropyridine-sensitive Ca2+ channel agonist, on [3H]norepinephrine (NE) release from the hypothalamus of spontaneously hypertensive rats (SHR). The electrical stimulation-evoked [3H]NE release was greater in hypothalamic slice of SHR than in those of Wistar Kyoto (WKY) rats. Bay K 8644 (10(-6) M) significantly increased the stimulation-evoked [3H]NE release in SHR. However, the agonist showed no significant effects in normotensive WKY rats. The results suggest that the dihydropyridine-sensitive Ca2+ channels might participate actively in the regulation of the central sympathetic tone of hypertension.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium Channel Agonists; Calcium Channels; Dihydropyridines; Hypertension; Hypothalamus; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System

Topics: Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Isradipine

In order to complement earlier short-term observations, we studied the effects of isradipine (1.25 or 2.5 mg twice daily) on blood pressure as well as its action in reversing cardiac hypertrophy in 25 moderately hypertensive patients. We observed that the treatment produced short-term (3 month) and longer-term (9 month) control of blood pressure [decreases in mean arterial pressure (MAP) from 128 +/- 2.3 to 112 +/- 2.7 mm Hg and to 105.5 +/- 2.9 mm Hg; p less than 0.001] while heart rate remained constant throughout the study (from 76.6 +/- 2.3 to 74.7 +/- 2.4 beats/min; NS). Reversal of left ventricular hypertrophy (LVH) obtained after 3 months of treatment (LV mass index from 173.7 +/- 8.8 to 135.7 +/- 4.5 g/m2; p less than 0.001) was accentuated with continued therapy (to 131.0 +/- 4.0 and 124.4 +/- 3.1 g/m2 at 6 and 9 months, respectively; p less than 0.01). These results indicate that significant regression of LVH can be obtained with short-term treatment of hypertension with isradipine and that this effect will be fully obtained with longer-term (9 month) therapy.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Female; Humans; Hypertension; Isradipine; Male; Middle Aged

The effect of the calcium antagonist isradipine on serotonin metabolism and platelet aggregation was studied in 17 patients with essential hypertension. Platelet serotonin content, plasma serotonin, 5-hydroxyindoleacetic acid levels, and platelet aggregation [induced ex vivo by serotonin and low-density lipoprotein (LDL)] were measured after a 4-week placebo period and after 12 weeks of oral treatment with isradipine. Isradipine treatment significantly inhibited platelet aggregation induced by LDL and serotonin; the amplifying effect of LDL on serotonin-induced aggregation seen with placebo was not observed after 12 weeks of treatment with isradipine. Platelet serotonin content increased significantly during isradipine treatment; this increase was inversely related to the pretreatment content of serotonin in platelets. The results indicate that treatment with isradipine restores the impaired handling of platelet serotonin as well as the platelet response to serotonin and LDL in hypertensive patients. This effect of isradipine may be regarded as one of the cellular mechanisms of thrombovascular protection and may be of clinical significance in terms of platelet and vessel wall interaction.

Topics: Adult; Aged; Blood Platelets; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; In Vitro Techniques; Isradipine; Lipoproteins, LDL; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Serotonin

To assess the effect of isradipine on blood pressure, and uteroplacental and fetal blood flows in pregnancy-induced hypertension, 41 women with a diastolic blood pressure greater than or equal to 95 mm Hg were included in our study. Of these, 27 received isradipine 5 mg twice daily. Uteroplacental blood flow index was calculated from the activity-time curve of the very low radiation from the placenta after intravenous injection of 18.5 MBq indium-113m. Blood flow velocity was measured in the uterine and umbilical arteries, and fetal aorta, using the pulsed Doppler technique. Investigations were performed before and after 1 week of isradipine. A control group of 14 women was examined in the same way. The isradipine group showed a significant reduction in mean arterial pressure (from 117 to 112 mm Hg) whereas there was no change in the controls. Uteroplacental blood flow indices were similar before treatment in both groups and did not change during treatment. Furthermore, the pulsatility indices were the same in both groups at the first examination and also did not change. Isradipine had no adverse effects on the fetus. In conclusion, isradipine lowered blood pressure without altering uteroplacental or fetal blood flows.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Fetus; Heart Rate; Heart Rate, Fetal; Hemodynamics; Humans; Hypertension; Isradipine; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Regional Blood Flow; Uterus

Topics: Dihydropyridines; Humans; Hypertension

Lacidipine is a long-lasting 1,4-dihydropyridine calcium antagonist that has been reported to protect salt-loaded Dahl-S rats from vascular damage and accelerated mortality when it is administered prophylactically at 0.1 and 0.3 mg/kg p.o. once a day (equivalent to the recommended dose in humans). The aim of this study was to investigate the vasoprotective properties of lacidipine in Dahl-S rats that had already developed sustained hypertension after 4 weeks of a salt-rich diet. Although none of the dosages of lacidipine (0.3, 1, and 3 mg/kg) reduced the elevated values of blood pressure, an almost complete protection from mortality was obtained. Moreover, lacidipine dose-dependently inhibited the development of macroscopic and microscopic alterations in the distal branches of mesenteric arteries and in the brain. A clear regression of vascular damage and cardiac hypertrophy was observed at the highest dose tested (3 mg/kg). These findings further support the assumption that the protective properties of lacidipine are not restricted to a reduction in blood pressure.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Heart; Heart Rate; Hypertension; Male; Organ Size; Rats; Rats, Inbred Strains; Retinal Diseases; Vascular Diseases

Topics: Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

The effects of nifedipine SR and lacidipine on blood pressure, left ventricular (LV) hypertrophy, and diastolic function were evaluated in 15 male patients (mean age of 45 +/- 8 years) with mild-to-moderate hypertension. Clinical evaluation and complete echocardiography were performed at baseline (after 15 days of washout). Seven patients received nifedipine SR (20-40 mg twice daily) and eight lacidipine (4-6 mg once daily). Clinical evaluation and complete echocardiography studies were repeated after 1 and 6 months of active treatment. In addition, full echocardiographic evaluations were carried out in 10 normotensive subjects (for comparison). Results were similar with either drug. After 1 month of therapy, systolic and diastolic blood pressures were significantly decreased (p less than 0.05); after 6 months of therapy, further changes were observed, confirming their significance. Analysis of our data suggests that (a) mild essential hypertension induces early modifications of LV geometry with consequent LV diastolic function characterized by a prolonged and incomplete diastolic filling; thus, LV wall thickness may be increased with a simultaneous reduction in LV end-diastolic short-axis diameter and volume; and (b) antihypertensive treatment with calcium antagonists such as nifedipine SR and lacidipine leads to early normalization of LV geometry and diastolic function without a significant change in total LV mass.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Heart Rate; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Models, Cardiovascular; Nifedipine; Ultrasonography; Ventricular Function, Left

The effect of lacidipine, a dihydropyridine calcium antagonist on lipid metabolism, has been followed in 8 patients with uncomplicated mild to moderate essential hypertension treated for up to 14 months. There were significant reductions in the systolic and diastolic pressures, from 167/102 to 146/91 mm Hg at 2 months, and to 137/85 mm Hg at the end of the study. Blood lipid concentrations did not change during the observation period (cholesterol 5.1 vs 5.3 mmol.l-1, triglycerides 1.1 vs 1.0 mmol.l-1, HDL-cholesterol 1.1 vs 1.2 mmol.l-1). The results show that lacidipine did not affect lipid metabolism and suggest that calcium antagonists may be safely prescribed for a prolonged period to patients with combined hypertension and hyperlipidaemia.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Female; Follow-Up Studies; Humans; Hypertension; Lipids; Male; Middle Aged

To determine whether it is possible to assess baroreceptor sensitivity by measuring changes in blood velocity in the carotid artery and changes in the heart rate, we performed a series of 108 experiments in 19 hypertensives aged 20-57 years (mean 46.6 +/- 8.6). In each experiment, we took simultaneous measurements of carotid artery blood flow velocity (Doppler technique), the brachial intra-arterial blood pressure and the heart rate, during a rapid and transient increase in blood pressure induced by injections of phenylephrine. We then calculated the maximum slope of the regression lines correlating blood velocity with the heart period (Trieste method) and blood pressure with the heart period (Oxford method). We obtained good accuracy from the Trieste method compared with the Oxford method, as assessed by the mean of the sum of the squares (difference + 5%, NS). After the administration of 4 mg oral lacidipine to 13 essential hypertensives, aged 37-54 years (47.6 +/- 5.3), baroreflex sensitivity was not changed, as assessed by either method (Oxford method 10.1 +/- 5.5 versus 9.8 +/- 6.2 ms/mmHg; Trieste method - 0.57 +/- 0.32 versus - 0.49 +/- 0.31 ms/Hz). The coefficients of variation for the two methods, calculated for the measurements taken before and after the administration of lacidipine, were not statistically different (Oxford method 25.0 +/- 18.4 versus 36.2 +/- 16.0; Trieste method 36.7 +/- 19.2 versus 39.7 +/- 19.2). The new non-invasive Trieste method thus showed the same accuracy and precision as the invasive Oxford method in measuring baroreflex sensitivity and can be used in pharmacological studies.

Topics: Antihypertensive Agents; Blood Flow Velocity; Carotid Arteries; Dihydropyridines; Heart Rate; Humans; Hypertension; Middle Aged; Phenylephrine; Pressoreceptors; Reflex; Reproducibility of Results; Ultrasonography

In a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery [MCAO]), various 1,4-dihydropyridine calcium antagonists have been shown to attenuate brain damage and the resultant functional impairment when administered after MCAO. Dose-response curves reveal that isradipine is one of the most potent and efficacious representatives of this class of compounds, reducing the infarct size by more than 60%. These results suggest that isradipine, when administered shortly after stroke onset, may have beneficial effects in patients suffering from brain ischemia. When isradipine is used to normalize the high blood pressure in spontaneously hypertensive rats, it will, in addition, also protect the brain from damage engendered by a subsequent stroke. This is not the case if blood pressure is controlled with a calcium antagonist which does not cross the blood-brain barrier, suggesting that the brain protection seen with isradipine is not due to blood pressure normalization. Isradipine, when used as an antihypertensive, appears to have an additional beneficial effect within the brain itself. As high blood pressure is a major risk factor for stroke, such an additional benefit with isradipine would be particularly valuable in antihypertensive therapy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Isradipine; Male; Prognosis; Pyridines; Rats; Rats, Inbred SHR

To investigate the relation between the small artery structure and different blood pressure parameters, spontaneously hypertensive rats were treated from 4 to 24 weeks of age (20 weeks in total) with five different antihypertensive therapies: two angiotensin converting enzyme inhibitors (perindopril and captopril), a calcium antagonist (isradipine), a beta-blocker (metoprolol), and a vasodilator (hydralazine). At 24 weeks of age, 24-hour blood pressure was measured, and two mesenteric resistance vessels were taken from each animal. Blood pressure was 227/135 mm Hg (systolic/diastolic) and 161/106 mm Hg in untreated hypertensive and normotensive control rats, respectively. Heart rates were 376 min-1 and 295 min-1 for the two strains. All treatments reduced all blood pressure parameters except for metoprolol, which did not reduce pulse pressure. In the small arteries, the media cross-sectional area was unaffected by the treatments. When a simple correlation analysis was made, pulse pressure was found to correlate more closely (r = 0.64, p less than 0.001) to the resistance vessel media/lumen ratio than any of the other pressure parameters studied: systolic (r = 0.51, p = 0.011), mean (r = 0.41, p = 0.05), or diastolic (r = 0.28, p = 0.19). When an analysis of covariance was performed that included pulse pressure, mean blood pressure, and heart rate, which also correlated significantly to the media/lumen ratio, 81% of the variation in the media/lumen ratio could be accounted for by the variation in the three covariates (p less than 10(-5)), pulse pressure being the major factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Arteries; Blood Pressure; Captopril; Dihydropyridines; Heart Rate; Hydralazine; Hypertension; Indoles; Isradipine; Male; Metoprolol; Perindopril; Pulse; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regression Analysis

Topics: Adrenal Gland Neoplasms; Adult; Blood Pressure; Calcium Channel Blockers; Catecholamines; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pheochromocytoma

The present study was designed to assess the effect of long-term isradipine treatment on the morphology of different-sized coronary artery branches in spontaneously hypertensive rats (SHR). Male SHR (12-week-old) received 1 mg/kg/day isradipine or vehicle (control group) orally for 12 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats were used as a reference group and did not receive any treatment. The animals were perfused with a fixative solution through the left ventricle and left ventricle blocks were embedded in resin. Sections including different-sized coronary artery branches were examined under a light microscope connected with an image analyser. The area occupied by the medial layer and the wall-to-lumen ratio were assessed in coronary artery branches of small (diameter less than 100 microns), medium (diameter 100-250 microns) and large (diameter greater than 250 microns) size. In control SHR, the blood pressure values and morphometric parameters examined significantly increased (p less than 0.001) in comparison with normotensive WKY rats. Isradipine treatment normalized blood pressure values in SHR and significantly reduced the area occupied by the medial layer and the wall-to-lumen ratio in small and medium-sized, but not in large-sized, coronary artery branches. These results indicate that isradipine treatment is able not only to reduce blood pressure elevation in SHR, but also to counteract the hypertension-dependent changes in the morphology of arterial branches controlling coronary resistances.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Vessels; Dihydropyridines; Hypertension; Isradipine; Male; Rats; Rats, Inbred SHR

In this study we used casual and 24-h blood pressure (BP) monitoring and Doppler echocardiographic data to investigate the antihypertensive and hemodynamic effects of isradipine 5 mg in the new slow-release oral (SRO) formulation administered once daily for 12 weeks to 10 patients with mild to moderate hypertension. The antihypertensive action of SR isradipine was revealed by the normalized values of casual BP in 60 patients and by the significant reduction of 24-h BP variability as assessed by mean standard variation, coefficient of variation and the percent incidence of abnormal levels of both systolic and diastolic BP during 24 h (p less than .001). The echocardiographic data showed some beneficial hemodynamic effects (improvement of systolic and diastolic indices) without significant variation of left ventricular structure. The drug was well tolerated, with a low incidence of side effects. In conclusion, SR isradipine can be considered a safe and effective first-choice drug for the treatment of mild to moderate hypertension.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Delayed-Action Preparations; Dihydropyridines; Echocardiography, Doppler; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Isradipine; Male; Middle Aged; Monitoring, Physiologic

The duration and magnitude of the hypotensive effect of a new, once daily dihydropyridine calcium channel blocking drug, OPC-13340, was assessed in 14 patients with essential hypertension during normal daily activities and programmed exercise testing. Intra-arterial ambulatory blood pressure (BP) monitoring was performed before and after one month's treatment. Mean reduction in day-time BP was 27/14 mmHg and night-time BP 18/11 mmHg (P less than 0.001 and 0.05 respectively). There was no change in heart rate throughout the 24 h. Satisfactory day-time control of systolic and diastolic BP using the drug as monotherapy was achieved in 58% and 88% of patients respectively, although adequate control of nocturnal systolic and diastolic BP occurred in only 54% and 50% of patients respectively. No postural hypotension occurred during tilt testing, and there was a significant reduction in the peak BP observed during both dynamic and isometric exercise. Side effects were mild and transient. Thus OPC-13340, given once daily, is an effective and well tolerated anti-hypertensive drug, with a prolonged 24-h action.

Topics: Adult; Aged; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Drug Administration Schedule; Exercise; Female; Humans; Hypertension; Isometric Contraction; Male; Middle Aged; Monitoring, Physiologic

We recorded the contractile responses to calcium in mesenteric resistance arteries of Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) during depolarization or stimulation with noradrenaline. The effects of Bay-K8644 and nimodipine on these responses were evaluated. Calcium sensitivity was greater in noradrenaline-stimulated than in depolarized vessels. Nimodipine decreased and Bay-K8644 increased calcium sensitivity. Both substances were more potent in the presence of potassium than in the presence of noradrenaline. Calcium sensitivity was greater in SHR than in WKY vessels only during stimulation with noradrenaline. The rhythmic responses of SHR vessels during stimulation with noradrenaline were abolished by nimodipine. Rhythmicity could be induced in WKY vessels by Bay-K8644. Modulation of calcium sensitivity by dihydropyridines during electrochemical as well as pharmacological stimulation suggests that, in resistance arterial smooth muscle, the function of potential-operated calcium channels can be modulated by noradrenaline. This modulation could differ quantitatively between mesenteric resistance arteries of SHR and WKY.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Arteries; Calcium; Calcium Channel Blockers; Dihydropyridines; Electrochemistry; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Nimodipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

The effects of LF 2.0254, a new 1,4-dihydropyridine derivative, were studied in rabbit aorta stimulated by various contractile agents and in isolated guinea pig atria. LF 2.0254 inhibited in a time-dependent fashion K(+)- and CA2(+)-induced contractions of rabbit aorta with respective IC50 of 2.7 nM and 1.7 nM. An action of LF 2.0254 at the voltage operated calcium channel was consistent with the finding that LF 2.0254 antagonized 45Ca2(+)-uptake induced by depolarisation of smooth muscle, and since contractile responses evoked by (-) norepinephrine and the calcium ionophore A23187 were insensitive to the drug. In isolated paced left atria and spontaneously beating right atria of guinea pig, LF 2.0254 added for 60 min at 1 microM only slightly decreased the contractile force and beating rate. In anesthetized open-thorax dogs, LF 2.0254 (1 to 100 micrograms/kg, iv) dose-dependently lowered systemic blood pressure and increased cardiac output with a slower onset of action than nifedipine. LF 2.0254 and nifedipine decreased total peripheral, coronary, femoral and vertebral resistance. In marked contrast to nifedipine, LF 2.0254 induced only a slight decrease in left ventricular dP/dt. In conscious hypertensive dogs LF 2.0254 (0.1 and 0.3 mg/kg per os) decreased blood pressure and concomitantly increased heart rate and plasma renin activity. It is concluded that LF 2.0254 differ markedly from nifedipine in its more gradual onset of action and greater selectivity for the vasculature with respect to the myocardium.

Topics: Anesthesia; Animals; Calcimycin; Calcium Channel Blockers; Calcium Chloride; Calcium Radioisotopes; Dihydropyridines; Dogs; Female; Guinea Pigs; Heart; Hemodynamics; Hypertension; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nifedipine; Norepinephrine; Potassium; Rabbits; Rats

To determine whether endothelin could act as a circulating hormone in the regulation of blood pressure and sodium-water excretion, we assessed the chronic effects of synthetic endothelin on systolic blood pressure, urine volume and urinary sodium excretion in conscious rats, and also evaluated the effects of benidipine or nilvadipine, newly developed calcium channel blockers, in rats infused chronically with synthetic endothelin. Continuous infusion of endothelin at a rate of 60 micrograms/kg/day into the jugular vein via osmotic minipumps induced a significant increase in systolic blood pressure, but did not induce any significant changes in urine volume and urinary sodium excretion, compared to those in vehicle-infused rats. On the contrary, the infusion of endothelin at a rate of 6 micrograms/kg/day did not induce any significant changes in systolic blood pressure, urine volume and urinary sodium excretion, compared to those in vehicle-infused rats. When 6 mg/kg/day of benidipine or 10 mg/kg/day of nilvadipine was administered simultaneously with 60 micrograms/kg/day of endothelin, the systolic blood pressure rose on Day I to only 137.0 +/- 2.4 mmHg (p less than 0.05) and 119.7 +/- 5.9 mmHg (p less than 0.05) compared to the rise to 163.8 +/- 4.7 mmHg when endothelin alone was infused. The antihypertensive effect of benidipine or nilvadipine was sustained for the entire experimental period and was not associated with any significant changes in urine volume and urinary sodium excretion. The present results suggest that endothelin can act as a circulating hormone and might be involved in the regulation of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Endothelins; Hypertension; Male; Nifedipine; Peptides; Rats; Rats, Inbred Strains; Sodium

Dihydropyridines with 1,4,4-trisubstitution were synthesized and tested for antihypertensive activity in a spontaneously hypertensive rat model. This substitution pattern on the dihydropyridine nucleus differs markedly from that found most active in the structure-activity relationship established for nifedipine-like compounds. However, some were found to significantly lower blood pressure at testing doses (30 mg/kg, ip and 100 mg/kg, po) for up to 24 h. Methyl 1,4-dihydro-4,4-dimethyl-1-pyridinepropanoate (2-1), for example, lowered blood pressure 71 mmHg at 30 mg/kg, ip and the effect endured for greater than 24 h. Unlike prototypical dihydropyridines such as nifedipine, these compounds did not seem to have any effect on calcium channels.

Topics: Animals; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dihydropyridines; Hypertension; Molecular Structure; Rats; Rats, Inbred SHR; Structure-Activity Relationship

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dihydropyridines; Drug Design; Fibrinolytic Agents; Humans; Hypertension; Imidazoles; Nitrendipine; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

The essential amino acid, tryptophan, has been shown to lower blood pressure in rats when administered orally or intravenously. In order to potentially enhance this action, a brain-targeting chemical delivery system (CDS) approach was applied to this compound. The CDS is based on a dihydropyridine----pyridinium ion redox system, chemically analogous to the naturally occurring NADH----NAD+ system. The dihydropyridine moiety containing carrier is chemically attached to the amino group by an amide-type bonding while the carboxylic acid functionality is esterified to various alcohols. Physicochemical studies of the new derivatives were performed. The determined chromatographic Rm values indicate an increased lipophilicity for the CDSs compared to the parent compound. Oxidation stability studies performed on selected compounds using a ferricyanide-mediated method showed that the CDSs are oxidized to the respective quaternary salt forms. Activity studies performed in deoxycorticosterone acetate induced hypertensive rats, demonstrated that the delivery system for tryptophan reduced blood pressure more efficiently for a longer time than did the parent compound.

Topics: Animals; Antihypertensive Agents; Blood-Brain Barrier; Brain; Chemical Phenomena; Chemistry, Physical; Cyclodextrins; Desoxycorticosterone; Dihydropyridines; Drug Carriers; Hypertension; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Oxidation-Reduction; Pyridinium Compounds; Rats; Rats, Inbred Strains; Solubility; Spectrophotometry, Ultraviolet; Tryptophan

Renal effects of CV-4093, a newly developed dihydropyridine calcium channel blocker, were examined using anesthetized stroke-prone spontaneously hypertensive rats, and the findings were compared with those of nicardipine. An intravenous injection of CV-4093 (2 micrograms/kg) produced long-lasting hypotension with a slow-onset accompanied by moderate renal vasodilation. There were no appreciable alterations in glomerular filtration rate (GFR) and urine formation, except that urine flow (UF) increased significantly during the first 10 min after injection. When CV-4093 was administered at 10 micrograms/kg, the hypotensive action was markedly augmented. Eighty minutes after the injection, a decrease in mean arterial pressure of about 45 mmHg was observed. Simultaneously, renal blood flow increased significantly from the control value of 5.76 +/- 0.46 ml/g.min to 6.94 +/- 0.28 ml/g.min. Renal vascular resistance decreased immediately after the injection, and the response lasted for over 3 hr, thereby indicating the marked and sustained renal vasodilating effect of CV-4093. GFR was constant throughout the experiment, but UF and urinary excretion of sodium were increased significantly. Fractional excretion of sodium was also elevated, thereby suggesting an inhibitory action of CV-4093 on renal tubular reabsorption of sodium. Nicardipine at a dose of 10 micrograms/kg, a dose producing an effective hypotensive action, caused no significant increases in RBF and urine formation. The renal vasodilating and diuretic actions of CV-4093 may provide a beneficial effect in the treatment of hypertension.

Topics: Animals; Body Weight; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hemodynamics; Hypertension; Injections, Intravenous; Kidney Function Tests; Male; Nicardipine; Nitrobenzenes; Organ Size; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Urodynamics

CS-905 is a potent dihydropyridine calcium blocker that has a gradual and long-lasting antihypertensive action with little tachycardia in SHR. In this study, we investigated chronic and acute effects of CS-905 on renal functions in SHR. To examine the chronic effects, 23 week-old male SHR were treated with CS-905 (1 or 3 mg/kg/day, p.o.) or 0.3% CMC (carboxymethylcellulose). After the 15 week-treatment, the agent dose-relatedly lowered systolic blood pressure measured 24 hr after the final administration (184 +/- 2 and 173 +/- 3 mmHg at 1 and 3 mg/kg/day vs. 218 +/- 4 mmHg for the control group). Natriuresis and the reduction of urinary protein excretion were also observed in the CS-905 treated groups. Urinary NAG (N-acetyl-beta-D-glucosaminidase) activity tended to decrease, but not significantly. Histopathological changes observed in the SHR kidney were reduced by chronic treatment with CS-905. On a single oral administration in 38 week-old SHR, CS-905 caused natriuresis at a dose of 3 mg/kg, but did not affect urinary protein excretion and urinary NAG activity. These effects of CS-905 on renal functions may be beneficial in the treatment of hypertension.

Topics: Acetylglucosaminidase; Animals; Azetidinecarboxylic Acid; Azetines; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.

Topics: Anesthesia; Animals; Antihypertensive Agents; Aorta; Azetidinecarboxylic Acid; Azetines; Blood Pressure; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Heart Rate; Hypertension; Hypertension, Renal; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred Strains

We have previously shown that a calcium channel activator (BAY K 8644) and a calcium channel inhibitor (CCI) (nifedipine), both dihydropyridine derivatives (DHP), can modulate in opposite fashion calcium dependent mechanisms involved in the central control of blood pressure and heart rate in SHR but not in Wistar rats. These results suggested that central DHP receptor sites might modulate baroreflex function. Therefore, we studied in pentobarbital anaesthetized SHR, the effects of BAY K 8644 and PN (200-110) (CCI) on central integration of baroreflex function (ramp method: phenylephrine 2 microgram i.v.). In order to rule out peripheral vascular effects, BAY and PN were administered intracerebroventricularly (i.c.v.) at doses which did not change BP. Baroreflex sensitivity (BRS) increased with time following the onset of anesthesia. In SHR, i.c.v. injection of BAY (3 microgram/kg) but not PN (0.6 micrograms/kg) suppressed the time dependent increase in BRS. The inhibitory effect of BAY on the time-dependent increase in BRS was suppressed by a pretreatment with PN (0.6 micrograms/kg i.c.v.) and by a pretreatment with the muscarinic antagonist atropine methylnitrate (80 micrograms/kg i.c.v.). BAY i.c.v. dit not change BRS in Wistar rats. These results indicate that DHP may centrally modulate BRS in SHR and suggest a central sympatho-excitatory effect for BAY mediated by an enhanced release of acetylcholine.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Blood Pressure; Calcium; Calcium Channels; Dihydropyridines; Heart Rate; Hypertension; Nifedipine; Phenylephrine; Pressoreceptors; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Nicotinic; Sympathetic Nervous System

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Humans; Hypertension; Rats; Receptors, Nicotinic

Topics: Calcium Channel Blockers; Dihydropyridines; Diltiazem; Hypertension; Verapamil