dihydropyridines and Kidney-Diseases

Delayed rectifier K(+)-channels (Kv1.3) are predominantly expressed in T lymphocytes. Based on patch-clamp studies, the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models, in vivo studies then revealed the clinically relevant relationship between the channel expression and the pathogenesis of autoimmune diseases. In renal diseases, in which "chronic inflammation" or "the overstimulation of cellular immunity" is responsible for the pathogenesis, the overexpression of Kv1.3-channels in lymphocytes promotes their cellular proliferation and thus contributes to the progression of tubulointerstitial fibrosis. We recently demonstrated that benidipine, a potent dihydropyridine calcium channel blocker, which also strongly and persistently inhibits the lymphocyte Kv1.3-channel currents, suppressed the proliferation of kidney lymphocytes and actually ameliorated the progression of renal fibrosis. Based on the recent in vitro evidence that revealed the pharmacological properties of the channels, the most recent studies have revealed novel therapeutic implications of targeting the lymphocyte Kv1.3-channels for the treatment of renal diseases.

Topics: Animals; Dihydropyridines; Humans; Kidney Diseases; Kv1.3 Potassium Channel; Lymphocyte Activation; Lymphocytes

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

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

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of their α1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective action of L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is more potent in reducing proteinuria than that with L-type CCBs, although no difference is found in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Humans; Kidney Diseases; Nitrophenols; Organophosphorus Compounds

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

The main effects of classic calcium antagonists are mediated by the inhibition of L-type calcium channels broadly distributed within the renal vascular bed. Calcium antagonists act predominantly on the afferent arterioles, and dihydropyridines can favour the increase in glomerular hypertension and progression of kidney diseases, in particular when systemic blood pressure remains uncontrolled.. Calcium antagonists have been widely used in clinical practice because of their antihypertensive capacity. The prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease in the general population. Non-dihydropyridines such as verapamil have been shown to possess an antiproteinuric effect that could be particularly relevant.. Recent data from clinical trials have confirmed that, in hypertensive patients with preserved renal function or with chronic kidney disease, calcium antagonists are effective antihypertensive drugs to be considered alone or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In those patients presenting with proteinuric kidney disease, non-dihydropyridines could reduce proteinuria to a greater degree than dihydropyridines.

Topics: Albuminuria; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Calcium; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Proteinuria

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

Since conventional Ca(2+) antagonists, with predominant blockade of L-type voltage-dependent Ca(2+) channels, elicit preferential dilation of afferent arterioles, they might ostensibly aggravate glomerular hypertension. Recently, novel Ca(2+) antagonists, with inhibitory action on L-/T-type Ca(2+) channels, have been reported to dilate both afferent and efferent arterioles. The present review attempted to characterize the renal action of these Ca(2+) antagonists and evaluated the consequences following the treatment with these agents. In contrast to conventional Ca(2+) antagonists (e.g., nifedipine), novel antagonists (e.g., benidipine, efonidipine) potently dilated afferent and efferent arterioles; their action on efferent arterioles appeared to be mediated by the T-type Ca(2+) channel blockade, probably through the inhibition of the intracellular Ca(2+) release. The comparison of the anti-proteinuric action in subtotally nephrectomized rats showed that efonidipine exerted more prominent action than nifedipine. Furthermore, Ca(2+) antagonists with T-type Ca(2+) inhibitory action inhibited renin/aldosterone release and proinflammatory process. Finally, patients with chronic renal disease given a 48-week efonidipine treatment showed reduced proteinuria, and this effect was seen even when mean arterial blood pressure failed to become less than 100 mmHg. Collectively, T-type Ca(2+) channel blockade provides beneficial action in renal injury. Various mechanisms serve to protect against renal injury, including systemic/glomerular hemodynamic action and non-hemodynamic mechanisms.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Humans; Kidney; Kidney Diseases; Microcirculation; Nitrophenols; Organophosphorus Compounds; Renal Circulation; Signal Transduction

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

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

Cyclosporine (CsA) treatment in solid organ transplantation has represented one of the greatest advances in the past 20 years, reducing acute rejection and increasing long-term survival. However, CsA has an important side effect, producing renal vasoconstriction and systemic hypertension. The main histological findings in the kidney are vascular lesions in the endothelium and smooth muscle cells. On proximal tubule cells, severe atrophy, vacuolization and thickening of the basal membrane can be found. The main mechanisms of vasoconstriction are secondary to endothelium disorders, increasing vasoconstrictor substances like endothelin, thromboxane, free radicals, etc., and reducing vasodilator substances like nitric oxide and prostaglandins. CsA acute nephrotoxicity produces haemodynamic changes with minor histological lesions, which will disappear when the medication is discontinued. Long-term CsA nephrotoxicity has been widely discussed in the literature. For some authors, a limited number of patients can develop end-state renal failure but others did not suffer these complications. Nevertheless, it seems clear that high doses of CsA can produce renal lesion and renal insufficiency, being difficult to evaluate in renal transplant patients because of the frequent association with chronic rejection lesions. Several types of drugs have been used to treat CsA nephrotoxicity in renal transplant patients but calcium antagonists and angiotensin converting enzyme-inhibitors are the most frequently used, especially the former due to their effect on the afferent arteriole vasodilatation, their natriuretic properties and their reducing intracellular calcium. The greatest experience has been with nifedipine, but other drugs like verapamil, diltiazem, amlodipine, felodipine, isradipine, etc., have also been used. Lacidipine, a 1,4-dihydropiridine, has demonstrated a beneficial effect during the short term after renal transplantation, and a multicentre, multinational, double-bind, placebo-controlled clinical trial for the long term currently ongoing.

Topics: Calcium Channel Blockers; Cyclosporine; Dihydropyridines; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation

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

Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs,

Topics: Adult; Aged; Aged, 80 and over; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Evaluation; Drug Interactions; Humans; Kidney Diseases; Liver Diseases; Propylamines; Tiapamil Hydrochloride

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C

Topics: Adolescent; Adult; beta-Thalassemia; Blood Transfusion; Cyclohexanones; Dihydropyridines; Dose-Response Relationship, Drug; Humans; Iron Chelating Agents; Kidney Diseases; Middle Aged; Siderophores; Thiazoles; Young Adult

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

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

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

To compare the taste of equivalent doses of pulverized amlodipine and lercanidipine, two calcium channel blockers, among children with kidney disease.. Each child received a test dose of 1 mg of amlodipine besylate and 2 mg of lercanidipine in a single-blinded fashion. Children indicated their preference by pointing to the appropriate face on a visual analogue scale (VAS) that depicts five degrees of pleasure.. The VAS palatability score assigned to lercanidipine was higher than that assigned to amlodipine both in nine children 4-7 years of age (P < 0.005) and in 10 children 8-11 years of age (P < 0.005). The preference for lercanidipine was statistically significant in both girls (P < 0.02) and boys (P < 0.001) and in both children initially presented amlodipine (P < 0.005) and children initially presented lercanidipine (P < 0.005).. There is a lack of appropriate formulations for children prescribed drugs originally designed for adults, such as calcium channel blockers. Parents therefore crush available tablets and administer the medication mixed with solid food or a palatable drink. From the perspective of the child, the taste of pulverized lercanidipine is superior to that of pulverized amlodipine.

Topics: Administration, Oral; Amlodipine; Calcium Channel Blockers; Child; Child, Preschool; Dihydropyridines; Female; Humans; Kidney Diseases; Male; Patient Compliance; Patient Satisfaction; Single-Blind Method; Smell; Statistics as Topic; Taste

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

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

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

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

Dihydropyridine-type calcium channel blockers (dihydropyridine CCB) adversely affect renal function in diabetes. The effects of dihydropyridine CCB on 24-h urinary protein excretion rate and GFR decline (deltaGFR) were prospectively evaluated in 117 nondiabetic patients with chronic, proteinuric nephropathies enrolled in the Ramipril Efficacy in Nephropathy study and randomized to angiotensin-converting enzyme inhibition (ACEI) or placebo plus conventional antihypertensive therapy. Sixty-three percent of patients were treated with dihydropyridine CCB. During follow-up, CCB-treated compared with no CCB patients had higher proteinuria (mean+/-SEM: 4.8+/-0.2 g/24 h versus 4.2+/-0.2 g/24 h, respectively, P = 0.015) and mean arterial BP (MAP). The difference in proteinuria was significant in the placebo group (5.1+/-0.2 g/24 h versus 4.3+/-0.3 g/24 h, P = 0.02), but not in the ACEI group (4.4+/-0.2 g/24 h versus 4.1+/-0.2 g/24 h). Of note, CCB-treated patients had significantly less proteinuria (P = 0.028) in the ACEI group compared with placebo. CCB-treated versus no CCB patients had a faster deltaGFR in the overall study population and in the placebo group, but not in the Ramipril group. Proteinuria was comparable in CCBtreated and no CCB patients for MAP < or = 100 mmHg, but was higher in CCB-treated patients for MAP >100 mmHg. Similarly, proteinuria was comparable in the placebo and in the ACEI group for MAP < or = 100 mmHg, but was higher in the placebo group for MAP >100 mmHg. In CCB- and placebo-treated patients, a linear correlation (P = 0.006 for both groups) was found between proteinuria and MAP values. MAP, proteinuria, and deltaGFR in patients given nifedipine versus those given other dihydropyridine CCB were comparable. Thus, in nondiabetic proteinuric nephropathies, dihydropyridine CCB may have an adverse effect on renal protein handling that depends on the severity of hypertension and is minimized by ACEI therapy or tight BP control. ACE inhibitors may electively limit proteinuria in patients on dihydropyridine CCB treatment and/or with uncontrolled hypertension.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Chronic Disease; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies

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

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

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

Dihydropyridine-type calcium channel blockers (CCBs) exert potent antihypertensive effects. The CCB azelnidipine decreases heart rate by suppressing sympathetic nerve activity, which affects afferent and efferent arterioles in the glomeruli. We examined whether azelnidipine can improve progressive glomerular injury in comparison with amlodipine by suppressing renal sympathetic nerve activity in Dahl salt-sensitive rats. Glomerular circulation in Dahl salt-sensitive rats was monitored with a charge-coupled device camera before and after administration of amlodipine (0.5 mg kg(-1), bolus injection) or azelnidipine (0.1 mg kg(-1), bolus injection). Systemic sympathetic nerve activity was also compared by analysis of heart rate variability with a telemetry blood pressure monitoring system after crossover administration of amlodipine (1.0 mg kg(-1) per day) and azelnidipine (3.0 mg kg(-1) per day) for 1 week. To investigate renoprotective effects, rats were treated with amlodipine (1.0 mg kg(-1) per day) or azelnidipine (3.0 mg kg(-1) per day) for 3 weeks with or without renal denervation. The efferent arteriole contracted in response to acute amlodipine but not azelnidipine treatment. The low frequency/high frequency ratio, an index of parasympathetic nerve activity, decreased in response to azelnidipine but not amlodipine treatment. In response to chronic treatment, proteinuria and glomerular injury improved to a greater extent with azelnidipine compared with amlodipine. The renoprotective effects of azelnidipine were diminished by renal denervation. Azelnidipine decreased glomerular damage in Dahl salt-sensitive rats to a greater extent than amlodipine. Azelnidipine appeared to decrease intraglomerular pressure by suppressing sympathetic nerve activity.

Topics: Amlodipine; Animals; Arterioles; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Heart Rate; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Inbred Dahl; Sympathectomy; Sympathetic Nervous System

Although the recommended target blood pressure for patients with chronic kidney disease is <130/80 mm Hg, this is difficult to achieve by treatment with an angiotensin receptor blocker alone. Addition of either a calcium channel blocker or a diuretic is suggested as second-line medication; however, which combination is most beneficial for target-organ protection remains unknown.. SHR/NDmcr-cp rats were administered no medications (control) or low-dose olmesartan for 2 weeks and then either olmesartan at an increased dose, azelnidipine, or the hydrochlorothiazide for 3 weeks. We assessed oxidative stress in the kidney and aorta, and endothelial function.. Urinary protein excretion was lower in all treated rats than in control rats. Oxidative stress caused by activation of NAD(P)H oxidase was observed in the glomeruli and aorta of control rats and was significantly suppressed in the olmesartan/azelnidipine (Olm/Azl) groups. Combination therapy with olmesartan and hydrochlorothiazide (Olm/HCTZ) however failed to suppress oxidative stress. The Olm/Azl groups maintained the endothelial surface layer in the glomeruli and protected endothelial function in the aorta.. In an animal model of metabolic syndrome, a combination of Olm/Azl is superior to a combination of Olm/HCTZ in terms of prevention of glomerular and vascular injuries.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Dihydropyridines; Drug Therapy, Combination; Hydrochlorothiazide; Imidazoles; Kidney Diseases; Oxidative Stress; Rats; Rats, Inbred SHR; Tetrazoles; Vascular Diseases

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

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

Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury.. Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 microg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22 and gp91). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22 and gp91, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells.. These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.

Topics: Aldosterone; Animals; Azetidinecarboxylic Acid; Blood Pressure; Body Weight; Calcium Channel Blockers; Collagen Type IV; Connective Tissue Growth Factor; Creatinine; Dihydropyridines; Ethidium; Gene Expression; Kidney; Kidney Diseases; Male; Mesangial Cells; NADPH Oxidases; Organ Size; Proteinuria; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?

Topics: Administration, Oral; Animals; Cebus; Dihydropyridines; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Iron; Iron Chelating Agents; Iron Overload; Kidney Diseases; Ligands; Lipids; Male; Molecular Conformation; Rats; Rats, Sprague-Dawley; Stereoisomerism; Thiazoles; Water

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

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

We aimed to compare regimens including calcium channel blockers (CCBs) to non-CCBs agents such as angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) regarding progression in nondiabetic chronic kidney disease (CKD). There was no difference in reaching serum creatinine concentration (Cr) to more than 7 mg/dL and/or commencing dialysis. The CCB group compared to non-CCBs displayed a higher mean Cr (as well as a higher rate of increase) and proteinuria. Medication with CCBs and younger age were associated with adverse renal function outcome. It is concluded that CCBs are less effective than ACEIs or ARBs on preserving renal function and ameliorating proteinuria in nondiabetic CKD.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Female; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria

The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine.. Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation.. Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group.. Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action.

Topics: Amlodipine; Animals; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dietary Sucrose; Dihydropyridines; Disease Models, Animal; Hypertension, Renal; Kidney Diseases; Male; Metabolic Syndrome; Rats; Rats, Inbred Dahl; Treatment Outcome

Diabetic nephropathy is a leading cause of end-stage renal disease in industrialized countries. Although the molecular mechanisms for the development and progression of diabetic nephropathy are not fully understood, the formation and accumulation of advanced glycation end products (AGEs) have been considered to play a major role in the pathogenesis of diabetic nephropathy. Hypertension is also an independent risk factor for the progression of diabetic nephropathy. However, functional cross-talk between AGEs and blood pressure and their involvement in diabetic nephropathy remain to be elucidated. In this study, we examined the effects of oral administration of azelnidipine, a commercially available dihydropyridine-based calcium antagonist, on renal injury in AGE-treated rats. Administration of azelnidipine inhibited the increase of systolic and diastolic blood pressure levels and urinary N-acetyl-beta-D-glucosaminidase activity in exogenously AGE-injected rats. Furthermore, azelnidipine treatment also prevented glomerulosclerosis in AGE-treated rats. These results indicate that renal damage in AGE-injected rats could be mediated, at least in part, by the elevation of blood pressure. Our present study suggests that azelnidipine would represent a valuable drug for the treatment of diabetic nephropathy by blocking the deleterious effects of AGEs.

Topics: Acetylglucosamine; Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium; Dihydropyridines; Glycation End Products, Advanced; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Serum Albumin; Time Factors

Experimental studies suggest that some long-acting calcium antagonists decrease glomerular hypertension and suppress the progression of nephropathy, but clinical evidence is lacking. To investigate clinically whether a long-acting calcium antagonist, benidipine, lowers glomerular capillary hydraulic pressure via a decrease in efferent arteriolar resistance and decreases proteinuria, we examined hypertensive patients with nondiabetic nephropathy. The subjects were 7 patients with chronic glomerulonephritis or glomerulosclerosis. Before and during the administration of benidipine (4 mg/day), systemic pressure, glomerular hemodynamics, the sodium sensitivity index (reciprocal of the pressure-natriuresis curve), and urinary excretion of proteins (total protein, albumin, and immunoglobulin G) were investigated. The glomerular hemodynamics in terms of glomerular capillary hydraulic pressure and resistance of afferent and efferent arterioles were calculated from the renal clearance, plasma total protein concentration, and pressure-natriuresis relationship. Benidipine lowered the mean arterial pressure from 105 +/-5 to 99 +/- 4 mm Hg (p = 0.002; mean +/- SD) and glomerular pressure from 48 +/- 8 to 39 +/- 5 mmHg (p = 0.006) by decreasing the resistance of efferent arterioles. Benidipine made the pressure-natriuresis curve steeper and decreased the median sodium sensitivity index from 0.099 (0.084 and 0.117; 25th and 75th percentiles) to 0.048 (0.017 and 0.058; p = 0.018). Urinary excretion of proteins did not change. Our clinical study showed that benidipine lowered the glomerular pressure by decreasing the resistance of efferent arterioles and decreased the sodium sensitivity of blood pressure, but did not affect proteinuria in patients with nondiabetic nephropathy.

Topics: Aged; Arterioles; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Hemodynamics; Humans; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Natriuresis; Proteinuria; Vascular Resistance

The effect of lacidipine (LA), a new calcium channel blocker with an antioxidant effect, has been studied on cyclosporine (CsA)-induced nephrotoxicity in male Wistar rats. Lacidipine (1 mg/kg BW) was administered orally 3 days before and 14 days concurrently with CsA (50 mg/kg BW orally). Urine volume, Na+, K+, Li+ and creatinine in urine, and blood urea, serum creatinine, lithium, plasma malondialdehyde (MDA) and CsA levels were estimated in blood after 14 days CsA treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 305 and 211%, respectively, with CsA when compared to the saline-treated animals. Creatinine clearance (Ccr) and lithium clearance (Licr) were decreased and proximal tubule fractional reabsorption 1-(Licr/Ccr) was significantly increased with CsA. Lacidipine protected rats from CsA-induced nephrotoxicity. Changes in blood urea, serum creatinine, Ccr, Licr and proximal tubule fractional reabsorption induced by CsA were significantly prevented by LA. There was a 160% rise in MDA levels with CsA, which was significantly reduced equal to control with LA. Histomorphology showed microcalcification with CsA, while it was normal with LA. In rats treated with LA, CsA did not show any microcalcification. Our data suggest that supplementation of LA may be helpful to reduce CsA nephrotoxicity.

Topics: Animals; Calcium Channel Blockers; Cyclosporine; Dihydropyridines; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Lipid Peroxidation; Lithium; Male; Rats; Rats, Wistar

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

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

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

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

A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5-dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.

Topics: Animals; Cebus; Deferoxamine; Dihydropyridines; Feces; Gastrointestinal Diseases; Iron; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Siderophores; Thiazoles

Topics: Animals; Antihypertensive Agents; Dihydropyridines; Humans; Hypertension; Kidney; Kidney Diseases; Nitrobenzenes; Piperazines