dihydropyridines and Cardiovascular-Diseases

The current review discusses the different synthetic pathways for one of the most important and interesting heterocyclic ring systems, 1,4-dihydropyridine. This cyclic system depicts diverse pharmacological action on several receptors, channels, and enzymes. Dihydropyridine moiety plays an important role in several calcium-channel blockers. Moreover, it has been exploited for the treatment of a variety of cardiovascular diseases due to its potential antihypertensive, anti-angina, vasodilator, and cardiac depressant activities. Furthermore, it also shows antibacterial, anticancer, anti-leishmanial, anticoagulant, anticonvulsant, anti-tubercular, antioxidant, antiulcer, and neuroprotective properties. Several reports have demonstrated dihydropyridine derivatives as a potentiator of cystic fibrosis transmembrane conductance regulator protein, potent antimalarial agent and HIV-1 protease inhibitor. Herein, we have briefly reviewed different novel chemistry and the synthesis of 1,4-dihydropyridine.

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Catalysis; Chitosan; Coordination Complexes; Dihydropyridines; Humans; Ionic Liquids; Microwaves; Nanoparticles

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

The data are presented on using the first, second and third generation calcium antagonists in cardio-vascular pathology patients. The accent has been made on the improved pharmacokinetic profile of the third generation calcium antagonists where modern preparation lerkanidipin belongs to. It is shown that lerkanidipine has expressed antihypertensive effect with no significant impact on the cardiac contraction frequency and its metabolic neutrality enables using the said preparation with diabetes mellitus and other metabolic disorders patients. Besides, an improved pharmacokinetic lerkanidine profile leads to organoprotective and antiaterogeneous effect. Significantly fewer side reactions as connected with activised simpatico-adrenal system, and peripheral edemas are observed as compared against other representatives of the said preparations category.

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans

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

The combination of renin-angiotensin system blockers with calcium channel blockers appears to be one of the most effective options for treating hypertension and diabetes.Nevertheless, not all calcium blockers behave in the same manner. Manidipine, unlike other third-generation dihydropyridine derived drugs, blocks T-type calcium channels present in the efferent glomerular arterioles, reducing intraglomerular pressure and microalbuminuria. In addition,T-type channels are related to proliferation, inflammation,fibrosis, vasoconstriction and activation of the renin-angiotensin system. The inhibition of these factors could explain the non-haemodynamic effects of manidipine as compared to other blockers.

Topics: Albuminuria; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans; Insulin Resistance; Nitrobenzenes; Oxidative Stress; Piperazines

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

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

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

Calcium channel antagonists have a well-established role in the management of cardiovascular diseases. L-type calcium channels in vascular cells are a key therapeutic target in hypertension and are the preferred molecular target of the initial calcium channel antagonists. However, third-generation dihydropyridine (DHP) calcium channel antagonists, including manidipine, nilvadipine, benidipine and efonidipine, appear to have effects in addition to blockade of the L-type calcium channel. Voltage-gated calcium channels are widely expressed throughout the cardiovascular system. They constitute the main route for calcium entry, essential for the maintenance of contraction. Cardiac and vascular cells predominantly express L-type calcium channels. More recently, T-type channels have been discovered, and there is emerging evidence of their significance in the regulation of arterial resistance. A lack of functional expression of L-type channels in renal efferent arterioles may be consistent with an important role of T-type channels in the regulation of efferent arteriolar tone. Although the exact role of T-type calcium channels in vascular beds remains to be determined, they could be associated with gene-activated cell replication and growth during pathology. The three major classes of calcium channel antagonists are chemically distinct, and exhibit different functional effects depending on their biophysical, conformation-dependent interactions with the L-type calcium channel. The DHPs are more potent vasodilators, and generally have less cardiodepressant activity than representatives of other classes of calcium channel antagonist such as diltiazem (a phenylalkylamine) and verapamil (a benzothiazepine). In contrast to older calcium channel antagonists, the newer DHPs, manidipine, nilvadipine, benidipine and efonidipine, dilate not only afferent but also efferent renal arterioles, a potentially beneficial effect that may improve glomerular hypertension and provide renoprotection. The underlying mechanisms for the heterogenous effects of calcium channel antagonists in the renal microvasculature are unclear. A credible hypothesis suggests a contribution of T-type calcium channels to efferent arteriolar tone, and that manidipine, nilvadipine and efonidipine inhibit both L and T-type channels. However, other mechanisms, including an effect on neuronal P/Q-type calcium channels (recently detected in arterioles), the microheterogeneity of vascular beds, and other types o

Topics: Animals; Antihypertensive Agents; Arteries; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, P-Type; Calcium Channels, T-Type; Cardiovascular Diseases; Dihydropyridines; Humans; Hypertension, Renal; Ion Channel Gating; Kidney Glomerulus; Muscle Contraction; Muscle, Smooth, Vascular; Nitrobenzenes; Piperazines; Renal Circulation

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

Drugs classified as calcium channel blockers (CHBs) are now among the most frequently prescribed drugs for the treatment of cardiovascular disease. Although the currently available CCBs have major differences in their structural and cardiovascular effects, they share the common property of blocking the transmembrane flow calcium ions through voltage gated L-type channels. These drugs have been approved for the treatment of hypertensive heart disease: they reduce left ventricular hypertrophy and improve its sequelae, such as ventricular dysrhythmias, impaired filling and contractility, and myocardial ischemia. Long-acting CCBs have been shown to reduce mortality and morbidity in elderly patients with systolic hypertension, appear to be extremely useful in patients with cyclosporin-induced hypertension, and can be used as alternatives to ACE inhibitors in patients with hypertension and concomitant diabetes mellitus, renal disease, Raynaud's phenomenon or migraine. Long-acting dihydropyridine have been shown to be effective and safe in the treatment classic angina pectoris and vasospastic angina, supraventricular arrhythmias, particularly reentrant AV-nodal tachycardia, others to be beneficial in patients with congestive heart failure, and all of them have potential for decreasing atherogenesis.

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans

Topics: Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans; Intraoperative Complications; Nicardipine; Perioperative Care

The risk of interference with anaesthesia and the risk of decompensation of the disease must be considered for each drug. Beta-blockers reduce the body's capacity to react to hypovolaemia, but they are beneficial by limiting the response to nociceptive stimuli and by reducing the incidence of myocardial ischaemia. Treatment should therefore be continued. Interferences with the dihydropyridine class of calcium channel blockers on peripheral vasomotor activity are moderate and additive. These agents are well tolerated and can be continued until the operation. Verapamil and diltiazem have a chronotropic and negative inotropic effect which is additive with that of anaesthetics. Administration of these drugs before the operation does not raise any major problems, nor does their discontinuation. Angiotensin-converting enzyme (ACE) inhibitors, used in hypertension and heart failure, considerably reduce the tolerance of factors modifying the blood pressure equilibrium, especially hypovolaemia or haemorrhage. In practice, ACE inhibitors carry a risk of intraoperative hypotension, requiring the use of vasopressor amines to maintain blood pressure. Continuation of treatment has only minimal advantages, regardless of the indication and there is no risk of rebound effect after stopping treatment. The treatment washout period depends on the duration of action of the product. However, discontinuation of treatment is never imperative, regardless of the context.

Topics: Adrenergic beta-Antagonists; Anesthesia, General; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiotonic Agents; Cardiovascular Diseases; Dihydropyridines; Drug Interactions; Drug Monitoring; Hemodynamics; Humans; Hypotension; Intraoperative Care; Intraoperative Complications; Monitoring, Intraoperative; Patient Selection; Risk Factors

Irregular functions in Ca2+ channels are intimately involved in many aspects of cardiovascular diseases. We can obtain a wide variety of L-type Ca2+ channel antagonists to treat hypertension and angina pectoris. Dihydropyridines (DHPs) have, first of all, been extensively developed due to their high selectivity for L-type Ca2+ channel and safety in pharmacological aspects. In contrast, many lines of evidence suggest that clinical efficacy of those DHPs are limited and undesirable effects are sometimes observed because of the specific distribution of L-type Ca2+ channels. As well as the L-type, peripherally distributed N-type Ca2+ channel plays a key role in cardiovascular regulation through autonomic nervous system. Recently, we developed a unique DHP derivative, cilnidipine (FRC8653) which has a dual antagonistic action on both L-type and N-type Ca2+ channels. Our recent studies with this DHP have made it clear that the N-type Ca2+ channel is also a new therapeutic target in cardiovascular diseases. We review the recent advances in pharmacology of the N-type Ca2+ channel and therapeutic implications of their antagonists.

Topics: Amino Acid Sequence; Animals; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels; Cardiovascular Diseases; Cardiovascular System; Dihydropyridines; Humans; Molecular Sequence Data; Mollusk Venoms; Nerve Endings; Peptides; Rats

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

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Clinical Trials as Topic; Dihydropyridines; Diltiazem; Humans; Prognosis; Verapamil

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

Over the last 10 years, accumulating evidence has confirmed the ability of dihydropyridine calcium antagonists to improve red blood cell deformability. In this review of the literature, particular attention is paid to results obtained with isradipine, a second-generation derivative of the 1,4-dihydropyridine family. Isradipine appears to be more selective in various pharmacological properties, well tolerated, easy to administer, and effective in controlling blood pressure and reducing the frequency of ischemic events. While manifesting these desirable attributes, isradipine retains an unimpaired ability to improve red blood cell deformability. It is suggested that the therapeutic efficacy of dihydropyridine calcium antagonists is attributable, at least in part, to their ability to affect blood rheology by improving red blood cell deformability.

Topics: Blood Circulation; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans

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

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

The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines-nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine-are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications. Nisoldipine is a potent arterial vasodilator with minimal electrophysiological and negative inotropic effects. Although data are still preliminary, the drug has shown some efficacy in both exertional angina and essential hypertension. The dosing interval is not yet clearly established, but may be twice daily. Utility in congestive heart failure awaits confirmation, but preliminary studies are promising. Nicardipine is an especially potent peripheral, cerebral and coronary arterial vasodilator that causes 10-fold less myocardial depression in animals than nifedipine, and may provide important cardioprotective effects during ischaemia. Human haemodynamic studies have confirmed nicardipine's lack of negative inotropism, its ability to reduce coronary and peripheral vascular resistance, and its lack of effect on cardiac conduction. Several controlled trials have documented its efficacy in exertional angina, vasospastic angina, and essential hypertension. Nicardipine's potential as an antiatherosclerotic agent is currently under investigation. Nimodipine is undergoing a unique clinical development programme aimed at cerebrovascular disorders. In almost all species, nimodipine selectively increases cerebral blood flow and reverses cerebral artery spasm without altering cerebral oxidative metabolism or systemic blood pressure. In humans, a large, double-blind, placebo-controlled trial in subarachnoid haemorrhage showed that nimodipine significantly reduced the severity of neurological deficits associated with delayed cerebral vasospasm. Several uncontrolled trials with larger numbers of patients support these results. Nimodipine has also proved useful in reducing cerebral artery spasm during intracranial surgery, and in the prophylactic treatment of migraine headaches. A preliminary study of nimodipine in acute stroke showed promising results in limiting neurological disability. Felodipine is a very potent systemic arterial vasodilator with negligible myocardial depressant activity. It is also a renal artery vasodilator. Unlike the other new dihydropyridines, felodipine prolongs the A-H interval on electrophysi

Topics: Animals; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans

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

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

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

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

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

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

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 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

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

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, a dual L-/N-type calcium channel blocker, dilates both efferent and afferent arterioles and is renoprotective. Our multi-center, open-labeled, and randomized trial compared the antiproteinuric effect of cilnidipine with that of amlodipine in hypertensive patients with kidney disease. A group of 339 patients, already receiving renin-angiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine. The primary endpoint was a decrease in the urinary protein to creatinine ratio. After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them. The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group. Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level. This study suggests that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients when coupled with a renin-angiotensin system inhibitor.

Topics: Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Creatinine; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension, Renal; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Apoptosis; Blood Pressure; Calcium; Cardiovascular Diseases; Dihydropyridines; Humans; Prevalence; Recurrence; Risk; Stroke; Time Factors; Treatment Outcome

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 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

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 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

What is the central question of this study? Head-to-head comparison of the therapeutic efficacy among commercial iron chelators and a dual T- (TTCC) and L-type calcium channel (LTCC) blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in iron-overloaded conditions has not been assessed. What is the main finding and its importance? The dual TTCC and LTCC blocker efonidipine could provide broad beneficial effects in the heart, liver, plasma and mitochondria in both wild-type and thalassaemic mice in iron-overloaded conditions. Its beneficial effects are of the same degree as the three commercial iron chelators currently used clinically. It is possible that efonidipine could be an alternative choice in patients unable to take iron chelators for the treatment of iron-overload conditions. Iron chelation therapy is a standard treatment in thalassaemia patients; however, its poor cardioprotective efficacy and serious side-effects are a cause for concern. Previous studies have shown that treatment with L-type calcium channel (LTCC) blockers or dual T-type calcium channel (TTCC) and LTCC blockers decreases cardiac iron and improves cardiac dysfunction in an iron-overloaded rodent model. Currently, the head-to-head comparison of therapeutic efficacy among commercial iron chelators, a dual TTCC and LTCC blocker and an LTCC blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in an iron-overloaded state has never been investigated. An iron-overloaded state was induced in β-thalassaemic and wild-type mice. Cardiac iron overload was induced to a greater extent than in a previous study by feeding the mice with an iron-enriched diet for 4 months. Then, an LTCC blocker (amlodipine) or a dual TTCC and LTCC blocker (efonidipine) or one of the commercial iron chelators (deferoxamine, deferasirox or deferiprone) was administered for 1 month with continuous iron feeding. All treatments reduced cardiac iron deposition and improved mitochondrial and cardiac dysfunction in both types of mice. Only efonidipine and the iron chelators reduced liver iron accumulation, liver malondialdehyde and plasma malondialdehyde in these mice. Although all pharmacological interventions reduced cardiac iron deposition, they did not alter the protein expression levels of cardiac iron transporter. These findings indicated that efonidipine provided a

Topics: Animals; Benzoates; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiovascular Diseases; Deferasirox; Deferiprone; Deferoxamine; Dihydropyridines; Heart; Iron Chelating Agents; Iron Overload; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mitochondria; Nitrophenols; Organophosphorus Compounds; Pyridones; Thalassemia; Triazoles

Topics: Blood Pressure; Cardiovascular Diseases; Carotid Artery Diseases; Circadian Rhythm; Dihydropyridines; Female; Humans; Hypertension; Male; Office Visits

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

Topics: Blood Pressure; Cardiovascular Diseases; Dihydropyridines; Female; Humans; Hypertension; Male; Metabolic Syndrome; Nitrophenols; Organophosphorus Compounds

CV-159 is a unique dihydropyridine Ca(2+) antagonist with an anti-calmodulin (CaM) action. A pathogenic feature of atherosclerosis is vascular inflammatory change. In the present study, we examined whether CV-159 exerts protective effects on smooth muscle inflammatory responses. After pretreatment of rat mesenteric arterial smooth muscle cells (SMCs) with CV-159 (0.1 - 10 microM, 30 min), TNF-alpha (10 ng/ml) was applied for 20 min or 24 h. CV-159 inhibited TNF (24 h)-induced vascular cell adhesion molecule (VCAM)-1 as determined by Western blotting. CV-159 inhibited TNF (20 min)-induced phosphorylation of Akt (Ser473) and NF-kappaB p65 (Ser536). An Akt inhibitor, LY294002, and an NF-kappaB inhibitor, pyrrolidine dithiocarbamate, inhibited TNF-induced VCAM-1. An antioxidant drug, N-acetyl-L-cysteine (NAC) inhibited TNF-induced VCAM-1. NAC also inhibited TNF-induced phosphorylation of Akt and NF-kappaB. Furthermore, CV-159 inhibited TNF-induced reactive oxygen species (ROS) production as determined fluorometrically using dichlorodihydrofluorescein diacetate. A CaM inhibitor, W-7, and a calcium/CaM-dependent protein kinase type II inhibitor, KN93, inhibited TNF-induced VCAM-1. W-7 and KN93 inhibited TNF-induced phosphorylation of Akt but not NF-kappaB. The present results indicate that in vascular SMCs, CV-159 inhibits TNF-induced VCAM-1 through inhibition of NF-kappaB and Akt phosphorylation. CV-159 prevents NF-kappaB phosphorylation by inhibiting ROS, while it prevents Akt phosphorylation by inhibiting both ROS and CaM.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Cardiovascular Diseases; Cells, Cultured; Dihydropyridines; Down-Regulation; Male; Muscle, Smooth, Vascular; NF-kappa B; Osmolar Concentration; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

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

Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs.. The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of > or =55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models.. In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality (n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality (n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem.. The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown.

Topics: Adaptor Proteins, Signal Transducing; Aged; Calcium Channel Blockers; Cardiovascular Diseases; Cohort Studies; Dihydropyridines; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proportional Hazards Models

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

Topics: Adrenergic beta-Antagonists; Aortic Aneurysm; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans; Perioperative Care; Postoperative Complications

We have previously reported the changing clinical characteristics of patients with vasospastic angina (VSA) before and after the introduction of new calcium channel blockers (benidipine and amlodipine) in 1990. In this subanalysis study, we compared the prognostic effects of 3 calcium channel blockers (benidipine, diltiazem, and amlodipine) on the incidence of cardiovascular events in patients with VSA in our cohort study, where 527 patients (318 men and 209 women) enrolled after 1990 (from January 1990 to December 2002) were followed-up for a mean period of 5.2 years. There was no significant difference in the clinical characteristics among the 3 calcium channel blocker groups. Multivariate analysis demonstrated that 4 factors, including smoking, hypertension, diabetes mellitus and reduced left ventricular ejection fraction, were significant risk factors for cardiovascular events. Among the 3 calcium channel blockers examined, benidipine (n = 148) tended to be associated with a lower incidence of total events, cardiovascular events, and cerebral infarction, compared with diltiazem (n = 313) and amlodipine (n = 111). Furthermore, benidipine significantly reduced the incidence of vascular infarction events, a possible indicator of atherosclerosis, as compared with diltiazem. These results suggest that benidipine may be more useful for the treatment of VSA as compared with diltiazem and amlodipine.

Topics: Adult; Aged; Aged, 80 and over; Amlodipine; Angina Pectoris; Calcium Channel Blockers; Cardiovascular Diseases; Cohort Studies; Coronary Vasospasm; Dihydropyridines; Diltiazem; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors

In an effort to assess the cardiovascular benefits of combined angiotensin receptor blockage and calcium channel antagonism, we assessed the chronic effects of the angiotensin type 1 receptor blocker candesartan, the calcium channel blocker benidipine, and the use of a combination therapy in Dahl salt-sensitive (DS) rats. DS rats receiving a high salt diet were treated with either benidipine (4 mg/kg), candesartan (1 mg/kg) or both. Rat blood pressure was measured using a tail-cuff method. Following 12 weeks, the effect on heart weight, plasma-oxidized low-density lipoprotein (ox-LDL) level, endothelium-dependent vasorelaxation, and histology of the heart and aorta was assessed. Blood pressure, heart weight and plasma ox-LDL levels increased, while endothelium-dependent vasorelaxation decreased in the DS rats. Candesartan and benidipine inhibited the increase in blood pressure and heart weight, and the decrease in endothelium-dependent vasorelaxation. The use of benidipine alone or a combination significantly inhibited the increase in ox-LDL levels, whereas candesartan alone had no significant effect on ox-LDL levels. The present findings indicate that, if the monotherapy using ARB could not achieve adequate control of blood pressure, the combination therapy with ARB and benidipine provides the additional reductions in hypertension and cardiac hypertrophy. Moreover, the combination therapy inhibits cardiovascular dysfunction and ox-LDL levels more effectively than use of ARB alone. These results contribute to the possibility of lowering ox-LDL levels as a means of enhancing cardiovascular protection.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Heart; Hypotension; Lipoproteins, LDL; Male; Muscle, Smooth, Vascular; Organ Size; Phenylephrine; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Tetrazoles; Time Factors; Vasoconstriction; Vasoconstrictor 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

Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications.

Topics: Age Factors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Disease Models, Animal; Down-Regulation; Endothelin-1; Insulin Resistance; Male; Myocardium; Rats; Rats, Inbred OLETF; Rats, Long-Evans

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

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Databases, Factual; Dihydropyridines; Female; Humans; Male; Middle Aged

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: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Dihydropyridines; Humans; Hypertension

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans

Calcium channel antagonists have gained widespread acceptance for treatment of a variety of cardiovascular disorders. Newer drugs of the dihydropyridine class are especially attractive for treating hypertension and angina because of their increased vascular selectivity, favorable side-effect profile, and pharmacokinetics that allow once-daily dosing. In the future, calcium channel antagonists may also play a role in antiatherogenic therapy and in treatment of congestive heart failure and cerebrovascular disease as results of prospective studies become available and new agents are developed.

Topics: Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Cerebrovascular Disorders; Dihydropyridines; Diltiazem; Heart Failure; Humans; Verapamil

The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris.

Topics: Animals; Arteriosclerosis; Atrioventricular Node; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular System; Coronary Circulation; Dihydropyridines; Dogs; Electric Stimulation; Female; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; Rabbits

Over the past decade the calcium antagonist drugs, also known as calcium channel blockers, have become established for use in a variety of cardiovascular diseases. A bewildering (and ever-growing) number of drugs in this class now becoming available. This article summarises the important characteristics of the calcium antagonists and discusses their practical use in hypertension, angina and other conditions in general practice.

Topics: Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Diltiazem; Family Practice; Female; Humans; Male; Verapamil

Topics: Animals; Antihypertensive Agents; Cardiovascular Diseases; Dihydropyridines; Humans; Isradipine