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[Figure: see text].

Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells., (Copyright © 2020 Wang, Ma, Tong, Zhang, Wen and Li.)

Background: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use., Methods: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth., Results: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na + current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K + channel subspecies (for Class III), and novel molecular targets related to Ca 2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation., Conclusions: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

Background: When drug-induced coronary spasm provocation tests are performed, a washout period of >48h for calcium channel blockers (CCBs) is uniformly recommended. However, each CCB has a distinct half-life, and little is known about the influence of prior oral administration of CCBs on acetylcholine provocation test to evaluate coronary vasomotor reaction., Methods and Results: We examined 245 consecutive patients with suspected vasospastic angina who had undergone acetylcholine provocation test. Of those patients, 29 patients had been on amlodipine, an ultra-long term acting CCB (group A), 34 on other CCBs (group O), and 182 patients on no CCB (group N). After CCBs had been withheld > 48h, we performed acetylcholine provocation, which resulted in 152 positive, 36 intermediate, and 57 negative reactions. We evaluated coronary artery tone calculated as follows: (luminal diameter after nitrate-baseline luminal diameter)÷(luminal diameter after nitrate)×100 (%). In group A patients, coronary artery tone was lower (A:9.1±6.9% vs. O:11.7±8.3% vs. N:12.1±8.5%, p=0.0011) and the positive rate of acetylcholine provocation test was lower than group O and group N (A:41% vs. O:68% vs. N:64%, p=0.047). Multivariate logistic analysis showed that taking amlodipine until 2days before acetylcholine provocation test was a significant inverse predictor for acetylcholine-provoked coronary spasm (odds ratio 0.327; 95% confidence interval 0.125-0.858, p=0.023)., Conclusions: Residual vasodilatory effects of ultra-long acting CCB may decrease coronary artery tone and the vasoconstrictive reaction to acetylcholine suggesting that a 2-day pre-test drug holiday may not be long enough., (Copyright © 2017 Elsevier B.V. All rights reserved.)

L-type voltage-gated calcium channels play a key role in the regulation of arterial vascular smooth muscle tone and blood pressure levels and L-type calcium channel blockers (CCBs) are widely used antihypertensive drugs. Additionally, T-type channels regulate vascular tone in small-resistance vessels and renin and aldosterone secretion, and N-type channels, expressed in sympathetic nerve terminals, regulate the release of neurotransmitters. As compared with L-type CCBs, L/N-and L/T-type CCBs decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors. Thus, dual L/N-and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. However, further large-scale, long-term comparative trials are needed to confirm that these differences translate into an improvement in clinical outcomes. © 2017 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved., (Copyright © 2017 Sociedad Española de Hipertension-Liga Española para la Lucha de la Hipertensión Arterial (SEH-LELHA). Publicado por Elsevier España, S.L.U. All rights reserved.)

Calcins are a novel family of scorpion peptides that bind with high affinity to ryanodine receptors (RyRs) and increase their activity by inducing subconductance states. Here, we provide a comprehensive analysis of the structure-function relationships of the eight calcins known to date, based on their primary sequence, three-dimensional modeling, and functional effects on skeletal RyRs (RyR1). Primary sequence alignment and evolutionary analysis show high similarity among all calcins (≥78.8% identity). Other common characteristics include an inhibitor cysteine knot (ICK) motif stabilized by three pairs of disulfide bridges and a dipole moment (DM) formed by positively charged residues clustering on one side of the molecule and neutral and negatively charged residues segregating on the opposite side. [(3)H]Ryanodine binding assays, used as an index of the open probability of RyRs, reveal that all eight calcins activate RyR1 dose-dependently with Kd values spanning approximately three orders of magnitude and in the following rank order: opicalcin1 > opicalcin2 > vejocalcin > hemicalcin > imperacalcin > hadrucalcin > maurocalcin >> urocalcin. All calcins significantly augment the bell-shaped [Ca(2+)]-[(3)H]ryanodine binding curve with variable effects on the affinity constants for Ca(2+) activation and inactivation. In single channel recordings, calcins induce the appearance of a subconductance state in RyR1 that has a unique fractional value (∼20% to ∼60% of the full conductance state) but bears no relationship to binding affinity, DM, or capacity to stimulate Ca(2+) release. Except for urocalcin, all calcins at 100 nM concentration stimulate Ca(2+) release and deplete Ca(2+) load from skeletal sarcoplasmic reticulum. The natural variation within the calcin family of peptides offers a diversified set of high-affinity ligands with the capacity to modulate RyRs with high dynamic range and potency., (© 2016 Xiao et al.)

Recent studies have shown that visit-to-visit blood pressure (BP) variability was emerging as an independent risk factor for stroke. Although the mechanism is not fully understood, artery remodeling would be closely associated with the relationship between visit-to-visit BP variability and stroke. In addition, the class of antihypertensive agents is suggested to be an important determinant of visit-to-visit BP variability. This review article summarizes the recent literature on these topics. In the elderly hypertensives, strict BP control using calcium channel blockade would play a crucial role to prevent stroke via reducing the visit-to-visit BP variability.

The four major classes of antihypertensive drugs—diuretics, β-blockers, calcium channel blockers, and renin-angiotensin system inhibitors (including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)—have significant qualitative and quantitative differences in the adverse effects they cause. Structural and chemical differences have been identified within these classes, especially among the calcium channel blockers and, to a lesser extent, among the thiazide/thiazide-like diuretics. However, it has been more difficult to demonstrate that these differences translate into differential effects with respect to either the surrogate endpoint of blood pressure reduction or, more importantly, hypertension-related cardiovascular complications. Based on a hierarchy-of-evidence approach, differences are apparent between hydrochlorothiazide and chlorthalidone based on evidence of moderate quality. Low-quality evidence suggests atenolol is less effective than other β-blockers. However, no significant intraclass differences have been established among the other classes of antihypertensive drugs.

Inhibition of voltage-gated L-type calcium channels by organic calcium channel blockers is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac ischemia. Since decades these antihypertensives (such as the dihydropyridines amlodipine, felodipine or nifedipine) belong to the most widely prescribed drugs world-wide. Their tolerability is excellent because at therapeutic doses their pharmacological effects in humans are limited to the cardiovascular system. During the last years substantial progress has been made to reveal the physiological role of different L-type calcium channel isoforms in many other tissues, including the brain, endocrine and sensory cells. Moreover, there is accumulating evidence about their involvement in various human diseases, such as Parkinson's disease, neuropsychiatric disorders and hyperaldosteronism. In this review we discuss the pathogenetic role of L-type calcium channels, potential new indications for existing or isoform-selective compounds and strategies to minimize potential side effects.

Background: High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension., Methods and Findings: PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference = -15.19, 95% CI -19.65 - -10.72, p<1×10(-5)), proteinuria (mean difference = -0.73, 95% CI -0.88 - -0.57, p<1×10(-5)), protein to creatinine ratio (mean difference = -0.22, 95% CI -0.41 - -0.03, p = 0.02), and urinary albumin to creatinine ratio (mean difference = -55.38, 95% CI -86.67 - -24.09, p = 0.0005); no significant difference was noted for systolic blood pressure (SBP) (p = 0.76) and diastolic blood pressure (DBP) (p = 0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p = 0.98), DBP (p = 0.86), glomerular filtration rate (p = 0.93), albuminuria (p = 0.97), creatinine clearance rate (p = 0.24), and serum creatinine (p = 0.27) in patients with hypertension., Conclusion: In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal function were enhanced compared with L-type CCBs but did not differ from RAS antagonists. Their protective effects on renal function were independent of blood pressure.

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

Dihydropyridines (DHP), which nifedipine is a member of, preferentially block Ca(2+) channels of different cell types. Moreover, influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) activates Ca(2+) signaling pathways, which in turn contribute to numerous cellular processes. Although LTCCs are expressed in undifferentiated cells, very little is known about its contributions to the transcriptional regulation of mesodermal and cardiac genes. This study aimed to examine the contribution of LTCCs and the effect of nifedipine on the commitment of pluripotent stem cells toward the cardiac lineage in vitro. The murine embryonic stem (ES, cell line D3) and induced pluripotent stem (iPS, cell clone 09) cells were differentiated into enhanced green fluorescence protein (EGFP) expressing spontaneously beating cardiomyocytes (CMs). Early treatment of differentiating cells with 10 µM nifedipine led to a significant inhibition of the cardiac mesoderm formation and cardiac lineage commitment as revealed by gene regulation analysis. This was accompanied by the inhibition of spontaneously occurring Ca(2+) transient and reduction of LTCCs current density (I(CaL)) of differentiated CMs. In addition, nifedipine treatment instigated a pronounced delay of the spontaneous beating embryoid body (EB) and led to a poor surface localization of L-type Ca(2+) channel α(1C) (Ca(V)1.2) subunits. Contrary late incubation of pluripotent stem cells with nifedipine was without any impact on the differentiation process and did not affect the derived CMs function. Our data indicate that nifedipine blocks the determined path of pluripotent stem cells to cardiomyogenesis by inhibition of mesodermal commitment at early stages of differentiation, thus the proper upkeep Ca(2+) concentration and pathways are essentially required for cardiac gene expression, differentiation and function.

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.

Background: Observational studies suggest that there are differences in adherence to antihypertensive medications in different classes. Our objective was to quantify the association between antihypertensive drug class and adherence in clinical settings., Methods and Results: Studies were identified through a systematic search of English-language articles published from the inception of computerized databases until February 1, 2009. Studies were included if they measured adherence to antihypertensives using medication refill data and contained sufficient data to calculate a measure of relative risk of adherence and its variance. An inverse-variance-weighted random-effects model was used to pool results. Hazard ratios (HRs) and odds ratios were pooled separately, and HRs were selected as the primary outcome. Seventeen studies met inclusion criteria. The pooled mean adherence by drug class ranged from 28% for β-blockers to 65% for angiotensin II receptor blockers. There was better adherence to angiotensin II receptor blockers compared with angiotensin-converting enzyme inhibitors (HR, 1.33; 95% confidence interval, 1.13 to 1.57), calcium channel blockers (HR, 1.57; 95% confidence interval, 1.38 to 1.79), diuretics (HR, 1.95; 95% confidence interval, 1.73 to 2.20), and β-blockers (HR, 2.09; 95% confidence interval, 1.14 to 3.85). Conversely, there was lower adherence to diuretics compared with the other drug classes. The same pattern was present when studies that used odds ratios were pooled. After publication bias was accounted for, there were no longer significant differences in adherence between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors or between diuretics and β-blockers., Conclusion: In clinical settings, there are important differences in adherence to antihypertensives in separate classes, with lowest adherence to diuretics and β-blockers and highest adherence to angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. However, adherence was suboptimal regardless of drug class.

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

Calcium channel blockers have been widely recognized as important medicines for the treatment of cardiovascular diseases, including hypertension and angina pectoris. In Japan, more than 15 calcium channel blockers are clinically available, and their pharmacological profiles are known to vary in terms of action on subtypes of voltage-dependent Ca(2+) channels, tissue selectivity, and influence on the sympathetic nerve activity. Thus, the classification of calcium channel blockers is useful for understanding the similarity and differences of the drugs' action, leading to optimum prescription.

Calcium channel blockers continue to be used for the management of a wide variety of adult and pediatric conditions including hypertension, angina pectoris, atrial arrhythmias, Raynaud phenomenon, and migraine headaches. With increased use comes increased potential for misuse and abuse. This article serves as a review of calcium channel blocker physiology with emphasis on presentation and management of the pediatric patient with calcium channel blocker toxicity.

Despite their presence in many tissues and their potential implication in various disease states, low-voltage activated T-type calcium channels (T-channels) have only recently become targets of interest. Unfortunately, the lack of selective T-channel blockers has hampered further characterisation of these channels. The recent availability of cloned T-channels, the Ca(V)3 proteins, facilitates identification of novel T-channel blockers. Also, studies performed in knockout animals have fostered novel interest. Selective inhibition of T-channels may have clinical importance in cardiovascular diseases, some forms of epilepsy, sleep disorders, pain and possibly cancer. This review focuses on novel research approaches to discover potent and selective T-channel modulators. These molecules may be potential drugs for treating human diseases, as well as important tools to decipher the physiological role of these channels.

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

Background: Hypertension is a leading cause of cardiovascular diseases. To evaluate sex-specific differences in the prescription pattern of antihypertensive therapy, registry data from the regional health insurance fund "Burgenländische Gebietskrankenkasse" (BGKK) were analyzed., Material and Methods: In a retrospective cross sectional cohort study data from 41499 individuals covered by the BGKK in 2003, and who had been treated with cardiovascular drugs were analyzed. Data were evaluated according to drug classifications., Results: Among subjects treated with cardiovascular medication 38.3 % were males and 61.7 % females. The drug classes acting on the renin-angiotensin-system were prescribed more frequently than beta-blockers, calcium channel blockers, diuretics and antihypertensives. Women were treated more often with diuretics and beta-blockers, whereas men received more antihypertensives and drugs acting on the renin angiotensin system (p < 0.01 between groups of sexes)., Conclusion: Sex-specific differences exist regarding the prevalence of antihypertensive drug prescriptions between men and women. Further, the prescription pattern of equivalently effective medications differs between sexes.

As a drug class, calcium channel blockers encompass a heterogeneous group of compounds with distinctive structures and pharmacologic characteristics. These agents are widely used in the treatment of hypertension, chronic coronary ischemia, and/or supraventricular arrhythmias. Much of the early debate alluding to increased cardiovascular risk associated with calcium channel blocker use has been silenced by an array of outcomes trials that show these drugs to be both safe and effective in reducing hard cardiovascular end points. The most common side effects associated with calcium channel blockers are vasodilatory in nature and include a non-volume-dependent form of peripheral edema, flushing, and headache. Despite the sometimes discomforting side effects seen with calcium channel blocker therapy, their robust blood pressure-lowering effect makes them an important component of most multidrug regimens used for blood pressure control.

All children aged > or = 3 years should have an annual blood pressure (BP) measurement taken during a routine physical examination. Physicians should become familiar with recommended pediatric normative BP tables. BP above the 95th percentile may require drug therapy. There are several categories of antihypertensives available to the clinician. Calcium channel antagonists (CCAs) are a class of drugs that exert their antihypertensive effect by inhibiting the influx of calcium ions across the cell membranes. This results in dilatation of peripheral arterioles. When given orally, CCAs are metabolised in the liver by cytochrome P450 (CYP) enzyme CYP3A4; hence, some CCAs will affect the half-life of drugs that share this enzyme system for their metabolism. CCAs can be safely used in children with renal insufficiency or failure and as a general rule there is no need to modify drug dosage in this population. CCAs are generally well tolerated; most adverse effects appear to be dose related. Headache, flushing, gastrointestinal upset, and edema of the lower extremities are the most common symptoms reported with the use of CCAs. Pediatric data regarding safety and efficacy of CCAs have mostly been obtained from retrospective analyses. Extended-release nifedipine and amlodipine are the two most commonly used oral CCAs in the management of pediatric hypertension. These drugs can be given once a day, although many children require twice-daily administration. Extended-release nifedipine has to be swallowed whole; hence, its use in younger children who cannot swallow pills is limited. Amlodipine can be made into a solution without compromising its long duration of action; therefore, it is the CCA of choice for very young children. Oral short-acting nifedipine and intravenous nicardipine are safe and effective CCAs for the management of hypertensive crisis in children. Short-acting nifedipine can cause unpredictable changes in BP; hence, it should be used cautiously and in low doses. Intravenous nicardipine has a rapid onset of action and a short half-life. Intravenous infusion of nicardipine can be titrated for effective control of BP. Intravenous nicardipine has been used safely in hospitalized children and newborns for the management of hypertensive crisis, and for controlled hypotension during surgery. CCAs are a class of antihypertensives that are safe and effective in pediatric patients. They have relatively few adverse effects and are well tolerated by children. This article reviews CCAs as antihypertensives in the management of pediatric hypertension.

The least squares support vector machine (LSSVM), as a novel machine learning algorithm, was used to develop quantitative and classification models as a potential screening mechanism for a novel series of 1,4-dihydropyridine calcium channel antagonists for the first time. Each compound was represented by calculated structural descriptors that encode constitutional, topological, geometrical, electrostatic, quantum-chemical features. The heuristic method was then used to search the descriptor space and select the descriptors responsible for activity. Quantitative modeling results in a nonlinear, seven-descriptor model based on LSSVM with mean-square errors 0.2593, a predicted correlation coefficient (R(2)) 0.8696, and a cross-validated correlation coefficient (R(cv)(2)) 0.8167. The best classification results are found using LSSVM: the percentage (%) of correct prediction based on leave one out cross-validation was 91.1%. This paper provides a new and effective method for drug design and screening.

alpha-Conotoxins are selective antagonists of neuromuscular or neuronal nicotinic acetylcholine receptors. Individual family members are often highly selective towards distinct receptor subclasses, most notably within neuronal nicotinic acetylcholine receptors. As such they are being used as tools to probe for the type and diversity of receptor subclasses in distinct parts of the central and peripheral nervous systems. Many new alpha-conotoxins are being identified every year, broadening the available armoury because small variations in their sequences and structures often confer altered selectivity towards receptor subunits and subclasses. Many neurological diseases are being associated wholly or in part with functional changes within specific subclasses of nicotinic acetylcholine receptors. Significantly, with more structures of alpha-conotoxins also becoming available this enables ready comparison of their similarities and, more notably, of their subtle differences, which dictate subclass selectivity. As such, alpha-conotoxins offer the potential to become templates for the creation, through rational drug design strategies, of pharmaceuticals highly selective for specific subclasses of nicotinic acetylcholine receptors.

Calcium channel blockers (CCBs) comprise a heterogeneous group of compounds with unique structures and pharmacologic characteristics. These agents are employed in the treatment of hypertension, coronary ischemia, and/or supraventricular arrhythmias. CCBs are both substrates for, and in the instance of verapamil and diltiazem inhibitors of, cytochrome P450 3A4. In the case of verapamil and diltiazem, this inhibitory effect increases the likelihood of drug-drug interactions with other compounds similarly metabolized by cytochrome P450 3A4. Much of the debate with reference to a cardiovascular risk for CCBs has been quieted with the advent of sustained-release delivery systems that offer a more gradual rate of drug delivery. The most common side effects with CCBs are vasodilatory in nature and include peripheral edema, flushing, and headache. Despite the potential for side effects with CCBs, their potent blood pressure-lowering effect makes them a prerequisite for blood pressure control in many patients.

L-type calcium channel antagonist is clinically used for treatment of cardiovascular diseases such as angina, hypertension and arrhythmia. Recent large clinical trials indicated that calcium antagonist is effective in the prevention of cardiovascular event as well as the treatment of hypertension. Recently, calcium antagonists, not stimulating sympathetic nerve activity, have been newly developed. In the future, clinical application of N-type or T-type calcium antagonist are expected.

Background: Numerous studies suggest that the dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) have differential antiproteinuric effects. Proteinuria reduction is a correlate of the progression of renal disease. In an earlier systematic review, calcium antagonists were shown as effective antihypertensive drugs, but there was uncertainty about their renal benefits in patients with proteinuria and renal insufficiency., Methods: A systematic review was conducted to assess the differential effects of DCAs and NDCAs on proteinuria in hypertensive adults with proteinuria, with or without diabetes, and to determine whether these differential effects translate into altered progression of nephropathy. Studies included in the review had to be randomized clinical trials with at least 6 months of treatment, include a DCA or NDCA treatment arm, have one or more renal end points, and have been initiated after 1986. Summary data were extracted from 28 studies entered into two identical but separate databases, which were compared and evaluated by independent reviewers. The effects of each drug class on blood pressure (N= 1338) and proteinuria (N= 510) were assessed., Results: After adjusting for sample size, study length, and baseline value, there were no statistically significant differences in the ability of either class of calcium antagonist to decrease blood pressure. The mean change in proteinuria was +2% for DCAs and -30% for NDCAs (95% CI, 10% to 54%, P= 0.01). Consistently greater reductions in proteinuria were associated with the use of NDCAs compared with DCAs, despite no significant differences in blood pressure reduction or presence of diabetes., Conclusion: This analysis supports (1) similar efficacy between subclasses of calcium antagonists to lower blood pressure, and (2) greater reductions in proteinuria by NDCAs compared to DCAs in the presence or absence of diabetes. Based on these findings, NDCAs, alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria.

The present study evaluates the possible role of dihydropyridine calcium channel antagonist nimodipine on diclofenac analgesia in formalin-induced facial pain model in rats. Adult Wistar rats of either sex received an injection of 50 microl of 5% v/v subcutaneous formalin into one vibrissal pad and consequent facial grooming behaviour was monitored. Animals exhibited two distinct periods of nocifensive grooming: i) an acute phase lasting 0-6 min; and ii) a tonic phase lasting 6-45 min. The individual analgesic response of nimodipine and diclofenac was noted at doses of 5, 10 and 20 mg/kg i.p. and 1, 2 and 4 mg/kg i.p., respectively, administered 5 min prior to formalin injection. Diclofenac 1, 2 and 4 mg/kg i.p. produced dose-dependent inhibition of facial grooming in both acute and tonic phases. Nimodipine per se had antihyperalgesic effect, but to a very small extent. Nimodipine 10 and 20 mg/kg significantly potentiated the subanalgesic dose of diclofenac, i.e., 0.2 mg/kg. Results of the study showed that low dose nimodipine per se has insignificant antihyperalgesic effect. However, it potentiated the subanalgesic dose of diclofenac showing a synergistic response. These results imply that nimodipine can be used as an adjunct to the treatment of various neuropathic pains, postherpetic and diabetic neuropathies but the clinical efficacy needs to be evaluated in patients.

Over the last 20 years the combination of patch clamp and molecular biology techniques have resulted in an explosion in our knowledge of the different calcium channel types and their roles in physiology. A crucial component to this advance has been the discovery of specific blockers for different calcium channel types. These blockers have not only permitted researchers to assign specific functions to different channel types, but their specificity allowed them to be used to treat diseases that resulted from enhanced calcium channel function. In some cases, the enhanced calcium channel function is secondary to other problems leading to increased cellular excitability. The specificity of calcium channel blockers, however, has provided a means to treat symptoms of the pathophysiology until more effective treatments become available to address the underlying problems. The goal of this review is to introduce the various types of calcium channels, their primary physiologic roles, drugs that block these channels, and diseases that are currently being treated with these drugs., (Copyright 2004 Wiley-Liss, Inc.)

Issue: Anticonvulsants are not a single therapeutic class, but are composed of multiple distinct subclasses with different mechanisms of action, efficacies, and side effects.

This paper reviews the current literature pertaining to calcium channel blockers, including their classification, properties, and therapeutic indications, in light of several recent trials that have addressed their safety. Calcium channel blockers are a structurally and functionally heterogeneous group of medications that are used widely to control blood pressure and manage symptoms of angina. They are classified as dihydropyridines or nondihydropyridines. As a class, they are well tolerated and are associated with few side effects. The question of whether they may precipitate cardiovascular events has been largely settled by recent trials, such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the International Verapamil Slow-Release/Trandolapril Study (INVEST), and the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) study, in which no such association was found. Even so, the use of these agents has been linked with an increased risk of heart failure. Thus, long-acting calcium channel blockers may be safely used in the management of hypertension and angina. However, as a class, they are not as protective as other antihypertensive agents against heart failure.

Although T-type calcium channel currents were observed almost 30 years ago, the genes that encode the pore-forming subunits have only been recently reported. When expressed in heterologous systems, three distinct alpha1 subunits (alpha1G (Cav3.1), alpha1H (Car3.2), and alpha1I (Cav3.3)) conduct T-type currents with insert similar but not identical electrophysiological characteristics that. Alpha 1G, alpha 1H, and alpha 1I transcripts are found throughout neural and nonneural tissues, suggesting multiple types of T-type channels (also called low voltage-activated calcium channels (LVAs)) are coexpressed by many tissues. The study of endogenous LVAs has been hampered by a lack of highly selective antagonists that differentiate between LVA subtypes. Furthermore, many pharmacological agents attenuate currents conducted by LVA and high voltage-activated calcium channels (HVAs). At least 15 classes of pharmacological agents affect T-type currents, and the therapeutic use of many of these drugs has implicated LVAs in the etiology of a variety of diseases. Comparison of the responses of recombinant and native LVAs to pharmacological agents and endogenous modulatory molecules will lead to a better understanding of LVAs in normal and diseased cells.

Voltage-gated calcium channels are key sources of calcium entry into the cytosol of many excitable tissues. A number of different types of calcium channels have been identified and shown to mediate specialized cellular functions. Because of their fundamental nature, they are important targets for therapeutic intervention in disorders such as hypertension, pain, stroke, and epilepsy. Calcium channel antagonists fall into one of the following three groups: small inorganic ions, large peptide blockers, and small organic molecules. Inorganic ions nonselectively inhibit calcium entry by physical pore occlusion and are of little therapeutic value. Calcium-channel-blocking peptides isolated from various predatory animals such as spiders and cone snails are often highly selective blockers of individual types of calcium channels, either by preventing calcium flux through the pore or by antagonizing channel activation. There are many structure-activity-relation classes of small organic molecules that interact with various sites on the calcium channel protein, with actions ranging from selective high affinity block to relatively nondiscriminatory action on multiple calcium channel isoforms. Detailed interactions with the calcium channel protein are well understood for the dihydropyridine and phenylalkylamine drug classes, whereas we are only beginning to understand the molecular actions of some of the more recently discovered calcium channel blockers. Here, we provide a comprehensive review of pharmacology of high voltage-activated calcium channels.

Calcium antagonists (CAs) or calcium-channel blockers, are a common group of antihypertensive medications. These drugs have the property of blocking the calcium channels of the vascular and cardiac smooth-muscle fibers. They have been associated with cutaneous reactions ranging from exanthems to severe adverse events. The frequency of these reactions may be as high as 48 percent. The most common are ankle or pedal edema (up to 30 %), gingival hyperplasia (up to 21 %), and flushing (up to 10 %). Less common are facial or truncal telangiectasia, photosensitivity reactions, new-onset psoriasis (as well as exacerbation of it), purpuric exanthems, pemphigoid manifestations, subacute cutaneous lupus erythematosus, gynecomastia, erythromelalgia, and oral ulcers. Particular adverse manifestations relate to drug potency, degree of vasodilatation, patient age, coexistence of other diseases, co-administration of other cytochrome P450 CYP3A-metabolized medications, fibroblast stimulation, and blood cell effects. Calcium antagonists are associated with a wide range of skin reactions, and the dermatologist should include these in the differential diagnosis of cutaneous diseases.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Calcium channel blockers (CCBs) were developed as vasodilators, and their use in cardiovascular disease treatment remains largely based on that mechanism of action. More recently, with the evolution of second- and third-generation CCBs, pleiotropic effects have been observed, and at least some of CCBs' benefit is attributable to these mechanisms. Understanding these effects has contributed greatly to elucidating disease mechanisms and the rationale for CCB use. Furthermore, this knowledge might clarify why drugs are useful in some disease states, such as atherosclerosis, but not in others, such as heart failure. Although numerous drugs used in the treatment of vascular disease, including statins and angiotensin-converting-enzyme inhibitors, have well-described pleiotropic effects universally accepted to contribute to their benefit, little attention has been paid to CCBs' potentially similar effects. Accumulating evidence that at least 1 CCB, amlodipine, has pharmacologic actions distinct from L-type calcium channel blockade prompted us to investigate the pleiotropic actions of amlodipine and CCBs in general. There are several areas of research; foci here are (1) the physicochemical properties of amlodipine and its interaction with cholesterol and oxidants; (2) the mechanism by which amlodipine regulates NO production and implications; and (3) amlodipine's role in controlling smooth muscle cell proliferation and matrix formation.

In the last 15 years, calcium channel blockers have been widely used for treating cardiovascular diseases. These agents are a heterogeneous group of drugs with differing cardiovascular effects, and are effective in the treatment of angina and hypertension. These synthetic compounds bind separately with receptor sites located in or near the calcium channel, at molecular sites still to be fully identified. Verapamil, nifedipine and diltiazem are the most representative calcium channel blockers and used as prototypes for the design and development of new anticalcium molecules with potential efficacy and reduced toxic effects. There are three different types of voltage-operated calcium channels (VOCs): L-type, T-type and N-type, which are considered extra-cellular, but some anti-calcium agents as bepridil possess potential intracellular calcium activity. Many synthetic compounds containing heterocyclic ring in their structures have attracted considerable interest since current studies revealed their mechanisms and sites of action. This article reviews the new advances in the calcium channel antagonist group, showing new structures with longer-acting and higher vascular selectivity.

Chronic stable angina pectoris (CSAP) resulting from coronary artery disease (CAD) is common in elderly patients, and significantly reduces their quality of life. Myocardial revascularisation procedures in this age group entail significant risks, largely related to comorbidities rather than advanced age itself. Coronary artery anatomy is more likely to be technically unsuitable for revascularisation and angina more resistant to drug treatment. Therefore, elderly patients often take combinations of antianginal drugs. Calcium channel antagonists (CCAs) are effective antianginal drugs first introduced for clinical use in the late 1970's. They reduce myocardial ischaemia by both causing vasodilatation of coronary resistance vessels and reducing cardiac workload (negative inotropic effect). However, adverse effects related to abrupt arterial vasodilatation limited the tolerability of these short acting 'first generation' drugs (nifedipine, verapamil and diltiazem). Furthermore, short acting nifedipine may occasionally increase both the frequency of angina pectoris and mortality in patients with CAD. Since then, long acting formulations of first generation agents and new chemical entities (second and third generation drugs) have been developed. These are well tolerated and effective at attenuating both myocardial ischaemia and the frequency and severity of angina pectoris in most patients with stable CAD. Current guidelines on the drug treatment of CSAP propose that beta-adrenoceptor antagonists (beta-blockers) should be used as first line medication primarily for their prognostic benefits, and that CCAs need only be introduced if beta-blockers are not tolerated, contraindicated or ineffective. Despite this, there is a wealth of evidence from clinical trials that demonstrate equal antianginal efficacy for CCAs and beta-blockers. The presence of chronic heart failure and prior myocardial infarction are clear indications for the use of beta-blockers in preference to CCAs for the treatment of CSAP. However, in patients with both CSAP and hypertension, second and third generation CCAs may offer prognostic benefits of similar magnitude to those provided by beta-blockers. Therefore, antianginal drug therapy must be tailored to the individual needs and comorbidities of each elderly patient.

Over the past 30 years, a considerable body of experimental and clinical evidence has accumulated to support the suggestion that calcium channel blockers (CCBs) have significant antiatherosclerotic effects that are independent of their hypotensive effects. Early research using animal models of atherosclerosis and CCBs in concentrations that exceeded the normal therapeutic dose range showed definite antiatherosclerotic effects, especially in the development of new lesions. Investigations of these effects in humans have used quantitative coronary angiography and B-mode ultrasonography and have demonstrated some antiatherosclerotic effects. This article reviews the currently available evidence of antiatherosclerotic effects of CCBs in animal models and in clinical trials., (Copyright 2002, Elsevier Science (USA). All rights reserved.)