Slow calcium channel blockers and the calcium paradox: comparative studies in the rat with seven drugs

In studies of the calcium paradox, the isolated perfused rat heart was used to characterize the relationship between myocardial protein leakage and the concentration of calcium antagonist (verapamil and D600) or calcium in the perfusion fluid during a cycle of calcium depletion and repletion. The results indicated a dose-dependency such that protein leakage could be progressively reduced by decreasing the concentration of calcium during calcium repletion and/or by increasing the concentrations of drug. Detailed dose-response studies with seven calcium antagonists (verapamil, D600, nifedipine, terodiline, diltiazem, fendiline and prenylamine) and a calcium concentration of 1.0 mmol/l during a 20 min period of calcium repletion following a 10 min period of calcium depletion revealed complex dose-response characteristics for each drug. In the dose range studied (0 to 40 mumol/l) all drugs with the exception of prenylamine were able to reduce protein leakage by up to 25 to 30% Optimal concentrations for verapamil, nifedipine, D600, diltiazem and terodiline were all between 2.0 and 4.0 mumol/l. With the exception of D600, which provided a constant reduction of protein leakage at all concentrations above this optimum, all drugs exhibited bell-shaped dose-response curves with a loss of efficacy at higher concentrations. Fendiline also had a bell-shaped dose-response curve with 23% as a maximal reduction of leakage; however, the optimal concentration for this drug was 21.0 mumol/l. Additional studies with verapamil revealed that the drug acted during the calcium repletion phase and did not influence events during calcium depletion. Simultaneous use of two drugs, verapamil and nifedipine, at their optimal concentrations failed to improve the reduction in protein leakage over and above that observed with one drug alone.     

钙离子拮抗剂治疗偏头痛患者的疗效观察

目的 探讨钙拮抗剂对偏头痛的预防作用。方法 应用前瞻性研究和双盲对照实验,观察口服尼莫地平(30mg,3/日)、尼莫地平缓释片(30mg,3/日)、特来斯(30mg,3/日)、盐酸氟桂嗪(10mg,3/日)、尼卡地平(40mg,3/日)、依拉地平(40mg,3/日)对212例偏头痛病人的疗效,随访1年。结果 治疗结束时有171例坚持服用钙拮抗剂,13例被排除试验。服药后各组的头痛天数和头痛强度均有下同程度的下降,尼莫地平缓释片和特来斯对偏头痛的远期预防效果较好,依拉地平近期预防效果较好,安慰剂对偏头痛发作有一定的预防作用。结论 尼莫地平、尼莫地平缓释片、特来斯、尼卡地平、依拉地平、安慰剂对偏头痛有预防作用,但疗效不同。     

Inhibitory activity of blockers of the slow inward current in rat myocardium, a study in steady state and of rate of action

The inhibitory effects of verapamil (84.4% inhibition) and D-600 (70.4% inhibition) on the conductance of the slow inward current were compared with that of Mn²⁺ (99.7% inhibition). Hill coefficients of 2 for Mn²⁺ and D-600 and one for verapamil were found. For racemic mixtures of verapamil and D-600 the apparent dissociation constants (K_0.5) were 1.4 and 3.6 μm respectively, whereas the apparent dissociation constant of Mn²⁺ was 625 μm. With such high affinities, as compared to Mn²⁺, time constants of inhibition for D-600 and verapamil were larger and their offset rates were slower. It is concluded that Mn²⁺ and the organic blockers have different mechanisms of action, that varapamil and D-600 have to pass through or enter into the membrane, and that the molecules of D-600 and verapamil possess one and two active groups respectively.     

二氢吡啶类钙通道阻滞剂在慢性稳定性冠心病中应用中国专家共识

<正>引言钙通道阻滞剂(CCB)是临床广泛应用的一类心血管药物。20世纪60年代,Fleckenstein发现CCB有抗心绞痛作用,1975年硝苯地平开始用于治疗心绞痛。1995年Furberg等根据短效硝苯地平小规模临床研究的荟萃分析,对CCB的安全性提出质     

The cyclic AMP-dependent modulation of cardiac sarcolemmal slow calcium channels

The epinephrine-induced abbreviation of systole is well explained by the cAMP-dependent phosphorylation of phospholamban, the activator of the cardiac sarcoplasmic reticulum calcium pump, and of the inhibitory component of the troponin complex. In contrast, the molecular mechanism of the β-agonist inotropic effects remained unclear until the recent finding that the depolarization-induced Ca²⁺ uptake by cardiac sarcolemmal vesicles, the in vitro equivalent of the slow Ca²⁺ channel, is activated upon cAMP-dependent phosphorylation of a sarcolemmal integral protein, calciductin [34]. This paper provides additional evidence for this mechanism by showing a linear correlation between calciductin phosphorylation and voltage-dependent Ca²⁺ uptake. At no detectable radiolabelling with (³²P)-phosphate, the latter is still ca 28% of its maximal value, suggesting the possibility of residual unlabeled protein-bound phosphate. Calciductin is an excellent substrate of cAMP-dependent protein kinase, since low levels of its catalytic subunit (ca 6% of the subunit liberated after complete dissociation of the enzyme) are capable of submaximally phosphorylating calciductin and activating Ca²⁺ uptake. The Ca²⁺ channels of phosphorylated vesicles are similar to those of non-phosphorylated vesicles and of other excitable cells in their inhibition by the calcium antagonist verapamil, lanthanum and other divalent cations. In contrast to the voltage-dependent Ca²⁺ uptake, $\text{Na}{}^{\mathrm{+}}\text{Ca}{}^{\mathrm{2+}}$ exchange was not modulated by cAMP-dependent phosphorylation. Sarcolemmal proteolipids were entirely extracted by acidic organic solvent mixtures and purified by high performance liquid chromatography. They made up 2% (w/w) of sarcolemmal proteins and contained essentially calciductin (97%) together with a 14 000 to 16 000 dalton component (3%). Sarcolemmal proteolipids were phosphorylated on seryl residues only. Their amino acid composition indicated the presence of a large number of acidic and hydrophobic residues, accounting for the behaviour of calciductin as an acidic integral proteolipid, similar to phospholamban.     

The relative sensitization by acidosis of five calcium blockers in cat papillary muscles

We have previously reported that the negative inotropic effects of both verapamil and nifedipine on cat papillary muscles are enhanced as pH is lowered from 7.4 to 6.8 and 6.0. These studies have now been extended to compare the relative sensitization by acidosis of verapamil, nifedipine, lidoflazine, perhexilene and diltiazem. Developed tension was recorded in cat papillary muscles and the calcium concentration was adjusted over the range 2 to 10 mM. At pH 7.4, addition of all five drugs moved the dose response curve to the right with pA2 values from 4.82 (lidoflazine) to 9.94 (nifedipine). At pH 6.0, there was eight-fold sensitization by acidosis for verapamil, but four, three, and two-fold sensitization for nifedipine, lidoflazine and perhexilene. Diltiazem, however, was not sensitized by acidosis. The differential effects of acidosis on the negative inotropic properties of the five drugs may reflect their ancillary properties opposite gating of the calcium channel, local anaesthesia, intracellular calcium movement or Na+/Ca2+ exchange, but also suggest that diltiazem may have the property of inhibiting the effects of low pH on cell membranes.     

钙离子拮抗剂和血管紧张素转换酶抑制剂对高血压患者动脉僵硬度影响的荟萃分析

目的系统评价钙离子拮抗剂（calciumchannelblockers,CCBs）和血管紧张素转换酶抑制剂（angiotensin～converting-enz）,meinhibitor,ACEI）对原发性高血压（高血压）患者血管功能作用的差异。方法按循证医学的要求,制定相应的纳入、排除标准及其检索策略。通过PubMed、EMBASE、OvidEBMReviews、中国期刊全文数据库、中文科技期刊全文数据库、万方数据库。检索相关的临床对照研究,计算机检索时间从各数据库建库至2012年1月;同时辅助其他检索,纳入CCBs和ACEI治疗高血压患者的随机对照试验（randomizedcontrolledtrials,RCT）。两名评价者独立评价纳入研究的质量,并用统一的表格提取资料,采用RevMan5．0软件进行统计分析。比较CCBs和ACEI对高血压患者脉搏波传导速度、收缩压、舒张压、脉压等指标的影响。结果共纳入4篇RCT,共计226例患者。文献异质性检验显示数据存在异质性（Q=54．80,P〈0．001）。荟萃分析结果显示,ACEI在改善动脉僵硬度方面优于CCBs,差异有统计学意义（标准差：135．01,95％CI：59．87。210．16;Z=3．52,P=O．0004,P〈0．05）：但在降低收缩压（标准差=-4．73,95％CI：-9．35—0．12,P〈0．04）和舒张压（标准差=-10．42,95％CI：-19．16—1．69．P〈0．02）方面较CCBs弱;在降低脉压（标准差-6．12,95％CI：-2．3～14．55,P〈O．15）方面与CCBs相比．差异无统计学意义。结论ACEI在改善高血压患者动脉僵硬度方面优于CCBs．该作用与其降压作用无关。     

The rs1458038 variant near FGF5 is associated with poor response to calcium channel blockers among Filipinos

Genetic variation is known to affect response to calcium channel blockers (CCBs) among different populations. This study aimed to determine the genetic variations associated with poor response to this class of antihypertensive drugs among Filipinos.One hundred eighty one hypertensive participants on CCBs therapy were included in an unmatched case-control study. Genomic deoxyribonucleic acid were extracted and genotyped for selected genetic variants. Regression analysis was used to determine the association of genetic and clinical variables with poor response to medication.The variant rs1458038 near fibroblast growth factor 5 gene showed significant association with poor blood pressure-lowering response based on additive effect (CT genotype: adjusted OR 3.41, P = .001; TT genotype: adjusted OR 6.72, P < .001).These findings suggest that blood pressure response to calcium channels blockers among Filipinos with hypertension is associated with gene variant rs1458038 near fibroblast growth factor 5 gene. Further studies are recommended to validate such relationship of the variant to the CCB response.     

选择性钙离子通道阻滞剂联合选择性5-羟色胺再摄取抑制剂治疗肠易激综合征的Meta分析

目的 系统评价选择性钙离子通道阻滞剂(SCCBs)联合选择性5-羟色胺再摄取抑制剂(SSRIs)治疗肠易激综合征(IBS)的疗效和安全性.方法 检索PubMed、Embase、Web of Science、Cochrane Library、CBM、CNKI、万方和维普等数据库,获取2020年1月30日之前发表的SCCB...     

Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy

Background

We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy.

Methods

PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I² statistic.

Results

Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31–1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04–1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12–1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =−3.56; 95% CI, −7.76–0.63; P=0.10) and DBP (RR =−3.03; 95% CI, −6.51–0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01).

Conclusions

The results of our meta-analysis demonstrate that adding an ARB to CCB after initial ineffective CCB monotherapy, significantly improved blood pressure control and the percentage of on-target hypertension treatment with significantly reduced incidence of adverse events compared with continued CCB monotherapy.     

Comparative effects of prolonged therapy with four calcium ion antagonists (diltiazem,nicardipine, tiapamil and verapamil) in patients with chronic stable angina pectoris

Summary The comparative effects of prolonged chronic therapy with diltiazem, nicardipine, tiapamil and verapamil on exercise tolerance, ST-segment changes and heart rate were examined in 63 patients with established chronic stable angina pectoris. Multistage computer-assisted symptom-limited tread-mill exercise tests were performed after 2 weeks of placebo (baseline) and then after 4 months of open-label chronic drug therapy. Diltiazem improved the exercise duration by 95% (p<0.001), nicardipine by 45% (p<0.001), tiapamil by 69% and verapamil by 79% (p<0.001). Maximal ST-segment depression was not altered by any of the drugs, but time to the development of 1 mm ST-segment depression was significantly improved in all cases. Diltiazem and verapamil reduced the heart rate at rest significantly by 6 and 8 beats/minute, respectively, whereas nicardipine increased it by 10 beats/minute (p<0.02), and tiapamil did not produce any significant change. Maximal heart rate at the peak of exercise was increased by 14% with nicardipine (p<0.001) and 6% with verapamil (p<0.05), whereas diltiazem and tiapamil did not produce any appreciable effect. The rate-pressure product at the peak of exercise remained unaltered with diltiazem, tiapamil and verapamil, but with nicardipine it increased significantly to 222±10 units from a baseline of 175±6 units with placebo. During diltiazem treatment, 1 patient died of myocardial infarction after 8 weeks of therapy. During tiapamil, 2 patients were withdrawn after 10 weeks because they developed unstable angina. During verapamil therapy, 4 patients were withdrawn; 1 developed myocardial infarction after 4 weeks, 2 patients developed worsening angina and 1 patient showed prolongation of the PR interval after 8 weeks of treatment. Constipation was reported by 7 patients during verapamil therapy. During nicardipine treatment one patient reported pedaloedema and dyspnoea after 16 weeks and was withdrawn. At the dosages used, all 4 calcium ion antagonists studied have been shown to be effective antianginal agents during long-term therapy, but differing effects on heart rate and rate-pressure product suggest that they do not have a similar mechanism of action.     

Efficacy and safety of calcium channel blockers in hypertensive patients with concomitant left ventricular dysfunction.

The use of calcium channel blockers (CCBs) in the treatment of hypertension and concomitant left ventricular dysfunction is reviewed. Some CCBs, particularly second-generation dihydropyridine agents such as felodipine, isradipine, nicardipine, nimodipine, and nitrendipine, have properties that enhance their usefulness in these patients. All CCBs have a similar mechanism of action. Differences in their selective action at various tissue sites determine which are most appropriate for patients with concomitant hypertension and left ventricular dysfunction. Most CCBs do not produce reflex stimulation of the heart or induce intravascular expansion. While all CCBs produce arteriolar dilation, all local beds and regional circulations in target organs are not affected equally. Most CCBs can decrease cardiac mass, and second-generation CCBs tend to have little or no negative inotropic effects at therapeutic dosages. In addition, they increase blood flow and reduce myocardial oxygen requirements. Because of differences in functional and electrophysiologic effects, specific CCBs may not be appropriate for all patients. Since second-generation dihydropyridine CCBs lack clinically relevant negative inotropic effects, and have been shown to improve exercise tolerance and coronary artery perfusion, they are appropriate for hypertensive patients with left ventricular dysfunction, angina, and coronary heart disease. Second-generation CCBs tend to lack cardiodepressant side effects and are less likely to react with digoxin than are first-generation CCBs.     

硝苯地平控释片对慢性阻塞性肺疾病,肺心病的长期疗效

观察硝苯地平控释剂型对慢性阻塞性肺疾病（ＣＯＰＤ）、肺心病患者的长期疗效。方法用随机、双盲有安慰剂对照的设计方法，观察了硝苯地平控释片对ＣＯＰＤ、肺心病患者［一秒钟用力呼气容积（ＦＥＶ１）／用力肺活量（ＦＶＣ）＝４７．３５％±８．１０％］的２年疗效。在２０２例患者中，硝苯地平组１０２例（２０ｍｇ／片，每日２次），安慰剂组１００例（１片每日２次）。结果二组均衡性检验有可比性。２年随访率分别为９４％和８９％。硝苯地平组与安慰剂组比较，呼吸困难、疲乏、体力活动量等症状好转者明显增多（Ｐ＜０．０５）；ＦＥＶ１和动脉血二氧化碳分压（ＰａＣＯ２）恶化不明显（Ｐ〈０．０５）；反映肺血管顺应性的肺阻抗容积图Ｂ－Ｙ１改善明显（Ｐ＜０．０５）；病死率降低（Ｐ＝０．０５１）。但某些心电图右室负荷指标（ＱＲＳ电轴右偏、Ｐ１１和ＲａＶＲ电压）恶化。结论长期服用硝苯地平控释片是一安全、方便、具有提高ＣＯＰＤ、肺心病患者生命质量，并可能减少病死率的药物，可作为ＣＯＰＤ、肺心病患者综合治疗中的一项辅助治疗，但其不能阻止和逆转病情的发展     

The beneficial effect of a calcium channel blocker, Diltiazem, on the ischemic-reperfused heart

Diltiazem-HCl,^® a potent calcium channel blocker, was found to be effective in moderating the harmful effects of reperfusion on the severely ischemic myocardium. In isolated working rat heart preparations it was found that 120 min of global ischemia followed by 15 min of reperfusion resulted in a massive leakage of creatine phosphokinase into the coronary effluent, and in many cases, in fibrillation and/or contracture. Left ventricular end-diastolic pressure increased sharply during reperfusion in these hearts. Reperfusion did not affect tissue ATP levels, but did increase creatine phosphate somewhat. When Diltiazem was added to the perfusate (final concentration 0.4 μm) 5 min prior to re-establishment of flow, the deleterious effects of reperfusion were greatly reduced. None of the hearts fibrillated on reperfusion, and none developed contracture. Left-ventricular end-diastolic pressure was increased only slightly in these hearts. The amount of creatine phosphokinase released into the coronary effluent during re-flow was only one-half that which was released by hearts reperfused in the absence of Diltiazem. In the Diltiazem-treated hearts reperfusion restored creatine phosphate to near-normal levels, although ATP levels were not increased. The beneficial effects of Diltiazem are probably related to its ability to reduce the rapid and massive mitochondrial calcium overloading which normally accompanies reperfusion of severely ischemic myocardium.     

The efficacy and safety of arotinolol combined with a different calcium channel blocker in the treatment of Chinese patients with essential hypertension: a one-year follow-up study

Background: Combined treatment of a calcium antagonist and α/β-adrenoreceptor blocker is expected to offer some advantages in the management of hypertension; however, their antihypertensive efficacy and safety remain relatively under-explored.

Methods: The current study addresses the 24-h antihypertensive efficacy and safety of arotinolol combined with a different calcium channel blocker. One-hundred fifty-two patients were randomly divided into three groups: nifedipine, amlodipine and felodipine group. In each group, the antihypertensive treatment dose was 30?mg/d, 5?mg/d, 5?mg/d long acting nifedipine, amlodipine, felodipine plus 20?mg/d arotinolol, respectively. Blood pressure was measured in ABPM devices and mercury manometer.

Results: The result showed that the effective rate of one year antihypertensive treatment of arotinolol combined with nifedipine was 51 of 53, significantly effective (p?p?>?0.05) in controlled rate of morning peak blood pressure between treatment of arotinolol combined with amlodipine and arotinolol combined with nifedipine, but there was a significant difference (p?Conclusions: The therapy approached of arotinolol combined with nifedipine or amlodipine could be effective and well-tolerated, and they can be used as the better chosen antihypertensive drug.