钙通道阻滞剂在冠心病心绞痛治疗中的应用

钙通道阻滞剂又称钙拮抗剂,是一类选择性阻滞钙通道,抑制细胞外钙离子内流,降低细胞内钙离子浓度从而对心肌收缩性、窦房结功能、房室传导、周围血管、脑血管和冠脉循环有广泛作用的药物[1]。各种制剂目前广泛应用于心血管系统疾病,包括高血压病、冠心病、心律失常和心肌病等,长期应用可保护血管床,抗动脉粥样硬化,     

钙通道阻滞剂在心血管疾病中的应用

钙离子在人体的组织细胞及亚细器正常的生理功能中发挥着重要作用。如平滑肌的收缩 ,某些细胞的分泌、代谢等 ,都有赖于钙离子的参与。当由于各种病理生理因素 ,引起局部组织或细胞内钙离子超载或对钙离子敏感性增高时 ,则可引起它们的功能异常或发生疾病。钙通道阻滞剂 (CCB)能阻止细胞外钙离子内流或亚细器 (线粒体 ,肌浆网等 )钙离子的释放 ,降低细胞浆钙离子含量等 ,故可广泛用于钙离子超载等与钙离子有关的许多疾病的防治。本文着重介绍了钙通道阻滞剂在心血管疾病中的应用 ,概述如下 :1 常用钙通道阻滞剂及其特点　临床常用的钙通道…     

钙通道阻滞剂在冠心病心绞痛治疗中的应用

钙通道阻滞剂又称钙拮抗剂,是一类选择性阻滞钙通道,抑制细胞外钙离子内流,降低细胞内钙离子浓度从而对心肌收缩性、窦房结功能、房室传导、周围血管、脑血管和冠脉循环有广泛作用的药物[1].各种制剂目前广泛应用于心血管系统疾病,包括高血压病、冠心病、心律失常和心肌病等,长期应用可保护血管床,抗动脉粥样硬化,减少高血压引起的左室肥厚和改善舒张功能.     

钙拮抗剂对射出精液中人精子活力的刺激作用

已知钙通道阻滞剂可以抑制钙通过细胞膜,而钙离子载体如A23187则增加细胞内钙离子浓度。本文对钙通道阻滞剂地尔硫(?)(Diltiazem)、氟桂嗪(Flunari-zine)、维拉帕米(异博定)和普尼拉明(心可定,Prenyla-mine)的作用,以及钙通道阻滞剂与钙离子载体和钙螯合剂(EGTA,EDTA)之间的相互作用进行了研究。收集健康受试者新鲜精液,每分按100μl 等量分     

脑内药物和神经递质的受体

钙通道阻滞剂受体阻滞钙离子透过细胞膜上电压依存性钙通道的药物称钙通道阻滞剂,如双氧吡啶类(Di-hydropyridines)药物硝苯吡啶、戊脉安类药物     

钙通道阻滞剂的新用途

钙通道阻滞剂能阻滞钙离子进入细胞内,引起各组织系统的平滑肌松弛、减轻缺血性细胞中毒。钙通道阻滞剂在结构上主要分四类;二氢吡啶类、硫氮(艹卓)酮类、异博定类、氟桂嗪类。常用的钙通道阻滞剂见表。     

钙拮抗剂的若干临床新概念

钙拮抗剂又称钙通道阻滞剂,其临床应用显示了心血管治疗学的重要发展。钙通道(慢通道)是细胞膜上可供钙离子流动的孔道,其内、外表面均有“闸门”,当肌细胞受到电化刺激后,钙通道被激活,闸门开放以致钙离子流入细胞内。静息的心肌和血管平滑肌细胞溶质内游离钙浓度为0.05～0.5μM,细胞外浓度则为1～5μM。钙通道被激活后,由于跨膜钙内流及/或细胞内储存的钙释放,以致细胞内游离钙浓度及其利用率增加。钙内流及/或利用率增加,使肌细胞     

硝苯啶在消化系统的临床应用

硝苯啶是一慢钙通道阻滞剂,可选择性地阻滞细胞膜的慢钙通道而抑制钙离子内流,使肌肉兴奋——收缩脱耦联,故其对许多器官的肌运动均有影响.目前除用于心脑血管等疾病外,在消化系统也展现了良好的前景。     

钙离子通道阻滞剂治疗高血压病新进展

自从1960年世界上第一个钙离子通道阻滞剂-维拉帕米问世以来,陆续有许多种钙离子通道阻滞剂应用于临床治疗高血压、心绞痛、动脉硬化等获得成功。随着钙离子通道阻滞剂的广泛临床应用,其副作用也随之出现,于是发生了1995年关于钙离子通道阻滞剂安全性大争论,经过大量循证医学研究及临床实践,证明了钙离子通道阻滞剂用于治疗高血压是安全、有效、副作用少的一线药物。近些年来,日本研制出L、T、N三亚型钙通道阻滞剂-盐酸贝尼地平(可力洛),用于临床治疗高血压、特别合并肾功能损伤的高血压患者,效果较好。     

日服一剂的新型钙通道阻滞剂——拉西地平

钙通道阻滞剂能阻滞钙离子进入细胞内,使各组织系统的平滑肌松弛,减轻缺血性细胞中毒。钙通道阻滞剂在结构上主要分四类:二氢吡啶、硫氮 酮、异搏定、氟桂嗪。第一代钙通道阻滞剂(如硝苯地平)对血管平滑肌和非血管平滑肌的收缩均有抑制作用,故对心肌收缩力和房室传导有不同程度的抑制作用,还可以产生额外的副作用(如便秘、腹胀等)。因此,这类药物不宜用于伴有房室传导阻滞和     

Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R

Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.     

Mechanism of action of calcium antagonists on myocardial and smooth muscle membranes

Although calcium channel blockers vary considerably in their chemical structure and pharmacologic profile, the widely accepted mechanism of their action is an inhibition of Ca2+ influx - via voltage-activated slow channels - into smooth and cardiac muscle. Other ways of Ca2+ entry, such as passive diffusion and Na+/Ca2+ and K+/Ca2+ exchange, are not affected by these compounds. However, various blockers exert a slightly different inhibitory action on the slow channels, which indicates that various binding sites in the cell membranes, or even in intracellular sites, may be involved. Potential sites of action of calcium channel blockers in the myocardium include: the slow calcium channels; Na+/Ca2+ channels; mitochondria; sarcoplasmic reticulum; myofilaments; and calcium efflux. However, experimental evidence has been given for only the first site, and the third and fourth sites are still controversial. In the vascular smooth muscles, calcium channel blockers could possibly block the potential-dependent or receptor-operated channels, or bind to calmodulin. Again, only the first site of action has been experimentally proven. An important feature of calcium channel blockers is their different affinities for various tissues. For instance, cinnarizine and its difluorinated derivative flunarizine are 1000 times more effective in blocking slow channels in vascular smooth muscles than those in the myocardium. Even within the same system, such as the cardiovascular system, differences in tissue specificity are encountered. Thus, while nimodipine acts preferentially on cerebral vessels, diltiazem has more affinity for the coronary vasculature. Tissue specificity is exhibited even for different myocardial structures; thus, while verapamil affects the nodal and conductive tissues in the myocardium (hence its use as an antiarrhythmic agent), nifedipine is almost devoid of such activity. Organ selectivity of calcium channel blockers is one of the attractive features of this group of compounds; hence their use in a variety of cardiovascular conditions.     

Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications

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.     

Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole

The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.     

钙通道阻滞药与心肌顿抑

心肌顿抑是指短暂缺血后可逆性心肌收缩功能异常 ,是再灌注损伤的一种形式 ,临床上常出现该现象。钙通道阻滞药是心血管疾病常用药物 ,目前大量研究证明可以抑制心肌顿抑。本文综述了钙通道阻滞药治疗心肌顿抑的实验证据、理论基础以及在临床心肌顿抑中的应用等问题     

Clinical potential of lomerizine, a Ca2+ channel blocker as an anti-glaucoma drug: effects on ocular circulation and retinal neuronal damage

Glaucoma is defined as an optic neuropathy with characteristic changes in the optic nerve head and ultimate loss of visual field. Previous studies have suggested that (a) mechanical damage due to raised intraocular pressure and (b) a compromised tissue circulation in the optic nerve head play significant roles in the development of glaucomatous damage in the optic nerve head. Recently, we found that lomerizine, a new Ca(2+) channel blocker, increased ocular circulation and protected neuronal cells against retinal neurotoxicity both in vitro and in vivo with minimal cardiovascular side effects. We examined the effect of lomerizine on the ocular circulation and compared it with those of other Ca(2+) channel blockers in normal rabbits and in rabbits with an endothelin-1-disturbed circulation in the optic nerve head. In anesthetized rabbits, lomerizine and the other Ca(2+) channel blockers increased the ocular circulation and also inhibited the hypoperfusion induced in optic nerve head tissue by an intravitreous injection of endothelin-1. Whereas the other Ca(2+) channel blockers produced changes in blood pressure and heart rate, the effects of lomerizine on these parameters were slight. In healthy humans, lomerizine increased blood velocity in the optic nerve head, without significantly altering blood pressure or heart rate. Moreover, lomerizine reduced retinal damage in rats both in vitro and in vivo, presumably through a Ca(2+) channel blocking effect via an action that may involve a direct protection of retinal neurons as well as an improvement in the ocular circulation. These results indicate that lomerizine may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that involve a disturbance of the ocular circulation.     

Differential susceptibility of cholinergic and noncholinergic neurogenic responses to calcium channel blockers and low Ca2+ medium in rat urinary bladder.

1. The influence of calcium channel blockers and low Ca2+ medium on the neurogenic responses to single pulse electric field stimulation in rat urinary bladder has been examined. 2. Single pulse stimulation evoked a biphasic contractile response consisting of a fast component with a time to peak of 0.72 +/- 0.05 s and a slow component that reached a maximal tension at 2.8 +/- 0.21 s, possibly mediated by two different neurotransmitters. 3. Atropine (3 x 10(-6) M) selectively inhibited the slow component without altering the fast component, suggesting the involvement of cholinergic and non-cholinergic neurotransmitters, respectively. 4. Reducing Ca2+ in the medium to 1/4 of the normal, abolished the slow component of the neurogenic response while the fast contractile response was not altered which may indicate a relatively greater dependence of the cholinergic component on extracellular Ca2+ than the noncholinergic one. 5. The IC50 values for the fast component with respect to verapamil and diltiazem were 1.08 microM and 1.76 microM, respectively. The greater susceptibility of the slow component to calcium channel blockers (IC50 values of verapamil: 0.07 microM and of diltiazem: 0.25 microM) indicates the differential activation of slow calcium channels by the endogenously released substances. 6. Calcium channel blockers inhibited the ATP-induced contraction which was comparable to that of the non-cholinergic component of the neurogenic response suggesting the involvement of ATP as a possible neurotransmitter. 7. Ach-induced contractions were relatively less susceptible to calcium channel blockers and low Ca2+ medium than was the atropine-sensitive cholinergic component of the neurogenic response.     

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.     

钙离子拮抗剂类降压药的临床应用及不良反应

目的 对钙离子拮抗剂在临床中的临床应用及不良反应做系统的分析,总结钙离子拮抗剂在临床中的应用及注意事项,为药师在临床用药监测中提供了理论支持。方法 通过查阅文献的方式,系统学习钙离子拮抗剂的临床应用及不良反应。结果 钙离子拮抗剂广泛应用于心血管等多种疾病,其不良反应有心律失常、低血压、房室传导阻滞、心力衰竭、牙龈增生、外周水肿、便秘等。药物使用应关注其常见和罕见的不良反应,促进合理用药。结论 药物在使用过程中,不仅要注重药物的药理作用及临床疗效,最好在使用之前就预见药物的不良反应,才能做到及时防治,最大地发挥药物疗效。     

Antinociceptive effects of Ca2+ channel blockers.

The antinociceptive action of four Ca2+ channel blockers, nifedipine, nimodipine, verapamil and diltiazem, was evaluated and compared to that of morphine using three algesiometric tests in mice and rats, namely, formalin, writhing and modified hot-plate test. Dose-response curves for all the drugs tested were similar and a significant dose-dependent antinociceptive action was evident in the formalin and writhing tests. However, in the hot-plate test, only nimodipine exhibited a significant analgesic effect, confirming the misleading results previously reported for this test. The findings suggest a pharmacological role of Ca2+ channel blockers in the modulation of antinociception under acute conditions. The analgesic action of Ca2+ channel blockers could be mediated by an increase in the nociceptive threshold resulting from interference with Ca2+ influx at opioid receptors, because Ca2+ influx is critical for the release of neurotransmitters and other substances implicated in nociception and inflammation. It is suggested that if a substance has a Ca2+ channel blocking effect, it should probably have some antinociceptive properties.