Opie L H, Thandroyen F T
Fed Proc. 1983 May 15;42(8):2465-9.
Early experiments with the calcium antagonist verapamil showed that it could inhibit the transsarcolemmal influx of calcium ions induced by isoproterenol in ventricular myocardium without inhibiting the effect of beta stimulation to increase tissue cyclic AMP. Current views of the effects of the beta-receptor-adenylate cyclase-cyclic AMP system of the calcium channel suggest that both calcium antagonists and beta-adrenoceptor antagonists should inhibit transsarcolemmal calcium influx if calcium is the third messenger of beta-agonist catecholamines. When high concentrations of circulating catecholamines are added to normal isolated hearts, two of the effects include increased vulnerability to ventricular fibrillation and high rates of enzyme release. These effects are antagonized by beta-adrenoceptor inhibitors and by calcium antagonists, which suggests a classical second (cyclic AMP) and third (calcium) messenger effect. In the presence of coronary artery ligation, the ventricular fibrillation threshold falls and enzyme release is enhanced. Both effects are associated with an increased tissue cyclic AMP level in the ischemic zone and are susceptible to calcium antagonist procedures. Neither effect can be fully stopped by beta-adrenoceptor antagonism. Therefore the evidence from this model with coronary artery ligation favors the views that 1) cyclic AMP accumulates in ischemic tissue by a process not fully susceptible to inhibition by beta-adrenoceptor antagonists; and 2) calcium ions are associated with the development of ventricular fibrillation and enzyme release by a process susceptible to inhibition by calcium antagonist agents such as verapamil, nifedipine, and diltiazem.
早期对钙拮抗剂维拉帕米的实验表明，它可以抑制异丙肾上腺素在心室肌中诱导的钙离子跨肌膜内流，而不抑制β刺激增加组织环磷酸腺苷（cAMP）的作用。关于钙通道的β受体 - 腺苷酸环化酶 - 环磷酸腺苷系统作用的当前观点表明，如果钙是β激动剂儿茶酚胺的第三信使，那么钙拮抗剂和β肾上腺素能受体拮抗剂都应抑制跨肌膜钙内流。当向正常离体心脏添加高浓度的循环儿茶酚胺时，其中两种作用包括心室颤动易感性增加和酶释放率升高。这些作用可被β肾上腺素能受体抑制剂和钙拮抗剂拮抗，这表明存在经典的第二信使（环磷酸腺苷）和第三信使（钙）效应。在冠状动脉结扎的情况下，心室颤动阈值降低，酶释放增强。这两种作用都与缺血区组织环磷酸腺苷水平升高有关，并且对钙拮抗剂治疗敏感。β肾上腺素能受体拮抗作用均不能完全阻止这两种作用。因此，来自冠状动脉结扎这个模型的证据支持以下观点：1）环磷酸腺苷在缺血组织中通过一种不完全受β肾上腺素能受体拮抗剂抑制的过程积累；2）钙离子通过一种易受维拉帕米、硝苯地平、地尔硫䓬等钙拮抗剂抑制的过程与心室颤动和酶释放的发生相关。
