Kloner R A, Braunwald E
Am J Cardiol. 1987 Jan 30;59(3):84B-94B. doi: 10.1016/0002-9149(87)90087-7.
Numerous studies have been conducted over the past 10 years on the effects of calcium antagonists on regional myocardial ischemia and infarct size. Verapamil, for example, reduced the degree of adenosine triphosphate degradation during 15 minutes of coronary occlusion followed by reperfusion in an anesthetized canine preparation. It also preserved the ultrastructural appearance of mitochondria in myocardium subjected to 1 hour of ischemia. Using an 8-hour permanent coronary artery occlusion model in which risk zone was assessed with radioactive microspheres and infarct size determined by tetrazolium staining, verapamil, administered 1 hour after occlusion, resulted in a modest decrease in infarct size. In a reperfusion model in which anesthetized dogs were subjected to 3 hours of coronary artery occlusion followed by 3 hours of reperfusion, verapamil decreased infarct size when it was administered during the period of ischemia, but failed to decrease infarct size when administered only during the reperfusion phase, i.e., after 3 hours of ischemia. Although verapamil is known to have negative inotropic effects, the newer calcium antagonist agent nisoldipine is less negatively inotropic, and might therefore be preferable in the situation of compromised hemodynamics. In a 6-hour permanent coronary artery occlusion model, nisoldipine decreased infarct size without decreasing left ventricular contractility. Most published reports support the concept that calcium antagonists decrease infarct size in models of experimental infarction. Of 4 major clinical studies, only 1 has shown that calcium antagonists are capable of reducing infarct size in man. However, in most of these studies, drug therapy commenced relatively late--4 or more hours after symptoms. In order for these drugs to demonstrate beneficial effects, the risk zone may have to be small and the degree of collateral flow adequate, the drug may have to be given very early or even before coronary occlusion (in a prophylactic fashion) and administration of the drug may have to be coupled to early coronary reperfusion.
在过去10年里，人们针对钙拮抗剂对局部心肌缺血和梗死面积的影响进行了大量研究。例如，在麻醉犬实验中，维拉帕米可减轻冠状动脉闭塞15分钟后再灌注期间三磷酸腺苷的降解程度。它还能维持缺血1小时心肌中线粒体的超微结构外观。在一个用放射性微球评估危险区、用四氮唑染色确定梗死面积的8小时永久性冠状动脉闭塞模型中，闭塞1小时后给予维拉帕米，可使梗死面积适度减小。在一个再灌注模型中，麻醉犬冠状动脉闭塞3小时后再灌注3小时，维拉帕米在缺血期间给药可减小梗死面积，但仅在再灌注阶段（即缺血3小时后）给药则不能减小梗死面积。虽然已知维拉帕米有负性肌力作用，但新型钙拮抗剂尼索地平的负性肌力作用较小，因此在血流动力学受损的情况下可能更适用。在一个6小时永久性冠状动脉闭塞模型中，尼索地平可减小梗死面积而不降低左心室收缩力。大多数已发表的报告支持钙拮抗剂在实验性梗死模型中可减小梗死面积这一观点。在4项主要临床研究中，只有1项表明钙拮抗剂能够减小人类的梗死面积。然而，在这些研究中的大多数，药物治疗开始得相对较晚——症状出现后4小时或更久。为使这些药物显示出有益效果，危险区可能必须较小且侧支血流充足，药物可能必须尽早给予甚至在冠状动脉闭塞之前（预防性给药），并且药物给药可能必须与早期冠状动脉再灌注相结合。
