Thomas G P, Ferrier G R, Howlett S E
Department of Pharmacology, Delhousie University, Halifax, Nova Scotia, Canada.
J Pharmacol Exp Ther. 1996 Sep;278(3):1090-7.
The purpose of this study was to determine whether specific angiotensin II (AII) type 1 receptor blockade with losartan would affect arrhythmia generation in an isolated guinea pig ventricular model of simulated ischemia and reperfusion. Effects of losartan were evaluated in the presence and absence of exogenous AII. Transmembrane potentials and an electrocardiogram were recorded during perfusion with normal Tyrode's solution, exposure to simulated ischemia for 15 min (hypoxia, acidosis, lactate, hyperkalemia, glucose-free) and reperfusion for 30 min. Under normal conditions, losartan did not affect endocardial or transmural conduction times, action potential duration at 90% repolarization or effective refractory period (ERP). However, losartan and AII each had significant effects on electrophysiological parameters during simulated ischemia and reperfusion. Further, losartan and AII, both independently and in combination, exerted antiarrhythmic effects in early reperfusion. Neither losartan nor AII affected action potential duration at 90% repolarization during simulated ischemia or reperfusion. However, AII exerted antiarrhythmic effects by preventing pronounced shortening of ERP in simulated ischemia and early reperfusion. Losartan by itself had no effect on ERP, but completely blocked the antiarrhythmic action of AII on ERP. Nevertheless, losartan preserved antiarrhythmic efficacy by attenuating prolongation of transmural conduction times in stimulated ischemia and early reperfusion. This antiarrhythmic action occurred in the absence or presence of AII. Our results indicate that losartan has antiarrhythmic efficacy which is independent of AII type 1 receptor blockade.
本研究的目的是确定用氯沙坦进行特异性血管紧张素II（AII）1型受体阻断是否会影响豚鼠离体心室模拟缺血再灌注模型中的心律失常发生。在有或无外源性AII的情况下评估氯沙坦的作用。在用正常台氏液灌注期间、暴露于模拟缺血15分钟（缺氧、酸中毒、乳酸、高钾血症、无糖）以及再灌注30分钟期间记录跨膜电位和心电图。在正常条件下，氯沙坦不影响心内膜或跨壁传导时间、90%复极化时的动作电位持续时间或有效不应期（ERP）。然而，在模拟缺血和再灌注期间，氯沙坦和AII各自对电生理参数均有显著影响。此外，氯沙坦和AII单独或联合使用在再灌注早期均发挥抗心律失常作用。在模拟缺血或再灌注期间，氯沙坦和AII均不影响90%复极化时的动作电位持续时间。然而，AII通过防止模拟缺血和再灌注早期ERP的明显缩短发挥抗心律失常作用。氯沙坦本身对ERP无影响，但完全阻断了AII对ERP的抗心律失常作用。尽管如此，氯沙坦通过减轻模拟缺血和再灌注早期跨壁传导时间的延长而保留了抗心律失常疗效。这种抗心律失常作用在有或无AII的情况下均会出现。我们的结果表明，氯沙坦具有独立于AII 1型受体阻断的抗心律失常疗效。
