Takeo S, Tanonaka K, Hayashi M, Yamamoto K, Liu J X, Kamiyama T, Yamaguchi N, Miura A, Natsukawa T
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Japan.
J Pharmacol Exp Ther. 1995 Jun;273(3):1403-9.
The present study was undertaken to test the hypothesis that the degree of sodium channel blockade by class-I-type antiarrhythmic agents accounts for enhancement of postischemic contractile recovery of ischemic/reperfused hearts. Electrophysiological studies showed that the class-I-type antiarrhythmic agents quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide and pilsicainide suppressed the Vmax value of the rat left ventricular muscle cell, a marker of sodium channel blockade, in a concentration-dependent manner. Isolated rat hearts were subjected to 35 min of ischemia and 60 min of reperfusion. Postischemic contractile recovery, which was never detected in untreated hearts, was enhanced in hearts pretreated with these antiarrhythmic agents during the last 3 min before ischemia at concentrations ranging from 3 to 300 microM. Tissue Na, but not Ca, accumulation was also detected in the ischemic heart, and tissue Na and Ca accumulation was observed in the reperfused heart, which suggests that sodium overload occurs during ischemia, followed by sodium and calcium overload during reperfusion. The degree of postischemic contractile recovery seen in the presence of these antiarrhythmic agents was inversely related to tissue Na or Ca accumulation after reperfusion, which suggests that class-I-type antiarrhythmic agents inhibit sodium overload occurring in ischemic/reperfused myocardial cells. A close relationship between postischemic contractile recovery of the perfused heart and depression in the Vmax value of the ventricular muscle was also observed. These results suggest that the ability class-I-type antiarrhythmic agents to inhibit myocardial sodium channels plays a significant role in the enhancement of postischemic contractile recovery of the ischemic/reperfused heart.
I类抗心律失常药物对钠通道的阻滞程度可解释缺血/再灌注心脏缺血后收缩恢复的增强。电生理研究表明，I类抗心律失常药物奎尼丁、丙吡胺、普鲁卡因胺、利多卡因、美西律、氟卡尼和吡西卡尼以浓度依赖性方式抑制大鼠左心室肌细胞的Vmax值，该值是钠通道阻滞的一个指标。将离体大鼠心脏进行35分钟的缺血和60分钟的再灌注。在缺血前最后3分钟用这些抗心律失常药物预处理的心脏中，缺血后收缩恢复增强，而在未处理的心脏中从未检测到这种恢复，药物浓度范围为3至300微摩尔。在缺血心脏中也检测到组织钠而非钙的蓄积，在再灌注心脏中观察到组织钠和钙的蓄积，这表明缺血期间发生钠超载，随后再灌注期间发生钠和钙超载。在这些抗心律失常药物存在下观察到的缺血后收缩恢复程度与再灌注后组织钠或钙的蓄积呈负相关，这表明I类抗心律失常药物抑制缺血/再灌注心肌细胞中发生的钠超载。还观察到灌注心脏的缺血后收缩恢复与心室肌Vmax值降低之间存在密切关系。这些结果表明，I类抗心律失常药物抑制心肌钠通道的能力在缺血/再灌注心脏缺血后收缩恢复的增强中起重要作用。
