Effects of a Novel Cyclohexane Dicarboximide Derivative, ST-6, on Reperfusion-Induced Arrhythmia in Rats

Abstract

The present study was designed to determine whether a novel cyclohexane dicarboximide derivative, ST-6, 2-[4-[4-(chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-isoindol-1,3(2H)-dione, prevents reperfusion-induced ventricular arrhythmias. Pentobarbital-anesthetized rats were subjected to left coronary artery occlusion for 4 min followed by 4-min reperfusion, and the incidence of their ventricular arrhythmias was examined. The coronary occlusion of control rats induced ventricular tachycardia and fibrillation, eventually leading to sudden death. The intravenous injection of 0.1 to 2 mg/kg ST-6 prior to the occlusion resulted in a dose-dependent suppression of the ventricular arrhythmias. The suppression of ventricular fibrillation was also observed on the intraperitoneal and intradoudenal administration of 2 to 10 mg/kg ST-6 15 min prior to coronary occlusion. Antiarrhythmic effects of this agent (0.5 mg/kg per min) were compared with those of other antiarrhythmic agents including lidocaine (0.1 mg/kg per min), sematilide (0.3 mg/kg per min), and diltiazem (0.5 mg/kg per min) by administrating the agents from 1 min after the coronary occlusion to the end of 4-min reperfusion. Antiarrhythmic effects of ST-6 were similar in degree to those of lidocaine and diltiazem, whereas no significant prevention by sematilide was seen. The results suggest that ST-6 may be capable of suppressing reperfusion-induced arrhythmias following oral or intravenous administration.