Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles

Abstract

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.