Cellular electrophysiological effects of MS‐551, a new class III antiarrhythmic agent

Abstract

AbstractThe cellular electrophysiological effects of MS‐551, a pure class III antiarrhythmic agent lacking beta‐blocking activity, were compared with those of d‐sotalol and dofetilide in canine Purkinje fibers and ventricular muscles and in guinea pig atrial muscles using the standard microelectrode technique. MS‐551 prolonged the action potential duration (APD) of these cardiac tissues to the same extent in a concentration‐dependent manner (10−6−10−4 M). MS‐551 did not affect other action potential parameters of these tissues except for the Vmax, which was depressed approximately 10% at 10−4 M MS‐551. The extents of prolongation after 10−5 M of MS‐551 were 36, 27, and 35% for canine Purkinje and ventricular muscle and guinea pig atrial muscle, respectively. d‐Stalol at a concentration 10 times higher than MS‐551 produced a similar prolongation of the APD of canine cardiac tissues but only a slight prolongation of the APD of guinea pig atrial muscles. Dofetilide at a concentration 30 times lower than MS‐551 produced a prolongation of the APD of canine Purkinje fibers but a relatively slight prolongation of the APD of both canine ventricular muscles and guinea pig atrial muscles. In canine Purkinje fibers, MS‐551 did not prevent the APD shortening induced by high extracellular potassium (8 and 12 mM), but the APD under these conditions was lengthened compared with controls. Under simulated ischemic conditions (pO2 25–30 mmHg, pH 6.5, extracellular K 8 mM and no glucose) for 30 min, the APD was abruptly shortened during the first 5 min, then gradually shortened further up until 30 min. MS‐551 did not prevent the abrupt APD shortening, but slowed the later gradual shortening. The APD prolonging action of MS‐551 was enhanced at low frequency. These data indicate that (1) MS‐551 is a pure class III antiarrhythmic agent with electrophysiological characteristics basically similar to d‐sotalol and dofetilide; (2) MS‐551 has a relatively greater potency in guinea pig atrial muscle than d‐sotalol and dofetilide; (3) the APD prolonging action of MS‐551 is preserved under high K+ or simulated ischemic conditions; and (4) MS‐551 exhibits a reverse use‐dependence in prolonging APD. © 1995 Wiley‐Liss, Inc.