Mechanism of inhibition by SUN 1165, a new Na channel blocking antiarrhythmic agent, of cardiac glycoside-induced triggered activity

Abstract

The mechanism of the antiarrhythmic action of SUN 1165, a selective Na channel blocker, in digitalis-induced arrhythmias was investigated by means of conventional microelectrode and suction pipette methods with isolated canine Purkinje fibers and guinea-pig single ventricular cells, respectively. SUN 1165 decreased acetylstrophanthidin-induced delayed afterdepolarization and completely blocked the initiation of triggered activity by acetylstrophanthidin in Purkinje fibers. Delayed afterdepolarization, which was completely abolished either by intracellular dialysis with EGTA or by extracellular superfusion with caffeine, was decreased by SUN 1165 in a concentration-dependent manner in single ventricular cells. These results suggest that an increase in intracellular Ca2+ concentration is a requirement for delayed afterdepolarization. Furthermore, the antiarrhythmic action of SUN 1165 in cardiac glycoside-induced arrhythmias in dogs could be mediated not only by an inhibition of sodium channels and subsequent reduction in the intracellular sodium activity, but also by a reduction of intracellular calcium activity due to the Na+-Ca2+ exchange mechanism.