Electrophysiologic Effects of McN-4130, a New Antiarrhythmic Compound, on Isolated Cardiac Tissue

Abstract

McN-4130 has antiarrhythmic efficacy in a number of animal models of ventricular arrhythmia and fibrillation. We used standard microelectrode techniques to characterize the electrophysiological effects of McN-4130 on isolated cardiac tissue. In canine Purkinje fibers, McN-4130 reduced the maximum rate of depolarization (Vmax) and shortened action potential duration at 50% repolarization (APD50) in a concentration-dependent manner (2-10 microM). These effects occurred without significant changes in membrane potential. APD100 tended to prolong with continued superfusion with McN-4130. The depression of Vmax was rate dependent and accompanied by increases in conduction time. The reductions in Vmax and APD50 induced by McN-4130 did not reach a steady-state until 90-150 min of superfusion. At 10 microM, fibers became inexcitable within 60-90 min. In addition, the effects on the action potential were not readily reversible. McN-4130 depressed membrane responsiveness in Purkinje fibers. It shortened the effective refractory period slightly but had a much greater effect on APD50. McN-4130 also reduced Vmax in ventricular muscle preparations. In contrast to its effects on the Purkinje fiber action potential, McN-4130 prolonged the duration of the ventricular muscle transmembrane potential and effective refractory period. Slow-response action potentials induced by high [K+]o and isoproterenol were not affected by McN-4130 at concentrations up to 10 microM. McN-4130 (2 and 4 microM) had no significant effect on normal Purkinje fiber automaticity. However, continued exposure to McN-4130 at 4 microM induced early afterdepolarizations and triggered activity in five of eight spontaneously discharging fibers. In guinea pig papillary muscle, McN-4130 caused marked rate-dependent depression of Vmax at concentrations that caused minimal tonic depression of Vmax. These results indicate that McN-4130 has effects at the cellular level that are similar to those of other potent local anesthetic antiarrhythmic agents. These effects may contribute to the antiarrhythmic and antifibrillatory activity of McN-4130.