Electrophysiological effects of mexiletine (Kö1173) on ovine cardiac Purkinje fibers.

To clarify the electrophysiological mechanisms of the antiarrhythmic effects of mexiletine, we examined the actions of mexiletine (0.1--30 mg/l) on action potential characteristics (phase 0 amplitude, overshoot, maximum upstroke velocity, maximum diastolic and activation voltages, duration at 50% and 90% repolarization) of cardiac Purkinje fibers using standard microelectrode techniques. In fibers stimulated at constant rate, mexiletine decreased phase 0 amplitude and Vmax and shortened the action potential. Mexiletine shortened action potential duration at lower concentrations than those which altered phase 0 depolarization. The effect of mexiletine on normal automaticity in cardiac Purkinje fibers was studied in fibers made automatic either by hypokalemia or by isoproterenol. Mexiletine suppressed normal automaticity by shifting activation voltage, so that spontaneous phase 4 depolarization reached a stable resting voltage without triggering regenerative phase 0 depolarization. The effects of mexiletine on abnormal automaticity were studied in Purkinje fibers intoxicated by ouabain. Mexiletine decreased the amplitude of or abolished either early or delayed after depolarizations induced by ouabain.