A Comparison of the Cellular Electrophysiology of Mexiletine and Sotalol, Singly and Combined, in Canine Purkinje Fibers

Abstract

To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1–100 μM), sotalol (3.1–400 μM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 μM of one drug combined with 3.1, 12.5, and 50 μM of the other. Mexiletine caused a concentration dependent depression of V_max, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 μM, sotalol depressed V_max slightly. Increasing the stimulation frequency did not result in further V_max depression. The addition of sotalol did not alter the V_max depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.