Sotalol and Mexiletine: Combination of Rate-Dependent Electrophysiological Effects

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Abstract
Summary The rate-dependent electrophysiological effects of sotalol (30 μM), mexiletine (10 and 18 μM), and their coadministration were examined in isolated dog cardiac Purkinje fibers following abrupt changes in pacing cycle length. Combination of 30 μM sotalol with 10 μM mexiletine significantly lengthened premature action potential durations at diastolic intervals of < 50 ms while the basic action potential duration evoked at a stimulus frequency of 2 Hz was not affected. This effect on the premature action potential duration was attenuated when the higher mexiletine concentration (18 μM) was coadministered with sotalol. The fast time constant for restitution of the action potential duration was significantly slowed by either combination. Coadministration of sotalol and mexiletine, like mexiletine alone, produced a rate-dependent depression of ±max that displayed a second slow time component during recovery. This slow component for recovery of ±max was not distinguished in the absence of drug or in the presence of sotalol alone. Sotalol-induced lengthening of the action potential duration observed at slow pacing frequencies was also attenuated by addition of mexiletine; and, under these conditions, Purkinje fiber early afterdepolarizations were prevented. In addition, the range of premature action potential durations was significantly decreased by mexiletine and by the combination, while sotalol alone increased this range slightly. These results indicate that coadministration of sotalol and mexiletine may provide beneficial electrophysiological effects expected to provide enhanced antiarrhythmic efficacy and fewer proarrhythmic complications in patients.