Frequency-dependent effect of quinidine, mexiletine, and their combination on postrepolarization refractoriness in...

Combination therapy with mexiletine and quinidine has been shown to enhance antiarrhythmic efficacy. To assess further the underlying electrophysiological mechanism, the effect of therapeutic concentrations of mexiletine and quinidine, and of their combination, on action potential duration (at the level of 90% repolarization, APD90), effective refractory (ERP), and the relationship between these two parameters (ERP-APD90) was determined in 21 in vivo canine hearts. The frequency dependence of these effects was assessed over a range of paced steady-state cycle lengths from 250-600 ms. A modified contact electrode technique allowed measurements of both APD90 and ERP simultaneously and at the same ventricular site. In the drug-free state, both APD90 and ERP shortened linearly with shorter cycle lengths, maintaining a constant relationship (ERP-APD90) difference = -9 +/- 2 ms) at all cycle lengths. Quinidine prolonged APD90 by a near constant amount of 11 +/- 1 ms over the entire range of cycle lengths, while mexiletine tended to shorten it. Both mexiletine and quinidine increased ERP and ERP-APD90 in a rate-dependent fashion, the effect increasing with shorter cycle lengths. When used in combination, mexiletine attenuated the lengthening effect of quinidine on APD90 but augmented the rate-dependent increase in ERP, thereby producing greater postrepolarization refractoriness than either drug alone. This effect may explain the clinically favorable antiarrhythmic efficacy of mexiletine and quinidine combination therapy.