Mexiletine and Quinidine in Combination in an Ischemic Model: Supra-Additive Antiarrhythmic and Electrophysiologic Actions

Abstract

Combination therapy with mexiletine and quinidine has been shown to be more effective than either agent alone in the treatment of ventricular tachycardia in humans. To assess the electrophysiologic correlates of this enhanced antiarrhythmic effect, concentration-response relationships of mexiletine and quinidine alone and in combination were evaluated in 117 isolated perfused rabbit hearts after circumflex occlusion-reperfusion. Normal and infarct zone recordings included monophasic action potential duration, ventricular effective refractory period, and conduction time during constant rate pacing. Ventricular fibrillation occurred in all 18 "vehicle only"-treated hearts during programmed electrical stimulation (S2). High-concentration mexiletine therapy was more effective in protecting against malignant ventricular arrhythmias than was quinidine. Both therapies produced concentration-dependent prolongation of ischemic zone conduction and refractoriness. When low concentrations of mexiletine and quinidine were combined (concentrations which when given alone had little or no electrophysiologic or antiarrhythmic activity) antiarrhythmic activity was seen which was greater than that seen with high-concentration single treatment. Low-concentration combination therapy was also associated with significantly greater prolongation of infarct zone conduction time and refractoriness. In conclusion, low-concentration combination treatment with mexiletine and quinidine prolonged infarct zone conduction time and refractoriness to a greater extent than was seen with single therapy at matched concentrations. These electrophysiologic effects were associated with enhanced antiarrhythmic activity.