Duff H J, Cannon N J, Sheldon R S
Department of Medicine, University of Calgary, Faculty of Medicine, Alberta, Canada.
Cardiovasc Res. 1989 Jul;23(7):584-92. doi: 10.1093/cvr/23.7.584.
Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.
