Mexiletine-quinidine in isolated hearts: an interaction involving the sodium channel

Abstract

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.

Sodium MRI of the human heart at 7.0 T: preliminary results

“…Previous animal studies reported a decrease in Na + /K + ‐ATPase activity for HCM, which resulted in a 40% increase in intracellular sodium concentration . 23 Na MR at 7.0 T could also be beneficial for scrutinizing alterations in the myocardial Na + concentration evoked by cardiac drugs acting upon sodium ion channels .…”

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

“…Simulations using a Luo–Rudy model indicated that when I Na(late) is selectively increased two‐fold, enough inward current is present during repolarization to trigger EADs 13 . It has been shown that combination therapy with quinidine (class IA agent) and mexiletine (class IB agent and sodium channel blocker) is more effective in the prevention of ventricular tachycardia (VT) and ventricular fibrillation (VF) in animal models, 25,26 and in humans 27 . In isolated hearts and tissues, 28 these effects have been shown to be due to sodium channel blockade 25 .…”

“…Below, averaged Nav1. 5 channel blocker) is more effective in the prevention of ventricular tachycardia (VT) and ventricular fibrillation (VF) in animal models, 25,26 and in humans. 27 In isolated hearts and tissues, 28 these effects have been shown to be due to sodium channel blockade.…”

“…27 In isolated hearts and tissues, 28 these effects have been shown to be due to sodium channel blockade. 25 EAD generation is thought to be a major cause of torsades de pointes (TdP) in humans. Class III antiarrhythmics (I Kr blockers) which have been shown to also be proarrhythmic cause greater lengthening in Purkinje fiber action potentials relative to those in ventricular muscle, [29][30][31] presumably due to a greater contribution of I Kr in repolarization of Purkinje fibers (Fig.…”