Broad antiarrhythmic effect of mexiletine in different arrhythmia models

Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS).

In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: −43 ms, P < 0.01; veratridine: −26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the I_K-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: −18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation.

Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.