Ryanodine-receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long-QT syndrome.

Abstract

A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole-heart model of drug-induced long-QT syndrome (LQTS). In 12 isolated rabbit hearts, long-QT-2-syndrome was simulated by infusion of erythromycin (300 μM). Twelve rabbit hearts were treated with veratridine (0.5 μM) to mimic long-QT-3-syndrome. Monophasic action potentials and ECG showed a significant prolongation of QT-interval (+71ms, P<0.01) and action potential duration (APD, +43ms, P<0.01) after infusion of erythromycin as compared with baseline. Similar results were obtained in veratridine-treated hearts (QT-interval: +43ms, P<0.01; APD: +36ms, P<0.01). Both erythromycin (+36ms, P<0.05) and veratridine (+38ms) significantly increased dispersion of repolarization. Additional infusion of dantrolene (20 μM) did not significantly alter QT-interval and APD but resulted in a significant reduction of dispersion of repolarization (erythromycin group: -33ms, P<0.05; veratridine group: -29ms, P<0.05). Lowering of potassium concentration resulted in the occurrence of early afterdepolarizations (EAD) and polymorphic ventricular tachycardia (VT) in 9 of 12 erythromycin-treated hearts (175 episodes) and 8 of 12 veratridine-treated hearts (66 episodes). Additional infusion of dantrolene significantly reduced occurrence of polymorphic VT and resulted in occurrence of EAD and polymorphic VT in 1 of 12 erythromycin-treated hearts (18 episodes) and 1 of 12 veratridine-treated hearts (3 episodes). Inhibition of the ryanodine receptor by dantrolene significantly reduced occurrence of polymorphic VT in drug-induced LQTS. A significant reduction of spatial dispersion of repolarization represents a major antiarrhythmic mechanism. These results imply that dantrolene may represent a promising antiarrhythmic option in drug-induced LQTS.