THE EFFECT OF FLUNARIZINE AND RYANODINE ON ACQUIRED TORSADES-DE-POINTES ARRHYTHMIAS IN THE INTACT CANINE HEART

Introduction: Ryanodine, a specific blocker of the Ca2+ release channe l of the sarcoplasmic reticulum, and flunarizine, a [Ca2+](i) overload blocker, possess antiarrhythmic effects against delayed afterdepolari zations (DADs) and DAD-dependent arrhythmias. In vitro controversy exi sts about their effect on early afterdepolarizations (EADs): no effect was reported on cesium-induced EADs, while ryanodine did prevent EADs induced by isoproterenol. To study the possible role of intracellular Ca2+ overload in acquired EAD-dependent torsades de pointes (TdP) arr hythmias, we tested the effects of flunarizine and ryanodine in our an imal model of TdP. Methods ana Results: Anaesthetized dogs with chroni c AV block received d-sotalol or almokalant followed by pacing. A subs et of dogs with reproducible TdP (greater than or equal to 3 times) we re selected to receive flunarizine (2 mg/kg per 2 min) or ryanodine (1 0 mu g/kg per 10 min). After d-sotalol, TdP was induced at a mean cycl e length of the idioventricular rhythm (CL-IVR) of 2070 +/- 635 msec a nd a QT(U) interval of 535 +/- 65 msec. Induction of TdP was prevented by flunarizine in all experiments (8/8): electrophysiologically this was associated with a decrease in CL-IVR, QT(U), and QT(c) interval (3 90 +/- 100 to 320 +/- 45, P < 0.05). Ryanodine prevented TdP induction in 4 of 5 experiments and decreased the CL-IVR, QT(U), and the QT(c) interval from 385 +/- 75 to 320 +/- 20 msec (P < 0.05). Both drugs als o suppressed the almokalant-induced EADs and related ectopic activity. This antiarrhythmic action corresponded with the inability to reinduc e TdP by pacing. Conclusions: Blockade of the Ca2+ release channel of the sarcoplasmic reticulum by ryanodine or the reduction of [Ca2+](i) overload by flunarizine prevents induction of EAD-dependent acquired T dP arrhythmias, suggesting a role for [Ca2+](i) overload in acquired T dP.