Received for publication February 6, 2008.
Revised March 4, 2008.
Accepted for publication March 4, 2008.

Anti-Torsadogenic Effects of Ranolazine in Anesthetized Rabbits

Abstract

Ranolazine is novel anti-ischemic agent which has been shown to inhibit late I_Na and I_Kr and to have anti-arrhythmic effects in various pre-clinical in vitro models. This study was undertaken to investigate the effects of ranolazine on drug-induced Torsade de Pointes (TdP) in vivo. TdP was induced by an I_Kr blocker, clofilium, in anesthetized, ₁-agonist -sensitized rabbits. Clofilium prolonged QTc (52 ± 9%), MAPD₉₀ (56 ± 9%) and caused TdP in 8/8 rabbits. Pretreatment with ranolazine (480 µg/kg/min) or lidocaine (200 µg/kg/min) reduced the clofilium-induced prolongation of QTc (15 ± 3% and 19 ± 3%, respectively, p<0.001 vs vehicle) and MAPD₉₀ (21 ± 4% and 20 ± 2%, respectively, p<0.001 vs vehicle), and prevented the occurrence of TdP (0/8 and 0/8 respectively). Administration of ranolazine after the first episode of TdP terminated TdP and prevented its recurrence (0/4 vs vehicle 4/4). To rule out a ₁-adrenoceptor antagonistic activity of ranolazine, we compared the effects of ranolazine on blood pressure to those of the ₁-antagonist, prazosin. While prazosin (10 µg/kg/min) markedly shifted the phenylephrine (₁-agonist) dose-response curve to the right, it did not have any effect on clofilium-induced prolongation of QTc and MAPD₉₀ (43 ± 7% and 53 ± 9%, respectively) or the occurrence of TdP (7/8). In contrast, ranolazine completely suppressed TdP, but did not cause any shift in the phenylephrine dose-response curve at the highest dose tested (480 µg/kg/min). We conclude that ranolazine antagonizes the ventricular repolarization changes caused by clofilium and suppresses clofilium-induced TdP in rabbits.

Key words: Anti-anginal, Anti-arrhythmic, Arrhythmias, Late Na Current Inhibitor, Ranolazine, Torsades de Pointes