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CARDIOVASCULAR

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

Department of Pharmacology, CV Therapeutics, Inc., Palo Alto, California

Ranolazine [Ranexa; (±)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] is novel anti-ischemic agent that has been shown to inhibit late I_Na and I_Kr and to have antiarrhythmic effects in various preclinical 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 QT interval corrected for heart rate (QTc) (52 ± 9%) and monophasic action potential duration (MAPD)₉₀ (56 ± 9%) and caused TdP in eight of eight 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 versus vehicle) and MAPD₉₀ (21 ± 4 and 20 ± 2%, respectively, p < 0.001 versus vehicle) and prevented the occurrence of TdP (zero of eight and zero of eight, respectively). Administration of ranolazine after the first episode of TdP terminated TdP and prevented its recurrence (zero of four versus vehicle, four of four). To rule out an ₁-adrenoceptor antagonistic activity of ranolazine, we compared the effects of ranolazine on blood pressure with those of the ₁-antagonist, prazosin. Although 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 (seven of eight). 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.

Address correspondence to: Dr. Arvinder K. Dhalla, Department of Pharmacological Sciences, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: arvinder.dhalla{at}cvt.com