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

• DOI: 10.1124/jpet.108.137729
• Publication Date: 2008-03-06T02:40:28Z
• Authors: Wei-Qun Wang; Chelsea Robertson; Arvinder K. Dhalla; Luiz Belardinelli
• Keywords: Ranolazine; Phenylephrine; Piperazine

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) have antiarrhythmic effects in various preclinical vitro models. This study was undertaken investigate the of ranolazine on drug-induced Torsade de Pointes (TdP) vivo. TdP induced by an blocker, clofilium, anesthetized, alpha(1)-agonist-sensitized rabbits. Clofilium prolonged QT interval corrected for heart rate (QTc) (52 +/- 9%) monophasic action potential duration (MAPD)(90) (56 caused eight Pretreatment with (480 microg/kg/min) or lidocaine (200 reduced clofilium-induced prolongation QTc (15 3 19 3%, respectively, p < 0.001 versus vehicle) MAPD(90) (21 4 20 2%, prevented occurrence (zero zero eight, respectively). Administration after first episode terminated its recurrence four vehicle, four). To rule out alpha(1)-adrenoceptor antagonistic activity ranolazine, we compared blood pressure those alpha(1)-antagonist, prazosin. Although prazosin (10 markedly shifted phenylephrine (alpha(1)-agonist) dose-response curve right, it did not any effect (43 7 53 9%, respectively) (seven eight). In contrast, completely suppressed but cause shift at highest dose tested microg/kg/min). We conclude antagonizes ventricular repolarization changes clofilium suppresses