We tested the effect of the antianginal agent ranolazine on ventricular arrhythmias in an ischemic model using two protocols. In protocol 1, anesthetized rats received either vehicle or ranolazine (10 mg/kg, iv bolus) and were subjected to 5 min of left coronary artery (LCA) occlusion and 5 min of reperfusion with electrocardiogram and blood pressure monitoring. In p rotocol 2, rats received either vehicle or three doses of ranolazine (iv bolus followed by infusion) and 20 min of LCA occlusion. With protocol 1, ventricular tachycardia (VT) occurred in 9/12 (75%) vehicle-treated rats and 1/11 (9%) ranolazine-treated rats during reperfusion ( P = 0.003). Sustained VT occurred in 5/12 (42%) vehicle-treated but 0/11 in ranolazine-treated rats ( P = 0.037). The median number of episodes of VT during reperfusion in vehicle and ranolazine groups was 5.5 and 0, respectively ( P = 0.0006); median duration of VT was 22.2 and 0 s in vehicle and ranolazine rats, respectively ( P = 0.0006). With p rotocol 2, mortality in the vehicle group was 42 vs. 17% ( P = 0.371), 10% ( P = 0.162) and 0% ( P = 0.0373) with ranolazine at plasma concentrations of 2, 4, and 8 μM, respectively. Ranolazine significantly reduced the incidence of ventricular fibrillation [67% in controls vs. 42% ( P = 0.414), 30% ( P = 0.198) and 8% ( P = 0.0094) in ranolazine at 2, 4, and 8 μM, respectively]. Median number (2.5 vs. 0; P = 0.0431) of sustained VT episodes, incidence of sustained VT (83 vs. 33%, P = 0.0361), and the duration of VT per animal (159 vs. 19 s; P = 0.0410) were also significantly reduced by ranolazine at 8 μM. Ranolazine markedly reduced ischemia-reperfusion induced ventricular arrhythmias. Ranolazine demonstrated promising anti-arrhythmic properties that warrant further investigation.
Antiarrhythmic Plasma Concentrations of Pirmenol on Canine Ventricular Arrhythmias