First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model

Abstract

There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine is a promising late INa blocker with antiarrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between ranolazine and other antiarrhythmic agents in an ischemia/reperfusion setting. HYPOTHESIS AND METHODS: To determine whether ranolazine was as effective as sotalol and lidocaine to reduce ischemia/reperfusion-induced arrhythmias, anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, which causes severe ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats (n = 20 per group) were randomized to receive either sotalol (intravenous [IV] bolus 5 mg/kg, 10 mg/kg per hour infusion), lidocaine (IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion), ranolazine (IV bolus 3.3 mg/kg, 3.2 mg/kg per hour infusion), or saline (control). The incidence of ventricular arrhythmias in the sotalol (S), lidocaine (L), ranolazine (R), and control (C) groups was 7/20, 10/20, 9/20, and 16/20, respectively (P = .01 S vs C, P = .10 L vs C, and P = .048 R vs C). Duration of ventricular tachycardia (VT) episodes was reduced from 15.5 seconds (mean) in C to 1.3 seconds in S, 1.4 sec in L and 0.09 sec in R (P < .05 for S vs C and R vs C by Wilcoxon test). The number of rats with any (≥ 10 seconds) sustained VT was 3 in C versus 1, 0, and 0 in the S, L, and R groups, respectively. Two rats in C had reversible ventricular fibrillation versus 0 in the S, L, and R groups. The number of ventricular premature beats (VPBs) per rat was 10.9 in C, 2.3 in S, 4.9 in L, and 5.7 in R (P < .05 for S, L, or R vs C). P = NS for R versus L or S for all analyses. In this first head-to-head comparison of R vs other antiarrhythmic agents at therapeutic doses in an ischemia/reperfusion model, ranolazine (which lacks pro-arrhythmic effects) was as effective as either sotalol or lidocaine to reduce reperfusion-induced ventricular arrhythmias.