Ranolazine, an Inhibitor of the Late Sodium Channel Current, Reduces Postischemic Myocardial Dysfunction in the Rabbit

Abstract

Ranolazine is a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces the frequency of angina attacks, but there is little information on its effects on myocardial stunning after short-term ischemia. The objective of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial stunning after ischemia/reperfusion in rabbits. Myocardial stunning was induced in rabbits by 15 minutes of coronary artery occlusion (CAO) followed by 3 hours reperfusion. Ten minutes before CAO, rabbits were randomly assigned to vehicle (n = 15) or ranolazine (2 mg/kg bolus plus 60 microg/kg/min infusion, IV, n = 15). Myocardial stunning was assessed by LV 2-dimensional echocardiography using, as a marker of severity, ischemic free-wall fractional thickening (FWft; systolic wall thickness - diastolic wall thickness/diastolic wall thickness). Regional ejection fraction (EF) was also assessed. During CAO, FWft was depressed in both groups, indicating an ischemic insult (FWft was reduced from 0.62 +/- 0.05 at baseline to 0.10 +/- 0.04 in vehicle and from 0.73 +/- 0.05 to 0.26 +/- 0.07 in ranolazine, P < 0.05, ranolazine vs vehicle). After reperfusion, previously ischemic myocardium remained stunned; however, FWft recovered significantly better in ranolazine (0.51 +/- 0.05) than in vehicle (0.35 +/- 0.04, P = .027). Baseline EF was 0.65 +/- 0.02 in the ranolazine and 0.68 +/- 0.02 in vehicle (P = ns). During CAO, EF was reduced by 36% +/- 6% in vehicle versus only 20% +/- 6% in ranolazine (P < .05). At the end of reperfusion, EF remained depressed in both groups, but the reduction in the vehicle group (25% +/- 5%) was significantly worse than in ranolazine (9% +/- 4%, P = .017). Improvement in function was independent of necrosis (negligible) or differences in hemodynamics (no differences between groups). Ranolazine treatment reduced myocardial stunning following brief ischemia/reperfusion suggesting that inhibiting the late sodium channel current may be a novel approach to treating stunning independent of effects on hemodynamics.