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Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 11, No. 4, 249-255 (2006)
DOI: 10.1177/1074248406294607

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

Sharon L. Hale, BS

Heart Institute of Good Samaritan Hospital and the Keck School of Medicine, Division of Cardiovascular Medicine, University of Southern California, Los Angeles; sharon.hale{at}netscape.com

Robert A. Kloner, MD, PhD, FACC

Heart Institute of Good Samaritan Hospital and the Keck School of Medicine, Division of Cardiovascular Medicine, University of Southern California, Los Angeles

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 µg/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.

Key Words: ranolazine • LV function • myocardial stunning • late sodium channel current

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