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Protective Effects of Ranolazine on Ventricular Fibrillation Induced by Activation of the ATP-Dependent Potassium Channel in the Rabbit Heart

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

Liguo Chi, MD, PhD

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

James L. Park, BS

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

Gregory S. Friedrichs, PhD

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

Elaine J. Tanhehco

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

James G. McCormack, PhD, DSc

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

Benedict R. Lucchesi, PhD, MD

Department of Pharmacology; University of Michigan Medical School, Ann Arbor, Michigan, and Syntex Research Centre, Heriot-Watt University Research Park, Riccarton, Edinburgh, Scotland

Background: The authors studied the antifibrillatory effects of the adenosine-triphosphate (ATP)-sparing metabolic modulator ranolazine in a rabbit isolated heart model in which ventricular fibrillation occurs under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener pinacidil.

Methods and Results: Ten minutes after ranolazine or vehicle administration, addition of pinacidil (1.25 µM) to the buffer was followed by a 12-minute hypoxic period and 40 minutes of reoxygenation. At a reduced concentration of ranolazine (10 µM), ventricular fibrillation occurred in 60% of the hearts. compared to 89% in the control group (P = NS). In contrast, only three of nine hearts (33%) treated with 20 µM ranolazine developed ventricular fibrillation (P <.05 vs vehicle). Hemodynamic parameters including coronary perfusion pressure, left ventricular developed pressure, and ±dP/dt were not affected by the presence of ranolazine in the perfusion medium. Ranolazine did not prevent or modify the negative inotropic or coronary vasodilator actions of pinacidil, suggesting a mechanism of action independent of potassium channel antagonism.

Conclusions: Ranolazine significantly reduced the incidence of ventricular fibrillation in the hypoxic/reoxygenated heart exposed to the ATP-dependent potassium channel opener, pinacidil. The reported ability of ranolazine to prevent the decrease in cellular ATP during periods of a reduced oxygen supply may account for its observed antifibrillatory action. By maintaining intracellular ATP, ranolazine may modulate or prevent further opening of the ATP-dependent potassium channel in response to hypoxia and/or pinacidil.

Key Words: arrhythmia • pyruvate dehydrogenase • antiarrhythmic • antifibrillatory.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 1, No. 2, 141-148 (1996)
DOI: 10.1177/107424849600100208


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