Jpn. J. Pharmacol. 77 (1), 31-39 (1998)

Protective Effects of Ranolazine, a Novel Anti-ischemic Drug, on the Hydrogen Peroxide-Induced Derangements in Isolated, Perfused Rat Heart: Comparison With Dichloroacetate

Hisao Matsumura, Akiyoshi Hara (*), Hiroko Hashizume, Kazuyasu Maruyama and Yasushi Abiko

Department of Pharmacology, Asahikawa Medical College, Asahikawa 078-8510, Japan
(*) To whom correspondence should be addressed.

Abstract: The effect of ranolazine, a novel anti-ischemic drug that stimulates the activity of pyruvate dehydrogenase, on hydrogen peroxide (H202)-induced mechanical and metabolic derangements was studied in isolated rat heart and compared with that of dichloroacetate (DCA), an activator of pyruvate dehydrogenase. The heart was perfused aerobically by the Langendorff's technique at a constant flow and driven electrically. H202 (600 microM) decreased the left ventricular developed pressure and increased the left ventricular end-diastolic pressure (i.e., mechanical dysfunction), decreased the tissue level of adenosine triphosphate (i.e., metabolic derangement), and increased the tissue level of malondialdehyde (MDA) (i.e., lipid peroxidation). These mechanical and metabolic derangements induced by H202 were significantly attenuated by ranolazine (10 or 20 microM). On the other hand, DCA (1 mM) was ineffective in attenuating the H202-induced mechanical and metabolic derangements. Ranolazine, however, did not modify the tissue MDA level, which was increased by H202. In the normal (H202-untreated) heart, ranolazine did not alter the mechanical function and energy metabolism. These results demonstrate that ranolazine attenuates mechanical and metabolic derangements induced by H202. It is suggested that the protective action of ranolazine against the H202-induced derangements is due to neither the energy-sparing, DCA-like, nor anti-oxidant effects.

Keywords: Ranolazine, Dichloroacetate, Hydrogen peroxide, Lipid peroxidation, Rat heart

Copyrightę The Japanese Pharmacological Society 1998

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