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