Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

From the Department of Physiology, New York Medical College, Valhalla.

Correspondence to Michael S. Wolin, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595.

Abstract—This study was designed to investigate the potential role of endogenous peroxynitrite (ONOO^-) formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation. Isometric contraction of isolated rat left ventricular posterior papillary muscle was virtually eliminated at the end of an exposure to 15 minutes of hypoxia and remained 40±5% depressed an hour after the reintroduction of O₂. O₂ uptake by rat left ventricular cardiac muscle, measured by a Clark-type O₂ electrode, was also inhibited by 24±2% at 10 minutes after reoxygenation. The inhibition of contractility and respiration during posthypoxic reoxygenation was markedly attenuated by the NO synthase inhibitor nitro-L-arginine, exogenous superoxide dismutase, and the ONOO^- scavenger urate but not by the hydroxyl radical scavenger mannitol. Generation of ONOO^- with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) plus the superoxide-releasing agent pyrogallol caused an irreversible inhibition of cardiac contractile and respiratory function. Unlike ONOO^-, exogenous (SNAP) and endogenous (bradykinin) sources of NO inhibited contractility in a reversible manner. Under conditions of comparable amounts of respiratory inhibition in unstimulated incubated muscle, the NO-dependent agents and the mitochondrial antagonist NaCN produced a smaller degree of suppression of contractility compared with ONOO^- and posthypoxic reoxygenation. These results are consistent with a contributing role for endogenous ONOO^- formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation.

Key Words: cardiac contractility • mitochondrial respiration • hypoxia/reoxygenation • nitric oxide • superoxide

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