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(Circulation Research. 1995;77:773-783.)
© 1995 American Heart Association, Inc.

Articles

Nuclear Magnetic Resonance Studies of Cationic and Energetic Alterations With Oxidant Stress in the Perfused Heart

Modulation With Pyruvate and Lactate

Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 1994.

S. Yanagida, C.S. Luo, M. Doyle, G.M. Pohost, M.M. Pike

From the Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham.

Correspondence to Dr M.M. Pike, Department of Medicine, Division of Cardiovascular Disease, 703 S 19th St, ZRB 308, Birmingham, AL 35294-0007.

Abstract The postischemic generation of oxygen-derived free radicals may contribute to myocardial reperfusion injury by affecting sarcolemmal ion transport. Recent evidence indicates that exposure to reactive oxygen intermediates induces rapid increases in myocardial cytosolic free Ca²⁺ (Ca²⁺_i). The mechanism is undetermined but may involve disturbances in Na⁺ homeostasis. We tested this hypothesis by interleaving ²³Na and ³¹P nuclear magnetic resonance (NMR) measurements of Na⁺_i and high-energy phosphates in glucose-perfused rat hearts exposed to hydroxyl radicals generated from H₂O₂ and Fe³⁺. In separate experiments, K⁺_i and Ca²⁺_i were measured with ³⁹K and ¹⁹F NMR, respectively. The hearts rapidly exhibited contracture. Threefold Na⁺_i increases and substantial K⁺_i depletion were observed. Glycolytic inhibition was indicated by rapid sugar phosphate accumulation and cellular energy depletion. Notably, however, severe functional and energetic deterioration and substantial elevation of Ca²⁺_i occurred before substantial Na⁺_i accumulation or K⁺_i depletion was observed. Further experiments investigated the ability of pyruvate to scavenge H₂O₂ and to protect the myocardium from oxidant stress. Pyruvate (1 or 2.5 mmol/L) dramatically attenuated functional and energetic alterations and alterations in Na⁺_i and K⁺_i, whereas acetate (2.5 mmol/L) offered no protection. Unlike pyruvate, lactate (5 mmol/L) has little or no capacity to scavenge H₂O₂ but has similar protective effects. In conclusion, pyruvate effectively protects against H₂O₂/Fe³⁺, largely by direct H₂O₂ scavenging. Protection with lactate may involve intracellular pyruvate augmentation. Without exogenous pyruvate or lactate, myocardial Na⁺ homeostasis can be substantially altered by oxidant stress, possibly via cellular energy depletion. Excess Na⁺_i accumulation may, in turn, hasten metabolic and functional deterioration, but a causal link with the initial alterations in function or Ca²⁺_i was not supported.

Key Words: free radicals • intracellular Na⁺ • nuclear magnetic resonance • high-energy phosphates • pyruvate

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