• Robert T Mallet, Jeffrey E Squires, Shimona Bhatia, and Jie Sun.
• Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA. malletr@hsc.unt.edu
• J. Mol. Cell. Cardiol. 2002 Sep 1;34(9):1173-84.

PurposePyruvate, a natural energy-yielding fuel in myocardium, neutralizes peroxides by a direct decarboxylation reaction, and indirectly augments the glutathione (GSH) antioxidant system by generating NADPH reducing power via citrate formation. The possibility that pyruvate's antioxidant actions could mediate its enhancement of contractile performance in prooxidant-challenged myocardium was investigated in isolated working guinea-pig hearts reversibly injured by hydrogen peroxide.MethodsHearts were challenged by 10 min perfusion with 100 microM H(2)O(2), followed by 90 min H(2)O(2)-free perfusion. Metabolic and antioxidant treatments (each 5m M) were administered at 30-90 min post-H(2)O(2). Phosphocreatine phosphorylation state, GSH/glutathione disulfide redox potential (GSH/GSSG) and key enzyme activities were measured in snap-frozen myocardium.ResultsH(2)O(2) exposure depleted myocardial energy and antioxidant reserves and produced marked contractile impairment that persisted throughout the H(2)O(2) washout period. Relative to untreated post-H(2)O(2) myocardium, pyruvate restored contractile performance, increased GSH/GSSG 52% and maintained phosphocreatine phosphorylation state; in contrast, lactate lowered cardiac performance and phosphorylation state. Neither the pharmacological antioxidant N -acetylcysteine (NAC) nor the pyruvate analog alpha-ketobutyrate increased cardiac function; both treatments increased GSH/GSSG but lowered phosphocreatine potential. H(2)O(2) partially inactivated aconitase, creatine kinase and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), but all three enzymes spontaneously recovered during H(2)O(2) washout. Pyruvate did not further activate these enzymes and unexpectedly inhibited GAPDH by 60-70%.ConclusionPyruvate promoted robust contractile recovery of H(2)O(2)-challenged myocardium by the combination of citrate-mediated antioxidant mechanisms and maintenance of myocardial energy reserves.

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