Antioxidant pyruvate inhibits cardiac formation of reactive oxygen species through changes in redox state.
Myocardial ischemia-reperfusion is associated with bursts of reactive oxygen species (ROS) such as superoxide radicals (O(2)(-).). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O(2)(-)., implying the NADH concentration-to-NAD(+) concentration ratio ([NADH]/[NAD(+)]) as a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS formation were measured as influenced by pyruvate or L-lactate. Pre- and postischemic Langendorff guinea pig hearts were perfused at different pyruvate/L-lactate concentrations to alter cytosolic [NADH]/[NAD(+)]. NADHox and ROS were measured with the use of lucigenin chemiluminescence and electron spin resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 mM) and the NADHox blocker hydralazine markedly inhibited NADHox (16 +/- 2%, 58 +/- 9%). In postischemic hearts, pyruvate (0.1-5.0 mM) dose dependently inhibited ROS up to 80%. However, L-lactate (1.0-15.0 mM) stimulated both basal and postischemic ROS severalfold. Furthermore, L-lactate-induced basal ROS was dose dependently inhibited by pyruvate (0.1-5.0 mM) and not the xanthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xanthine oxidase. The data suggest a substantial influence of cytosolic NADH on cardiac O(2)(-). formation that can be inhibited by submillimolar pyruvate. Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be alleviated by redox reactants such as pyruvate.
Bassenge
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Institute for Applied Physiology, University of Freiburg, D-79104 Freiburg/Breisgau, Germany. angphys@uni-freiburg.de
Sommer
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Schwemmer
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Bünger
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D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D003373:Coumaric Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D003373:Coumaric Acids; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D006830:Hydralazine; D019344:Lactic Acid; C018254:alpha-cyano-3-hydroxycinnamate; D019289:Pyruvic Acid; D014969:Xanthine Oxidase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases