Antioxidant pyruvate inhibits cardiac formation of reactive oxygen speciesthrough changes in redox state

Myocardial ischemia-reperfusion is associated with bursts of reactive oxyge n species (ROS) such as superoxide radicals (O-2(-).). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O-2(-)., implyin g the NADH concentration-to-NAD(+) concentration ratio ([ NADH]/[NAD(+)]) a s a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS for mation were measured as influenced by pyruvate or L-lactate. Pre- and posti schemic 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 spi n resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 m M) 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 basa l ROS was dose dependently inhibited by pyruvate (0.1-5.0 mM) and not the x anthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xan thine oxidase. The data suggest a substantial influence of cytosolic NADH o n cardiac O-2(-). formation that can be inhibited by submillimolar pyruvate . Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be allevi ated by redox reactants such as pyruvate.