Antioxidant Properties of Pyruvate Mediate its Potentiation of β -Adrenergic Inotropism in Stunned Myocardium

This study tested the hypothesis that pyruvateʹs antioxidant actions, particularly its enhancement of the endogenous glutathione system, mediate its potentiation of β -adrenergic inotropism in stunned myocardium. Isolated working guinea pig hearts, metabolizing 10 m glucose and stunned by 45 min of low flow ischemia, were treated with 5 m pyruvate, 5 m N-acetylcysteine (NAC) and/or 2 n isoproterenol beginning 15 min after reperfusion. The antioxidant NAC alone did not increase cardiac power (mJ/min/g wet: 11±1 in untreated and 15±2 in NAC treated stunned hearts), but NAC potentiated the increase in power produced by 2 n isoproterenol (isoproterenol alone: 50±10; NAC plus isoproterenol: 133±24). Addition of NAC doubled cyclic AMP content but lowered cytosolic phosphorylation potential by 32% in isoproterenol-stimulated hearts. Stunning decreased the glutathione antioxidant ratio (GSH/GSSG) by 68%. The antioxidant ratio was completely restored by pyruvate alone or in combination with isoproterenol, but only partially restored by isoproterenol alone. Combining isoproterenol and NAC increased the GSH/GSSG ratio by an additional 36%. The combined treatment of pyruvate and isoproterenol increased the NADPH/NADP+ratio almost three-fold, and produced the greatest accumulation of glucose-6-phosphate of any treatment. Conclusions: like pyruvate, the antioxidant NAC potentiated β -adrenergic inotropism of stunned myocardium. Unlike pyruvate, NAC did not increase cellular energy reserves, thus effectively limiting its potentiation of β -adrenergic stimulation. Thus, pyruvateʹs potentiation of β -adrenergic stimulation in stunned myocardium is most likely the result of the combined effects of its antioxidant and energetic properties.