Metabolic modulation of cellular redox potential can improve cardiac recovery from ischemia–reperfusion injury

Objective: Ischemia–reperfusion heart injury is an important pathologic condition against which many strategies, mainly involving antioxidants or radical scavengers, have been developed, but without satisfactory results. In the present experiment, modulation of the cytosolic NADH/NAD ratio by pyruvate and aspartate was tested in order to protect the heart from ischemia–reperfusion injury. Methods: Effects of pyruvate and aspartate on cardiac function recovery and redox potential were analyzed in the isolated heart of male Sprague–Dawley rats. Hearts were made globally ischemic for 20 min and then reperfused for 30 min. Results: Pyruvate and aspartate protected against tissue injury and improved contractile function after reperfusion of ischemic hearts, and these substances effectively decreased the tissue and cytosolic NADH/NAD ratio of the myocardium in a dose-dependent manner. Postischemic cardiac functions were negatively related to tissue and cytosolic NADH/NAD ratios. Increased NADH selectively inhibited myocardial xanthine dehydrogenase in vitro. It was thus expected that a decrease of NADH might limit the production of reactive oxygen species through the recovery of xanthine dehydrogenase activity. Conclusion: These results indicate that a decrease of NADH is related to pyruvate and aspartate-induced protection of ischemic myocardium.