Oxygen-derived free radicals are produced during myocardial ischemia and reperfusion in animal modes. Conditions of ischemia and reperfusion are routinely created in the setting of cardiac surgery and heart transplantation. However, the extent to which oxy-radicals are responsible for causing myocardial damage in the clinically relevant setting has not been determined. Myocardial cells are equipped with defense systems to combat the deleterious effects of oxy radicals. Supplementation of cardioplegic solutions with radical scavengers and agent capable of inducing defensive antioxidant enzymes have been shown to be cardioprotective. Nitric oxide ( NO as a cytoprotectant during ischemia and reperfusion is unknown. We hypothesize that intracellular free radical production is in part responsible for myocardial damage during ischemia and reperfusion and the extent of free radical mediated damage may be modulated by manipulating the intracellular levels of glutathione, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, and by endothelium-derived nitric oxide. This hypothesis will be tested in both the rat and rabbit models. In this proposal, we will: 1) determine whether increasing the intracellular concentrations of radical traps during ischemia will improve post- ischemic functional recovery, 2) assess whether glutathione-deficient hearts are more susceptible to reperfusion-induced injury, 3) determine whether selenoperoxidase-deficient hearts are more susceptible to myocardial injury, 4) determine the intracellular origin of oxy radicals in isolated rat and rabbit hearts, and 5) assess the interaction between oxy radicals formed in the myocardium and NO released by the vascular endothelium and nitrovasodilators. Techniques to be used include electron spin resonance (ESR), gas chromatography-mass spectrometry (GC- MS) and high performance liquid chromatography (HPLC) with electrochemical detection. It is our expectation that this comprehensive approach to understanding the free radical component of myocardial injury will contribute new mechanistic information that will help develop strategies to improve myocardial management during clinically relevant ischemic situations such as cardiac surgery and organ preservation for transplantation.
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