The overall objective is to test the hypothesis that postischemic myocardial dysfunction (myocardial """"""""stunning"""""""") is caused by oxygen- derived free radicals, and to develop potentially useful antioxidant therapies. The oxy-radical hypothesis will be directly investigated by in vivo detection and quantification of free radicals with spin traps and electron paramagnetic resonance (EPR) spectroscopy. A comprehensive, in-depth analysis will be performed by using different spin traps with complementary properties [OBN, (MO)3 PBN, DMPO, 4-POBN] and a new generation of spin traps with unique diagnostic potential (14 C-labeled PBN, deuterated PBN, alpha-13 C PBN, 2,6-Difluoro PBN). The time-course and intensity of radical production will be correlated with the time-course and intensity of contractile dysfunction. Specific scavengers of .O2-, H2O2, or .OH and chelators of iron will be evaluated to determine their ability to suppress radical formation and to identify the most effective antioxidant therapy. To establish whether the radicals produced are responsible for dysfunction, the effects of antioxidants on radical production will be correlated with their effects on recovery of contractility. Antioxidants will be given before ischemia, at reperfusion, or shortly after reperfusion and the results compared to identify the time-window during which the critical radical- mediated damage develops and to determine the optimal time for antioxidant therapy. To elucidate the sources of the injurious radicals, interventions that inhibit neutrophils, autoxidation of catecholamines, and cyclooxygenase will be evaluated. The molecular structure of the radicals will be identified by solvent separation, HPLC, electrochemical detection, EPR spectroscopy, gas chromatography, and mass spectrometry. To test the hypothesis that oxy-radical generation is a common mechanism underlying the entire spectrum of postischemic dysfunction, studies will be performed in three different settings of stunning, i.e., in reversible ischemic insult (15-min coronary occlusion), multiple cumulative ischemic insults (ten 5-min occlusions), or a prolonged ischemic insult associated with subendocardial infarction (980-min occlusion). This proposal should provide important new insights into the mechanism of myocardial stunning. The results should be relevant to several clinical situations in which transient ischemia may precipitate LV dysfunction, namely, unstable or variant angina, cardiopulmonary bypass surgery, cardiac transplantation, and thrombolysis in acute myocardial infarction.
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