Myocardial Reperfusion Injury: Its Protection By a Free Radical Scavenger, N-2-Mercaptopropionyl Glycine (Infarctina, Sulfhydryl Compounds, Oxygen Free Radicals, Antioxidants).

N-2-Mercaptopropionyl glycine (MPG), a free radical scavenger, was evaluated for its ability to limit the extent of irreversible injury resulting from 90 minutes of ischemia followed by 6 hours of reperfusion in a canine model of myocardial infarction. Administration of MPG (20 mg/kg; intraatrially) at the onset of ischemia and throughout the early phase of reperfusion, or before the onset of reperfusion and continuing throughout the early phase of reperfusion resulted in a 34% reduction in myocardial infarct size. Hemodynamic and radioactive microsphere studies revealed that the cardioprotective effects of MPG could not be attributed to a reduction in myocardial oxygen consumption or the redistribution of regional myocardial blood flow. In vitro studies indicated that MPG effectively scavenges superoxide anion generated by the hypoxanthine-xanthine oxidase reaction as well as by activated canine polymorphonuclear leukocytes (PMNs). In order to determine if the cardioprotective effect of MPG was (1) attributable to its reaction with oxygen metabolites generated by myocardial sources or (2) secondary to effects on PMNs and their secretory products (e.g. oxygen metabolites), MPG was evaluated for its ability to limit the extent of myocardial injury resulting from ischemia and reperfusion in dogs which were depleted on PMNs with specific antisera. Administration of neutrophil antiserum resulted in a 33% reduction in infarct size (from 45.6 (+OR-) 3.7% in dogs receiving nonimmune serum to 30.7 (+OR-) 2.7% in dogs treated with neutrophil antiserum, p < 0.01). The combined administration of neutrophil antiserum plus MPG reduced infarct size by 63% in comparison to controls which received nonimmune serum (17.1 (+OR-) 2.7% vs. 45.6 (+OR-) 3.7%, p < 0.01). The reduction in infarct size with neutrophil depletion plus MPG was significantly greater than with neutrophil depletion alone (p < 0.01), suggesting that MPG exerts its protective influence in part by reacting with oxygen metabolites derived from myocardial sources. MPG and related sulfhydryl compounds (cysteine, reduced glutathione, n-acetylcysteine) inhibited myoglobin-H(,2)O(,2) mediated peroxidation reactions, indicating that the protective effects of MPG may be related to its ability to inhibit oxidative damage secondary to the formation of reactive species generated via the interaction of H(,2)O(,2) with myoglobin. These observations, taken together, suggest that reactive oxygen metabolites derived from myocardial sources as well as from invading inflammatory cells contribute to irreversible injury that occurs upon reperfusion of the ischemic myocardium. These data further suggest that the antioxidant properties of MPG are of central importance in explaining its protective effects against reperfusion-induced myocardial injury.Ph.D.PharmacologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160837/1/8600504.pd