Improving myocardial preservation during ischemia and reperfusion has been the goal of our laboratory for the last six years of this research effort. There are an increasing number of reports, including from our own laboratory, which indicate that abnormal lipid metabolism resulting in modification of membrane structure and function and accumulation of lipid degradation products is one of the major factors in the pathogenesis of ischemic-reperfusion injury. The three major cellular events responsible for these lipid metabolic abnormalities during ischemia and reperfusion are: 1) enhanced lipolysis, 2) inhibition of beta-oxidation, and 3) degradation of membrane phospholipids. Our work supports the conclusion that unmodified hypothermic crystalloid cardioplegic arrest permits these abnormalities in lipid metabolism to persist, although significantly less than in the unprotected heart. The proposed research concerns interventions in the isolated pig heart model 1) to assure more efficient energy utilization during ischemia and reperfusion, 2) to evaluate approaches to prevent endogenous lipolysis, and 3) to study ways to preserve membrane function an phospholipid content. The first goal will be accomplished by increasing energy supply through a) increasing beta-oxidation, b) stimulating glycolysis, and c) inhibiting fatty acid metabolism in favor of glycolysis. The second goal, to limit lipolysis, will be accomplished by administration of antilipolytic agents and by use of beta-adrenergic blockade. The final goal, preservation of membrane structure and function, will be address by using phospholipase inhibitors, by administration of calcium slow channel blocking agents, and by use of oxygen free radical scavengers. The methods to be used for evaluation of these interventions will employ the quantitative techniques already established in our laboratory which can correlate biochemical changes with functional and metabolic data. Additionally, new studies of glycolytic activity and beta-oxidation using tritiated glucose and 14C-labelled palmitic acid will be utilized as well. Measurements of calcium influx during reperfusion will be completed to determine the influence of both cardioplegia and our new interventions on intracellular calcium accumulation and enzyme activity. The goal of this investigation is to improve cellular viability during ischemia and reperfusion. The interventions to be studied are applicable to patient care for reduction of myocardial injury during ischemia and reperfusion.
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