Our goal continues to be an examination of the early events associated with acute myocardial ischemia that promotes cell damage and death. The current application continues our interest with the following three goals: 1) To develop further and characterize a chronic partial coronary constriction model in dog for studies of the influence of pacing and exercise on platelet activation. The chronic model allows examination of these factors without acute endothelial disruption; parameters to be examined include thromboxane and prostacyclin production, hemodynamic function, and the influence of a variety agents thought to alter platelet aggregation and vascular resistance. 2) To characterize the mechanism by which complement activation occurs, its relationship to leukocyte chemotaxis, and to correlate these with evidence of oxidative stress by measuring lipid hydroxy-acids and hydroperoxides as well as the redox of various sulfhydryl compounds (glutathione, protein mixed disulfides) in cardiac lymph and myocardial biopsy samples. 3) To examine the early events in myocardial ischemia which disrupt mitochondrial function, fatty acid oxidation, and allow the buildup of amphipathic metabolites and influence their distribution. We will specifically examine molecular consequences of altered sulfhydryl redox as manifested by mitochondrial glutathione redox and sulfhydryl oxidation reduction state of several key enzymes in fatty acid metabolism. In addition, the level of lipid hydroxy-acid content will be assessed. We will examine factors which alter the association of amphipathic fatty acyl metabolites with both control and ischemic subcellular membranes examining the effects of pH, enzyme ligands, and fatty acid binding protein (FABP).
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