We wish to evaluate the mechanism by which myocardial ischemia results in irreversible damage to myocardial cells within a short period of time after its onset. Based on previous studies by ourselves and others, we wish to pursue the following areas: 1) The role of fatty acyl metabolities and calcium and their interaction resultant in mitochondrial damage associated with ischemia and its attendant impairment of cardiac function. We will determine factors controlling calcium flux in 2 populations of mitochondria isolated from normal and ischemic hearts, especially under different metabolic conditions. The level of metabolites present in these mitochondria and the role of pH and transmembrane potentials will be assessed. 2) The onset and consequence of increased microvascular alterations and sarcolemmal permeability will be assessed utilizing a model developed in our laboratory in an awake unanesthetized dog with a cannulated cardiac lymph duct. We will evaluate vascular alterations specifically with respect t components of complement and platelets metabolism. We will evaluate sarcolemmal permeability utilizing the transmembrane flux of various cardiac enzymes. Specifically to be studied are the flux of cardiac phosphorylase isozymes and their appearance in cardiac lymph and systemic blood in early ischemia and the correlation with the appearance of other enzymes. 3) We will continue our ultrastructural investigation of early myocardial ischemia. In the current grant period we will evaluate alterations in myofibrillar structures found in early ischemia and by quantitative examination of this. The overall goal is to evaluate events in early myocardial ischemia which might contribute to the onset of irreversibility.
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