Post-ischemic myocardium exhibits a physiologic abnormality which is manifested by delayed recovery of ATP content and contractile function, and increased oxygen consumption per unit work. The mechanism responsible for the contractile dysfunction and for the higher oxygen consumption when stimulated to perform work is not understood. In order to test the hypothesis that post-ischemic cardiac dysfunction in the adult heart is due to impaired cytosolic calcium regulation associated with altered high energy phosphate energetics, we plan to measure free cytosolic calcium in the reperfused beating heart using calcium sensitive fluorescent dyes. 31P NMR spectroscopy will be used to measure high energy phosphate content and allow calculation of the free energy released from ATP hydrolysis. We plan to utilize the differences between newborn and adult hearts with respect to calcium regulation for excitation-contraction coupling in order to determine the cause and precise location of the regulatory defect in the adult. The role of the sarcoplasmic reticulum in post-ischemic contractile dysfunction will e determined by utilizing measurements of the phasic changes in cytosolic calcium concentration during the cardiac cycle. Because of the increased demand for oxygen per unit work in the post- ischemic adult heart, we plan to test the hypothesis that the energetic inefficiency in the """"""""stunned"""""""" heart is at least in part due to altered substrate utilization by the myocytes. We plan to analyze the effects of providing substrates that yield a higher ATP production per mole of oxygen consumed (P:O ratio) on post-ischemic energetic efficiency. We expect that by combining substrates that have high P:O ratios with metabolic inhibitors of other substrates, we will be able to correct the abnormality in the oxygen consumption to work relationship. Post-operative myocardial dysfunction leading to significant mortality and morbidity after cardiac surgery or transplantation remains an important clinical problem. Considerable information regarding the mechanisms for the energetic inefficiency and delayed metabolic and functional recovery of the post-ischemic heart should result from this project.
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