The objective of the proposed research is the examination of several basic aspects of myocardial metabolism and function with the specific aims of: 1) assessing the effects of intracellular pH (pHi) and inorganic phosphate concentration ((Pi)) on myocardial injury produced by ischemia and hypoxia. 2) determining the uptake and utilization of substrates in the previously ischemic, reperfused myocardium and evaluating the role of specific substrates in the metabolic and physiologic function (recovery) in the models employed. 3) evaluating the relationship of glycolytic intermediates and (AMP) to irreversible injury in the ischemic myocardium. Specifically, what is the, composition and significance of the phosphomonoester (PME) signal detected by 31 P NMR in preliminary studies of global ischemia. The appearance of this signal is tightly correlated with the development of contracture upon reperfusion. 4) Determine the relationship of pHi, (Pi) and duration of exposure of the myocardium to low pH, high (Pi), and (lactate) to the development of Ca+2 sensitivity for reperfusion injury. The hypothesis to be tested is that a Ca sensitization produces myocardial damage with reflow and that this is related to the pHi, (Pi) and exposure time at these altered conditions. These studies are intended to examine fundamental aspects of the biochemical events which produce myocardial injury and the predictive value of noninvasively determined metabolites and pHi for irreversible injury in the ischemic myocardial. The causative factors in myocardial ischemic injury remain in question. Improved understanding of the biochemical nature of this injury can yield important insight into prevention and treatment of myocardial damage. The proposed research relies upon the use of high resolution NMR techniques to make non-destructive measurements of high energy phosphates (HEP), intracellular pH (pHi), and intracellular orthophosphate 1((Pi)) in the myocardium (31P NMR); myocardial tissue lactate levels with 1H NMB, and substrate uptake and utilization in heart muscle with 13 C-labeled substrates. Studies will be done in situ (perfused rabbit heart) and in vivo (rabbit, dog).
