Controversy exists as to the relative roles of ATP decline and glycolytic byproduct accumulation in the pathogenesis of ischemic myocardial injury. Although both processes are detrimental to the overall survival of the myocardium, some evidence suggests that high tissue levels of glycolytic catabolites may be harmful to the heart, independent of ATP levels. Since pressure overload hypertrophy in the leads to an increased glycolytic potential, glycolytic catabolites would be expected to accumulate faster in hypertrophied hearts compared to normal hearts. This could explain the increased susceptibility to ischemic injury in hypertrophied hearts. To investigate the mechanisms responsible for the deleterious effects of ischemia and post-ischemic reperfusion on the hypertrophied heart, we propose to test the following hypothesis: The hypertrophied has an increased glycolytic potential compared to nonhypertrophied hearts, and the resultant greater accumulation of glycolytic catabolites during ischemia is responsible for the more rapid development of irreversible injury. We will use hypertrophied hearts with aortic banding at 21 days of age, studied on a Langendorff perfusion system with global ischemia or continuous hypoxic perfusion. Function will be monitored by LV pressure changes measured with a LV balloon. High energy phosphates and intracellular pH will be continuously monitereed by 31P NMR spectroscopy. Adenine nucleotides and breakdown products will be measured by HPLC, and glycogen, lactate, and LDH will be measured by spectrophotometric assay. Morphologic changes will be evaluated by light and electron microscopy on perfusion fixed hearts. Using these models we will evaluate the separate contributions of ATP decline and glycolytic byproduct accumulation on the structure and function of ischemic or hypoxic normal and hypertrophied myocardium. In addition, modification of the reperfusion conditions following ischemia will enable us to characterize the functional and structural changes during reperfusion to determine mechanisms responsible for the development of reperfusion injury. We will also use isolated myocytes in culture to evaluate inherent metabolic and structural differences in myocytes from normal and hypertrophied hearts subjected to hypoxia. The experiments outlined in these studies including time course studies with NMR spectroscopy and isolated myocytes in culture will provide new information regarding the role of glycolytic metabolites on the response of the normal and hypertrophied heart to ischemia.
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