Previous studies supported by this grant have defined mechanisms for abnormal perfusion in the hypertrophied heart and have defined alterations of myocardial high energy phosphate content and kinetics. This proposal includes studies to examine mechanisms responsible for control of oxygen uptake and ATP production in the intact heart, and alterations responsible for perturbed high energy phosphate utilization in hypertrophied myocardium. Left ventricular hypertrophy will be produced by ascending aortic banding in dogs; myocardial phosphocreatine and ATP will be assessed using 31P NMR spectroscopy. An initial study will determine whether treadmill exercise causes loss of purines from the hypertrophied heart, and whether this can account for the decreased ATP levels. A corollary study will determine whether supplying the nucleotide precursor ribose can restore myocardial ATP levels toward normal in the hypertrophied myocardium. Several studies will examine the role of ATP sensitive potassium channels (KATP) located on coronary vascular smooth muscle, the sarcolemma of myocardial myocytes, and mitochondria in the regulation of ATP synthesis and myocardial oxygen consumption. A study will determine whether the increase of myocardial oxygen consumption during coronary hyperperfusion is the result of activation mitochondrial KATP channels, which accelerates mitochondrial respiration in vitro. A study will determine whether the decreased myocardial oxygen uptake and contractile performance caused by nonselective KATP channel with glibenclamide is the result of decreased myocardial blood flow and oxygen availability (ischemia), or whether this effect is the result of a specific effect on mitochondrial KATP channels. A fourth study will employ 1H NMR measurements of deoxymyoglobin to determine whether the decreased contractile performance produced by glibenclamide is due to the reduction of blood flow and oxygen insufficiency, or whether these changes result from a primary decrease of mitochondrial respiration and ATP production. A fifth study will use 13C NMR to examine the disposition of the increased glucose taken up by the hypertrophied myocardium and determine the relative rates of glucose utilization for glycolysis, glucose oxidation and glycogen synthesis in the hypertrophied heart. A final study will determine whether alterations of substrate utilization in the hypertrophied heart contribute to the observed increase of free ADP, and whether these alterations in the severely hypertrophied failing heart are sufficient to limit oxygen consumption.
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