The majority of experiments examining the effects of myocardial ischemia have been conducted in laboratory animals, most commonly dogs, cats and rats. There are relatively little data available on the effects of myocardial ischemia in primates. The objective of this research proposal is to examine the effects of coronary artery occlusion and reperfusion on measurements of regional myocardial function, i.e. endocardial and epicardial wall thickening and segment shortening, regional blood flow (radioactive microspheres), and regional biochemistry and molecular biology in chronically instrumented, conscious baboons, pigs, and dogs. There are seven specific aims. 1) To determine the relationship among the timing of coronary artery reperfusion on infarct size and recovery of regional myocardial function in conscious dogs, pigs, and baboons. 2) To determine whether the salvaged myocardium or stunned myocardium responds appropriately to inotropic stress in terms of either mechanical function or beta-adrenergic receptor signalling. 3) To determine whether collateral dependent myocardium responds appropriately to inotropic stress in terms of either mechanical function or beta-adrenergic receptor signalling. 4) To determine if the decrease in adenylyl cyclase activity in reperfused or collateralized hearts is due to a decrease in the number of units of catalyst per mg sarcolemma or due to a decrease in specific activity of the catalyst. To do this, we will: a) Use highly purified sarcolemma and perform immunoblotting to detect the amount of catalyst per mg sarcolemma. In addition, messenger RNA levels will be quantitated for the predominant cardiac isoforms of adenylyl cyclase, i.e., Types IV, V and VI. b) The catalyst of adenylyl cyclase will be purified from sarcolemma by affinity chromatography and the specific activity determined. 5) To determine whether myocardial stunning is augmented by pretreatment with Nw-nitro-L-arginine or diminished by pretreatment with L-arginine. 6) To determine whether pre-treatment can reduce """"""""myocardial stunning"""""""" with brief periods of coronary artery occlusion in the conscious baboon using agents that affect: a. O2 free radicals or b. Calcium. 7) To determine ryanodine and dihydropyridine receptor density in membrane preparations from canine, baboon, and porcine hearts during myocardial stunning. These studies are designed to provide insight into basic mechanisms of myocardial ischemia and its relief by coronary artery reperfusion by comparing responses in chronically instrumented, conscious dogs, pigs and baboons. there are three novel features of this application. 1) To study mechanisms of myocardial ischemia in conscious primates. 2) The direct and continuous measurement of regional subendocardial vs. subepicardial function in response to ischemia in chronically-instrumented, conscious animals. 3) The ability to correlate the physiological studies above with studies at the cellular and molecular level.
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