The studies in this proposal will examine responses of the coronary vessels to myocardial ischemia, and determine whether alterations of nitric oxide (NO) or superoxide (02-) influence vascular or myocardial responses in ischemic regions. Studies will be performed in chronically instrumented dogs in which coronary artery blood flow is measured with a Doppler flowmeter while regional systolic wall thickening is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurements of coronary NO production. Three different groups of studies are planned. The first group will examine collateral vessel development in response to five daily 2-minute coronary artery occlusions; collateral development will be assessed from blood flow measurements obtained by administering microspheres during occlusion. Myocardial interstitial fluid will be collected using a chronically implanted catheter for measurement of vascular endothelial growth factor, NO metabolites and mitogenic activity in cultured endothelial and smooth muscle cells. Since NO is an important mediator for collateral vessel growth, and since superoxide (O2-) produced during ischemia and reoxygenation consumes NO, a study will determine whether scavenging 02- with a superoxide dismutase (SOD) mimetic can augment collateral growth. Since HMG CoA reductase inhibitors increase NO bioavailability in cultured endothelial cells, another study will determine whether the HMG CoA reductase inhibitor atorvastastin can augment collateral vessel development. A second group of studies will examine mechanisms responsible for endothelial dysfunction in collateral vessels and microvessels perfused through collateral channels. In vivo and in vitro studies will determine whether NO production is decreased and/or 02- production increased in coronary microvessels in collateral-dependent regions. The role of 02- will be examined by determining whether the SOD mimetic can improve endothelial function in microvessels perfused through collateral channels. A final group of studies will examine bioenergetic alterations in myocardium perfused through collateral channels. These studies will determine whether viable collateral-dependent myocardium with persistent contractile dysfunction (""""""""hibernating myocardium"""""""") demonstrates a unique pattern of high energy phosphate (HEP) content at rest or during stress different from ischemic or stunned myocardium. Interrogation of myocardial deoxymyoglobin content will demonstrate whether contractile abnormalities in collateralized myocardium at rest or during catecholamine-induced stress are the result of oxygen insufficiency. A final study will examine the influence of NO on the energy supply/demand relationship in collateralized myocardium.
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