CORONARY COLLATERAL FUNCTION

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The long term objectives are to elucidate mechanisms of coronary collateral growth and function, and to better characterize feedback control of coronary blood flow in the conscious animal. The specific aims are: (1) to test the hypothesis that ischemia is not required for increasing conductance or reversing regression of newly developed collaterals. (2) to test in an improved animal model the hypothesis of others that chronic perfusion through collaterals produces endothelial dysfunction in the recipient vasculature, (3) to evaluate the importance of endothelial derived nitric oxide (EDNO) in coronary and collateral blood flow regulation, and (4) to characterize the expression of heparan sulfate proteoglycans during collateral growth. Ponies will be employed because of similarities between equidae and humans in coronary anatomy. The studies will be performed in conscious animals chronically instrumented with: (1) a pneumatic cuff occluder for stimulating collateral growth by an intermittent coronary occlusion method. (2) Doppler flow probe, sonomicrometry crystals, and micromanometer for measuring coronary blood flow velocity, myocardial wall function, and left ventricular pressure, and (3) catheters in the left atrium, left coronary artery, and anterior coronary vein for injecting microspheres, studying myocardial metabolism, measuring coronary artery pressure, and administering substances into the coronary circulation. This animal model provides a means for creating periods of continuous or discontinuous blood flow through newly developed collaterals and for studying collateral regression non-invasively. Protocols involving various modes of continuous and discontinuous collateral perfusion, isoproterenol stress testing, intracoronary administration of drugs, including cyclooxygenase and EDNO inhibitors, stepwise reductions in coronary artery pressure and molecular biological studies on myocardial tissues will be employed. This research could provide new information on (1) the role of flow-dependent mechanisms in coronary collateral growth and function, (2) the physiological importance of EDNO in feedback control of coronary blood flow and reactive hyperemia, and (3) molecular regulation of collateral growth. Ultimately, this research could lead to new strategies for reducing subendocardial ischemia in pre-and post infarction coronary heart disease. It could also provide a better understanding of the physiological basis for exercise as a coronary risk reduction factor.