The broad objective of this application is to define the role of the endothelium in the humoral regulation of the coronary circulation with specific focus upon endothelin in human coronary atherosclerosis. Our broad working hypothesis is that during the evolution of coronary atherosclerosis the activity of the local coronary endothelin system is enhanced and contributes to the endothelial dysfunction which characterizes early and late atherosclerosis. To address our working hypothesis, five specific aims are proposed: To determine the activity of coronary endothelin in early and late atherosclerosis by evaluating the relationship between coronary circulating and tissue endothelin immunoreactivity, to determine if coronary endothelin is released and associated with acetylcholine-mediated coronary endothelial dysfunction, to determine the functional role of endogenous endothelin in regulation of basal coronary vascular tone, to determine if chronic L-arginine therapy modulates the activity of coronary endothelin, and to determine if endothelin is a sensitive marker for coronary endothelial dysfunction. Demonstration of our working hypothesis will enhance early diagnosis and therapeutic strategies in delaying the progression of this important clinical syndrome.
