The applicant proposes to study atherosclerosis and estrogen effects on EDRF metabolism. He hypothesizes that the profile of S-nitrosothiol species will change in the presence of atherosclerosis as a direct result of decreased EDRF production, inactivation, or transport, and proposes several lines of investigation using intact miniature swine and an isolated heart model. Specifically, he proposes to establish the chemical identity and characteristics of endogenous S- nitrosothiol species in the resting state and in response to known stimulants of EDRF; to examine the characteristics of S- nitrosothiol species in the coronary circulation of atherosclerotic and regressed miniature swine and in the conscious, chronically instrumented swine model, and relate them to abnormal vasomotion; to characterize the effect(s) of endogenous estrogens, 17B-estradiol replacement, and estrogen withdrawal on both coronary endothelial vasomotor function and S-nitrosothiol species in a hypercholesterolemic swine model; and to test the hypothesis that loss of endogenous estrogen in female swine will lead to alteration in both vasomotor function and S-nitrosothiol production.
