Recent studies have shown that functional abnormalities of atherosclerotic coronary arteries contribute to the production of myocardial ischemia by producing constriction and/or thrombus formation. It is now clear that the vascular endothelium plays a central role in controlling vascular tone and that atherosclerosis has an adverse effect on endothelial vasodilator function. In the proposed training period, the applicant will test the hypothesis that disturbance of the vasomotor function of the endothelium contributes to the production of coronary artery constriction in response to clinically relevant stimuli and that these disturbances are reversible. The effect of L-arginine (the precursor of endothelium-dependent relexating factor, EDRF) on the response to increased blood flow and infused phenylephrine will be examined in patients with coronary artery disease undergoing cardiac catheterization. Arterial function will be assessed by infusing endothelium-dependent agents and examining diameter responses with quantitative angiography and flow responses with Doppler-flow catheter. A placebo-controlled trial is proposed that will determine whether reduction of serum cholesterol can produce an improvement in coronary vasodilator function in patients. The applicant proposes to further examine these issues in an animal model (cholesterol-fed/balloon-injured miniature swine). The vasomotor responses of the iliac and coronary arteries to increased blood flow and infused catecholamines in atherosclerosis will be studied before and after treatment with L-arginine, mono-methyl arginine, D-arginine, methylene blue and specific adrenergic antagonists. Arterial segments will then be excised for study in the organ chamber, providing an opportunity to correlate these experimental methods and to determine the importance of smooth muscle dysfunction in these responses. The issue of reversibility of functional abnormalities will be studied by examining diameter responses in the same animal during cholesterol feeding and during regression. The period of training will provide an opportunity for the applicant to develop new skills and experience as a clinical investigator in the field of ischemic heart disease. The applicant proposes that these studies will provide insight into pathologic mechanisms and suggest new approaches for management of patients with coronary artery disease.
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