ENDOTHELIAL CONTROL OF LARGE CORONARY ARTERY VASOACTIVI

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This research is designed to elucidate the mechanisms of vascular control that account for the abnormal vasoactivity associated with coronary artery disease. Damage to vascular endothelial cells, high serum cholesterol, atherosclerosis, and changes in blood flow velocity, are factors which alter vascular reactivity. However, few studies have systematically studied the mechanisms responsible for this altered vasoactivity. Furthermore, most previous work concerning the role of endothelial cells and elevated cholesterol levels in vascular control has been conducted in isolated vessels or anesthetized animals and, therefore, may not be indicative of control mechanisms in the intact, conscious animal. This research proposal will systematically evaluate the effects of changes in (1) coronary blood flow, (2) removal of endothelium, (3) acute and (4) chronic dietary elevation of serum cholesterol and plasma lipoproteins on the control of large coronary artery diameter in the conscious dog. Specific attention will be paid to the effects of these interventions on adrenergic and cholinergic autonomic vasoconstriction and vasodilation, and the receptor subtypes involved in these mechanisms. We will also examine the effects of endothelium removal and acute or chronic cholesterol elevation on the elastic properties of the coronary vessel wall. Regional myocardial function will be assessed in order to determine the possible effects of altered myocardial metabolic demand on large coronary artery caliber. The central hypothesis of this proposal is that removal of coronary artery endothelial cells, or elevated plasma cholesterol levels, will reduce the response to autonomic vasodilator stimuli, while enhancing the response to autonomic vasoconstrictor stimuli. The cumulative effects of these alterations may account for the greater degree of vasoconstriction observed during episodes of vasospasm. Clarification of the mechanisms responsible for the altered vasoactivity will yield fundamental knowledge of large coronary artery control mechanisms, and ultimately provide insight into the pathogenesis of coronary artery spasm.