ADRENERGIC LIMITATION OF CORONARY FLOW DURING EXERCISE

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DESCRIPTION (Adapted from the applicant's abstract): Hypertensive patients have a limited tolerance to exercise, but the mechanistic reasons for this limitation are not clear. Studies from the PI's laboratory in chronically instrumented dogs indicate that during exercise an alpha1 - adrenergic constrictor tone competes with coexisting metabolic and endothelial mediated vasodilation in the coronary vasculature. These studies indicate that a coronary constrictor tone is exaggerated in dogs with renovascular hypertension. The goal of this proposal is to determine the adrenergic and neurohumoral mechanisms responsible for the greater coronary vascular resistance after renovascular hypertension. The general hypothesis to be tested is that renovascular hypertension alters the neural, paracrine and autocrine control systems of the coronary circulation through exaggeration of vasoconstrictor inputs and attenuation of vasodilator influences. These alterations would cause exaggerated vasoconstrictor reflex influences on the coronary vessels and a reduced ability to increase coronary blood flow. The applicant proposes that the renovascular hypertension-induced imbalance among vasoconstrictor and dilator mechanisms results in a reduction in myocardial work efficiency and an increased susceptibility to myocardial hypoperfusion and ischemia, especially during exercise. The long-range goal is to demonstrate that coronary blood flow regulation is the result of interactions between neural, hormonal and endothelial control mechanisms. However, the concept is that under pathophysiological conditions, the balance between these control mechanisms is altered such that vasoconstriction dominates. The applicant indicates that the results of these experiments should address fundamental questions regarding alterations in sympathetic nervous system and endothelial function and the mechanisms by which these systems are altered by renovascular hypertension. The applicant also suggests that these studies should clarify the mechanistic rationale for different medical therapies to treat patients with hypertension. The following hypotheses will be tested both in vivo using conscious instrumented dogs and in vitro using isolated coronary vessel models. 1) Renovascular hypertension increases coronary vasoconstriction at rest and during exercise such that the myocardium, specifically the endocardium, becomes hypoperfused in relation to oxygen demand. 2) Renovascular hypertension induced changes in coronary vascular function are due to adaptations in the vascular neural-humoral control mechanisms.