CARDIOVASCULAR ADAPTATIONS TO RENOVASCULAR HYPERTENSION

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DESCRIPTION (Applicant's abstract): Hypertensive patients have a limited tolerance to exercise, but the mechanisms for this limitation are not known. Studies in chronically instrumented dogs indicate that an alpha1-adrenergic constrictor tone competes with coexisting metabolic and endothelial mediated vasodilation in the coronary vasculature during exercise. Data also indicate that a coronary constrictor tone is exaggerated in dogs with renovascular hypertension. The goal is to determine the adrenergic and neurohumoral mechanisms responsible for the greater coronary vascular resistance after renovascular hypertension. The overall hypothesis to be tested is that renovascular hypertension alters the neural, paracrine and autocrine control systems of the coronary circulation through exacerbation 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. We propose that renovascular hypertension causes an imbalance between vasoconstrictor and dilator mechanisms and results in a reduction in myocardial work efficiency and 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 neurohormonal and endothelial control mechanisms, but under pathophysiological conditions, the balance between these control mechanisms is altered such that vasoconstriction dominates. 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. These studies should clarify the mechanistic rationale for different medical therapies to treat patients with hypertension. The following hypotheses using both in vivo conscious instrumented dog and in vitro isolated coronary vessel models will be addressed. 1) Renovascular hypertension increases coronary vasoconstriction at rest and during exercise such that the myocardium, specifically the endocardium, becomes hypoperfused relative to oxygen demand. 2) Renovascular hypertension induced changes in coronary vascular function are due to adaptations in the vascular neural-humoral control mechanisms.