• Gwirtz, Patricia (PI)

Project Details


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
Effective start/end date15/01/9830/06/04


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