NITRIC OXIDE, CARDIAC CONTRACTILITY, AND HEART FAILURE

Project: Research project

Project Details

Description

The overall goal of this project is to examine the role of nitric oxide
(NO) as a modulator of autonomic cardiac regulation, and to test the
general hypothesis that abnormalities of NO regulation contribute to the
autonomic abnormalities characteristic of heart failure. beta-adrenergic
hyporesponsiveness and decreased parasympathetic tone are hallmarks of
heart failure, and NO has properties that could contribute to these
autonomic derangements. The heart expresses both constitutive and
inducible forms of nitric oxide synthase (cNOS and iNOS, respectively).
Whereas cNOS activity appears to be involved in both beta-adrenergic and
cholinergic contractile responses, the induction of iNOS by cytokines or
endotoxin depresses the beta-adrenergic contractile response.
Intracoronary infusions of a specific NOS inhibitor will be used to assess
the contribution of NO to beta-adrenergic and cholinergic contractile
responses in conscious dogs before and after the induction of heart
failure by rapid pacing and in patients with and without heart failure.
The intracoronary infusion technique isolates the cardiac effects of NOS
inhibition by reducing systemic responses. Specific aim 1 proposes to
test the hypotheses that NO accounts for the development within the heart
of 1) beta-adrenergic receptor pathway, 2) muscarinic receptor pathway,
and 3) myocardial adenylyl cyclase abnormalities associated with the
development of dilated cardiomyopathy in the dog. Specific aim 2 proposes
to test the hypothesis that the NO pathway acts independently of the
guanine-nucleotide binding protein signal transduction systems in
influencing cardiac sympathetic-parasympathetic interactions. Specific aim
3 proposes to test in humans the hypotheses that NO may l) modulate
parasympathetic-sympathetic interactions, 2) account, in part, for the
adrenergic and 3) muscarinic abnormalities characteristic of human heart
failure. The studies contained in this application should provide
important new insights into the control of myocardial inotropic state in
the normal and failing ventricle.
StatusFinished
Effective start/end date5/1/954/30/00

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

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