Circulation, Vol 81, 929-938, Copyright © 1990 by American Heart Association
JD Port, EM Gilbert, P Larrabee, P Mealey, K Volkman, R Ginsburg, RE Hershberger, J Murray and MR Bristow
To test the hypothesis that cardiac norepinephrine depletion related to
heart failure alters contractile responses to beta-adrenergic agonists with
a component of "indirect" action (acting by release of neuronal
norepinephrine), we examined the inotropic potential of several
pharmacologically distinct beta-agonists. Contractile responses to the
nonselective beta-agonist isoproterenol, the beta 2-selective agonist
zinterol, and the direct- and indirect-acting agonists dopamine and
dopexamine were compared in isolated right ventricular trabeculae removed
from failing, nonfailing innervated, and previously transplanted and,
therefore, denervated nonfailing human hearts. In failing hearts, the
contractile response to isoproterenol was significantly lower (41%) than
that in nonfailing innervated hearts. The responses to the mixed agonists
dopamine and dopexamine were even more attenuated in failing hearts, to a
level 76-90% lower than those of nonfailing innervated hearts. In
denervated, previously transplanted, nonfailing hearts, the contractile
responses to the mixed agonists dopamine and dopexamine were 66-72% lower
than those in the nonfailing innervated group, but the response to
isoproterenol was not significantly different. The response to zinterol was
not significantly different among the three groups. In subjects with severe
heart failure, in vivo hemodynamic responses to dopexamine were compared
with those of the direct-acting beta-agonist dobutamine. Responses to
dopexamine and dobutamine were measured before and after prolonged
continuous infusions of each drug. The response to dopexamine, but not to
dobutamine, diminished over time. We conclude that a large component of the
inotropic response to dopamine and dopexamine in human hearts is due to the
ability of these agonists to promote the release of neuronal
norepinephrine; when neuronal norepinephrine is depleted, indirect- acting
agonists are less able to produce an inotropic response.
ARTICLES
Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart
Department of Pharmacology, University of Utah, Salt Lake City.
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