Circulation, Vol 75, 331-339, Copyright © 1987 by American Heart Association
MD Feldman, L Copelas, JK Gwathmey, P Phillips, SE Warren, FJ Schoen, W Grossman and JP Morgan
We studied the effects of different classes of inotropic drugs on human
working myocardium in vitro that was isolated from the hearts of patients
with end-stage heart failure, and compared the responses to these drugs
with those noted in muscles from nonfailing control hearts. Although peak
isometric force generated in response to increased extracellular calcium
reached control levels in the muscles from patients with heart failure, the
time course of contraction and rate of relaxation were greatly prolonged.
The inotropic effectiveness of the beta-adrenergic agonist isoproterenol
and the phosphodiesterase inhibitors milrinone, caffeine, and
isobutylmethylxanthine was markedly reduced in muscles from the patients
with heart failure. In contrast, the effectiveness of inotropic stimulation
with acetylstrophanthidin and the adenylate cyclase activator forskolin was
preserved. After a minimally effective dose of forskolin was given to
elevate intracellular cyclic AMP levels, the inotropic responses of muscles
from the failing hearts to phosphodiesterase inhibitors were markedly
potentiated. These data indicate that an abnormality in cyclic AMP
production may be a fundamental defect present in patients with end- stage
heart failure that can markedly diminish the effectiveness of agents that
depend on generation of this nucleotide for production of a positive
inotropic effect.
ARTICLES
Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure
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