Abstract
BACKGROUND. In chronic heart failure, the positive inotropic effects
of beta-adrenergic receptor agonists are greatly reduced, in part
as a result of two alterations of the cardiac beta-adrenergic receptors:
loss of their function (receptor uncoupling) and reduction of their
number (downregulation). In vitro studies have shown that a major
mechanism leading to beta-adrenergic receptor uncoupling involves
phosphorylation of the receptors by the specific beta-adrenergic
receptor kinase (beta ARK). METHODS AND RESULTS. We have therefore
investigated expression of beta ARK and beta-adrenergic receptors
in samples from the left ventricles of patients with dilated cardiomyopathy
or ischemic cardiomyopathy and from nonfailing control ventricles.
Contractile responses to beta-receptor stimulation were decreased
in the failing hearts compared with control hearts, whereas those
to forskolin and calcium remained unchanged. The messenger RNA (mRNA)
levels of beta ARK, beta 1- and beta 2-receptors, and of glyceraldehyde
phosphate dehydrogenase and beta-actin as controls were measured
by quantitative polymerase chain reactions. In addition, beta ARK
enzyme activity assays were performed, and the levels of beta 1-
and beta 2-receptors were determined by radioligand binding. beta
ARK mRNA levels were increased almost threefold in both forms of
heart failure, and beta ARK activity was enhanced. beta 1-Receptor
mRNA levels and beta 1-receptor numbers were decreased by approximately
50% in both failing groups, whereas these levels were unaltered for
beta 2-receptors. There were no differences between dilated and ischemic
cardiomyopathy for any of these parameters. CONCLUSIONS. In addition
to other alterations found in failing hearts, the diminished response
to beta-receptor agonists appears to involve the combined effects
of enhanced expression of beta ARK and reduced expression of beta
1-receptors.
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