Circulation, Vol 84, 1024-1039, Copyright © 1991 by American Heart Association
MR Bristow, FL Anderson, JD Port, L Skerl, RE Hershberger, P Larrabee, JB O'Connell, DG Renlund, K Volkman and J Murray
BACKGROUND. We measured the content and activities of components of the
beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic
neurotransmitter levels in left and right ventricular myocardial
preparations derived from 77 end-stage failing human hearts from patients
with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated
cardiomyopathy (ISCDC). METHODS AND RESULTS. The results were compared with
data obtained in 21 nonfailing hearts removed from organ donors. Compared
with ISCDC ventricles, IDC left and right ventricles exhibited a greater
degree of total beta- or beta 1-receptor downregulation. In contrast,
compared with IDC right ventricles, isolated tissue preparations of ISCDC
right ventricles exhibited a greater degree of subsensitivity to the
inotropic effect of isoproterenol, indicating a relatively greater degree
of functional uncoupling of right ventricular ISCDC beta-receptors from
mechanical response. In addition, relative to IDC left ventricles,
preparations of ISCDC left ventricle exhibited greater subsensitivity to
beta-agonist- mediated adenylate cyclase stimulation, indicating functional
uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP
generation. The uncoupling of beta-receptors in ISCDC left and right
ventricles may have been a result of abnormalities in G protein activation
of adenylate cyclase; compared with age- and cardiac function-matched
respective left or right IDC ventricles, ISCDC left ventricles exhibited
less stimulation of adenylate cyclase by NaF or forskolin but no change in
Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation
by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right
ventricles exhibited a "selective" (not present in IDC left ventricles or
ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+.
Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP
ribosylation were altered to similar extents in IDC and ISCDC. CONCLUSIONS.
These data indicate that potentially important differences exist in the
regulatory behavior of components of the beta-adrenergic receptor-G
protein-adenylate cyclase complex in IDC versus ISCDC, differences that
presumably relate to the distinct pathophysiologies of these two types of
heart muscle disease.
ARTICLES
Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy
Heart Failure Treatment Program, University of Utah, Salt Lake City.
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