Circulation, Vol 90, 1225-1238, Copyright © 1994 by American Heart Association
M White, R Roden, W Minobe, MF Khan, P Larrabee, M Wollmering, JD Port, F Anderson, D Campbell and AM Feldman
BACKGROUND: Aging decreases cardiac beta-adrenergic responsiveness in model
systems and in humans in vivo. The purpose of this study was to
comprehensively evaluate the age-related changes in the beta-receptor-G
protein-adenylyl cyclase complex in nonfailing human hearts. METHODS AND
RESULTS: Twenty-six nonfailing explanted human hearts aged 1 to 71 years
were obtained from organ donors and subjected to pharmacological
investigation of beta-adrenergic neuroeffector systems. When the population
was subdivided into the 13 youngest and 13 oldest subjects, total
beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was
reduced in older hearts by 37% in left ventricles and 31% in right
ventricles (both P < .05), and the downregulation was confined to the
beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age).
Older donor hearts exhibited a 3- to 4-fold rightward shift of
ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer
receptors in a high-affinity agonist binding state (P < .05). Older
hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol
(beta 2-agonist), and by the G protein- sensitive probes forskolin,
Gpp(NH)p, and NaF. In contrast, there was no change in response to
manganese, a specific activator of the adenylyl cyclase catalytic subunit.
Toxin-catalyzed ADP ribosylation in membranes prepared from older versus
younger hearts revealed a 29% to 30% reduction (P < .05) with cholera
toxin (Gs) but no difference with pertussis toxin (Gi). The systolic
contractile response of isolated right ventricular trabeculae to ISO was
decreased by 46%, with a 10- fold increase in ISO EC50 in older relative to
younger donor hearts. CONCLUSIONS: There is a profound decrease in cardiac
beta-adrenergic responsiveness with aging. This occurs by multiple
mechanisms including downregulation and decreased agonist binding of beta
1-receptors, uncoupling of beta 2-receptors, and abnormal G
protein-mediated signal transduction.
ARTICLES
Age-related changes in beta-adrenergic neuroeffector systems in the human heart
Division of Cardiology, University of Utah Medical Center, Salt Lake City.
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