Age-Related Changes in f3-Adrenergic Neuroeffector Systems in the Human Heart

Background Aging decreases cardiac 83-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 /3-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 ,8-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total ,8-receptor density assessed by maximum ['1'I]ICYP binding (P8ma) 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 131 subtype (r= -.78 left ventricle 13, density versus donor age). Older donor hearts exhibited a 3to 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 ($3-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 (Ga) but no difference with pertussis toxin (Ga). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC,0 in older relative to younger donor hearts. Conclusions There is a profound decrease in cardiac 83-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of 3,l-receptors, uncoupling of 132-receptors, and abnormal G protein-mediated signal transduction. (Circulation. 1994;90:1225-1238.)