Age‐Related Changes in β‐Adrenergic Neuroeffector Systems in the Human Heart

BackgroundAging decreases cardiac β–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 β-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. Methods and ResultsTwenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of β-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total β-receptor density assessed by maximum [125I]ICYP binding (βmax) 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 β1 subtype (r= −.78 left ventricle β1 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 (β2-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 (Gβs) but no difference with pertussis toxin (Gβi). 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. ConclusionsThere is a profound decrease in cardiac β-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of β1-receptors, uncoupling of β2-receptors, and abnormal G protein-mediated signal transduction.