title: Age-related changes in beta-adrenergic neuroeffector systems in the human heart.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Cardiology, University of Utah Medical Center, Salt Lake City.
authors.forename: M
authors.initials: M
authors.lastname: White
authors.forename: R
authors.initials: R
authors.lastname: Roden
authors.forename: W
authors.initials: W
authors.lastname: Minobe
authors.forename: M F
authors.initials: MF
authors.lastname: Khan
authors.forename: P
authors.initials: P
authors.lastname: Larrabee
authors.forename: M
authors.initials: M
authors.lastname: Wollmering
authors.forename: J D
authors.initials: JD
authors.lastname: Port
authors.forename: F
authors.initials: F
authors.lastname: Anderson
authors.forename: D
authors.initials: D
authors.lastname: Campbell
authors.forename: A M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000375:Aging / Q000502:physiology*; D001667:Binding, Competitive; D002648:Child; D002675:Child, Preschool; D003714:Denervation; D005260:Female; D006321:Heart / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009451:Neuroeffector Junction / Q000502:physiology*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism / Q000502:physiology*
chemical_list: D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol