title: Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases.
abstract: While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern beta-AR signaling must still be examined in aged hearts. Specifically, the contribution of beta-AR subtypes (beta1 versus beta2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (Gi) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both beta1-AR and beta2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both beta-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either beta1-AR or beta2-AR stimulation were not rescued by inhibiting Gi with pertussis toxin treatment. Further, the abundance or activity of beta-adrenergic receptor kinase, GRK5, or Gi did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both beta1- and beta2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both beta-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor Gi proteins appear to contribute to the age-associated reduction in cardiac beta-AR responsiveness.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA. XiaoR@GRC.NIA.NIH.Gov
authors.forename: R P
authors.initials: RP
authors.lastname: Xiao
authors.forename: E D
authors.initials: ED
authors.lastname: Tomhave
authors.forename: D J
authors.initials: DJ
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Ji
authors.forename: M O
authors.initials: MO
authors.lastname: Boluyt
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: E G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: W J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D037342:Pertussis Toxin; D016133:Polymerase Chain Reaction; D012313:RNA / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012969:Sodium Fluoride / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D007093:Imidazoles; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D012313:RNA; C002904:zinterol; D012969:Sodium Fluoride; C049763:CGP 20712A; D037342:Pertussis Toxin; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine