title: Enhanced G(i) signaling selectively negates beta2-adrenergic receptor (AR)--but not beta1-AR-mediated positive inotropic effect in myocytes from failing rat hearts.
abstract: BACKGROUND
  Myocardial contractile response to beta1- and beta2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G(i) signaling and the ratio of beta2/beta1 are often increased. Because beta2-AR but not beta1-AR couples to G(s) and G(i) with the G(i) coupling negating the G(s)-mediated contractile response, we determined whether the heart failure-associated augmentation of G(i) signaling contributes differentially to the defects of these beta-AR subtypes and, if so, whether inhibition of G(i) or selective activation of beta2-AR/G(s) by ligands restores beta2-AR contractile response in the failing heart.
  
  
  RESULTS
  Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either beta-AR subtype-mediated inotropic effect was markedly diminished, whereas G(i) proteins and the beta2/beta1 ratio were increased. Disruption of G(i) signaling by pertussis toxin (PTX) enabled beta2- but not beta1-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of beta2-AR ligands revealed that the contractile response mediated by most beta2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G(s) and G(i) activation. In contrast, fenoterol, another beta2-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX.
  
  
  CONCLUSIONS
  We conclude that enhanced G(i) signaling is selectively involved in the dysfunction of beta2- but not beta1-AR in failing SHR hearts and that disruption of G(i) signaling by PTX or selective activation of beta2-AR/G(s) signaling by fenoterol restores the blunted beta2-AR contractile response in the failing heart.
authors.affiliation: the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md 21224, USA. xiaor@grc.nia.nih.gov
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Sheng-Jun
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Pavel
authors.initials: P
authors.lastname: Avdonin
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bond
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002303:Cardiac Output, Low / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D005280:Fenoterol / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000032:analysis; D008024:Ligands; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D008024:Ligands; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins