title: Beta-adrenoceptor stimulation-induced increase in cardiac Gi-protein expression and in carbachol sensitivity.
abstract: Increased plasma concentrations of catecholamines are assumed to be responsible for the decreased sensitivity to catecholamines of the failing heart. We investigated in rat heart the influence of a 4-day infusion of isoprenaline (Iso; 2.4 mg.kg-1.d-1), propranolol (Prop; 9.9 mg.kg-1.d-1), Iso + Prop or 0.9% NaCl as control (Ctr) on myocardial Gi-mRNA and Gi-protein levels and on the negative inotropic effect of carbachol in papillary muscles. In Iso-treated rats, hybridization experiments with 32P-cDNAs revealed a 49 +/- 18% (n = 7-8) and 27 +/- 7% (n = 8) increase in Gi alpha-2- and Gi alpha-3-mRNA respectively, and pertussis toxin-catalyzed ADP-ribosylation revealed a 22 +/- 7% (n = 8) increase in Gi-protein as compared to Ctr. These alterations were accompanied by an increased potency of carbachol (mean EC50: 0.04 microM vs. 0.28 microM) in the presence of Iso in isolated electrically driven (1 Hz) papillary muscles. Prop had no effect on Gi-protein expression but antagonized all Iso-induced effects. In conclusion, beta-adrenergic stimulation leads to an increased expression of Gi and to an enhanced negative inotropic potency of muscarinic agonists. An enhanced muscarinic receptor coupling via Gi might play a pathophysiological role in heart diseases with increased plasma catecholamine levels.
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: U
authors.initials: U
authors.lastname: Mende
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.forename: H
authors.initials: H
authors.lastname: Scholz
authors.forename: J
authors.initials: J
authors.lastname: Schulte am Esch
authors.forename: R
authors.initials: R
authors.lastname: Sempell
authors.forename: A
authors.initials: A
authors.lastname: Warnholtz
authors.forename: J M
authors.initials: JM
authors.lastname: Wüstel
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000737:chemistry*; D010210:Papillary Muscles / Q000187:drug effects*; D037342:Pertussis Toxin; D011433:Propranolol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015854:Up-Regulation; D010566:Virulence Factors, Bordetella
chemical_list: D012333:RNA, Messenger; D010566:Virulence Factors, Bordetella; D002217:Carbachol; D011433:Propranolol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D007545:Isoproterenol