Beta-adrenoceptor stimulation-induced increase in cardiac Gi-protein expression and in carbachol sensitivity.
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.
Eschenhagen
T
T
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
Mende
U
U
Schmitz
W
W
Scholz
H
H
Schulte am Esch
J
J
Sempell
R
R
Warnholtz
A
A
Wüstel
J M
JM
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
D012333:RNA, Messenger; D010566:Virulence Factors, Bordetella; D002217:Carbachol; D011433:Propranolol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D007545:Isoproterenol