title: Relationship between desensitization and downregulation of beta-adrenoceptors in cardiac tissues after prolonged in vivo infusion of T-0509, a beta 1-adrenoceptor agonist.
abstract: To examine the contribution of beta-adrenoceptor (beta AR) downregulation to desensitization of beta ARs by chronic administration of a beta AR agonist, we compared the adenylyl cyclase (AC) activities in two kinds of cardiac ventricular membranes with decreased available beta ARs: one was derived from rats infused with a selective beta 1 AR agonist, T-0509 [(-)-(R)-1-(3,4-dihydroxyphenyl)- 2-[(3,4-dimethoxyphenethyl)-amino]ethanol hydrochloride], in vivo (40 micrograms/kg/hr, s.c. for 6 days); and the other was obtained from treatment of control membranes with an irreversible beta AR antagonist, bromoacetyl alprenolol methane (BAAM). T-0509 infusion decreased the densities of beta 1 ARs and beta 2 ARs by 26% and 32%, respectively, and reduced the maximal isoproterenol-stimulated AC activity by 53%. The amount of Gs alpha and Gi alpha proteins in the membranes was not significantly changed by T-0509 infusion. To make preparations that mimic the T-0509-induced downregulation, we treated the control membranes with 100 nM BAAM in vitro. The BAAM treatment decreased the Bmax value of [125I]iodocyanopindolol for beta 1 ARs and beta 2 ARs by 29% and 36%, respectively, whereas it reduced the maximal effect of isoproterenol on AC activity only by 37%. These results suggest that downregulation of beta ARs cannot fully account for the desensitization by chronic treatment of T-0509 and that other mechanism(s) can play a significant role in the loss of responsiveness.
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Kurose
authors.forename: T
authors.initials: T
authors.lastname: Nagao
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000526:Alprenolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D015536:Down-Regulation; D004347:Drug Interactions; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007279:Injections, Subcutaneous; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; C025342:RP333; C045331:bromoacetylalprenololmenthane; D020120:Iodocyanopindolol; D000526:Alprenolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol