Document Detail

Relationship between desensitization and downregulation of beta-adrenoceptors in cardiac tissues after prolonged in vivo infusion of T-0509, a beta 1-adrenoceptor agonist.
MedLine Citation:
PMID:  9165369     Owner:  NLM     Status:  MEDLINE    
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.
Y Sato; H Kurose; T Nagao
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Japanese journal of pharmacology     Volume:  73     ISSN:  0021-5198     ISO Abbreviation:  Jpn. J. Pharmacol.     Publication Date:  1997 Apr 
Date Detail:
Created Date:  1997-08-27     Completed Date:  1997-08-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2983305R     Medline TA:  Jpn J Pharmacol     Country:  JAPAN    
Other Details:
Languages:  eng     Pagination:  325-32     Citation Subset:  IM    
Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
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MeSH Terms
Adenylate Cyclase / metabolism
Adrenergic beta-Agonists / administration & dosage,  pharmacology*,  therapeutic use
Adrenergic beta-Antagonists / pharmacology*
Alprenolol / analogs & derivatives*,  pharmacology
Analysis of Variance
Binding, Competitive
Drug Interactions
Ethanolamines / administration & dosage,  pharmacology*,  therapeutic use
GTP-Binding Proteins / metabolism
Heart / drug effects
Heart Ventricles / drug effects,  enzymology,  metabolism
Injections, Subcutaneous
Isoproterenol / pharmacology
Myocardium / enzymology,  metabolism*
Pindolol / analogs & derivatives,  metabolism
Rats, Sprague-Dawley
Receptors, Adrenergic, beta-2 / drug effects*,  metabolism
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Adrenergic beta-Antagonists; 0/Ethanolamines; 0/Receptors, Adrenergic, beta-2; 13523-86-9/Pindolol; 13655-52-2/Alprenolol; 75241-20-2/RP333; 7683-59-2/Isoproterenol; 82870-40-4/bromoacetylalprenololmenthane; 83498-72-0/Iodocyanopindolol; EC 3.6.1.-/GTP-Binding Proteins; EC Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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