Jpn. J. Pharmacol. 73 (4), 325-332 (1997)


Relationship between Desensitization and Downregulation of beta-Adrenoceptors in Cardiac Tissues after Prolonged In Vivo Infusion of T-0509, a beta1-Adrenoceptor Agonist

Yoji Sato, Hitoshi Kurose and Taku Nagao (*)

Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan
(*) To whom correspondence should be addressed.

Abstract: To examine the contribution of beta-adrenoceptor (betaAR) downregulation to desensitization of betaARs by chronic administration of a betaAR agonist, we compared the adenylyl cyclase (AC) activities in two kinds of cardiac ventricular membranes with decreased available betaARs: one was derived from rats infused with a selective beta1AR agonist, T-0509 [(-)-(R)-1-(3,4-dihydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol hydrochloride], in vivo (40 microg/kg/hr, s.c. for 6 days); and the other was obtained from treatment of control membranes with an irreversible betaAR antagonist, bromoacetyl alprenolol methane (BAAM). T-0509 infusion decreased the densities of beta1ARs and beta2ARs 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 beta1ARs and beta2ARs 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 betaARs 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.

Keywords: T-0509, Cardiac ventricle, Adenylyl cyclase, Desensitization of beta-adrenoceptor, Irreversible beta-adrenoceptor antagonist


Copyrightę The Japanese Pharmacological Society 1997

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