Relationship between Desensitization and Downregulation of β1-Adrenoceptors in Cardiac Tissues after Prolonged In Vivo Infusion of T-0509, aβ1-Adrenoceptor Agonist

[摘要] References(22)To examine the contribution of β-adrenoceptor (βAR) downregulation to desensitization of βARs by chronic administration of a βAR agonist, we compared the adenylyl cyclase (AC) activities in two kinds of cardiac ventricular membranes with decreased available βARs: one was derived from rats infused with a selective β1AR agonist, T-0509 [(−)-(R)-1-(3, 4-dihydroxyphenyl)-2-[(3, 4-dimethoxyphenethyl)amino]ethanol hydrochloride], in vivo (40 μg/kg/hr, s.c. for 6 days); and the other was obtained from treatment of control membranes with an irreversible βAR antagonist, bromoacetyl alprenolol methane (BAAM). T-0509 infusion decreased the densities of β1ARs and, β2ARs by 26% and 32%, respectively, and reduced the maximal isoproterenol-stimulated AC activity by 53%. The amount of Gsα and Giα proteins in the membranes was not significantly changed by T-0509 infusion. To make preparations that mimic the T0509-induced downregulation, we treated the control membranes with 100 nM BAAM in vitro. The BAAM treatment decreased the Bmax, value of [125I] iodocyanopindolol for β1ARs and β2ARs by 29070 and 36070, respectively, whereas it reduced the maximal effect of isoproterenol on AC activity only by 37%. These results suggest that downregulation of βARs 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.

[学科分类] 药理学

[关键词] T-0509;Cardiac ventricle;Adenylyl cyclase;Desensitization of β-adrenoceptor;Irreversible β-adrenoceptor antagonist