- 著者
-
Sato Yoji
Kurose Hitoshi
Nagao Taku
- 出版者
- 公益社団法人 日本薬理学会
- 雑誌
- The Japanese journal of pharmacology (ISSN:00215198)
- 巻号頁・発行日
- vol.73, no.4, pp.325-332, 1997-04-01
- 参考文献数
- 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 β<SUB>1</SUB>AR agonist, T-0509 [(−)-(<I>R</I>)-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 β<SUB>1</SUB>ARs and, β<SUB>2</SUB>ARs by 26% and 32%, respectively, and reduced the maximal isoproterenol-stimulated AC activity by 53%. The amount of G<SUB>sα</SUB> and G</SUB>iα</SUB> 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 B<SUB>max</SUB>, value of [<SUP>125</SUP>I] 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.