Desensitization and Selective Down-Regulation of Rat Cardiac β1-Adrenoceptors by Prolonged In Vivo Infusion of T-0509, a β1-Adrenoceptor Full Agonist

The Japanese Journal of Pharmacology

Kazuhiro Imai¹  Satomi Adachi-Akahane²  Taku Nagao²  Pablo Prados¹  Yoji Sato² 

[1] Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Tokyo;Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo

关键词: T-0509;    β-Adrenoceptor;    Inotropic effect;    Desensitization;    Down-regulation;   

DOI  :  10.1254/jjp.69.343

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(37)Cited-By(4)We studied the effects of prolonged infusion of a selective β1-adrenoceptor (β1AR) full agonist, T-0509 [(-)-(R)-1-(3, 4-dihydroxyphenyl)-2-[(3, 4-dimethoxyphenethyl)amino]ethanol hydrochloride], with regard to its inotropic effect in vivo and cardiac βAR density. The results were compared with those for isoproterenol. Continuous infusion of isoproterenol at doses of 2.5-40 μg/kg/hr, s.c. for 6 days shifted the dose-response curves of isoproterenol (i.v.) for LVdP/dtmax to the right and increased the ED50 values up to fourfold. Isoproterenol infusion at 40 μg/kg/hr reduced the density of both β1- and β2ARs by 36010 and 43070 respectively, in left ventricular membranes. Following 6-day infusion of T-0509 at doses sufficient to induce a positive inotropic effect (5-40 μg/kg/hr), the ED50 value of T-0509 (i.v.) for LVdP/dtmax was also increased up to fourfold. In contrast to isoproterenol, infusion of T-0509 caused selective down-regulation of β1ARs by 30% without changing the number of β2ARs. These results indicate that long-term application of a selective β1AR full agonist causes desensitization to its inotropy in vivo, with subtype-selective down-regulation of β1ARs in cardiac ventricles.

【 授权许可】

Unknown