Yoji Sato (1), Satomi Adachi-Akahane (1), Pablo Prados (2), Kazuhiro Imai (2) and Taku Nagao (1,*)
(1) Department of Toxicology and Pharmacology and (2) Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan
Abstract: We studied the effects of prolonged infusion of a selective beta1-adrenoceptor (beta1AR) 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 betaAR density. The results were compared with those for isoproterenol. Continuous infusion of isoproterenol at doses of 2.5-40 microg/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 microg/kg/hr reduced the density of both beta1- and beta2ARs by 36% and 43% respectively, in left ventricular membranes. Following 6-day infusion of T-0509 at doses sufficient to induce a positive inotropic effect (5-40 microg/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 beta1ARs by 30% without changing the number of beta2ARs. These results indicate that long-term application of a selective beta1AR full agonist causes desensitization to its inotropy in vivo, with subtype-selective down-regulation of beta1ARs in cardiac ventricles.
Keywords: T-0509, beta-Adrenoceptor, Inotropic effect, Desensitization, Down-regulation