Desensitization and selective down-regulation of rat cardiac beta 1-adrenoceptors by prolonged in vivo infusion of T-0509, a beta 1-adrenoceptor full agonist.
We studied the effects of prolonged infusion of a selective beta 1-adrenoceptor (beta 1AR) 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 beta AR density. The results were compared with those for isoproterenol. Continuous infusion of isoproterenol at doses of 2.5-40 micrograms/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 micrograms/kg/hr reduced the density of both beta 1- and beta 2ARs 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 micrograms/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 beta 1ARs by 30% without changing the number of beta 2ARs. These results indicate that long-term application of a selective beta 1AR full agonist causes desensitization to its inotropy in vivo, with subtype-selective down-regulation of beta 1ARs in cardiac ventricles.
Sato
Y
Y
Department of Toxicology and Pharmacology, University of Tokyo, Japan.
Adachi-Akahane
S
S
Prados
P
P
Imai
K
K
Nagao
T
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004983:Ethanolamines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D018342:Receptors, Adrenergic, beta-1; C025342:RP333