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)-ad renoceptor (beta(1)AR) full agonist, T-0509 xyphenyl)-2-[(3,4-dimethox yphenethyl)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 mu g/kg/hr, s.c. for 6 days shifted the dose-response curves of isoproterenol (i.v.) for LVdP/dt(max) to the right and incre ased the ED(50) values up to fourfold. Isoproterenol infusion at 40 mu g/kg/hr reduced the density of both beta(1)- and beta(2)ARs by 36% an d 43% respectively, in left ventricular membranes. Following 6-day inf usion of T-0509 at doses sufficient to induce a positive inotropic eff ect (5-4 mu g/kg/hr), the ED(50) value of T-0509 (i.v.) for LVdP/d(max ) was also increased up to fourfold. In contrast to isoproterenol, inf usion of T-0509 caused selective down-regulation of beta(1)ARs by 30% without changing the number of beta(2)ARs. These results indicate that long-term application of a selective beta(1)AR full agonist causes de sensitization to its inotropy in vivo, with subtype-selective down-reg ulation of beta(1)ARs in cardiac ventricles.