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

Abstract

ABSTRACT-We studied the effects of prolonged infusion of a selective ~1-adrenoceptor (f3,AR) fullhydrochloride], with regard to its inotropic effect in vivo and cardiac (3AR density. The results were compared with those for isoproterenol. Continuous infusion of isoproterenol at doses of 2.5-40 ,ug/kg/hr, s.c. for 6 days shifted the dose-response curves of isoproterenol (i.v.) for LVdP/dtmx to the right and increased the ED50 values up to fourfold. Isoproterenol infusion at 40 pg/kg/hr reduced the density of both r3,-and ~2ARs 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 rig/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 (3,ARs by 30% without changing the number of hARs. These results indicate that long-term application of a selective /31AR full agonist causes desensitization to its inotropy in vivo, with subtype-selective down-regulation of ~1ARs in cardiac ventricles.

Sustained β-Adrenergic Stimulation Increased L-Type Ca2+ Channel Expression in Cultured Quiescent Ventricular Myocytes

“…3, B and C). In contrast to the in vivo effects [5], sustained β-AR stimulation did not attenuate the responsiveness of L-type Ca 2+ channels to β-AR signaling in cultured adult quiescent myocytes. An up-regulation of the L-type Ca 2+ channels induced by sustained ISO treatment was inhibited by propranolol (10 μM), a β-AR antagonist (Fig.…”

“…An analysis of α 1C subunit mRNA was performed in parallel with GAPDH mRNA analysis to provide an internal standard [5,10]. Each gel was photographed as shown in Fig.…”

“…In vivo studies have shown that the chronic administration of a β-agonist downregulates β-AR [5] and disrupts β-AR-mediated signal transduction leading to L-type channel modulation [6,7]. In contrast, we found that the sustained β-AR stimulation did not cause a desensitization of the signal transduction: the application of ISO increased I Ba amplitude and shifted I-V and steady-state inactivation curves to more-negative potentials in both the control and the ISO-treated cells.…”

“…In contrast, the responsiveness of the channel to β-AR agonists is significantly diminished: a high concentration of β-AR agonist (ISO, 1 or 10 μM) failed to increase the current amplitude [2,3]. Similarly, a chronic administration of a β-AR agonist downregulated β-AR in rat heart [5] without affecting the number and function of channels [6,7]. These results indicate that the changes in the number of functional L-type channels might vary depending on conditions, but the responsiveness to β-AR stimulation is reduced.…”

Agonist-Induced Receptor Internalization in Chinese Hamster Ovary Cells Stably Co-expressing β₁- and β₂-Adrenergic Receptors

“…16) However, down regulation of β 1 -AR is widely observed in cardiomyocytes treated with β-agonist. 30) It is commonly believed that receptor down regulation occurs following receptor internalization. It has been reported co-internalization between β 2 -AR and α 1D -adrenergic receptor (α 1D -AR) after stimulation by salbutamol, a β 2 -AR specific agonist, whereas α 1D -AR is hardly internalized by agonist stimulation when expressing alone.…”