EFFECTS OF XAMOTEROL ON THE REVERSIBLE CYCLING OF CARDIAC BETA-ADRENOCEPTORS

We have examined the effects of xamoterol, a partial β1-adrenoceptor agonist, on cardiac β-adrenoceptors using isolated myocytes and cell-free preparations. Xamoterol was considerably less effective than isoproterenol in stimulating adenylate cyclase activity but the difference was narrowed by 1 μM forskolin, presumably by inducing more efficient coupling to the catalytic subunit of the enzyme. Xamoterol mediated a time- and concentration-dependent loss of β-adrenoceptors from the cell surface of cardiac myocytes through a process of internalization sensitive to the cytoskeleton inhibitors, colchicine and cytochalasine. In cell-free preparations, loss of membrane-bound β-adrenoceptors induced by xamoterol, but not that induced by 1 μM isoproterenol, was prevented by the inhibitor of protein kinase A. In contrast, 100 nM heparin (an inhibitor of β-receptor kinase) prevented the isoproterenol- but not the xamoterol-mediated decline of β-receptors. In addition, 1 μM xamoterol attenuated the isoproterenol-mediated internalization of β-adrenoceptors in cardiac myocytes over a wide range of isoproterenol concentrations. This attenuation required activation of protein kinase A. These results suggest that the influence of xamoterol on the cycling of cardiac β-adrenoceptors involves different pathways than those utilized by isoproterenol. © 1990 Raven Press, Ltd., New York.