cytochalasin-b and Heart-Failure

We have examined the effects of xamoterol, a partial beta 1-adrenoceptor agonist, on cardiac beta-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 microM forskolin, presumably by inducing more efficient coupling to the catalytic subunit of the enzyme. Xamoterol mediated a time- and concentration-dependent loss of beta-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 beta-adrenoceptors induced by xamoterol, but not that induced by 1 microM isoproterenol, was prevented by the inhibitor of protein kinase A. In contrast, 100 nM heparin (an inhibitor of beta-receptor kinase) prevented the isoproterenol-but not the xamoterol-mediated decline of beta-receptors. In addition, 1 microM xamoterol attenuated the isoproterenol-mediated internalization of beta-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 beta-adrenoceptors involves different pathways than those utilized by isoproterenol.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Cell-Free System; Colchicine; Cytochalasin B; Heart; Heart Failure; Heparin; Isoproterenol; Myocardium; Propanolamines; Protein Kinases; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Xamoterol