title: Effects of xamoterol on the reversible cycling of cardiac beta-adrenoceptors.
abstract: 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.
authors.affiliation: Department of Medicine (Cardiovascular Division), University of Minnesota School of Medicine, Minneapolis 55455.
authors.forename: C J
authors.initials: CJ
authors.lastname: Limas
authors.forename: C
authors.initials: C
authors.lastname: Limas
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002474:Cell-Free System; D003078:Colchicine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D011412:Propanolamines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D017307:Xamoterol
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D003571:Cytochalasin B; D017307:Xamoterol; D006493:Heparin; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C033394:CGP 12177; D003078:Colchicine