title: In vivo regulation of human cardiac beta-adrenoceptors by a partial agonist as compared with a full antagonist: selective differences in coupling to adenylate cyclase.
abstract: Chronic therapy with the beta 1-selective adrenoceptor partial agonist xamoterol is not associated with the tolerance observed with other beta-adrenoceptor agonists. A possible explanation is that xamoterol therapy does not desensitise human cardiac beta-adrenoceptors in vivo. beta-Adrenoceptor density and adenylate cyclase activities were determined in right atrial appendages obtained from 40 patients randomised in a double-blind fashion to receive either xamoterol or atenolol for at least 5 weeks before coronary artery bypass surgery. There was no significant difference in total or subtype beta-adrenoceptor densities, but basal and isoproterenol stimulated adenylate cyclase activity were significantly greater in the atenolol-treated group, as was the intrinsic activity of the beta 2-adrenoceptor partial agonist procaterol, suggesting that chronic therapy with xamoterol does not downregulate human cardiac beta-adrenoceptors in vivo. Coupling of beta-adrenoceptors to adenylate cyclase, predominantly mediated by the beta 2 subtype, is enhanced, however, after therapy with atenolol relative to therapy with xamoterol.
authors.affiliation: Department of Clinical Pharmacology, Leicester Royal Infirmary, England.
authors.forename: I R
authors.initials: IR
authors.lastname: Arnold
authors.forename: R
authors.initials: R
authors.lastname: Mistry
authors.forename: D B
authors.initials: DB
authors.lastname: Barnett
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000787:Angina Pectoris / Q000188:drug therapy; D001262:Atenolol / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D015536:Down-Regulation; D004361:Drug Tolerance; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D017307:Xamoterol / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D001262:Atenolol; D017307:Xamoterol; D000262:Adenylyl Cyclases