title: Effect of short- and long-acting beta 2-adrenoceptor agonists on pulmonary beta 2-adrenoceptor expression in human lung.
abstract: beta-Adrenoceptor agonists induce the down-regulation of beta 2-adrenoceptors and mRNA expression in animal lung. The down-regulation of beta 2-adrenoceptors may limit the therapeutic efficacy of beta 2-adrenoceptor-mediated bronchodilators in obstructive airways disease. We examined the effects of three selective beta 2-adrenoceptor agonists, salbutamol, salmeterol and formoterol on beta 2-adrenoceptor binding and mRNA levels in human lung in vitro. Human lung was obtained from cardiac transplantation donors. Peripheral lung was chopped and incubated with three selective beta 2-adrenoceptor agonist for 3 h or 24 h at three different concentrations (0.1, 1 and 10 microM). The affinity and density of beta 2-adrenoceptors was determined by [125I]iodocyanopindolol equilibrium binding in a lung membrane preparation in the presence of 0.1 microM CGP 20712 A (1-{2-[(3-carbamoyl-4-hydroxy)phenoxy] ethylamino}-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-propan-2-ol), a selective beta 1-adrenoceptor antagonist. Although treatment with salbutamol for 3 h did not change beta 2-adrenoceptor density, both salmeterol and formoterol reduced beta 2-adrenoceptor density, and exposure to each agonist for 24 h reduced beta 2-adrenoceptor density at all concentrations. Treatment with 10 microM salmeterol increased the equilibrium dissociation constant (Kd), and also shifted the competition curves of (-)-isoprenaline to the left, beta 2-Adrenoceptor mRNA, measured by Northern blot analysis using a human beta 2-adrenoceptor cDNA probe, was reduced after exposure to all beta 2-adrenoceptor agonists at 3 h. Our data provide evidence for down-regulation of beta 2-adrenoceptor protein and mRNA after selective beta 2-adrenoceptor agonist treatment in human lung.
authors.affiliation: Department of Thoracic Medicine, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: J C
authors.initials: JC
authors.lastname: Mak
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D015152:Blotting, Northern; D015536:Down-Regulation; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000187:drug effects*; D000068299:Salmeterol Xinafoate
chemical_list: D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D007545:Isoproterenol; D000420:Albuterol; D000068759:Formoterol Fumarate