title: Agonist-independent alteration in beta-adrenoceptor-G-protein-adenylate cyclase system in an equine model of recurrent airway obstruction.
abstract: We examined the inhibitory sympathetic beta-adrenergic mechanisms in peripheral lung, bronchi and trachea of an equine model of recurrent airway obstruction (RAO), to support the hypothesis that the beta-adrenergic receptor dysfunction is not only restricted to cell surface receptor density but rather encompasses a mechanistic defect apart from the receptor, to the intracellular signaling components. The non-asthmatic lung possessed 3.2-fold more beta-adrenergic receptors than bronchi (496 +/- 19.4 vs. 155.1+/- 19.6 fmol/mg protein; P < 0.01) and 6.2-fold higher than in the trachea (79.8 +/- 12.6 fmol/mg protein; P < 0.001) (assessed by radioligand binding assays using (-)-[(125)I]-iodocyanopindolol, ICYP) and in all tissues a greater proportion of the beta(2)- than the beta(1)-subtype (75-80%). The receptor density (B(max)) in lung parenchyma and bronchial membranes was 33 and 42%, respectively, lower (P < 0.001) in RAO than in control animals, attributable to a decrease in the beta(2)-subtype. This receptor down-regulation was accompanied with an attenuated coupling efficiency of the receptor to the stimulatory G(S)-protein (P < 0.05 vs. control). Concomitantly, activation of adenylate cyclase evoked by isoproterenol was significantly reduced in lung and bronchial membranes of animals with RAO, whereas effects of 10 microM GTP, 10mM NaF, 10 microM forskolin and 10 mM Mn(2+) were not altered. There was no difference in beta-adrenergic receptor density, G(S)-protein or adenylate cyclase coupling in the trachea between asthmatic and control animals. In conclusion, in stable asthma the pulmonary beta-adrenergic receptor-G(S)-protein-adenylate cyclase system is impaired, thus the pathologic process involves all signaling components, and due to its close similarity, this animal model seems to serve as a suitable model, at least partly, of chronic asthmatic patients.
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, Leipzig University, Germany. gabraham@rz.uni-leipzig.de
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
authors.forename: Claudia
authors.initials: C
authors.lastname: Kottke
authors.forename: Stefan
authors.initials: S
authors.lastname: Dhein
authors.forename: Fritz Rupert
authors.initials: FR
authors.lastname: Ungemach
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000402:Airway Obstruction / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001665:Binding Sites; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006736:Horses; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol