title: Mechanism of adenosine-induced airways obstruction in allergic guinea pigs.
abstract: Inhaled adenosine induces airway obstruction in asthmatic but not healthy subjects, a phenomenon that is also observed in various animal species when they are immunised to a relevant antigen, but which does not occur in naïve animals. The purpose of this study was to investigate the mechanisms of airway responsiveness to adenosine receptor agonists in anaesthetised allergic guinea pigs. Inhaled adenosine 5'-monophosphate (AMP), the A1-selective adenosine receptor agonist N6-cyclopentyladenosine (CPA) and ovalbumin all caused airway obstruction in allergic guinea pigs, but not naïve animals, as assessed by changes in total lung resistance. In contrast, the A(2a)-selective (CGS 21680; 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxoamido adenosine) and A3-selective (IB-MECA; 1-deoxy-1-[6-[[3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-beta-D-ribofuranuronamide) adenosine receptor agonists failed to elicit airway obstruction in passively sensitised guinea pigs. Airway obstruction induced by AMP or CPA was not inhibited by the H1 receptor antagonist, mepyramine (1 mg kg(-1)) in passively sensitised guinea-pigs. In contrast, airway obstruction to ovalbumin was significantly inhibited by this antagonist. Airway obstruction induced by AMP and CPA was significantly inhibited in sensitised animals chronically treated with capsaicin. In contrast, airway obstruction to ovalbumin was not inhibited by this treatment. Airway obstruction induced by AMP, CPA and ovalbumin was significantly inhibited following bilateral vagotomy or pharmacological treatment with atropine (2 mg kg(-1)). Airway obstruction to CPA was inhibited by the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.1-1 mg kg(-1)). In contrast, airway obstruction to ovalbumin was not inhibited by this treatment. These observations provide evidence indicating that AMP and CPA may induce airway obstruction in sensitised guinea pigs by a mechanism unrelated to histamine release from mast cells, but is mediated via an adenosine A1-receptor-dependent mechanism. The inhibition of AMP- and CPA-induced airway obstruction by atropine, capsaicin and bilateral vagotomy suggests a neuronal-dependent mechanism with the particular involvement of capsaicin-sensitive nerves.
authors.affiliation: King's College London School of Biomedical and Health and Life Sciences, Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology and Therapeutics, 5th Floor Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL.
authors.forename: Sandra
authors.initials: S
authors.lastname: Keir
authors.forename: Victoria
authors.initials: V
authors.lastname: Boswell-Smith
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Clive
authors.initials: C
authors.lastname: Page
mesh_terms: D000241:Adenosine; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000402:Airway Obstruction / Q000139:chemically induced* / Q000503:physiopathology*; D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000758:Anesthesia; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002211:Capsaicin / Q000494:pharmacology; D000242:Cyclic AMP; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D010047:Ovalbumin / Q000276:immunology; D011738:Pyrilamine / Q000494:pharmacology; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000503:physiopathology*; D014628:Vagotomy; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D006634:Histamine H1 Antagonists; D014970:Xanthines; D010047:Ovalbumin; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D011738:Pyrilamine; D000241:Adenosine; D002211:Capsaicin