title: Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices.
abstract: There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca(2+) oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca(2+) sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca(2+) signaling and Ca(2+) sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma.
authors.affiliation: 1 Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia; and.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Bourke
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.forename: James G
authors.initials: JG
authors.lastname: Esposito
authors.forename: Xiahui
authors.initials: X
authors.lastname: Tan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sanderson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010477:Perfusion; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone