Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices
| Autor: | James Esposito, Michael J. Sanderson, Xiahui Tan, Jane E. Bourke, Yan Bai, Chantal Donovan |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Pulmonary and Respiratory Medicine
Agonist Male medicine.medical_specialty Time Factors medicine.drug_class Bronchoconstriction Clinical Biochemistry Adrenergic beta-Antagonists Myocytes Smooth Muscle Peroxisome proliferator-activated receptor In Vitro Techniques Bronchoconstrictor Agents Rosiglitazone Mice Bronchodilator Internal medicine medicine Animals Calcium Signaling Molecular Biology Lung Original Research chemistry.chemical_classification Mice Inbred BALB C Dose-Response Relationship Drug business.industry Antagonist Cell Biology respiratory system Adrenergic beta-Agonists respiratory tract diseases Bronchodilator Agents PPAR gamma Perfusion Endocrinology chemistry Methacholine Thiazolidinediones medicine.symptom business Endogenous agonist medicine.drug |
| Zdroj: | American journal of respiratory cell and molecular biology. 50(4) |
| ISSN: | 1535-4989 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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