PT  - JOURNAL ARTICLE
AU  - Jane Bourke
AU  - Chantal Donovan
AU  - Meaghan FitzPatrick
TI  - Endothelin-1-mediated contraction of mouse small airways is resistant to salbutamol, but sensitive to rosiglitazone
DP  - 2013 Sep 01
TA  - European Respiratory Journal
PG  - P673
VI  - 42
IP  - Suppl 57
4099  - http://erj.ersjournals.com/content/42/Suppl_57/P673.short
4100  - http://erj.ersjournals.com/content/42/Suppl_57/P673.full
SO  - Eur Respir J2013 Sep 01; 42
AB  - Introduction: In vitro investigations of bronchodilator efficacy routinely examine large airways and utilise methacholine (MCh) as a constrictor agent. However, small airway reactivity can be assessed in situ in lung slices, and increased levels of endothelin-1 (Et-1) detected in steroid-resistant asthma support its use as a clinically relevant alternative constrictor. We have identified rosiglitazone (RGZ) as a novel bronchodilator opposing small airway contraction to methacholine (MCh), but its efficacy against Et-1 is yet to be determined.Methods: Changes in airway lumen area in response to Et-1, MCh, RGZ and the β2-adrenoceptor agonist salbutamol (SALB) were visualized in lung slices from Balb/C mice. The effects of ETA- and ETB-selective antagonists (BQ123, BQ788) on contractions to Et-1 were also assessed.Results: Mouse small airways were >10-fold more sensitive to Et-1 than trachea or bronchi. Et-1 was ∼20-fold more potent than MCh in small airways (pEC50 8.5±0.1, 7.1±0.1, p<0.05), with contraction mediated predominantly by ETB-receptors. In reversing submaximal Et-1 contractions, RGZ had lower potency but greater efficacy than SALB (max %relaxation: RGZ 71±4%, SALB 51±14%). Relaxation to RGZ, but not SALB, was maintained in maximally contracted airways, and the development of Et-1-induced reductions in lumen area was inhibited by RGZ only.Conclusion: Et-1 is a potent bronchoconstrictor of mouse small airways. Contraction to Et-1 is relatively resistant to β2 -adrenoceptor-mediated relaxation. Characterisation of the mechanism underlying the greater efficacy of RGZ in this setting may identify novel approaches targetting small airways for asthma treatment.