title: Rosiglitazone is a superior bronchodilator compared to chloroquine and β-adrenoceptor agonists in mouse lung slices.
abstract: BACKGROUND
  Current therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where β-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices.
  
  
  METHODS
  Relaxation to RGZ and CQ was assessed following submaximal methacholine (MCh) pre-contraction, in slices treated overnight with either RGZ, CQ or albuterol (ALB) (to induce β-adrenoceptor desensitization), and in slices treated with caffeine/ryanodine in which contraction is associated with increases in Ca2+ sensitivity in the absence of contractile agonist-induced Ca2+ oscillations. Furthermore, the effects of RGZ, CQ, ALB and isoproterenol (ISO) on the initiation and development of methacholine-induced contraction were also compared.
  
  
  RESULTS
  RGZ and CQ, but not ALB or ISO, elicited complete relaxation with increasing MCh pre-contraction and maintained their potency and efficacy following β-adrenoceptor desensitization. RGZ, CQ and ALB maintained efficacy following overnight incubation with RGZ or CQ. Relaxation responses to all dilators were generally maintained but delayed after caffeine/ryanodine. Pre-treatment with RGZ, but not CQ, ALB or ISO, reduced MCh potency.
  
  
  CONCLUSIONS
  This study demonstrates the superior effectiveness of RGZ in comparison to CQ and β-adrenoceptor agonists as a dilator of mouse small airways. Further investigation of the mechanisms underlying the relatively greater efficacy of RGZ under these conditions are warranted and should be extended to include studies in human asthmatic airways.
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.forename: Mirjam
authors.initials: M
authors.lastname: Simoons
authors.forename: James
authors.initials: J
authors.lastname: Esposito
authors.forename: Jean
authors.initials: J
authors.lastname: Ni Cheong
authors.forename: Meaghan
authors.initials: M
authors.lastname: Fitzpatrick
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia. jane.bourke@unimelb.edu.au.
authors.forename: Jane Elizabeth
authors.initials: JE
authors.lastname: Bourke
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002738:Chloroquine