title: Prostaglandin E2 elicits greater bronchodilation than salbutamol in mouse intrapulmonary airways in lung slices.
abstract: BACKGROUND
  Current asthma therapy may not adequately target contraction of smaller intrapulmonary airways, which are a major site of airway obstruction and inflammation. The aim of this study was to characterise responses of mouse intrapulmonary airways to prostaglandin E(2) (PGE(2)) and compare its dilator efficacy with the β(2)-adrenoceptor agonist salbutamol in situ, using lung slices.
  
  
  METHODS
  Lung slices (150 μm) were prepared from male Balb/C mice. Changes in intrapulmonary airway lumen area were recorded and analysed by phase-contrast microscopy. Relaxation to PGE(2) and salbutamol were assessed following various levels of pre-contraction with methacholine, serotonin or endothelin-1, as well as following overnight incubation with PGE(2) or salbutamol. The mechanism of PGE(2)-mediated relaxation was explored using selective EP antagonists (EP(1/2) AH6809; EP(4) L-161982) and Ca(2+)-permeabilized slices, where airway responses are due to regulation of Ca(2+)-sensitivity alone.
  
  
  RESULTS
  PGE2 elicited EP(1/2)-mediated relaxation of intrapulmonary airways. PGE(2) was more potent than salbutamol in opposing submaximal pre-contraction to all constrictors tested, and only PGE(2) opposed maximal pre-contraction with endothelin-1. Relaxation to PGE(2) was maintained when contraction to methacholine was mediated via increased Ca(2+)-sensitivity alone. PGE(2) was less sensitive to homologous or heterologous desensitization of its receptors than salbutamol.
  
  
  CONCLUSIONS
  The greater efficacy and potency of PGE(2) compared to salbutamol in mouse intrapulmonary airways supports further investigation of the mechanisms underlying this improved dilator responsiveness for the treatment of severe asthma.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: m.fitzpatrick@student.unimelb.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: FitzPatrick
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: c.donovan@student.unimelb.edu.au.
authors.forename: C
authors.initials: C
authors.lastname: Donovan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: jane.bourke@unimelb.edu.au.
authors.forename: J E
authors.initials: JE
authors.lastname: Bourke
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D012701:Serotonin / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D019332:Endothelin-1; D016210:Methacholine Chloride; D012701:Serotonin; D015232:Dinoprostone; D000420:Albuterol; D002118:Calcium
keywords: Bronchodilation; Calcium sensitivity; Endothelin-1; Intrapulmonary airways; Prostaglandin E(2); Salbutamol