title: K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma.
abstract: BACKGROUND
  The Ca(2+)-activated K(+) channel K(Ca)3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca)3.1 modifies experimental asthma in sheep.
  
  
  RESULTS
  Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of the K(Ca)3.1-channel, or vehicle alone (0.5% methylcellulose) twice daily (orally). Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; n = 10, P = 0.0147). The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; n = 10, P = 0.0288). Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; n = 10, P = 0.0340). Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling.
  
  
  CONCLUSIONS
  These findings suggest that K(Ca)3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of K(Ca)3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans.
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Van Der Velden
authors.forename: Grace
authors.initials: G
authors.lastname: Sum
authors.forename: Donna
authors.initials: D
authors.lastname: Barker
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Koumoundouros
authors.forename: Garry
authors.initials: G
authors.lastname: Barcham
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Neil
authors.initials: N
authors.lastname: Castle
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.forename: Kenneth
authors.initials: K
authors.lastname: Snibson
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000473:pathology / Q000503:physiopathology*; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002217:Carbachol / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005260:Female; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D039981:Pyroglyphidae / Q000187:drug effects / Q000502:physiology; D012756:Sheep / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014320:Triphenylmethyl Compounds / Q000494:pharmacology
chemical_list: D000081:Acetamides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D014320:Triphenylmethyl Compounds; D002217:Carbachol; C472774:senicapoc