title: Bronchoprotection in conscious guinea pigs by budesonide and the NO-donating analogue, TPI 1020, alone and combined with tiotropium or formoterol.
abstract: OBJECTIVE
  Inhaled corticosteroids, anticholinergics and β₂-adrenoceptor agonists are frequently combined for treating chronic respiratory diseases. We examine the corticosteroid, budesonide, and novel NO-donating derivative, TPI 1020, against histamine- and methacholine-induced bronchoconstriction and whether they enhance the β₂-adrenoceptor agonist formoterol or muscarinic antagonist tiotropium in conscious guinea pigs.
  
  
  METHODS
  Dunkin-Hartley guinea pigs received inhaled histamine (3 mM) or methacholine (1.5 mM) and specific airway conductance (sG(aw)) was measured before and 15 or 75 min after treatment with budesonide, TPI 1020, tiotropium or formoterol alone or in combinations.
  
  
  RESULTS
  Formoterol (0.7-10 µM) and budesonide (0.11-0.7 mM) inhibited histamine-induced bronchoconstriction and tiotropium (2-20 µM) inhibited methacholine-induced bronchoconstriction by up to 70.8 ± 16.6%, 34.9 ± 4.4% and 85.1 ± 14.3%, respectively. Formoterol (2.5 µM) or tiotropium (2 µM) alone exerted small non-significant bronchoprotection. However, when co-administered with TPI 1020 0.11 mM, which alone had no significant effect, there was significant inhibition of the bronchoconstriction (45.7 ± 12.2% and 79.7 ± 21.4%, respectively). Co-administering budesonide (0.11 mM) with tiotropium (2 µM), which alone had no effect, also significantly inhibited the methacholine bronchoconstriction (36.5 ± 13.0%), but there was no potentiation of formoterol against histamine. The NO scavenger, CPTIO, prevented the bronchoprotection by SNAPand TPI 1020.
  
  
  CONCLUSIONS
  TPI 1020 potentiated the bronchoprotection by formoterol and tiotropium. Budesonide also enhanced the effects of tiotropium but not formoterol. Combination of TPI 1020 with a long-acting β₂-adrenoceptor agonist or muscarinic receptor antagonist may therefore be a more potent therapeutic approach for treatment of chronic respiratory diseases.
authors.affiliation: Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cathays Park Campus, Cardiff, Wales, UK.
authors.forename: D l
authors.initials: Dl
authors.lastname: Turner
authors.forename: N
authors.initials: N
authors.lastname: Ferrari
authors.forename: W R
authors.initials: WR
authors.lastname: Ford
authors.forename: E J
authors.initials: EJ
authors.lastname: Kidd
authors.forename: B
authors.initials: B
authors.lastname: Nevin
authors.forename: L
authors.initials: L
authors.lastname: Paquet
authors.forename: P
authors.initials: P
authors.lastname: Renzi
authors.forename: K J
authors.initials: KJ
authors.lastname: Broadley
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019819:Budesonide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D012140:Respiratory Tract Diseases / Q000188:drug therapy / Q000503:physiopathology; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D000069447:Tiotropium Bromide
chemical_list: D001993:Bronchodilator Agents; D004983:Ethanolamines; C492926:NCX 1020; D012602:Scopolamine Derivatives; D016210:Methacholine Chloride; D019819:Budesonide; D006632:Histamine; D000068759:Formoterol Fumarate; D000069447:Tiotropium Bromide