title: PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy?
abstract: BACKGROUND
  Asthma and chronic obstructive pulmonary disease are characterized by inappropriate constriction of the airway smooth muscle. In this context, the physiological response of the human airways to selective relaxant agonists like PGE(2) is highly relevant. The aim of this study was thus to characterize the PGE(2) receptor subtypes (EP(2) or EP(4)) involved in the relaxation of human bronchial preparations.
  
  
  METHODS
  Human bronchial preparations cut as rings were mounted in organ baths for isometric recording of tension and a pharmacological study was performed using selective EP(2) or EP(4) ligands.
  
  
  RESULTS
  In the presence of a thromboxane TP receptor antagonist and indomethacin, PGE(2) induced the relaxation of human bronchi (E(max) = 86 ± 04% of papaverine response; pEC(50) value = 7.06 ± 0.13; n = 6). This bronchodilation was significantly blocked by a selective EP(4) receptor antagonist (GW627368X, 1 and 10 μmol/L) with a pK(B) value of 6.38 ± 0.19 (n = 5). In addition, the selective EP(4) receptor agonists (ONO-AE1-329; L-902688), but not the selective EP(2) receptor agonist (ONO-AE1-259), induced potent relaxation of bronchial preparations pre-contracted with histamine or anti-IgE.
  
  
  CONCLUSIONS
  PGE(2) and EP(4) agonists induced potent relaxations of human bronchial preparations via EP(4) receptor. These observations suggest that EP(4) receptor agonists could constitute therapeutic agents to treat the increased airway resistance in asthma.
authors.affiliation: INSERM U698, CHU X. Bichat, 46 rue Huchard, 75018 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Benyahia
authors.forename: I
authors.initials: I
authors.lastname: Gomez
authors.forename: L
authors.initials: L
authors.lastname: Kanyinda
authors.forename: K
authors.initials: K
authors.lastname: Boukais
authors.forename: C
authors.initials: C
authors.lastname: Danel
authors.forename: G
authors.initials: G
authors.lastname: Leséche
authors.forename: D
authors.initials: D
authors.lastname: Longrois
authors.forename: X
authors.initials: X
authors.lastname: Norel
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003627:Data Interpretation, Statistical; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007073:Immunoglobulin E / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010208:Papaverine / Q000494:pharmacology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D008738:Methyl Ethers; C461399:ONO-AE1-329; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014665:Vasodilator Agents; D007073:Immunoglobulin E; D006632:Histamine; D010208:Papaverine; D015232:Dinoprostone; D000109:Acetylcholine