PGE2 receptor (EP4) agonists: Potent dilators of human bronchi and future asthma therapy?

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 (EP2 or EP4) 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 EP2 or EP4 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 EP4 receptor antagonist (GW627368X, 1 and 10 mu mol/L) with a pK(B) value of 6.38 +/- 0.19 (n = 5). In addition, the selective EP4 receptor agonists (ONO-AE1-329; L-902688), but not the selective EP2 receptor agonist (ONO-AE1-259), induced potent relaxation of bronchial preparations pre-contracted with histamine or anti-IgE. Conclusion: PGE(2) and EP4 agonists induced potent relaxations of human bronchial preparations via EP4 receptor. These observations suggest that EP4 receptor agonists could constitute therapeutic agents to treat the increased airway resistance in asthma. (C) 2012 Elsevier Ltd. All rights reserved.