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Background and Purpose: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE 2 and PGI 2 induce potent relaxation of human bronchi from non-PH (control) patients via EP 4 and IP receptors, respectively. However, the effects of PGE 2 /PGI 2 and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI 2 -mimetics approved for treating PH Group I with several PGE 2 -mimetics, in bronchial preparations derived from PH Group III and control patients., Experimental Approach: Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE 2 , PGI 2 , and cAMP levels were determined by ELISA., Key Results: Maximal relaxations induced by different EP 4 receptor agonists (PGE 2 , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI 2 -mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP 4 and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI 2 but not with PGE 2 levels., Conclusion and Implications: The PGI 2 -mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP 4 receptor agonists was decreased. Restoration of EP 4 receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit., (© 2019 The British Pharmacological Society.)

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., Conclusion: 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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 (Emax = 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. Conclusion: 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. [Copyright &y& Elsevier]