PGE2 receptor (EP4) agonists: Potent dilators of human bronchi and future asthma therapy?
PGE2 receptor (EP4) agonists: Potent dilators of human bronchi and future asthma therapy?
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DOI：
10.1016/j.pupt.2011.12.012
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发表时间：
2012-02-01
影响因子：
3.2
通讯作者：
Norel, X.
中科院分区：
文献类型：
--
作者：
Benyahia, C.;Gomez, I.;Norel, X.
背景：哮喘和慢性阻塞性肺疾病的特征是气道平滑肌的不适当收缩。在这种情况下，人体气道对选择性松弛剂激动剂如PGE（2）的生理反应是高度相关的。因此，本研究的目的是表征PGE（2）受体亚型方法：将人支气管标本切割成环状，置于器官浴槽中进行张力等长记录，并使用选择性EP 2或EP 4配体进行药理学研究。在血栓素TP受体拮抗剂和吲哚美辛存在下，PGE（2）诱导人支气管舒张（E-max =罂粟碱反应的86 +/- 04%; pEC（50）值= 7.06 +/- 0.13; n = 6）。选择性EP 4受体拮抗剂（GW 627368 X，1和10 μ mol/L）可显著阻断这种支气管扩张作用，pK（B）值为6.38 +/- 0.19（n = 5）。此外，选择性EP 4受体激动剂（ONO-AE 1 -329; L-902688）对组胺或抗IgE预收缩的支气管具有较强的舒张作用，而选择性EP 2受体激动剂（ONO-AE 1 -259）则无此作用。这些观察结果表明，EP 4受体激动剂可以构成治疗剂，以治疗哮喘气道阻力增加。(C)2012爱思唯尔有限公司保留所有权利。
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.