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

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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 PGE2 is highly relevant. The aim of this study was thus to characterize the PGE2 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, PGE2 induced the relaxation of human bronchi (Emax = 86 ± 04% of papaverine response; pEC50 value = 7.06 ± 0.13; n = 6). This bronchodilation was significantly blocked by a selective EP4 receptor antagonist (GW627368X, 1 and 10 μmol/L) with a pKB 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

PGE2 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.

Introduction

Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction and bronchoconstriction. Previous studies have shown that the use of beta-receptor agonists in asthma treatment has detrimental side effects. Beta-receptor agonists are associated with incident heart failure in patients treated with long lasting beta-agonists [1]. Researches are currently underway to identify new bronchodilators agents. Many in vitro studies using animal airways have reported relaxation induced by prostaglandin E2 (PGE2). The activation of EP2 or EP4 receptor subtypes by PGE2 is responsible for these effects. In mice, guinea-pig and cat, the EP2 receptor is involved [2], [3] while in rat the EP4 receptor has been implicated [4]. The initially characterized ligands: AH6809 (EP2, DP, EP1 receptor antagonist), AH23848B (TP, EP4 > EP2 receptor antagonist) and butaprost (EP2 > EP4 receptor agonist), used to discriminate between EP2 and EP4 receptor subtypes, had a poor selectivity [5]. PGE2 in presence of a thromboxane TP receptor antagonist or butaprost are also potent relaxants of human bronchial preparations [3], [6]. These pharmacological studies suggested the involvement of the EP2 receptor in human bronchi. In the context of asthma treatment, two phase I clinical trials were conducted using inhalation of a selective EP2 receptor agonist (AH13205) [7]. In these studies no bronchodilation was observed while AH13205 has been shown to produce airway irritancy in normal volunteers and coughing in mild asthmatics. In the last decade new selective (EP2/EP4) receptor agonists and antagonists have been developed [8], [9]. For this reason, the aim of the present study was to clarify and determine which EP receptor subtype (EP2/EP4) is involved in human bronchodilation using these new compounds.

Section snippets

Tissue preparations

All research programs involving the use of human tissue were approved and supported by the Ethics Committee of INSERM (the French National Institute for Health and Medical Research) and informed consent was obtained from each patient. Human lung tissue was obtained from patients (5 male and 5 female) who had undergone surgery for lung carcinoma. The mean age of the patients was 60 ± 4 years. Subsegmental (4th to 7th generation) bronchial preparations were used within 1–12 h post-surgery and cut

Results

The airway pre-contractions produced by the different receptor agonists (histamine, anti-IgE and acetylcholine) and maximal relaxations induced by papaverine are shown in Table 1. PGE2 induced concentration-dependent relaxations of human bronchial preparations pre-contracted with histamine (Fig. 1; Table 2). These bronchial relaxations were significantly blocked by GW627368X (1 and 10 μmol/L) as these EP4 receptor antagonist concentrations caused a rightward shift (5 and 15 fold) of the PGE2

Discussion

These data are clearly in favour of the involvement of the EP4 receptor in human bronchial preparations during the relaxation induced by PGE2. The calculated affinity value for GW62768X in the present report (6.38) is close to the pKi value (7.0) determined with this antagonist towards the human EP4 receptor in a previous competition-binding study [4]. In addition, both selective EP4 receptor agonists (ONO-AE1-329 and L-902688) induced potent relaxation of human bronchial preparations as well

Conflict of interest

None.

Acknowledgements

The authors would like to thank Dr. Takayuki Maruyama for providing the ONO compounds, Dr Dagen Xu for the Merck compounds, Dr Richard J. Wilson for the GSK compound, Dr Mary Osborne-Pellegrin for help in editing the manuscript and Michèle Saadoun (Anapathology laboratory, CHU X. Bichat) for assistance.

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