Vasoconstriction induced by activation of EP1 and EP3 receptors in human lung: effects of ONO-AE-248, ONO-DI-004, ONO-8711 or ONO-8713

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Abstract

This study investigated the effects and selectivity of ONO-AE-248, ONO-DI-004, ONO-8711 and ONO-8713 on EP1 and EP3 receptors in human pulmonary vessels. The prostanoid receptors involved in the vasoconstriction of human pulmonary arteries (HPA) are TP and EP3 whereas in pulmonary veins (HPV), this response is associated with TP and EP1. The experiments were performed in presence of BAY u3405 (TP antagonist). ONO-DI-004 (EP1 agonist) and ONO-AE-248 (EP3 agonist), exhibited little or no activity in HPV whereas contractions were induced in HPA with ONO-AE-248. In HPV, the contractions produced with sulprostone (EP1,3 agonist) were blocked in a non competitive manner by both EP1 antagonists (ONO-8711, 30 μM; ONO-8713, 10 μM). The involvement of EP1 mediated contraction in HPV was also observed during the vasorelaxations induced with PGE1 and 5-cis-carba-PGI2. In pre-contracted HPV treated with AH6809 (30 μM; EP1 antagonist) the PGE1 vasorelaxations were potentiated, while unchanged in HPA. These results demonstrate the selectivity of ONO-AE-248 for the EP3 receptor in HPA, ONO-DI-004 was ineffective on the EP1 receptor present in HPV while ONO-8713 was the more potent EP1 antagonist used in this tissue.

Introduction

Prostaglandins (PGs) and thromboxane (Tx) are essential endogenous regulator of the vascular tone. PGs may relax or contract vascular smooth muscle by activating different prostanoid receptor types or subtypes [1], [2], [3]. In isolated vascular preparations activation of EP2, EP4, DP or IP receptors produced smooth muscle relaxation by elevating intracellular cyclic AMP levels [4]. In contrast, activation of either the TP, FP, EP1 or EP3 receptor, present on smooth muscle, induced a contraction by increasing Ca2+ and/or reducing cyclic AMP intracellular levels [4].

Previous investigations have demonstrated that the prostanoid receptors involved in the vasoconstriction of human pulmonary arteries (HPA) are TP and EP3 receptors [5], [6] whereas in human pulmonary veins (HPV), this response is associated with TP and EP1 receptors [7], [8]. While a number of selective TP agonists and antagonists have been developed and examined on human vascular tone [6], [8], [9], [10], [11], [12], [13], [14], there are few compounds which selectively discriminate between EP1 and EP3 receptors. Although sulprostone and 17-phenyl-PGE2 are selective agonists for EP1 and EP3 receptors, these compounds activate both receptors and contract smooth muscle [6], [8], [15]. Recently, other compounds have been developed, namely, ONO-AE-248, which was reported to be a selective EP3 agonist [16] and ONO-DI-004 described as a selective EP1 agonist [17], [18]. In addition, ONO-8711 and ONO-8713 are two selective EP1 antagonists [19], [20]. These compounds have been investigated principally in rodent models involving cancer, neuronal and pain research [19], [20], [21], [22]. There are no reports on their actions in isolated vascular preparations or in the human circulation. The aim of the present investigation was to examine these compounds on human pulmonary vascular preparations in order to confirm their selectivity and potency for the EP1,3 receptors involved in the vasoconstriction.

Section snippets

Isolated vascular preparations

All research programs involving the use of human tissue were approved and supported by the medical ethics committee at “Centre Chirurgical Marie Lannelongue”. Human lung tissues were obtained from patients (13 male and one female) who had undergone surgery for lung carcinoma. The mean age was 60 ± 2 years. All lung samples were examined by a pathologist, the remaining macroscopically normal tissue (without carcinoma or other pulmonary pathology) was sent to our laboratory. HPA and HPV (3–6 mm

Results

The NE (10 μM) induced contractions were similar in HPA, 2.21 ± 0.67 g, (n = 8) and HPV, 2.64 ± 0.29 g, (n = 12).

The results presented in Fig. 1 and Table 1 show that in HPV, ONO-AE-248 exhibited little or no activity while in HPA, this compound induced dose-dependent contractions. These dose–response curves were significantly different. Cumulative concentrations of ONO-DI-004 failed to contract the HPV (Table 1). The contractions induced by sulprostone in HPV were blocked in a non-competitive

Discussion

The vasoconstrictions produced by ONO-AE-248, indicate that this compound is an efficient agonist on the EP3 receptor present in the HPA but not in the HPV. In addition, both EP1 antagonists (ONO-8711, ONO-8713) block sulprostone induced contractions in the HPV. Furthermore, in HPV the relaxation induced by PGE1 and 5-cis-carba-PGI2 via the IP-receptors is counterbalanced by the activation of the EP1 receptors. A similar IP/EP1 control has been described with PGI2 in HPV7. Together these data

Acknowledgement

The authors would like to thank Dr. Takayuki Maruyama for providing the ONO compounds and Dr. Kiyoto Sakata for the bibliographic help.

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