Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension

Lai, Ying-Ju and Pullamsetti, Soni Savai and Dony, Eva and Weissmann, Norbert and Butrous, Ghazwan S. and Banat, Gamal-Andre and Ghofrani, Hossein A. and Seeger, Werner and Grimminger, Friedrich and Schermuly, Ralph T. (2008) Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension. American Journal of Respiratory and Critical care Medicine, 178 (2). 188 -196 . ISSN 1073-449X . (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Rationale Iloprost is effective for the treatment of pulmonary hypertension. It acts through elevation of CAMP by binding to the prostacyclin receptor (IP receptor). However, there is evidence that patients with severe pulmonary hypertension have decreased expression of the IP receptor in the remodeled pulmonary arterial smooth muscle. Objectives: We hypothesized that prostanoid receptors other than the IP receptor are involved in signal transduction by iloprost. Methods: Immunoblotting was used to detect the IP and prostanoid EP4 receptor in lung tissue from patients with idiopathic pulmonary arterial hypertension, and immunohistochemistry was used to detect these receptors in lung sections from rats treated with monocrotaline (MCT28d). Protein and mRNA were isolated from pulmonary arterial smooth muscle cells (PASMCs) from control and MCT28d rats treated with AH6809 (an EP2 receptor antagonist) and AH23848 (an EP4 receptor antagonist) in combination with iloprost. Intracellular cAMP was also assessed in these tissues. Measurements and Main Results: IP receptor expression was reduced in idiopathic pulmonary arterial hypertension patient lung samples and MCT28d rat lungs compared with the controls. Reverse transcriptase-polymerase chain reaction and immunoblotting of MCT28d rat PASMC extracts revealed scant expression of the IP receptor but stable expression of EP4 receptor, compared with controls. Iloprost-induced elevation in intracellular CAMP in PASMCs was dose-dependently reduced by AH23848, but not by AH6809. Conclusions: Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.

Item Type: Article
Uncontrolled keywords: prostanoid EP4 receptor; iloprost; pulmonary artery hypertension
Subjects: R Medicine > R Medicine (General)
Divisions: Faculties > Science Technology and Medical Studies > Kent Institute of Medicine and Health Sciences (KIMHS)
Depositing User: Louise Dorman
Date Deposited: 18 Apr 2009 10:48
Last Modified: 13 May 2014 14:04
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