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Prostaglandin E 2 increases cyclic AMP and inhibits endothelin‐1 production/secretion by guinea‐pig tracheal epithelial cells through EP 4 receptors
Author(s) -
Pelletier Stéphane,
Dubé Jean,
Villeneuve Annie,
Gobeil Fernand,
Yang Quan,
Battistini Bruno,
Guillemette Gaétan,
Sirois Pierre
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703886
Subject(s) - medicine , endocrinology , prostaglandin e , receptor , chemistry , prostanoid , prostaglandin , adenosine , biology , biochemistry
Prostaglandin E 2 (PGE 2 ) increased adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP) formation in tracheal epithelial cells and concomitantly decreased the production/secretion of immunoreactive endothelin (irET). Naturally occurring prostanoids and selective and non‐selective EP receptor agonists showed the following rank order of potency in stimulating cyclic AMP generation by epithelial cells: PGE 2 (EP‐selective)>16,16‐dimethyl PGE 2 (EP‐selective)>11‐deoxy PGE 2 (EP‐selective)>>>iloprost (IP/EP 1 /EP 3 ‐selective), butaprost (EP 2 ‐selective), PGD 2 (DP‐selective), PGF 2α (FP‐selective). The lack of responsiveness of the latter prostanoids indicated that the prostanoid receptor present in these cells is not of the DP, FP, IP, EP 1 , EP 2 or EP 3 subtype. Pre‐incubating the cells with the selective TP/EP 4 ‐receptor antagonists AH23848B and AH22921X antagonized the PGE 2 ‐evoked cyclic AMP generation. This suggested that EP 4 receptors mediate PGE 2 effects. However, in addition to any antagonistic effects at EP 4 ‐receptors, both compounds, to a different extent, modified cyclic AMP metabolism. The selective EP 1 , DP and EP 2 receptor antagonist (AH6809) failed to inhibit PGE 2 ‐evoked cyclic AMP generation which confirmed that the EP 2 receptor subtype did not contribute to the change in cyclic AMP formation in these cells. The PGE 2 ‐induced inhibition of irET production by guinea‐pig tracheal epithelial cells was due to cyclic AMP generation and activation of the cyclic AMP‐dependent protein kinase since this effect was reverted by the cyclic AMP antagonist Rp‐cAMPS. These results provide the first evidence supporting the existence of a functional prostaglandin E 2 receptor that shares the pharmacological features of the EP 4 ‐receptor subtype in guinea‐pig tracheal epithelial cells. These receptors modulate cyclic AMP formation as well as ET‐1 production/secretion in these cells.British Journal of Pharmacology (2001) 132 , 999–1008; doi: 10.1038/sj.bjp.0703886