Prostaglandin E2 increases cyclic AMP and inhibits endothelin-1 production/secretion by guinea-pig tracheal epithelial cells through EP4 receptors

1 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). 2 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 PGE2 (EP-selective)> > >iloprost (IP/ EP1/EP3-selective), butaprost (EP2-selective), PGD(2) (DP-selective), PGF(2 alpha) (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, IF, EP1, EP2 or EP3 subtype. 3 Pre-incubating the cells with the selective TP/EP4-receptor antagonists AH23848B and AH22921X antagonized the PGE(2)-evoked cyclic AMP generation. This suggested that EPS receptors mediate PGE(2) effects. However, in addition to any antagonistic effects at EP4-receptors, both compounds, to a different extent, modified cyclic AMP metabolism. The selective EPI, DP and EP2 receptor antagonist (AH6809) failed to inhibit PGE(2)-evoked cyclic AMP generation which confirmed that the EP2 receptor subtype did not contribute to the change in cyclic AMP formation in these cells. 4 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. 5 These results provide the first evidence supporting the existence of a functional prostaglandin E-2 receptor that shares the pharmacological features of the EP4-receptor subtype in guinea-pig tracheal epithelial cells. These receptors modulate cyclic AMP formation as well as ET-1 production/secretion in these cells.