Intestinal Effects of Isoprostanes: Evidence for the Involvement of Prostanoid EP and TP Receptors1

The isoprostanes, which differ from prostaglandins by the cis orientation of their side chains, are believed to exert their bio-logical effects on either a prostanoid TP receptor or a “unique” isoprostane receptor. Preliminary experiments suggested that canine colonic epithelium possessed no prostanoid TP recep-tor activity, in contrast to the muscularis mucosae, which re-sponds well to the selective prostanoid TP receptor agonist U46619. To define the receptors involved, the in vitro re-sponses of the epithelium and muscularis mucosae from the canine proximal colon to both 8-iso-PGE2 and 8-iso-PGF2a were compared. The epithelium responded to 8-iso-PGE2 but not to 8-iso-PGF2a. Under basal conditions, 8-iso-PGE2 pro-duced concentration-dependent increases in short circuit cur-rent (pEC50 5 6.4 6 0.1) that were not antagonized by the selective prostanoid TP receptor antagonist SQ29548 (1026 M). Cross-desensitization experiments suggested that the stimu-lant effects involved a prostanoid EP receptor. Desensitization of the epithelium to PGE2 resulted in unexpected decreases in short circuit current in response to 8-iso-PGE2 (10 26 M). This effect was mimicked by the selective prostanoid TP recepto