INTESTINAL EFFECTS OF ISOPROSTANES - EVIDENCE FOR THE INVOLVEMENT OF PROSTANOID EP AND TP RECEPTORS

The isoprostanes, which differ from prostaglandins by the cis orientat ion of their side chains, are believed to exert their biological effec ts on either a prostanoid TP receptor or a ''unique'' isoprostane rece ptor. Preliminary experiments suggested that canine colonic epithelium possessed no prostanoid TP receptor activity, in contrast to the musc ularis mucosae, which responds well to the selective prostanoid TP rec eptor agonist U46619. To define the receptors involved, the in vitro r esponses of the epithelium and muscularis mucosae from the canine prox imal colon to both 8-iso-PGE(2) and 8-iso-PGF(2 alpha) were compared. The epithelium responded to 8-iso-PGE(2) but not to 8-iso-PGF(2 alpha) . Under basal conditions, 8-iso-PGE(2) produced concentration-dependen t increases in short circuit current (pEC(50) = 6.4 +/- 0.1) that were not antagonized by the selective prostanoid TP receptor antagonist SQ 29548 (10(-6) M). Cross-desensitization experiments suggested that the stimulant effects involved a prostanoid EP receptor. Desensitization of the epithelium to PGE(2) resulted in unexpected decreases in short circuit current in response to 8-iso-PGE(2) (10(-6) M). This effect wa s mimicked by the selective prostanoid TP receptor agonist U46619 (10( -5) M), and antagonized by three structurally different prostanoid TP receptor antagonists: L670596 (10(-6) M), SQ29548 (10(-6) M) and GR321 91 (10(-6) M). 8-Iso-PGE(2), 8-iso-PGF(2 alpha) and U46619 caused conc entration-dependent increases in the force of contraction of the muscu laris mucosae strips. These responses were antagonized by selective pr ostanoid TP receptor antagonists, arguing for the involvement of prost anoid TP receptors. Thus, the effects of isoprostanes on the canine co lon involve both prostanoid TP and EP receptors.