KW-3635

Thromboxane A(2) is a novel endogenous secretagogue of Cl(-) secretion in the distal colon. Here, we examined if the Cl(-) secretion caused by platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is mediated by thromboxane A(2) production using isolated mucosae of the rat colon. Furosemide (100 microM) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB; 300 microM) completely inhibited PAF (10 microM)-induced increase in short-circuit current (Isc) across the mucosa, indicating that PAF caused a Cl(-) secretion in the rat colon. A selective thromboxane A(2) receptor antagonist (sodium(E)-11-[2-(5, 6-dimethyl-1-benzimidazolyl)-ethylidene]-6,11-dihydrobenz[b, e]oxepine-2-carboxylate monohydrate; KW-3635), and a selective thromboxane synthase inhibitor (sodium 4-[alpha-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3, 5-dimethylbenzoate dihydrate; Y-20811) inhibited the PAF-induced Cl(-) current in a concentration-dependent manner. The IC(50) values of KW-3635 and Y-20811 were 2.1 and 0.5 microM, respectively. 30 microM KW-3635 and 1 microM Y-20811 inhibited the PAF response by 92% and 83%, respectively. These inhibitors did not affect the prostaglandin E(2)-induced increase in Isc. A 5-lipoxygenase-activating protein inhibitor (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2, 2-dimethyl-propanoic acid sodium; MK-886) (5 microM) did not affect the PAF-induced Cl(-) current. The present study suggests that the PAF-induced Cl(-) secretion in the rat colonic mucosa is mainly mediated by a release of thromboxane A(2).