Thromboxane A 2-mediated Cl − secretion induced by platelet-activating factor in isolated rat colon

Abstract

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 μM) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB; 300 μM) completely inhibited PAF (10 μM)-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-[α-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 μM, respectively. 30 μM KW-3635 and 1 μM 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 μM) 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.