Thromboxane A(2)-mediated Cl(-) secretion induced by platelet-activating factor in isolated rat colon.
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).
Suzuki
T
T
Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, 930-0194, Toyama, Japan.
Sakai
H
H
Takeguchi
N
N
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001584:Benzoxepins / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002712:Chlorides / Q000378:metabolism / Q000502:physiology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors; D058306:Receptors, Prostaglandin E, EP1 Subtype; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012636:Secretory Rate / Q000187:drug effects; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D001562:Benzimidazoles; D001584:Benzoxepins; D002352:Carrier Proteins; D002712:Chlorides; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C548594:Alox5ap protein, rat; C545637:Ptger1 protein, rat; C060893:MK-886; D002722:Chlorobenzenes; C049966:Y 20811; C065729:KW 3635