Nitric oxide-induced Cl- secretion in isolated rat colon is mediated by the release of thromboxane A2.
We have shown previously that thromboxane A2 (TXA2), which may be released by the anti-tumour drug irinotecan and by platelet-activating factor (PAF), causes Cl- secretion in the isolated rat colon. In the present study, the involvement of TXA2 in nitric oxide-induced Cl- secretion in isolated rat colon was investigated. In colonic mucosa set between Ussing chambers, the NO donor sodium nitroprusside (SNP; 100 microM) caused Cl- secretion, an effect that was almost completely inhibited by the NO scavenger carboxy-PTIO at 200 microM. The SNP-induced Cl- secretion was inhibited in a concentration-dependent manner by the TXA2 receptor antagonist ONO-3708 (IC50 = 2 microM) and the TX synthase inhibitor Y-20811 (IC50 = 0.4 microM). SNP significantly increased the release of TXA2 (measured as TXB2 release) from the mucosa. The SNP-induced increases in Cl- secretion and TXA2 release were blocked by a NO-sensitive guanylate cyclase inhibitor (ODQ). Dibutyryl cGMP (500 microM) also induced Cl- secretion, which was sensitive to ONO-3708 (10 microM) and Y-20811 (1 microM), and increased the release of TXA2 from the mucosa. PAF-induced (10 microM) Cl- secretion was inhibited by carboxy-PTIO (200 microM) and ODQ (10 microM), whereas irinotecan-induced (500 microM) Cl- secretion was not significantly inhibited by these drugs. A stable TXA2 analogue (STA2) but not SNP (100 microM) changed the membrane potential of epithelial cells in isolated colonic crypts under the whole-cell current-clamp condition. These results indicate that PAF elicits the NO-cGMP pathway and then stimulates the release of TXA2, which is a stimulant of colonic Cl- secretion. In contrast, the NO-cGMP pathway is not involved in the TXA2-mediated Cl- secretion induced by irinotecan.
Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. sakaih@ms.toyama-mpu.ac.jp
Hideki
H
Sakai
Tomoyuki
T
Suzuki
Miki
M
Murota
Yuji
Y
Takahashi
Noriaki
N
Takeguchi
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D000077146:Irinotecan; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D002712:Chlorides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020030:Nitric Oxide Donors; D010277:Parasympathomimetics; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D009599:Nitroprusside; C049966:Y 20811; D009569:Nitric Oxide; D013928:Thromboxane A2; D000077146:Irinotecan; C049855:ONO 3708; D006152:Cyclic GMP; D002166:Camptothecin