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Nitric oxide‐induced Cl − secretion in isolated rat colon is mediated by the release of thromboxane A 2
Author(s) -
Sakai Hideki,
Suzuki Tomoyuki,
Murota Miki,
Takahashi Yuji,
Takeguchi Noriaki
Publication year - 2002
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2002.021287
Subject(s) - nitric oxide , thromboxane , chemistry , secretion , thromboxane a2 , endocrinology , medicine , pharmacology , platelet , radiochemistry , biochemistry
We have shown previously that thromboxane A 2 (TXA 2 ), 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 TXA 2 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 μM) caused Cl − secretion, an effect that was almost completely inhibited by the NO scavenger carboxy‐PTIO at 200 μM. The SNP‐induced Cl − secretion was inhibited in a concentration‐dependent manner by the TXA 2 receptor antagonist ONO‐3708 (IC 50 = 2 μM) and the TX synthase inhibitor Y‐20811 (IC 50 = 0.4 μM). SNP significantly increased the release of TXA 2 (measured as TXB 2 release) from the mucosa. The SNP‐induced increases in Cl − secretion and TXA 2 release were blocked by a NO‐sensitive guanylate cyclase inhibitor (ODQ). Dibutyryl cGMP (500 μM) also induced Cl − secretion, which was sensitive to ONO‐3708 (10 μM) and Y‐20811 (1 μM), and increased the release of TXA 2 from the mucosa. PAF‐induced (10 μM) Cl − secretion was inhibited by carboxy‐PTIO (200 μM) and ODQ (10 μM), whereas irinotecan‐induced (500 μM) Cl − secretion was not significantly inhibited by these drugs. A stable TXA 2 analogue (STA 2 ) but not SNP (100 μM) 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 TXA 2 , which is a stimulant of colonic Cl − secretion. In contrast, the NO‐cGMP pathway is not involved in the TXA 2 ‐mediated Cl − secretion induced by irinotecan.