Cyclic AMP-dependent Cl− secretion induced by thromboxane A2 in isolated human colon |
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Authors: | Naoki Horikawa Tomoyuki Suzuki Takaoki Uchiumi Tetsuji Minamimura Kazuhiro Tsukada Noriaki Takeguchi Hideki Sakai |
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Affiliation: | Department of Surgery II, Faculty of Medicine;and Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan |
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Abstract: | Increased release of thromboxane A2 (TXA2) has been shown to be involved in inflammatory bowel diseases. In the present study, we have investigated the effect of a stable TXA2 analogue (STA2) on the electrical parameters in isolated human colonic mucosa. In the human mucosa set between Ussing chambers, STA2 stimulated Cl− secretion in a concentration-dependent manner with an EC50 of 0.06 μ m . The STA2-induced Cl− secretion was significantly inhibited by ONO-3708 (10 μ m ), a specific TXA2 receptor antagonist. The effect of STA2 (0.3 μ m ) was independent of the colonic segment from which the tissue was obtained, from caecum to rectum. Chromanol 293B, an inhibitor of the cAMP-dependent KvLQT1 channel, attenuated the STA2-induced Cl− secretion in the human colonic mucosa (IC50 value 1.18 μ m ). We found that KvLQT1 mRNA and protein were expressed in all the tested segments of the human colon. The STA2-induced Cl− secretion was significantly inhibited by 8-bromo-2'-monobutyryladenosine-3',5'-cyclic monophosphorothioate (50 μ m ), a membrane-permeant cAMP antagonist. STA2 (0.3 μ m ) significantly increased the intracellular cAMP levels and the short-circuit current via TXA2 receptor in a human colonic cell line. These results suggest that the TXA2-induced Cl− secretion in the colon is mediated via the cAMP pathway in addition to the Ca2+–calmodulin pathway which was previously reported. |
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