Cyclic AMP‐dependent Cl− secretion induced by thromboxane A2 in isolated human colon
Cyclic AMP‐dependent Cl− secretion induced by thromboxane A2 in isolated human colon
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血栓素 A2 在离体人结肠中诱导循环 AMP 依赖性 Cl− 分泌
DOI：
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
H. Sakai
中科院分区：
文献类型：
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作者：
N. Horikawa;Tomoyuki Suzuki;T. Uchiumi;T. Minamimura;K. Tsukada;N. Takeguchi;H. Sakai
血栓素 A2 (TXA2) 释放增加已被证明与炎症性肠病有关。在本研究中，我们研究了稳定的 TXA2 类似物 (STA2) 对离体人结肠粘膜电参数的影响。在 Ussing 室之间的人体粘膜中，STA2 以浓度依赖性方式刺激 Cl− 分泌，EC50 为 0.06 μm。 STA2 诱导的 Cl− 分泌可被特异性 TXA2 受体拮抗剂 ONO-3708 (10 μm) 显着抑制。 STA2 (0.3 μm) 的作用与获得组织的结肠段（从盲肠到直肠）无关。 Chromanol 293B 是一种 cAMP 依赖性 KvLQT1 通道抑制剂，可减弱 STA2 诱导的人结肠粘膜 Cl− 分泌（IC50 值为 1.18 μm）。我们发现 KvLQT1 mRNA 和蛋白质在人类结肠的所有测试片段中都有表达。 STA2 诱导的 Cl- 分泌被膜渗透性 cAMP 拮抗剂 8-溴-2'-单丁酰基腺苷-3',5'-环状单硫代磷酸酯 (50 μm) 显着抑制。 STA2 (0.3 μm) 显着增加人结肠细胞系中的细胞内 cAMP 水平和通过 TXA2 受体的短路电流。这些结果表明，除了先前报道的 Ca2+-钙调蛋白途径之外，TXA2 诱导的结肠中 Cl− 分泌还通过 cAMP 途径介导。
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 μm. The STA2‐induced Cl− secretion was significantly inhibited by ONO‐3708 (10 μm), a specific TXA2 receptor antagonist. The effect of STA2 (0.3 μm) 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 μm). 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 μm), a membrane‐permeant cAMP antagonist. STA2 (0.3 μm) 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.