Cyclic AMP‐dependent Cl − secretion induced by thromboxane A 2 in isolated human colon

Increased release of thromboxane A 2 (TXA 2 ) has been shown to be involved in inflammatory bowel diseases. In the present study, we have investigated the effect of a stable TXA 2 analogue (STA 2 ) on the electrical parameters in isolated human colonic mucosa. In the human mucosa set between Ussing chambers, STA 2 stimulated Cl − secretion in a concentration‐dependent manner with an EC 50 of 0.06 μ m . The STA 2 ‐induced Cl − secretion was significantly inhibited by ONO‐3708 (10 μ m ), a specific TXA 2 receptor antagonist. The effect of STA 2 (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 STA 2 ‐induced Cl − secretion in the human colonic mucosa (IC 50 value 1.18 μ m ). We found that KvLQT1 mRNA and protein were expressed in all the tested segments of the human colon. The STA 2 ‐induced Cl − secretion was significantly inhibited by 8‐bromo‐2′‐monobutyryladenosine‐3′,5′‐cyclic monophosphorothioate (50 μ m ), a membrane‐permeant cAMP antagonist. STA 2 (0.3 μ m ) significantly increased the intracellular cAMP levels and the short‐circuit current via TXA 2 receptor in a human colonic cell line. These results suggest that the TXA 2 ‐induced Cl − secretion in the colon is mediated via the cAMP pathway in addition to the Ca 2+ –calmodulin pathway which was previously reported.