Cyclic AMP-dependent Cl- secretion induced by thromboxane A2 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 microm. The STA(2)-induced Cl- secretion was significantly inhibited by ONO-3708 (10 microm), a specific TXA(2) receptor antagonist. The effect of STA(2) (0.3 microm) 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 microm). 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 microm), a membrane-permeant cAMP antagonist. STA(2) (0.3 microm) 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.