In isolated mucosa of the rat distal colon, we have found that endogenous thromboxane A2 (TXA2) released by anti-tumour drug irinotecan and 9, 11-epithio-11, 12-methano-thromboxane A2 (STA2), a stable TXA2 analogue, induces Cl– secretion (Sakai et al. 1997; 2002). But we do not yet know whether this function of TXA2 is restricted only to rats or if it is also present in human. Herein we investigated the effect of STA2 on the Cl– secretion in isolated human colorectal mucosa.
In accordance with the recommendations of the Declaration of Helsinki, the specimens of the normal mucosa were obtained from surgical resection of patients having colorectal adenocarcinomas. Informed consents were obtained from all patients at Toyama Medical and Pharmaceutical University Hospital. Effects of the chemicals on the short-circuit current (Isc), the potential difference across the mucosa (Pd) and the tissue conductance (Gt) were examined in isolated human colorectal mucosa mounted on Ussing chamber. Data are shown as means ± S.E.M. Differences between groups were analysed by one-way ANOVA. Comparison between the two groups was made with paired t test.
When STA2 (0.3 µM) was added to the serosal side, the Isc increased from 81 ± 11 to 170 ± 15 µA cm-2 (n = 12, P < 0.01), the Pd increased from 8.3 ± 0.9 to 13.0 ± 1.4 mV ( n = 10, P < 0.05), and the Gt increased from 9.8 ± 0.4 to 14.0 ± 0.8 mS cm-2 (n = 10, P < 0.01). The effect of STA2 was not apparently dependent on the location of colorectum (from cecum to rectum). The STA2-induced effect was significantly inhibited by ONO-3708, a TXA2 receptor antagonist (10 µM at the serosal side; n = 4, P < 0.05), NPPB, a Cl– channel blocker (300 µM at the mucosal side; n = 3, P < 0.05), and furosemide (100 µM at the serosal side; n = 4, P < 0.05). In the low-Cl– bathing solution, STA2 increased the Isc only by 7 ± 4 µA cm-2 (n = 4). These results suggest that STA2 induces Cl– secretion via a TXA2 receptor. The STA2 (0.3 µM)-induced Cl– secretion was inhibited by chromanol 293B (3 µM), a cAMP-dependent K+ channel blocker. (P < 0.01; n = 5).
Our results suggest that the TXA2 is an endogenous stimulant of the cAMP-mediated Cl– secretion in human colorectal mucosa.