Bile acids induce secretion throughout the intestinal tract and are actively absorbed via a Na+-dependent mechanism in the terminal ileum. UDCA is used clinically for the hepatic symptoms of CF and this study investigated UDCA action in the small intestine of normal (Swiss) and transgenic CF (Cftrtm2Cam) mice.
Paired sheets of stripped mid-intestine and ileum, removed from mice killed humanely, were mounted in Ussing chambers (0.5 cm2 aperture) and test agents added to the mucosal (M) and/or serosal (S) solution.
In mid-intestine from Swiss mice UDCA (1 mM, M) increased the short-circuit current (SCC) by 38 ± 2 (83) µA cm-2 (mean ± 1 S.E.M.). Absence of Cl– (gluconate), 10-3 M furosemide (S) or 5 Ω 10-4 M DPC (M) reduced this response by 51 ± 19 (8), 81 ± 5 (6) and 55 ± 8 (6)%, respectively (P < 0.05 in each case, paired t test), consistent with a stimulation of electrogenic Cl– secretion. In the ileum UDCA (1 mM, M) caused a biphasic rise in SCC with a rapid initial peak of 32 ± 1 (92) µA cm-2, followed by a more gradual increase of 55 ± 2 (92) µA cm-2. The initial response was decreased by 33 ± 8 (6) % (P < 0.01) when the mucosal Na+ concentration was reduced to 25 mM. The second phase was unaffected by low Na+, but inhibited by absence of Cl–, furosemide or DPC (by 57 ± 6 (8), 69 ± 14 (6) and 44 ± 12 (6)%, respectively, P < 0.05 in each case). This suggests that the first phase represents Na+-dependent bile acid absorption and the second phase electrogenic Cl– secretion.
Doxantrazole (10-3 M, M+S) abolished the UDCA-induced SCC in the mid-intestine (P < 0.001, n = 7) and reduced the secretory component in the ileum by 50 ± 16 (6)% (P < 0.05), but cromolyn (10-3 M, M+S) had no effect (P > 0.05, n = 6-7), so mucosal mast cells may contribute to UDCA-induced secretion. Mepyramine (10-4 M, S) or desensitization to 5-HT (10-4 M, S) inhibited (P < 0.05 in each case) UDCA-induced secretion in both mid-intestine (43 ± 6 (8)%; 80 ± 7 (7)%) and ileum (30 ± 11 (8)%; 44 ± 9 (7)%), but indomethacin (5 Ω 10-5 M, S), tetrodotoxin (10-5 M, S) and desensitization to substance P (10-6 M, S) did not (P > 0.05, n = 5-8).
In mid-intestine from CF mice UDCA (1 mM, M) did not increase the SCC (-9 ± 2 (9) µA cm-2). In the ileum it caused an initial peak (29 ± 4 (13) µA cm-2) that was reduced by 80 ± 17 (5)% (P < 0.01) with low mucosal Na+, but there was no second phase (-5 ± 3 (13) µA cm-2). Responses in tissues from wild-type littermates were similar to those observed in intestine from Swiss mice.
UDCA induces Cl– secretion in both the mid-intestine and ileum of the mouse with histamine and 5-HT contributing to the response. UDCA-induced secretion is absent in CF tissues. In the ileum Na+-dependent absorption also generates a SCC, but this is not reduced in CF.