Evidence for a 5-HT4 Receptor Pathway Mediating Chloride Secretion in the Rat Distal Colon

Serotonin (5-HT) is a potent secretagogue of chloride ion (Cl-) and a mediator of diarrhea in the carcinoid syndrome. We investigated the role of the 5-HT4 receptor pathway in mediating 5-HT-induced Cl- secretion that is seen as a rise in short circuit current (ISC) in the Ussing chamber. Rat distal colon was stripped of the muscularis, mounted in Ussing chambers, and short circuited. By cumulative concentration responses, 5-HT-induced rise in ISC was measured in the presence and absence of 0.1 μM of the nerve conduction blocker, tetrodotoxin (TTX). TTX was later added routinely to remove any effects of residual nerve tissue. 5-HT concentration response was measured in the presence and absence of the following 5-HT receptor antagonists: 10 μM 5-HTP-DP (5-HT1p), 1 μM methysergide (5-HT1-like and 5-HT2), 0.1 μM ketanserin (5-HT2), 0.3 μM ondansetron (5-HT3) 0.1, 0.5, 1 and 3 μM ICS 205-930 (5-HT3 and 5-HT4), and 0.1, 0.03, and 0.01 μM of the new selective 5-HT4 antagonist, SC 53606. Data were analyzed by ANOVA. TTX had no effect on EC50 for 5-HT. ICS 205-930 and SC 53606 produced dextral shifts in 5-HT concentration-response curves and at all concentrations a significant shift in the EC50 for 5-HT, except at 0.1 μM ICS 205-930. The Schild plot slopes for ICS 205-930 (0.8) and SC 53606 (0.7) were not significantly different from unity. The pA2 values were 6.5 and 7.2, respectively. Methysergide, ketanserin, ondansetron, and 5-HTP-DP had no significant effect on the EC50 for 5-HT. These results suggest that the 5-HT4 receptor pathway mediates 5-HT-induced Cl- secretion.