EVIDENCE FOR A 5-HT4 RECEPTOR PATHWAY MEDIATING CHLORIDE SECRETION INTHE 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 ro le of the 5-HT4 receptor pathway in mediating B-HT-induced Cl- secreti on that is seen as a rise in short circuit current (I-sc) in the Ussin g chamber. Rat distal colon was stripped of the muscularis, mounted in Ussing chambers, and short circuited. By cumulative concentration res ponses, 5-HT-induced rise in I-sc was measured in the presence and abs ence of 0.1 mu M 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 a bsence of the following 5-HT receptor antagonists: 10 mu M 5-HTP-DP (5 -HT1p), 1 mu M methysergide (5-HT1-like and 5-HT2), 0.1 mu M ketanseri n (5-HT2), 0.3 mu M ondansetron (5-HT3) 0,1, 0.5, 1 and 3 mu M ICS 205 -930 (5-HT3 and 5-HT4), and 0.1, 0.03, and 0.01 mu M of the new select ive 5-HT4 antagonist, SC 53606. Data were analyzed by ANOVA. TTX had n o effect on EC(50) for 5-HT. ICS 205-930 and SC 53606 produced dextral shifts in 5-HT concentration-response curves and at all concentration s a significant shift in the EC(50) for 5-HT, except at 0.1 mu MICS 20 5-930. The Schild plot slopes for ICS 205-930 (0.8) and SC 53606 (0.7) were not significantly different from unity. The pA(2) values were 6. 5 and 7.2, respectively. Methysergide, ketanserin, ondansetron, and 5- HTP-DP had no significant effect on the EC(50) for 5-HT. These results suggest that the 5-HT4 receptor pathway mediates 5-HT-induced Cl- sec retion. (C) 1994 Academic Press, Inc.