The role of the 5-HT4 receptor in Cl- secretion in human jejunal mucosa

5-Hydroxytryptamine (5-HT) is a mediator of chloride ion (Cl-) secretion in the intestine which can be seen as a rise in short circuit current (I-sc) in the Ussing chamber model. We investigated the 5-HT receptor mediating 5-HT-induced Cl- secretion in the human jejunum in vitro. Jejunal segments obtained from patients having gastric bypass surgery for obesity, were stripped of muscularis and mounted in Ussing chambers and short-circuited. The 5-HT receptor agonist-induced change (Delta) in I-sc was recorded in the presence and absence of 5-HT receptor antagonists. The rank order of agonist potency was: 5-HT > 5-methoxytryptamine > renzapride (BRL 24924) > alpha-methyl-5-HT > > 2-methyl-5-HT. In the presence of Cl--free media or 100 mu M furosemide, 5-HT-induced Delta I-sc was significantly reduced. It was also antagonized by greater than or equal to 1 mu M tropisetron (a 5-HT3/5-HT4 receptor antagonist) and greater than or equal to 10 nM GR 113808 (a selective 5-HT4 receptor antagonist) with pA(2) values of 6.5 and 7.9, respectively. Another 5-HT4 receptor antagonist, SC 53606 (0.1 mu M), antagonized the 5-HT-induced response with a pA(2) of 7.3. 5-HT1-like/5-HT2 (methysergide), 5-HT1P [N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP)], 5-HT2A (ketanserin) and 5-HT3 (ondansetron) receptor antagonists and tetrodotoxin, had no significant effect bn the EC(50) for 5-HT. In conclusion, this study demonstrates that in the human muscle-stripped jejunum in vitro, 5-HT induced change in short circuit current is mediated by a 5-HT4 receptor via a non-neural pathway.