The 5-HT4 receptor mediates 5-hydroxytryptamine-induced rise in short circuit current in the human jejunum in vitro

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Journal Article

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Background. 5-Hydroxytryptamine (5-HT) is a potent intestinal secretogogue for chloride and a mediator of diarrhea in the carcinoid syndrome. 5-HT- induced chloride secretion is seen as a change in short circuit current (I(sc)) in muscle-stripped, chambered human jejunum. The aim of this study was to determine which 5-HT receptors mediate a 5-HT-induced change in I(sc) in the human jejunum. Methods. Segments of jejunum obtained from patients (n = 23) having obesity surgery were stripped of muscularis, and the mucosal sheets were mounted in flux chambers and short-circuited. By a cumulative method, a 5-HT-induced change in I(sc) was measured in the presence or absence of 0.2 μmol/L of neural conduction inhibitor tetrodotoxin or 5-HT receptor antagonists (n = 4 to 5): 10 μmol/L 5-HTP-DP, a 5-HT(1p) antagonist; 0.1 μmol/L ketanserin, a 5-HT2 antagonist; 0.3 μmol/L ondansetron, a 5-HT3 antagonist; 0.05 and 1 μmol/L ICS 205-930, a selective 5-HT3 antagonist at 0.05 μmol/L and also a 5-HT4 antagonist at 1 μmol/L or more; and 0.01 μmol/L GR 113808, a new selective 5-HT4 antagonist. A chloride-free solution or furosemide (100 μmol/L) was used to show the relationship of a 5-HT-induced change in I(sc) to chloride secretion. Results. Data were analyzed by ANOVA; p < 0.05 was significant. The chloride- free solution and furosemide significantly (p < 0.05) depressed the maximum change in I(sc). Significant shifts occurred in the median effective concentration (1.5 ± 0.2 μmol/L) for 5-HT in the presence of 1 μmol/L ICS 205-930 (3 ± 0.2) and 0.03 μmol/L GR 113808 (2.4 ± 0.2), but not in the presence of 5-HTP-DP (1.2 ± 0.4), methysergide (1.8 ± 0.3), ketanserin (2.4 ± 0.6), ondansetron (1.6 ± 0.1), 0.05 μm ICS 205-930 (1.3 ± 0.1), or tetrodotoxin (1.4 ± 0.4). Conclusions. In the human jejunum in vitro, a 5- HT-induced change in I(sc) is mediated through a tetrodotoxin-insensitive pathway by the 5-HT4 receptor. Antagonists to this receptor may be useful in the treatment of diarrhea in carcinoid syndrome.

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