THE 5-HT4 RECEPTOR MEDIATES 5-HYDROXYTRYPTAMINE-INDUCED RISE IN SHORT-CIRCUIT CURRENT IN THE HUMAN JEJUNUM IN-VITRO

Background. 5-Hydroxytryptamine (5-HT) is a potent intestinal secretog ogue 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 o f this study was to determine which 5-HT receptors mediate a 5-HT-indu ced change in I-sc in the human jejunum.Methods. Segments of jejunum o btained 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 Isc was measured in the presence or absence of 0.2 mu mol/L of neural cond uction inhibitor tetrodotoxin or 5-HT receptor antagonists (n = 4 to 5 ): 10 mu mol/L 5-HTP-DP, a 5-HT1p antagonist; 0.1 mu mol/L ketanserin, a 5-HT2 antagonist; 0.3 mu mol/L ondansetron, a 5-HT3 antagonist; 0.0 5 and 1 mu mol/L ICS 205-930, a selective 5-HT3 antagonist at 0.05 mu mol/L and also a 5-HT4 antagonist at 1 mu mol/L or more; and 0.01 mu m ol/L GR 113803, a new selective 5-HR(4) antagonist. A chloride-free so lution or furosemide (100 mu mol/L) was used to show the relationship of a 5-HT-induced change in Isc to chloride secretion. Results. Data w ere analyzed by ANOVA; p < 0.05 was significant. The chloride-free sol ution and furosemide significantly (p < 0.05) depressed the maximum ch ange in I-sc. Significant shifts occurred in the median effective conc entration (1.5 +/- 0.2 mu mol/L) for 5-HT in the presence of 1 mu mol/ L ICS 205-930 (3 +/- 0.2) and 0.03 mu mol/L GR 113808 (2.4 +/- 0.2), b ut not in the presence of 5-HTP-DP (1.2 +/- 0.4), methysergide (1.8 +/ - 0.3), ketanserin (2.4 +/- 0.6), odanosetron (1.6 +/- 0.1), 0.05 mu m 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 medi ated through a tetrodotoxin-insensitive pathway by the 5-HT4 receptor. Antagonists to this receptor may be useful in the treatment of diarrh ea in carcinoid syndrome.