The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

Background: The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives: To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS) in different regions of the rat intestine. Materials and Methods: Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results: EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist) and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist), methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist) there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist) induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions: The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions. Keywords: Electric Stimulation Therapy; Serotonin 5-HT1 Receptor Antagonists; Intestine, Smal

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 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 \u3c 0.05 was significant. The chloride- free solution and furosemide significantly (p \u3c 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