Gastroenterology

Gastroenterology

Volume 115, Issue 4, October 1998, Pages 883-890
Gastroenterology

Alimentary Tract
Crucial role for 5-HT in cholera toxin but not Escherichia coli heat-labile enterotoxin-intestinal secretion in rats,☆☆

https://doi.org/10.1016/S0016-5085(98)70260-4Get rights and content

Abstract

Background & Aims: Many consider cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) to be functionally identical. Both increase intracellular adenosine 3',5'-cyclic monophosphate concentration; however, differences between the two and the severity of the diseases they cause have been reported. The secretagogue 5-hydroxytryptamine (5-HT) is implicated in CT-induced secretion, but its role in LT-induced secretion is unclear. We tested the hypothesis that LT fails to recruit 5-HT in its secretory processes. Methods: In vivo small intestinal perfusions were undertaken in adult male Wistar rats after incubation with equipotent doses of CT or LT, or saline. Small intestinal 5-HT release and the effect on net small intestinal water and electrolyte transport of (1) pharmacological depletion of 5-HT; (2) blockade of 5-HT type 2, 3, and 4 receptors; and (3) pretreatment with lidocaine, hexamethonium, and atropine were determined. Results: CT- but not LT-induced secretion was accompanied by 5-HT release, reduced by 5-HT depletion, and inhibited by each 5-HT antagonist. By contrast, lidocaine and hexamethonium inhibited secretion induced by both toxins. Conclusions: LT induces secretion without recruiting a 5-HT–dependent cascade. This may account for differences in clinical severity of the diseases CT and LT cause and has implications for the development of antisecretory therapies.

GASTROENTEROLOGY 1998;115:883-890

Section snippets

Tissue and luminal release of 5-HT

Experiments were carried out under a Home Office Project Licence. Habituated male adult Wistar rats (180-220 g) were fasted for 18 hours, with free access to water, and anesthetized with sodium pentobarbitone, 60 mg/kg intraperitoneally (IP) plus 10 mg/kg interval injections. Animals were kept at 37°C using a heat pad. After making a midline incision, the whole small intestine was isolated between proximal (5 cm distal to the duodenojejunal flexure) and distal (1-2 cm proximal to the ileocecal

Tissue and luminal release of 5-HT

Both CT and LT induced a gradual change from net intestinal water absorption to secretion over incubation time (Cuzick's test, P < 0.0002). There was no difference in the pattern of onset of secretion between CT and LT (P = 0.13; Figure 1).

. Onset of CT- and LT-induced net water secretion over time. Rats were incubated with CT (2) or LT (▩) for varying periods from 0 to 2 hours. No significant difference in onset of secretion at each time point was noted between CT and LT. Values are expressed

Discussion

The role of 5-HT in CT-induced secretion is well established in both animal and human models and is supported by the demonstration of a close temporal relationship between 5-HT release and the onset of CT-induced secretion.12, 13, 14, 35 The degree of 5-HT release that CT induces is substantial because, after 2 hours of incubation, total tissue levels are reduced by 50%. Numerous physicochemical stimuli, including intestinal distention, induce 5-HT release; however, the small intestinal

Acknowledgements

The authors thank Dr. P. Blower of SmithKline Beecham for assistance, Prof. D. Perrett and Dr. I. James of the Department of Metabolism and Endocrinology, St. Bartholomew's Hospital, and Dr. P. Connor of the Digestive Diseases Research Centre, St. Bartholomew's and The Royal London School of Medicine and Dentistry.

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    Address requests for reprints to: James L. Turvill, M.B., Ch.B., M.R.C.P., Digestive Diseases Research Centre, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Turner Street, London, E1 2AD, England. Fax: (44) 171-295-7192.

    ☆☆

    Supported by an educational grant from SmithKline Beecham Pharmaceuticals.

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