The inhibition of cholera toxin-induced 5-HT release by the 5-HT3 receptor antagonist, granisetron, in the rat

被引:44
作者
Turvill, JL [1 ]
Connor, P [1 ]
Farthing, MJG [1 ]
机构
[1] St Batholomews & Royal London Sch Med & Dent, Digest Dis Res Ctr, London E1 2AD, England
关键词
cholera toxin; small intestine; water transport; 5-hydroxytryptamine; granisetron;
D O I
10.1038/sj.bjp.0703414
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The secretagogue 5-hydroxytryptamine (5-MT) is implicated in the pathophysiology of cholera. 5-HT released from enterochromaffin cells after cholera toxin exposure is thought to activate non-neuronally (5-HT2 dependent) and neuronally (5-HT3 dependent) mediated water and electrolyte secretion. CT-secretion can be reduced by preventing the release of 5-MT. 2 Enterochromaffin cells possess numerous receptors that, under basal conditions, modulate 5-HT release. These include basolateral 5-HT3 receptors, the activation of which is known to enhance 5-HT release. 3 Until now, 5-HT3 receptor antagonists (e.g. granisetron) have been thought to inhibit cholera toxin-induced fluid secretion by blockading 5-HT3 receptors on secretory enteric neurones. Instead we postulated that they act by inhibiting cholera toxin-induced enterochromaffin cell degranulation. 4 Isolated intestinal segments in anaesthetized male Wistar rats, pre-treated with granisetron 75 mu g kg(-1), lidoocaine 6 mg kg(-1) or saline, were instilled with a supramaximal dose of cholera toxin or saline. Net fluid movement was determined by small intestinal perfusion or gravimetry and small intestinal and luminal fluid 5-HT levels were determined by HPLC with fluorimetric detection. 5 Intraluminal 5-HT release was proportional to the reduction in tissue 5-HT levels and to the onset of water and electrolyte secretion, suggesting that luminal 5-HT levels reflect enterochromaffin cell activity. 6 Both lidocaine and granisetron inhibited fluid secretion. However, granisetron alone, and proportionately, reduced 5-HT release. 7 The simultaneous inhibition of 5-HT release and fluid secretion by granisetron suggests that 5-HT release from enterochromaffin cells is potentiated by endogenous 5-MT, accentuated 5-HT release promotes cholera toxin-induced fluid secretion.
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页码:1031 / 1036
页数:6
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