Jl. Turvill et al., The inhibition of cholera toxin-induced 5-HT release by the 5-HT3 receptorantagonist, granisetron, in the rat, BR J PHARM, 130(5), 2000, pp. 1031-1036
1 The secretagogue 5-hydroxytryptamine (5-MT) is implicated in the pathophy
siology 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 condi
tions, modulate 5-HT release. These include basolateral 5-HT3 receptors, th
e activation of which is known to enhance 5-HT release.
3 Until now, 5-HT3 receptor antagonists (e.g. granisetron) have been though
t to inhibit cholera toxin-induced fluid secretion by blockading 5-HT3 rece
ptors 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-treat
ed 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 mo
vement was determined by small intestinal perfusion or gravimetry and small
intestinal and luminal fluid 5-HT levels were determined by HPLC with fluo
rimetric detection.
5 Intraluminal 5-HT release was proportional to the reduction in tissue 5-H
T levels and to the onset of water and electrolyte secretion, suggesting th
at luminal 5-HT levels reflect enterochromaffin cell activity.
6 Both lidocaine and granisetron inhibited fluid secretion. However, granis
etron alone, and proportionately, reduced 5-HT release.
7 The simultaneous inhibition of 5-HT release and fluid secretion by granis
etron suggests that 5-HT release from enterochromaffin cells is potentiated
by endogenous 5-MT, accentuated 5-HT release promotes cholera toxin-induce
d fluid secretion.