The inhibition of cholera toxin-induced 5-HT release by the 5-HT(3) receptor antagonist, granisetron, in the rat

Br J Pharmacol. 2000 Jul;130(5):1031-6. doi: 10.1038/sj.bjp.0703414.

Abstract

1. The secretagogue 5-hydroxytryptamine (5-HT) is implicated in the pathophysiology of cholera. 5-HT released from enterochromaffin cells after cholera toxin exposure is thought to activate non-neuronally (5-HT(2) dependent) and neuronally (5-HT(3) dependent) mediated water and electrolyte secretion. CT-secretion can be reduced by preventing the release of 5-HT. Enterochromaffin cells possess numerous receptors that, under basal conditions, modulate 5-HT release. 2. These include basolateral 5-HT(3) receptors, the activation of which is known to enhance 5-HT release. 3. Until now, 5-HT(3) receptor antagonists (e.g. granisetron) have been thought to inhibit cholera toxin-induced fluid secretion by blockading 5-HT(3) 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 microg 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-HT(3) receptors. The accentuated 5-HT release promotes cholera toxin-induced fluid secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholera Toxin / antagonists & inhibitors*
  • Electrolytes / metabolism
  • Granisetron / pharmacology*
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Lidocaine / pharmacology
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / physiology
  • Receptors, Serotonin, 5-HT3
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology*

Substances

  • Electrolytes
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin
  • Cholera Toxin
  • Lidocaine
  • Granisetron