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

Open Access
Publisher Website
Google Scholar
Abstract
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‐HT2 dependent) and neuronally (5‐HT3 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. These include basolateral 5‐HT3 receptors, the activation of which is known to enhance 5‐HT release. 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. Isolated intestinal segments in anaesthetized male Wistar rats, pre‐treated with granisetron 75 μg 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. 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. Both lidocaine and granisetron inhibited fluid secretion. However, granisetron alone, and proportionately, reduced 5‐HT release. 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‐HT3 receptors. The accentuated 5‐HT release promotes cholera toxin‐induced fluid secretion. British Journal of Pharmacology (2000) 130, 1031–1036; doi:10.1038/sj.bjp.0703414