Inhibition of cholera toxin-induced intestinal secretion by the 5-HT3 receptor antagonist ICS 205-930.

The secretory effect of cholera toxin on the gut has been ascribed to the activation of submucosal 5-hydroxytryptamine receptors by 5-hydroxytryptamine released from the enterochromaffin cells. The hypothesis that neuronally located 5-HT3 receptors are involved in cholera toxin-induced diarrhoea has now been tested. Intestinal secretion was stimulated in mice by oral administration of pure cholera toxin and the effects of ICS 205-930, a potent and selective antagonist at 5-HT3 receptors, and of ketanserin, a compound that blocks 5-HT2 receptors, were investigated. Oral administration of cholera toxin resulted in a significant accumulation of fluid in the intestine. Pretreatment of the animals with ICS 205-930 partly prevented this effect and a maximal reduction of about 50% was achieved with doses of 0.3 mg/kg i.p. and higher. Ketanserin had only minimal effects up to a high dose of 1 mg/kg i.p. when a 20% reduction of fluid accumulation was seen. The data support the view that activation of 5-HT3 receptors plays a major role in the secretory effect of cholera toxin in the gut.