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

Abstract

1 The secretagogue 5-hydroxytryptamine (5-HT) is implicated in the pathophysiology of cholera. 5-HT released from enterochroman cells after cholera toxin exposure is thought to activate nonneuronally (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. 2 Enterochroman cells possess numerous receptors that, under basal conditions, modulate 5-HT release. 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¯uid secretion by blockading 5-HT 3 receptors on secretory enteric neurones. Instead we postulated that they act by inhibiting cholera toxin-induced enterochroman cell degranulation. 4 Isolated intestinal segments in anaesthetized male Wistar rats, pre-treated with granisetron 75 mg kg 71 , lidoocaine 6 mg kg 71 or saline, were instilled with a supramaximal dose of cholera toxin or saline. Net¯uid movement was determined by small intestinal perfusion or gravimetry and small intestinal and luminal¯uid 5-HT levels were determined by HPLC with¯uorimetric 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 re¯ect enterochroman cell activity. 6 Both lidocaine and granisetron inhibited¯uid secretion. However, granisetron alone, and proportionately, reduced 5-HT release. 7 The simultaneous inhibition of 5-HT release and¯uid secretion by granisetron suggests that 5-HT release from enterochroman cells is potentiated by endogenous 5-HT 3 receptors. The accentuated 5-HT release promotes cholera toxin-induced¯uid secretion.

Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents

“…The 5-HT 1 , 5-HT 3 , and 5-HT 4 receptor subtypes play major roles in motor, sensory, and secretory function of the GI tract [Gershon, 1999]. Intestinal 5-HT release is associated with smooth muscle contraction, increased luminal secretions, and reduced GI transit time [Turvill et al 2000;Ruckebusch and Bardon, 1984]. The blockade of 5HT 3 receptors, notably by antiemetics such as ondansetron, has been observed to result in constipation [Haus et al 2004].…”

Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo

“…One mechanism, for which the evidence is very strong, is concomitant activation of the enteric nervous system. Enteric nervous components directly or indirectly involved with CT's actions are serotonin (5-HT) released from enterochromaffin cells (48), activation of 5-HT 3 receptors (3,4,34,49), activation of intrinsic primary afferent neurons (10), involvement of nicotinic interneurons (6,19), and a contribution of secretomotor neurons releasing vasoactive intestinal peptide (VIP) (5,33). These different components have been well documented in vivo, but the exact neurophysiological mechanisms are not well defined, because there is no good in vitro model as yet.…”

Gut Microbiota: The Conductor in the Orchestra of Immune–Neuroendocrine Communication

“…66,67 Serotonin release from enterochromaffin epithelial cells is stimulated by tryptamine 83 and is a key regulator of the gut motility and secretion. 84 Recently, it has been shown that gut microbiota, acting through SCFAs, is an important determinant of enteric serotonin production and homeostasis. The gut microbiota from ex-GF mice colonized with human gut microbiota and conventionally raised mice the colonic rate limiting for mucosal serotonin synthesis; tryptophan hydroxylase 1 mRNAs as well as the neuroendocrine secretion gene; chromogranin A with no effect on the serotonin transporter or serotonin catabolic gene; monoamine oxidase A.…”