The pharmacological properties of the novel selective 5‐HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat
- 1 June 1999
- journal article
- research article
- Published by Wiley in Neurogastroenterology & Motility
- Vol. 11 (3), 207-217
- https://doi.org/10.1046/j.1365-2982.1999.00148.x
Abstract
The purpose of this study was to investigate the pharmacological properties of the novel, selective 5‐HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration‐dependently inhibited radioligand binding in membranes containing rat and human 5‐HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5‐HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i.v. administration of alosetron inhibited 2‐methyl‐5‐HT induced bradycardia (Bezold Jarisch index) at 1 and 3 μg kg–1, with an agonist dose ratio of approximately 3.0 at 1.0 μg kg–1, = 3–5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120–60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5‐HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.Keywords
This publication has 28 references indexed in Scilit:
- Review article: irritable bowel syndromeAlimentary Pharmacology & Therapeutics, 1997
- 5-HT4 receptors are not involved in the control of small intestinal transit in the fasted conscious ratNeurogastroenterology & Motility, 1996
- Altered rectal perception is a biological marker of patients with irritable bowel syndromeGastroenterology, 1995
- Granisetron and Ondansetron: Effects on the Ileal Brake Mechanism in the RatJournal of Pharmacy and Pharmacology, 1993
- Review article: 5‐hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implicationsAlimentary Pharmacology & Therapeutics, 1992
- Diagnostic value of the Manning criteria in irritable bowel syndrome.Gut, 1989
- The effect of food protein-induced intestinal anaphylaxis on rate of transitCanadian Journal of Physiology and Pharmacology, 1989
- Accurate measurement of intestinal transit in the ratJournal of Pharmacological Methods, 1981
- [3H]Para-amino-clonidine: A novel ligand which binds with high affinity to α-adrenergic receptorsLife Sciences, 1979
- Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndromeGut, 1973