cilansetron and ramosetron

The effects of corticotropin releasing factor (CRF) and serotonin (5-HT)(3) receptor antagonists on intestinal water transport are not well understood. Hence, we established a CRF-induced abnormal water transport model in rat colon, and evaluated the effects of 5-HT(3) receptor antagonists including ramosetron, alosetron, and cilansetron, and the antidiarrheal agent loperamide, in this model. In addition, the effects of 5-HT(3) receptor antagonists and loperamide on abnormal defecation induced by CRF in rats were examined. Colonic water transport was measured in colonic loops in conscious rats. Centrally administered CRF (3-30 microg/kg) markedly decreased colonic fluid loss, whereas oral administration of ramosetron (3, 30 microg/kg), alosetron (300 microg/kg), cilansetron (300 microg/kg), or loperamide (3 mg/kg) significantly inhibited it. Ramosetron (1-10 microg/kg), alosetron (10-100 microg/kg), cilansetron (10-100 microg/kg), or loperamide (0.3-3 mg/kg) also showed dose-dependent inhibition of CRF-induced defecation in rats. These results suggest that 5-HT(3) receptors are involved in both abnormal colonic water transport and defecation induced by CRF, and that the inhibitory effects of 5-HT(3) receptor antagonists on CRF-induced abnormal defecation partly result from their ameliorating action on colonic water transport.

Topics: Animals; Antidiarrheals; Benzimidazoles; Carbazoles; Carbolines; Colon; Corticotropin-Releasing Hormone; Defecation; Dose-Response Relationship, Drug; Injections, Intraventricular; Loperamide; Male; Pyridines; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Water

We examined the pharmacological profile of ramosetron, a 5-HT(3)-receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT(3)-receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT(3) receptors, with K(i) values of 0.091 +/- 0.014 and 0.22 +/- 0.051 nmol/L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT(3) receptor was extremely slow (t(1/2) = 560 min), while alosetron (t(1/2) = 180 min) and cilansetron (t(1/2) = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA(2) values of 8.6 (8.5 - 9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED(50) value of 1.2 (0.93 - 1.6) microg/kg. In addition, oral ramosetron dose-dependently inhibited restraint stress-induced defecation in rats, with an ED(50) value of 0.62 (0.17 - 1.2) microg/kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT(3)-receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.

Topics: Animals; Benzimidazoles; Carbazoles; Carbolines; Carrier Proteins; Colon; Defecation; Gastrointestinal Agents; Guinea Pigs; Humans; Ion Channels; Irritable Bowel Syndrome; Loperamide; Male; Muscle, Smooth; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Restraint, Physical; Serotonin Antagonists; Stress, Psychological

The aim of this study was to establish a pathophysiologic model of irritable bowel syndrome, and then to evaluate the pharmaceutical efficacy of ramosetron, a potent serotonin 3 (5-HT(3)) receptor antagonist, and other anti-irritable bowel syndrome agents in this model. Rats stressed by a conditioned stress procedure exhibited marked prolongation of freezing time, an index of fear level, and an increase in the frequency of defecation (P<0.01). A corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF, inhibited both defecation and freezing behavior, while the antidiarrheal loperamide inhibited defecation only. The 5-HT(3) receptor antagonists ramosetron, cilansetron and alosetron also inhibited defecation (ED(50) values: 0.012, 0.094, 0.078 mg/kg p.o., respectively) without affecting freezing behavior. Ramosetron showed longer-lasting effect on defecation than cilansetron. Stress also resulted in increases in both proximal and distal colonic transit rates. Ramosetron and other 5-HT(3) receptor antagonists at doses inhibiting stress-induced defecation also ameliorated both stress-stimulated colonic transit rates. These results suggest that ramosetron, as well as agents used for the treatment of irritable bowel syndrome with diarrhea, has beneficial effects against emotional stress-induced colonic dysfunction. Furthermore, this emotional stress model may be useful in evaluation of drugs to treat irritable bowel syndrome presenting with diarrhea.

Topics: Animals; Behavior, Animal; Benzimidazoles; Carbazoles; Carbolines; Colon; Colonic Diseases, Functional; Conditioning, Psychological; Corticotropin-Releasing Hormone; Defecation; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Gastrointestinal Transit; Immobilization; Irritable Bowel Syndrome; Loperamide; Male; Peptide Fragments; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological; Time Factors; Treatment Outcome