Effects of serotonin 5-HT(3) receptor antagonists on CRF-induced abnormal colonic water transport and defecation in rats.
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.
Hirata
Takuya
T
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takuya.hirata@jp.astellas.com <takuya.hirata@jp.astellas.com>
Keto
Yoshihiro
Y
Nakata
Mari
M
Takeuchi
Asako
A
Funatsu
Toshiyuki
T
Akuzawa
Shinobu
S
Sasamata
Masao
M
Miyata
Keiji
K
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D003672:Defecation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014867:Water / Q000378:metabolism*
D000930:Antidiarrheals; D001562:Benzimidazoles; D002227:Carbazoles; D002243:Carbolines; D011725:Pyridines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014867:Water; C090840:alosetron; C084473:cilansetron; D008139:Loperamide; C071315:ramosetron; D003346:Corticotropin-Releasing Hormone