Effect of ramosetron on short-circuit current response in rat colonic mucosa.
We investigated the effects of ramosetron (YM060, (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) on the short-circuit current (Isc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT3 receptor antagonists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased Isc. The Isc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 ([[1-[(2-methyl-sulphonyl) amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1 H-indole-3-carboxylate). 2-Methyl-5-HT and 5-methoxytryptamine also increased Isc. The former response was inhibited by ramosetron, and the latter was abolished by GR113808. Ramosetron, YM114 (KAE-393, (-)-(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) and granisetron concentration-dependently antagonized the Isc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.40, 10.37 and 8.99, respectively. Ondansetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA2 value of 8.53. These results suggest that 5-HT increases Isc through the 5-HT3 and 5-HT4 receptors, and that ramosetron is a potent and selective 5-HT3 receptor antagonist in rat colonic mucosa.
Kiso
T
T
Pharmacology Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Ito
H
H
Miyata
K
K
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology*; D004347:Drug Interactions; D004594:Electrophysiology; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D001562:Benzimidazoles; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C042390:alpha-methylserotonin; D012701:Serotonin; D018738:Hexamethonium; D013779:Tetrodotoxin; C071315:ramosetron