EFFECT OF RAMOSETRON ON SHORT-CIRCUIT CURRENT RESPONSE IN RAT COLONICMUCOSA

We investigated the effects of ramosetron (YM060, 3-yl)carbonyl]-4,5,6 ,7-tetrahydro-1H-benzimidazole monohydrochloride) on the short-circuit current (I-sc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT3 receptor antago nists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased I-sc. The I-sc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 methylsulphonyl)ami no]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate). 2-M ethyl-5-HT and 5-methoxytryptamine also increased I-sc. The former res ponse was inhibited by ramosetron, and the latter was abolished by GR1 13808. Ramosetron, YM114 (KAE-393, 5-[(1-indolinyl)carbonyl]-4,5,6,7-1 H-benzimidazole monohydrochloride) and granisetron concentration-depen dently antagonized the I-sc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA(2) value s for these antagonists were 10.40, 10.37 and 8.99, respectively. Onda nsetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA(2) value of 8.53. These results sug gest that 5-HT increases I-sc through the 5-HT3 and 5-HT4 receptors, a nd that ramosetron is a potent and selective 5-HT3 receptor antagonist in rat colonic mucosa.