Effect of GK-128 [2-[(2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one monohydrochloride hemihydrate], a selective 5-hydroxytryptamine3 receptor antagonist, on colonic function in rats.
We investigated the effects of various selective 5-hydroxytryptamine (5-HT)3 receptor antagonists, including GK-128 [2-[(2-methylimidazol-1-yl)methyl]benzo[f]thiochromen-1-one monohydrochloride hemihydrate], on colonic function. In conscious rats, 5-HT and a 5-HT3 receptor agonist, 2-methyl-5-HT, dose-dependently increased fecal pellet output, but another 5-HT3 receptor agonist, m-chlorophenylbiguanide, did not affect output. The selective 5-HT3 receptor antagonists GK-128, granisetron, ramosetron, azasetron and ondansetron depressed the increase in fecal pellet output caused by 2-methyl-5-HT and by wrap-restraint stress. However, the rank order of potency of antagonists in the two defecation models was not consistent with that for the von Bezold-Jarisch reflex. Although granisetron and ramosetron dose-dependently reduced the spontaneous excretion of fecal pellets, GK-128 did not affect it. These results suggest that GK-128 may be used for the treatment of stress-induced gastrointestinal dysfunction. Furthermore, the present results suggest that the 5-HT3 receptor involved in colonic motility may be different from the classically defined 5-HT3 receptor and/or that the regulation of colonic motility mediated by 5-HT3 receptors during stress may be different from normal physiological conditions.
Ito
C
C
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Isobe
Y
Y
Kawamura
R
R
Kiuchi
Y
Y
Tsuchida
K
K
Higuchi
S
S
D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003672:Defecation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000145:classification / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D002867:Chromones; C097458:GK 128; D007093:Imidazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists