EFFECT OF FK1052, A POTENT 5-HYDROXYTRYPTAMINE(3) AND 5-HYDROXYTRYPTAMINE4 RECEPTOR DUAL ANTAGONIST, ON COLONIC FUNCTION IN-VIVO

5-Hydroxytryptamine (5-HT) is an important neurotransmitter and hormon e/paracrine agent mediating various enteric functions. Its precise phy siological and pathophysiological role remains unclear. This study inv estigated the effects of 5-HT on colonic function and the effects of t he newly developed 5-HT3 and 5HT4 receptor antagonist, FK1052, on colo nic responses to 5-HT or stress stimulus in vivo. In conscious rats, b oth 5-HT and 5-methoxytrytamine significantly increased fecal pellet o utput and accelerated colonic transit. In contrast, the effect of 2-me thyl-5-HT was slight. Although ondansetron and granisetron slightly re duced 5-HT (1 mg/kg s.c.) stimulated colonic transit, FK1052 imidazoly l)methyl]pyr-ido-[1,2-a]-indole-6(7H)-one hydrochloride}, at 0.1 mg/kg p.o., inhibited completely the increases in the colonic transit. Furt hermore, FK1052, ondansetron and granisetron significantly depressed t he increase in fecal pellet output caused by wrap-restraint stress, wi th ED50 values of 0.21, 3.0 and 1.1 mg/kg p.o., respectively. Intraper itoneal administration of 5-HT and 5-methoxytrytamine, but not 2-methy l-5-HT, produced a dose-related increase in the incidence of diarrhea in fasted mice. 5-HT (0.32 mg/kg i.p.)-induced diarrhea was also inhib ited by FK1052, ondansetron and granisetron, with ED50 values of 0.09, 2.3 and 0.88 mg/kg p.o., respectively. These findings suggest that 5- HT3 and 5-HT4 receptors may have an important role in colonic function and FK1052 may have therapeutic potential in the treatment of gastroi ntestinal dysfunction such as irritable bowel syndrome.