Effect of FK1052, a potent 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptor dual antagonist, on colonic function in vivo.
5-Hydroxytryptamine (5-HT) is an important neurotransmitter and hormone/paracrine agent mediating various enteric functions. Its precise physiological and pathophysiological role remains unclear. This study investigated the effects of 5-HT on colonic function and the effects of the newly developed 5-HT3 and 5-HT4 receptor antagonist, FK1052, on colonic responses to 5-HT or stress stimulus in vivo. In conscious rats, both 5-HT and 5-methoxytryptamine significantly increased fecal pellet output and accelerated colonic transit. In contrast, the effect of 2-methyl-5-HT was slight. Although ondansetron and granisetron slightly reduced 5-HT (1 mg/kg s.c.) stimulated colonic transit, FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl)methyl]pyrido- [1,2-a]-indole-6(7H)-one hydrochloride], at 0.1 mg/kg p.o., inhibited completely the increases in the colonic transit. Furthermore, FK1052, ondansetron and granisetron significantly depressed the increase in fecal pellet output caused by wrap-restraint stress, with ED50 values of 0.21, 3.0 and 1.1 mg/kg p.o., respectively. Intraperitoneal administration of 5-HT and 5-methoxytryptamine, but not 2-methyl-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 inhibited 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 gastrointestinal dysfunction such as irritable bowel syndrome.
Kadowaki
M
M
Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Nagakura
Y
Y
Tomoi
M
M
Mori
J
J
Kohsaka
M
M
D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013268:Stimulation, Chemical; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology
D007093:Imidazoles; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081308:FK 1052; D012701:Serotonin