Effect of FK1052, a potent 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptor dual antagonist, on colonic function in vivo

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 266; no. 1; pp. 74 - 80
• Main Authors: KADOWAKI, M, NAGAKURA, Y, TOMOI, M, MORI, J, KOHSAKA, M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.07.1993
• Subjects: Animals; Biological and medical sciences; Colon - drug effects; Colon - physiology; Diarrhea - chemically induced; Diarrhea - drug therapy; Digestive system; Gastrointestinal Transit - drug effects; Gastrointestinal Transit - physiology; Imidazoles - pharmacology; Indoles - pharmacology; Male; Medical sciences; Mice; Mice, Inbred Strains; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - physiology; Serotonin - pharmacology; Serotonin - physiology; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Stimulation, Chemical; Stress, Physiological - etiology; Stress, Physiological - physiopathology; Animal model; Serotonin; Serotonin antagonist; Interspecific comparison; Diarrhea; Gastrointestinal; Stress; Digestive transit; Chemotherapy; Treatment; Animal; S4 receptor; S3 receptor; Digestive diseases; Intestinal disease; Colon
• ISSN: 0022-3565; 1521-0103

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.