The function of 5-HT3 receptors on colonic transit in rats.
The function of serotonin (5-HT)3 receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 microgram intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro- 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ; 0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), did not. Azasetron (10 micrograms) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome.
Haga
K
K
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Asano
K
K
Fukuda
T
T
Kobayakawa
T
T
D000818:Animals; D001286:Atropine Derivatives / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003106:Colon / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D012149:Restraint, Physical; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013312:Stress, Physiological; D013779:Tetrodotoxin / Q000494:pharmacology
D001286:Atropine Derivatives; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008762:Methylhistidines; D010078:Oxazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D009388:Neostigmine; D013779:Tetrodotoxin; C070671:azasetron; C006649:methylatropine; D003346:Corticotropin-Releasing Hormone