| Abstrakt: |
The function of serotonin (5‐HT)3receptors 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 μg intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5‐HT3receptor antagonist, aza‐setron {(±)‐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.), and metoclopramide (30 mg/kg, p.o.) did not. Azasetron (10 μg) 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‐HT3receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5‐HT3receptors. Azasetron may improve bowel function in stress‐related colonic dysfunction like irritable bowel syndrome. |
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