Pathogenic mechanisms involved in mepirizole-induced duodenal damage in the rat.
Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 micrograms/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3- secretion, stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 micrograms/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3- secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1 alpha in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.
D015064:16,16-Dimethylprostaglandin E2 / Q000633:toxicity; D015121:6-Ketoprostaglandin F1 alpha / Q000633:toxicity; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D004381:Duodenal Ulcer / Q000139:chemically induced* / Q000503:physiopathology; D004840:Epirizole / Q000633:toxicity*; D005750:Gastric Juice / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D001639:Bicarbonates; D011453:Prostaglandins; D011720:Pyrazoles; D004840:Epirizole; D015121:6-Ketoprostaglandin F1 alpha; D015064:16,16-Dimethylprostaglandin E2