Decrease in alkaline secretion during duodenal ulceration induced by mepirizole in rats.
The mechanisms by which the potent antiinflammatory agent, mepirizole, causes duodenal ulceration were investigated in the rat. After subcutaneous administration of 200 mg/kg of mepirizole, basal gastric acid secretion remained unchanged for 5 h but duodenal alkaline output, reliably measured, decreased significantly (p less than 0.05) within 2 h. The decrease was maximal (-45%) at 3 h and persisted for a total of 6 h. The duodenal alkaline secretion returned to near normal by 24 h. A dose-response study showed that the threshold ulcerogenic dose of mepirizole (30 mg/kg) did not significantly reduce alkaline secretion, whereas higher doses did. Plasma levels of immunoreactivity of gastrin, pancreatic polypeptide, vasoactive intestinal polypeptide, and secretin were not changed at either 6 or 24 h after oral mepirizole. Vasoactive intestinal peptide levels in the duodenal mucosa were increased by 158% at 24 h after administration. Secretin levels in the duodenal mucosa were decreased by greater than 60% at both 6 and 24 h after drug treatment. Intravenous secretin (1 CU/kg X h) had no effect on duodenal alkaline secretion in either saline- (154 mM NaCl) or mepirizole-treated animals. Exogenous 16,16-dimethyl prostaglandin E2 (10 micrograms/kg X h, i.v.) reversed the action of mepirizole on duodenal alkaline secretion. These findings suggest that mepirizole causes a reduction in duodenal alkaline secretion that can be reversed by administration of an exogenous prostaglandin.
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000468:Alkalies / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism*; D004840:Epirizole / Q000008:administration & dosage / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D007279:Injections, Subcutaneous; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012633:Secretin / Q000097:blood; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000097:blood
D000468:Alkalies; D005755:Gastrins; D011720:Pyrazoles; D012633:Secretin; D014660:Vasoactive Intestinal Peptide; D004840:Epirizole; D015064:16,16-Dimethylprostaglandin E2