Prostaglandin deficiency by itself is not the cause of mepirizole-induced duodenal ulcers in rats.
The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE2, given at nonantisecretory doses (0.5-5 micrograms/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.
D015064:16,16-Dimethylprostaglandin E2 / Q000008:administration & dosage; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004381:Duodenal Ulcer / Q000209:etiology* / Q000517:prevention & control; D004386:Duodenum / Q000187:drug effects; D004840:Epirizole / Q000633:toxicity*; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects; D011453:Prostaglandins / Q000172:deficiency*; D011720:Pyrazoles / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors
D011453:Prostaglandins; D011720:Pyrazoles; D004840:Epirizole; D015064:16,16-Dimethylprostaglandin E2; D007213:Indomethacin