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.