Gastric acid is the key modulator in the pathogenesis of non‐steroidal anti‐inflammatory drug‐induced ulceration in rats

1. In the present study, we investigated the role of gastric acid (GA) secretion on non‐steroidal anti‐inflammatory drug (NSAID)‐induced ulcerogenesis in vivo. Rats were administered single oral doses of selective cyclo‐oxygenase (COX)‐1 (SC‐560; 2.5 mg/kg), COX‐2 (DFU; 25 mg/kg) or non‐selective COX (indomethacin; 25 mg/kg) inhibitors. Three groups (basal, histamine‐stimulated and histamine with lansoprazole) were pylorus ligated 2 h after inhibitor administration and killed 2 h later. Another group without pylorus ligation received only inhibitors and was killed after 18 h.

2. At 4 h, indomethacin increased the ulcer index (UI) and myeloperoxidase (MPO) activity in basal and histamine‐stimulated states, whereas SC‐560 only increased MPO activity. Histamine‐stimulated, but not basal, GA was further enhanced by indomethacin and SC‐560 via increased proton pump expression. Lansoprazole (10 mg/kg) reduced the UI, MPO activity and GA to basal levels with SC‐560 and DFU and to near basal with indomethacin. Indomethacin and SC‐560 significantly inhibited prostaglandin (PG) E₂, without significantly affecting COX‐1 and COX‐2 expression. Although DFU inhibited PGE₂ by one‐third, it did not affect COX expression.

3. At 18 h, indomethacin significantly increased the UI and MPO activity, whereas PGE₂ synthesis was less inhibited, indicating a return to control levels. In contrast, PGE₂ synthesis was higher than control with SC‐560. Furthermore, COX‐2 expression was significantly elevated with indomethacin and SC‐560, explaining the source of augmented PGE₂ synthesis. Proton pump expression remained elevated, comparable with 4 h levels, with indomethacin and SC‐560. However, DFU had no significant effect on the aforementioned parameters.

4. The data suggest that NSAID‐induced ulcerogenesis is dependent on the amount of GA secretion derived from increased proton pump expression and requires inhibition of both COX‐1 and COX‐2.