The role of acid in the pathogenesis of indomethacin-induced gastric antral ulcers in the rat.
BACKGROUND
The role of acid in the pathogenesis of indomethacin-induced ulcers of the rat gastric antrum was studied by comparing the effects of pretreating animals with both long-acting (loxtidine, AH22216) and short-acting (ranitidine and cimetidine) inhibitors of acid secretion.


RESULTS
Ranitidine and cimetidine were much weaker at inhibiting antral damage when compared to their reported potencies as antisecretory agents. In marked contrast, loxtidine and AH22216 inhibited indomethacin-induced antral ulcers at doses similar to their reported potencies as inhibitors of acid secretion. Histological analysis at doses causing near maximal inhibition of macroscopic damage revealed an almost complete absence of ulcers but a large and significant increase in mucosal damage due to superficial erosions. Hourly dosing with hydrochloric acid reversed the protective effect of ranitidine, cimetidine and loxtidine on macroscopic damage and, histologically, this was associated with the widespread appearance of antral ulcers and a reduction in the proportion of mucosal damage caused by superficial erosions.


CONCLUSIONS
The results of this study suggest that the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced antral ulcers involves at least two stages: (1) an initial acid-independent formation of mucosal erosions followed by (2) an acid-dependent conversion of erosions to frank ulcers. Clinically, drugs that suppress acid completely for long periods may be very effective in preventing NSAID-induced gastric antral ulcers.
Clayton
N M
NM
Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, UK.
Oakley
I
I
Williams
L V
LV
Trevethick
M A
MA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D000897:Anti-Ulcer Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002927:Cimetidine / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006851:Hydrochloric Acid / Q000633:toxicity*; D007213:Indomethacin / Q000633:toxicity*; D011706:Pyloric Antrum / Q000473:pathology; D011899:Ranitidine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D014230:Triazoles; C039993:loxtidine; D002927:Cimetidine; D011899:Ranitidine; D006851:Hydrochloric Acid; D007213:Indomethacin