Healing of duodenal ulcers is not impaired by indomethacin or rofecoxib, the selective COX-2 inhibitor, in rats.
OBJECTIVE
Studies have demonstrated an important role for endogenous PG and NO in the healing of chronic gastric ulcers. We investigated the effects of COX and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric ulcers, in rats.


METHODS
Gastric and duodenal ulcers were induced by serosal application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s, respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days after ulcer induction, while N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS inhibitor) was given s.c. twice daily during this period.


RESULTS
Both gastric and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to a minimal size. Daily administration of indomethacin or rofecoxib significantly delayed the healing of gastric but not duodenal ulcers. In contrast, the healing of both gastric and duodenal ulcers was delayed by repeated administration of either L-NAME or aminoguanidine. Ulceration markedly increased the PGE(2) content of the ulcerated mucosa in both the stomach and duodenum, and the increased PG biosynthetic response was inhibited by either indomethacin or rofecoxib in both tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the ulcerated mucosa of the stomach and duodenum.


CONCLUSIONS
These results suggest that COX-2/PG is actively involved in the healing of gastric but not duodenal ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after ulceration, as potently as in the gastric mucosa. In contrast, NO produced by both cNOS and iNOS plays a role in the healing of both gastric and duodenal ulcers.
Araki
Hideo
H
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Komoike
Yusaku
Y
Matsumoto
Masahiro
M
Tanaka
Akiko
A
Takeuchi
Koji
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004381:Duodenal Ulcer / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000503:physiopathology; D013450:Sulfones; D014945:Wound Healing / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin