The effect of nonsteroidal anti-inflammatory drugs on rat gastric mucosa. The role of endothelin.
OBJECTIVE
To investigate the role of endothelin on nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX2) enzyme inhibitors-induced effects on the gastric mucosa.


METHODS
This study was carried out in the Department of Pharmacology Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey during the period January to December 2002. In the first group a cyclooxygenase-1 (COX1) and COX2 enzyme inhibitor, indomethacin (25 mg/kg, subcutaneous injection (s.c), n=7), a selective COX2 enzyme inhibitor, NS398 (10 mg/kg, s.c) and normal saline were administered. In the second group, endothelin-1 (ET1) was administered (200 pmol/kg) alone, in the presence of an endothelin receptor antagonist bosentan, (100 mg/kg) and PGE1 [40 microg/kg, orally] with submucosal injection. In the third group, NS398 and indomethacin were applied in the presence of bosentan. In the fourth group, NS398 were applied in the presence of N (G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg, s.c).


RESULTS
Indomethacin caused gastric mucosal injury. The effect of NS398 on gastric mucosa did not differ considerably from that of the control group. Submucosal injection of ET1 caused a gastric damage, which could not be prevented by intragastric administration of bosentan, while pretreatment with PGE1 prevented ET1-induced ulcer. Pretreatment with bosentan did not attenuate indomethacin-induced gastric mucosal damage but it increased NS398-induced damage by 1.5 fold. Pretreatment with L-NAME increased NS398-induced gastric mucosal damage as bosentan did.


CONCLUSIONS
These results suggest that neither endothelin-induced nor indomethacin-induced ulcer is completely receptor dependent. Cyclooxygenase-2 inhibitors caused ulcer in the presence of bosentan. Protective effects of gastric mucosal injury of COX2 inhibitors may be via endothelin receptor related nitric oxide release.
Murat
Nergis
N
Advanced Professional School of Health Sciences, Dokuz Eylul University, Inciralti, Izmir, Turkey.
Gidener
Sedef
S
Koyuncuoglu
Meral
M
Yilmaz
Osman
O
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D000077300:Bosentan; D007213:Indomethacin