Novel role of prostacyclin in stress-induced gastric mucosal lesion formation in rats.
We investigated the novel role of prostacyclin (PGI2) in gastric mucosal lesion formation induced by stress in rats. Gastric 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels were significantly increased 30 minutes after water-immersion restraint stress (WIR). Subcutaneous indomethacin (IM) (5 mg/kg) inhibited this increase but significantly exacerbated gastric mucosal lesion formation in rats subjected to WIR. Although gastric myeloperoxidase (MPO) activity was not increased by WIR, it significantly increased with time after WIR in animals pretreated with IM. NS-398, a selective inhibitor of cyclooxygenase-2, did not inhibit the WIR-induced increase in gastric 6-keto-PGF1alpha. Neither the gastric lesion index nor gastric MPO activity were affected in animals pretreated with NS-398 and subjected to WIR. WIR-induced mucosal lesion formation was significantly inhibited in animals given iloprost, a stable analog of PGI2, and in those with nitrogen mustard-induced leukocytopenia. Iloprost prevented the gastric leukocyte accumulation and exacerbation of gastric mucosal lesions induced by IM in animals subjected to WIR. These IM-induced events also were prevented in animals subjected to WIR with nitrogen mustard-induced leukocytopenia. These observations implicate leukocytes in the process leading to gastric mucosal lesions induced by WIR. The increase in WIR-induced gastric PGI2 synthesis, mainly mediated by cyclooxygenase-1, appears important in preventing lesion formation, not only by maintaining gastric mucosal blood flow but also by inhibiting leukocyte activation.
Harada
N
N
Department of Emergency and Critical Care Medicine, School of Medicine, Fukuoka University, Japan.
Okajima
K
K
Murakami
K
K
Uchiba
M
M
Tanaka
K
K
Okabe
H
H
Takatsuki
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000502:physiology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D016285:Iloprost / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008466:Mechlorethamine; D009578:Nitrobenzenes / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D008466:Mechlorethamine; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D009195:Peroxidase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D016285:Iloprost; D007213:Indomethacin