Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1.
We previously reported that inhibition of both COX-1 and COX-2 is required for the gastrointestinal ulcerogenic properties of nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-1 up-regulates COX-2 expression, and the prostaglandins (PGs) produced by COX-2 help to maintain the mucosal integrity during inhibition of COX-1. In the present study we investigated whether dexamethasone damages rat gastrointestinal mucosa during inhibition of COX-1 and further developed the idea that COX-2 expression is a key event in the ulcerogenic actions of NSAIDs. Dexamethasone was given p.o. in the absence or presence of SC-560 (a selective COX-1 inhibitor), and the stomach or intestine was examined 8 or 24 hr later, respectively. Neither dexamethasone nor SC-560 alone damaged the gastrointestinal mucosa. In the presence of SC-560, however, dexamethasone damaged the stomach but not small intestine. SC-560 decreased PGE(2) levels in both tissues, with a gradual recovery accompanying the up-regulation of COX-2 expression, and both the recovery of PGE(2) levels and the expression of COX-2 were inhibited by dexamethasone. In the animals treated with SC-560, iNOS expression was up-regulated in the intestinal but not the gastric mucosa, and this response was also inhibited by dexamethasone. These results suggest a risk from steroid therapy in the stomach when COX-2 expression is up-regulated. Dexamethasone does not provoke damage in the intestine, despite inhibiting the up-regulation of COX-2 expression under conditions of PG deficiency; at least one of the reasons is that this agent prevents the expression of iNOS, a major factor in the pathogenesis of intestinal lesions.
Yokota
Aya
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Taniguchi
Masaki
M
Takahira
Yuka
Y
Tanaka
Akiko
A
Takeuchi
Koji
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000009:adverse effects*; D015232:Dinoprostone / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D000897:Anti-Ulcer Agents; D016861:Cyclooxygenase Inhibitors; D018727:Muscarinic Antagonists; D011720:Pyrazoles; C115461:SC 560; D001285:Atropine; D003907:Dexamethasone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D009853:Omeprazole