Investigations of indomethacin-induced gastric ulcer in rats.
The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulceration is still not completely understood, but it is possible that these effects are associated with a cytoprotective prostaglandin deficiency. Visible marks of gastric mucosa erosions induced by 25 mg/kg indomethacin in rats were determined parallel with the changes of PGE2, PGI2, TxA2 and leukotrienes content in gastric mucosa at various intervals. Beside the decreased level of the so-called cytoprotective prostaglandins caused by the inhibition of cyclooxygenase enzyme an overproduction of 5-lipoxygenase products (leukotrienes) was also found. To investigate the hypothesis that the gastric damage caused by NSAIDs is due not only to the decreased level of cyclooxygenase products but to the increased level of lipoxygenase products as well, different lipoxygenase inhibitors and leukotriene antagonists were tested. A lipoxygenase inhibitor and the structurally similar phenidone inhibited the ulcerogenic effect of indomethacin at the same high dose range. The selective lipoxygenase inhibitor nordihydroquaiaretic acid and dual inhibitors can reduce the severity of ulcer formation in lower concentrations as well. The first specific antagonist of SRS-A and a potent and selective antagonist of LTD4 produced a significant gastroprotective effect at i.p. treatment only at high doses. All of these results suggest that an overproduction of leukotrienes and other lipoxygenase products, following cyclooxygenase blockade induced by NSAIDs, may play a role in the development of gastric mucosal damage.
Kapui
Z
Z
Research Centre of Chinoin Pharmaceutical and Chemical Works Ltd., Budapest, Hungary.
Boér
K
K
Rózsa
I
I
Blaskó
G
G
Hermecz
I
I
D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology; D013928:Thromboxane A2 / Q000378:metabolism
D015777:Eicosanoids; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013928:Thromboxane A2; D011464:Epoprostenol; D015232:Dinoprostone; D007213:Indomethacin