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Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C 4 and prostanoid release: relation to ethanol‐induced injury
Author(s) -
Peskar B.M.,
Hoppe U.,
Lange K.,
Peskar B.A.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11483.x
Subject(s) - prostanoid , pharmacology , leukotriene , chemistry , gastric mucosa , leukotriene d4 , ethanol , medicine , prostaglandin , stomach , biochemistry , asthma
1 The effects of oral and subcutaneous administration of the non‐steroidal anti‐inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C 4 (LTC 4 ) prostaglandin E 2 (PGE 2 ), 6‐oxo‐PGF 1α and thromboxane B 2 (TXB 2 ) were investigated in rats under basal conditions as well as after challenge with ethanol. 2 Basal release of PGE 2 , 6‐oxo‐PGF 1α and TXB 2 was inhibited by oral administration of aspirin (0.6–400 mg kg −1 ) and indomethacin (4 or 20 mg kg −1 ), but not by sodium salicylate (up to 400 mg kg −1 ), in a dose‐dependent manner. Oral administration of aspirin in the dose range 3.2–400 mg kg −1 and of indomethacin (20 mg kg −1 ) additionally inhibited release of LTC 4 , while sodium salicylate (up to 400 mg kg −1 ) had no effect. Indomethacin (20 mg kg −1 ) and aspirin (400 mg kg −1 ) administered subcutaneously inhibited generation of cyclo‐oxygenase products of arachidonate metabolism, but did not significantly affect LTC 4 synthesis. 3 Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC 4 from rat gastric mucosa, while release of cyclo‐oxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanol‐stimulated gastric mucosal LTC 4 release in a dose‐dependent manner. Sodium salicylate had no effects on the release of PGE 2 and TXB 2 , while that of 6‐oxo‐PGF 1α was slightly increased. 4 Pretreatment with indomethacin (4 or 20 mg kg −1 p.o.) or aspirin in doses up to 25 mg kg −1 p.o. prior to oral instillation of ethanol did not inhibit gastric mucosal damage and had no effect on the stimulatory action of ethanol on LTC 4 release. Higher doses of aspirin (100 mg kg −1 or 400 mg kg −1 p.o.) reduced the mucosal damaging effect of ethanol and simultaneously inhibited LTC 4 release. 5 The results suggest that aspirin and indomethacin in concentrations higher than those necessary to inhibit the cyclo‐oxygenase pathway of arachidonate metabolism additionally inhibit gastric mucosal LTC 4 synthesis under basal conditions, while sodium salicylate has no such effect. On the other hand, sodium salicylate, but not indomethacin or low doses of aspirin (up to 25 mg kg −1 ), by an unknown mechanism inhibits stimulation of LTC 4 biosynthesis by ethanol and simultaneously protects the gastric mucosa against ethanol‐induced damage. Similar effects of high oral doses (> 100 mg kg −1 ) of aspirin might be due to significant formation of salicylate. These results suggest that there is a causal relationship between enhanced LTC 4 biosynthesis and the development of ethanol‐induced gastric injury.