Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C₄ and prostanoid release: relation to ethanol‐induced injury

Abstract

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 C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGFl, and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2 Basal release of PGE2, 6-oxo-PGF 1. and TXB2 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 400mg kg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400mgkg-' and of indomethacin (20mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400mg kg -1) had no effect. Indomethacin (20mg kg-1) and aspirin (400mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3 Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclooxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanolstimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGFe was slightly increased. 4 Pretreatment with indomethacin (4 or 20mg kg-p.o.) or aspirin in doses up to 25mg 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 LTC4 release. Higher doses of aspirin (100mgkg-1 or 400mgkg-1 p.o.) reduced the mucosal damaging effect of ethanol and simultaneously inhibited LTC4 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 LTC4 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 25mg kg 1), by an unknown mechanism inhibits stimulation of LTC4 biosynthesis by ethanol and simultaneously protects the gastric mucosa against ethanol-induced damage. Similar effects of high oral doses (> 100mgkg-1) of aspirin might be due to significant formation of salicylate. These results suggest that there is a causal relationship between enhanced LTC4 biosynthesis and the development of ethanol-induced gastric injury.

Eicosanoid and gastroprotection by copper derivatives and NDGA

“…These data are similar to the findings of other authors who showed a relationship between ethanol-induced gastric mucosal damage in vivo and increase in mucosally-synthesize LTC4 with no change in 6-keto-PGFl~ [12,13]. Pretreatment of rats with graded doses of NDGA, CuNSN and CuC12 protects against gastric mucosal injury caused by ethanol.…”

“…In rats, oral instillation of ethanol induces a concentration-dependent increase in the ex-vivo release of LTC4 from gastric mucosal parallel to the production of haemorrhagic mucosal lesions while prostaglandin formation is not significantly affected [12][13][14]. Inhibition of gastric LTC4 formation by compounds such as sodium salicylate [13], cysteamine [15], carbenoxolone, nordihydroguaiaretic acid (NDGA) [12], is accompanied by protection against ethanol-induced gastric mucosal injury.…”

“…Inhibition of gastric LTC4 formation by compounds such as sodium salicylate [13], cysteamine [15], carbenoxolone, nordihydroguaiaretic acid (NDGA) [12], is accompanied by protection against ethanol-induced gastric mucosal injury. It has been suggested that LTC4 release may be involved in ethanol-induced mucosal damage, by causing stasis of blood flow in the gastric mucosal microvasculature [12], even though it doesn't seem to be the primary mediator of acute damage [16].…”

Effect of ethanol on eicosanoid synthesis by human gastric and colonic mucosal pieces

“…Ethanol caused a concentration-dependent increase in the ex vivo or in vitro release of LTC4 from the rat gastric mucosa (Peskar et al, 1986; Boughton-Smith & Whittle, 1988a,b); prostaglandin formation was not significantly affected (Boughton-Smith & Whittle, 1988a;Peskar et al, 1988). Inhibition of gastric LTC4 formation by compounds such as sodium salicylate (Peskar et al, 1988), 16,16-dimethyl PGE2 (Boughton-Smith & Whittle, 1988a), cysteamine or diethyl maleate (Lange et al, 1987), carbenoxolone or nordihydroguaiaretic acid, protected the rat gastric mucosa against ethanol-induced damage (Peskar et al, 1986); again prostaglandin release was not significantly affected (Boughton-Smith & Whittle, 1988a;Peskar et al, 1988).…”

“…Inhibition of gastric LTC4 formation by compounds such as sodium salicylate (Peskar et al, 1988), 16,16-dimethyl PGE2 (Boughton-Smith & Whittle, 1988a), cysteamine or diethyl maleate (Lange et al, 1987), carbenoxolone or nordihydroguaiaretic acid, protected the rat gastric mucosa against ethanol-induced damage (Peskar et al, 1986); again prostaglandin release was not significantly affected (Boughton-Smith & Whittle, 1988a;Peskar et al, 1988).…”