l-663536 and Stomach-Ulcer

The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B4 release ex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B4 antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin. Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.

Topics: Administration, Oral; Animals; Benzopyrans; Female; Indazoles; Indoles; Indomethacin; Injections, Subcutaneous; Leukotriene Antagonists; Leukotriene B4; Microscopy, Electron; Pyloric Antrum; Rats; SRS-A; Stomach Ulcer

Studies in pigs and rats were undertaken to explore further the role of leukotrienes following administration of NSAIDs on the development of gastrointestinal damage. Increased leukotriene C4 production occurred in the gastric circulation in the early stages after administration of a single dose of indomethacin (10 mg/kg i.g.) to pigs. Gastric and intestinal mucosal lesions by NSAIDs were prevented by both prior (2-5 h)+ 0.25 or 0h oral dosing of the 5-lipoxygenase inhibitor, MK-886, but not when only one of these doses was given. These results show the importance of enhanced peptidoleukotriene production in relation to microvascular damage from cyclooxygenase inhibition by NSAIDs.

Topics: Administration, Oral; Animals; Arthritis; Aspirin; Female; Gastric Mucosa; Indoles; Indomethacin; Injections, Subcutaneous; Intestinal Mucosa; Leukotriene Antagonists; Leukotriene C4; Lipoxygenase Inhibitors; Rats; Rats, Inbred Lew; Stomach; Stomach Ulcer; Swine

Intragastric ethanol stimulates mucosal formation of leukotriene C4 in the rat stomach. The present study demonstrates that the increase in leukotriene C4 formation begins within 30 seconds and is maximal within 5 minutes, closely paralleled by the appearance of hemorrhagic lesions. Leukotriene C4 formation returns to prechallenge levels within 3 hours, although erosions still persist. Intragastric 0.2N NaOH, acidified 100 mmol/L taurocholate, 25% NaCl, or 0.6N HCl did not consistently increase leukotriene C4 formation despite severe mucosal injury. A number of sulfhydryl-containing or sulfhydryl-blocking agents as well as metals protected against mucosal damage and simultaneously prevented the stimulation of leukotriene C4 formation induced by ethanol. None of the agents increased and some virtually abolished mucosal formation of prostaglandin E2, indicating that gastroprotection can occur completely independently of the endogenous prostaglandin system. The leukotriene biosynthesis inhibitor MK-886 markedly suppressed gastric leukotriene C4 formation but did not protect against damage caused by ethanol, NaOH, NaCl, or acidified taurocholate. Oral indomethacin reduced the ex vivo formation of both prostaglandin E2 and, to a lesser extent, leukotriene C4 in the gastric mucosa, inducing a shift in the balance from protective prostaglandins to proulcerogenic leukotriene C4. Pretreatment with MK-886, however, did not significantly diminish indomethacin-induced lesions. These data suggest that leukotriene C4 is not the exclusive mediator of gastric injury caused by necrotizing agents or indomethacin. On the other hand, certain protective compounds exhibit a striking parallelism between protection and inhibition of ethanol-induced leukotriene C4 formation, suggesting that they may affect a target crucial for both mucosal injury and stimulation of 5-lipoxygenase.

Topics: Animals; Arachidonate 5-Lipoxygenase; Dinoprostone; Ethanol; Gastric Mucosa; Indoles; Indomethacin; Leukotriene Antagonists; Male; Necrosis; Rats; Rats, Inbred Strains; Sodium Chloride; Sodium Hydroxide; SRS-A; Stomach Ulcer; Taurocholic Acid