Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy

The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model. One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin (20 mg/kg per os). Three hours after indomethacin, the extent of macroscopically visible gastric damage was determined, and gastric LTB₄ synthesis was determined. The compounds tested were PF-5901, A-64077, nordihydroguaiaretic acid, and L-698,037. Each compound produced dose-related inhibition of gastric LTB₄ synthesis and a parallel reduction in the severity of indomethacin-inducec damage. The antioxidant properties of these compounds was assessed using an in vitro assay. There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage. In the second part of the study, the effects of intravenous administration of LTD₄ and LTB₄ receptor antagonists on indomethacin-induced gastric epithelial damage (measured by permeability to ⁵¹Cr]EDTA) were assessed. The two LTD₄ receptor antagonists (MK-571 and ICI-204,219) significantly reduced the permeability changes induced by indomethacin, while the two LTB₄ antagonists (SC-41930 and LY-255,283) were without significant effect. Despite the reduction of gastric epithelial injury, blockade of LTD₄ receptors did not markedly affect the extent of macroscopically visibls injury. These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs. However, it remains unclear to what extent leukotrienes are involved in the initiation of the injury, as opposed to its amplification.