verlukast and Stomach-Ulcer

Studies were performed in three models of acute gastric mucosal damage (induced by oral ethanol, aspirin and indomethacin) and a model of chronic gastritis (induced by 7 day treatment with iodoacetamide) in rats to establish the role of leukotrienes (LTs) in the pathogenesis of these lesions. The protective effects of highly selective 5-lipoxygenase (5-LO) inhibitors and leukotriene antagonists were thus examined in rats given these ulcerogens. Ethanol (1 mL, p.o.)-induced haemorrhagic lesions were significantly reduced by prior oral administration of the 5-LO inhibitor L-656224 (50 mg/kg), whereas lower doses of this drug were ineffective. Prior treatment with oral doses (5 and 10 mg/kg) of the 5-LO inhibitor L-655224 or the LT antagonists L-649923 or L-660711, failed to affect lesions induced by aspirin (100 mg/kg, p.o.) and indomethacin (400 mg/kg, s.c.), whereas higher doses of all three drugs (50 mg/kg) showed protective effects. Repeated prior dosing up to 5 h with the novel five lipoxygenase activating protein (FLAP) inhibitor, MK886 (50 and 100 mg/kg), reduced the lesions developed by indomethacin (30 mg/kg, s.c.). Twice daily dosing with the 5-LO inhibitor L-656224 (5 mg/kg) or the LT antagonist L-649923 (2 or 5 mg/kg) for 7 days significantly reduced the development of iodoacetamide-induced gastritis during the period of induction of this condition, but higher doses of these inhibitors were not protective. We conclude that 5-LO products partially mediate the production of gastric mucosal lesions induced by damaging agents, which varies according to the ulcer model employed; the limited protective effects of the respective 5-LO inhibitors and LT antagonists depend on their individual pharmacokinetics and their time of dosing.

Topics: Animals; Aspirin; Benzofurans; Ethanol; Female; Gastritis; Indomethacin; Iodoacetamide; Leukotriene D4; Leukotrienes; Lipoxygenase Inhibitors; Peptic Ulcer Hemorrhage; Phenylbutyrates; Propionates; Quinolines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

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-induced 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 visible 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.

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Benzopyrans; Carrier Proteins; Free Radical Scavengers; Gastric Mucosa; Hydroxyurea; Indoles; Indomethacin; Leukotriene Antagonists; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Masoprocol; Membrane Proteins; Organic Chemicals; Permeability; Phenylcarbamates; Propionates; Quinolines; Rats; Rats, Inbred Strains; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; Single-Blind Method; Stomach Ulcer; Sulfonamides; Tetrazoles; Tosyl Compounds

The role of endothelin, an endothelium-derived constricting factor, as a mediator of gastric ulceration was assessed using an ex vivo gastric chamber model in the rat. The rats were pretreated with indomethacin, and endothelin was infused intravenously or intra-arterially at various doses while the stomach was topically "challenged" with 20% ethanol. This concentration of ethanol did not, by itself, produce hemorrhagic damage in the stomach. However, infusion of endothelin rendered the mucosa vulnerable to damage induced by the ethanol. In a dose-dependent manner, endothelin increased the extent of hemorrhagic damage and the efflux of protein from the gastric mucosa. The effects of endothelin were less marked in rats not pretreated with indomethacin. The ulcerogenic actions of endothelin were not significantly affected by pretreatment with a platelet-activating factor antagonist or a leukotriene D4 antagonist. However, topical pretreatment with sodium nitroprusside produced a significant reduction in the damage induced by intravenous endothelin and topically applied ethanol. Endothelin also rendered the stomach vulnerable to damage induced by hydrochloric acid at a concentration (0.15 M) tolerated by control mucosa. Using an in vitro vascularly perfused rat stomach preparation, we found that endothelin produces marked increases in gastric vascular tone at nanomolar concentrations. These results suggest that the factors regulating the release of endothelin, and the balance between endothelial production of relaxing and contracting factors, may be important in the pathogenesis of ulcerative diseases of the stomach.

Topics: Animals; Blood Pressure; Diterpenes; Dose-Response Relationship, Drug; Endothelins; Endothelium, Vascular; Ethanol; Ginkgolides; Hydrochloric Acid; Indomethacin; Lactones; Male; Nitroprusside; Peptic Ulcer Hemorrhage; Peptides; Platelet Activating Factor; Propionates; Quinolines; Rats; Rats, Inbred Strains; SRS-A; Stomach; Stomach Ulcer; Vasoconstriction