Effect of E3040, an inhibitor of 5-lipoxygenase and thromboxane synthase, on rat bowel damage induced by lipopolysaccharide

Intravenous administration of lipopolysaccharide to rats that had been immu nized with lipopolysaccharide induced hemorrhagic damage in the large intes tine. We investigated the role of 5-lipoxygenase and thromboxane synthase p roducts in the damage of the large intestine induced by lipopolysaccharide. In the large intestine of lipopolysaccharide-immunized rats, intravenous i njection of lipopolysaccharide increased the vascular permeability, product ion of leukotriene B-4, leukotriene C-4/D-4, thromboxane B-2 and prostaglan din E-2 and also increased the activity of myeloperoxidase, a marker enzyme of neutrophils. Oral administration of E3040 (6-hydroxy-5,7-dimethyl-2-(me thylamino)-4-(3-pyridylmethyl)benzothiazole), a novel dual inhibitor of 5-l ipoxygenase and thromboxane synthase, at 30 and 100 mg/kg inhibited the inc rease in vascular permeability induced by lipopolysaccharide in the large i ntestine. E3040 inhibited the production of leukotriene B-4 and thromboxane B-2 and tended to increase the production of prostaglandin E-2 in the larg e intestine. Sulfasalazine (500 mg/kg) and prednisolone (10 mg/kg), drugs u sed for the treatment of inflammatory bowel disease, had no significant eff ect on eicosanoid production and vascular permeability, These results indic ate that E3040 inhibits the production of both leukotriene B-4 and thrombox ane B-2 and prevents lipopolysaccharide-induced damage in the large intesti ne of lipopolysaccharide-immunized rats. (C) 2001 Elsevier Science B.V. All rights reserved.