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 immunized with lipopolysaccharide induced hemorrhagic damage in the large intestine. We investigated the role of 5-lipoxygenase and thromboxane synthase products in the damage of the large intestine induced by lipopolysaccharide. In the large intestine of lipopolysaccharide-immunized rats, intravenous injection of lipopolysaccharide increased the vascular permeability, production of leukotriene B(4), leukotriene C(4)/D(4), thromboxane B(2) and prostaglandin E(2), and also increased the activity of myeloperoxidase, a marker enzyme of neutrophils. Oral administration of E3040 (6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole), a novel dual inhibitor of 5-lipoxygenase and thromboxane synthase, at 30 and 100 mg/kg inhibited the increase in vascular permeability induced by lipopolysaccharide in the large intestine. E3040 inhibited the production of leukotriene B(4) and thromboxane B(2) and tended to increase the production of prostaglandin E(2) in the large intestine. Sulfasalazine (500 mg/kg) and prednisolone (10 mg/kg), drugs used for the treatment of inflammatory bowel disease, had no significant effect on eicosanoid production and vascular permeability. These results indicate that E3040 inhibits the production of both leukotriene B(4) and thromboxane B(2) and prevents lipopolysaccharide-induced damage in the large intestine of lipopolysaccharide-immunized rats.
Oketani
K
K
Tsukuba Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai-5-chome, Tsukuba, Ibaraki 300-2635, Japan. k-oketani@hhc.eisai.co.jp
Inoue
T
T
Murakami
M
M
D000818:Animals; D052160:Benzothiazoles; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011239:Prednisolone / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012460:Sulfasalazine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D052160:Benzothiazoles; D015777:Eicosanoids; D005765:Gastrointestinal Agents; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D013844:Thiazoles; C095803:E 3040; D007975:Leukotriene B4; D012460:Sulfasalazine; D013929:Thromboxane B2; D011239:Prednisolone; D013930:Thromboxane-A Synthase; D015232:Dinoprostone