Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock.
Leukotrienes are one of the biological mediators that play a role in endotoxic shock. In this study, we investigated the effects of a leukotriene biosynthesis inhibitor, MK-886, in a rabbit model of endotoxic shock. Lipopolysaccharide (Escherichia coli serotype 055:B5) infusion (1 mg kg(-1) h(-1)) to rabbits caused a biphasic decline in arterial blood pressure and decreased the vasoresponsiveness to phenylephrine, potassium chloride, sodium nitroprusside and acetylcholine in abdominal aortic rings. Oral administration of MK-886 (3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl(-2,2-+ ++dimethylpropanoic acid) (5 mg/kg) 3 h prior to lipopolysaccharide infusion significantly inhibited the decline in arterial blood pressure and enhanced the responsiveness to phenylephrine and acetylcholine, whereas the changes in sodium nitroprusside and potassium chloride responses were not significant. However, the pD2 (-log EC50) values for sodium nitroprusside in this group were higher than those of the group that received lipopolysaccharide alone. Neither the administration of the vehicle alone to endotoxemic rabbits, nor MK-886 administration to control animals, caused significant changes. These data suggest that MK-886 attenuates the hypotension and partially reverses the impaired vascular responsiveness observed in endotoxic shock.
Department of Pharmacology, Faculty of Medicine, Ege University, Turkey. cenkcan@med.ege.edu.tr
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D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D012772:Shock, Septic / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002722:Chlorobenzenes
D004731:Endotoxins; D007211:Indoles; D015289:Leukotrienes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D009599:Nitroprusside; D010656:Phenylephrine; D014662:Vasoconstrictor Agents; C060893:MK-886; D002722:Chlorobenzenes; C044101:endotoxin, Escherichia coli