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 e ndotoxic shock. In this study, we investigated the effects of a leukot riene biosynthesis inhibitor, MK-886, in a rabbit model of endotoxic s hock. Lipopolysaccharide (Escherichia coli serotype 055:B5) infusion ( 1 mg kg(-1) h(-1)) to rabbits caused a biphasic decline in arterial bl ood pressure and decreased the vasoresponsiveness to phenylephrine, po tassium chloride, sodium nitroprusside and acetylcholine in abdominal aortic rings. Oral administration of MK-886 -thio-5-isopropylindol-2-y l(-2,2-dimethylpropanoic acid) (5 mg/kg) 3 h prior to lipopolysacchari de infusion significantly inhibited the decline in arterial blood pres sure and enhanced the responsiveness to phenylephrine and acetylcholin e, whereas the changes in sodium nitroprusside and potassium chloride responses were not significant. However, the pD(2) (-log EC50) values for sodium nitroprusside in this group were higher than those of the g roup that received lipopolysaccharide alone. Neither the administratio n of the vehicle alone to endotoxemic rabbits, nor MK-886 administrati on to control animals, caused significant changes. These data suggest that MK-886 attenuates the hypotension and partially reverses the impa ired vascular responsiveness observed in endotoxic shock. (C) 1998 Els evier Science B.V. All rights reserved.