C. Can et al., EFFECTS OF MK-886, A LEUKOTRIENE BIOSYNTHESIS INHIBITOR, IN A RABBIT MODEL OF ENDOTOXIC-SHOCK, European journal of pharmacology, 350(2-3), 1998, pp. 223-228
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.