E. Fujii et al., Evaluation of iNOS-dependent and independent mechanisms of the microvascular permeability change induced by lipopolysaccharide, BR J PHARM, 130(1), 2000, pp. 90-94
1 Subcutaneous injection of lipopolysaccharide (LPS) increases plasma leaka
ge in mouse skin. Pretreatment with LPS conditions mice tolerant to the LPS
-induced plasma leakage. Nitric oxide (NO) has been suggested to be involve
d in these LPS effects. A specific role of inducible NO synthase (iNOS) was
investigated in the LPS-induced plasma leakage using iNOS deficient mice.
2 Plasma leakage in mouse skin was measured by the local accumulation of Po
ntamine sky blue at the site of subcutaneous injection of LPS (Sal. typhimu
rium). LPS (100-400 mu g site(-1)) produced a dose-related increase in dye
leakage in both iNOS deficient and wild-type mice with about 40% less dye l
eakage in iNOS deficient mice.
3 Indomethacin (5 mg kg(-1)), N-[-2-cyclohexyloxy]-4-nitrophenyl methanesul
phonamide (NS-398) (1 mg kg(-1)), diphenhydramine (10 mg kg(-1)) and anti-T
NF-alpha antibody (dilution 1:400, 10 mi kg(-1)) inhibited the LPS-induced
dye leakage in both iNOS deficient and wild-type mice, whereas N-G-nitro-L-
arginine methyl ester (L-NAME) (10 mg kg(-1)) or aminoguanidine (10 mg kg(-
1)) inhibited that in wild-type but not in INOS deficient mice.
4 Pretreatment with LPS (0.15 mg kg(-1) i.p.)4 h before decreased the LPS-i
nduced dye leakage in wild-type but not in iNOS deficient mice. LPS pretrea
tment increased serum corticosterone levels in both mice, while it increase
d the serum nitrate/nitrite levels in wild-type but not in iNOS deficient m
ice.
5 These studies indicate that an increase in vascular permeability induced
by LPS is mediated by NO produced by iNOS, eicosanoids, histamine and TNF-a
lpha. The tolerance against LPS-induced vascular permeability change may be
mediated by INOS induction but not by an increased release of endogenous c
orticosteroids.