ROLE OF NITRIC-OXIDE AND PROSTAGLANDINS IN LIPOPOLYSACCHARIDE-INDUCEDINCREASE IN VASCULAR-PERMEABILITY IN MOUSE SKIN

To examine the possible role of increased vascular permeability in the circulatory shock induced by endotoxin (lipopolysaccharide), we exami ned whether lipopolysaccharide elicits plasma extravasation in the ski n of ddY strain mice. We also studied whether nitric oxide (NO) and pr ostaglandins may mediate the lipopolysaccharide-induced increase in va scular permeability. Subcutaneous injection of lipopolysaccharide (100 -400 mu g/site) induced a dose-related and delayed increase in vascula r permeability at the injection site as determined by the leakage of p ontamine sky blue. Concurrent administration of aminoguanidine (a puta tive inducible NO synthase inhibitor) (10 mg/kg, i.v.) inhibited the l ipopolysaccharide (4O0 mu g/site)-induced dye leakage by 71%. N-G-Nitr o-L-arginine methyl eater (an inhibitor for both constitutive and indu cible NO synthase) (10 and 20 mg/kg, i.v.) inhibited the lipopolysacch aride-induced dye leakage by 36% and 54%, respectively, whereas the in active enantiomer, N-G-nitro-D-arginine methyl ester (10 mg/kg, i.v.), had no effect. Pretreatment with an intraperitoneal injection of dexa methasone (500 mu g/kg) or indomethacin (a cyclooxygenase-1 and -2 inh ibitor) (5 mg/kg) almost completely inhibited the response induced by lipopolysaccharide, by 96% and 84%, respectively. (2-Cyclohexyloxy-4-n itrophenyl)methanesulphonamide (a cyclooxygenase-2-specific inhibitor) (0.01-1 mg/kg, i.p.) also induced a dose-related inhibition of dye le akage elicited by lipopolysaccharide: 38% and 80% suppression at the d oses of 0.1 and 1 mg/kg, respectively. Cycloheximide (a protein biosyn thesis inhibitor) (35 mg/kg, s.c.) suppressed the effect of lipopolysa ccharide by 74%. These results suggest that the increase in vascular p ermeability induced by lipopolysaccharide is mediated by both NO and p rostaglandins and that synthesis of inducible NO synthase and cyclooxy genase-2 may be involved in this effect of lipopolysaccharide.