ENDOTOXIN-INDUCED VASODILATATION IN ANESTHETIZED RAT SKIN INVOLVES NITRIC-OXIDE AND PROSTAGLANDIN SYNTHESIS

1 The effect of intradermally injected endotoxin on skin blood flow was investigated in anaesthetized male Wistar rats in vivo. 2 Local skin blood flow changes were measured hourly for 6 h in the shaved dorsal skin with a laser-Doppler flow probe and compared to changes in control sites which had been injected with 100-mu-l of phosphate-buffered saline. By 3 h, skin blood flow increased above basal by 129 +/- 27% and 186 +/- 29% with 1 and 10-mu-g of endotoxin respectively. Blood flow remained significantly elevated at 6 h, the corresponding figures being 129 +/- 24% and 154 +/- 31% (P < 0.05, n = 6 rats, mean +/- s.e.mean). 3 In further experiments, the response to 3-mu-g of endotoxin was measured at 4 h and treatment with a cyclo-oxygenase inhibitor, nitric oxide synthase inhibitors or a topical steroid all significantly inhibited this response (P < 0.05 in each case, n = 6 rats in each group with duplicate sites in each animal). 4 Indomethacin 3 x 10(-9) mol per site injected 3.5 h after injection of endotoxin suppressed the mean 4 h response to endotoxin by 78%; N(G)-nitro-L-arginine methyl ester (L-NAME) 10(-7) mol per site suppressed the response by 95%; N-monomethyl-L-arginine (L-NMMA) 10(-7) mol per site suppressed the response by 50%; whereas the D-isomer of N(G)-monomethyl-arginine 10(-7) mol per site had no significant effect. 5 Topical application of the corticosteroid, betamethasone 17-valerate (1% solution) 18 h before injection of endotoxin inhibited the mean 4 h response to endotoxin by 66% and the 6 h response by 48%. 6 In the same model, the vasodilator response to arachidonic acid was inhibited by both indomethacin and nitric oxide synthase inhibitors (P<0.05 in each case). 7 These data suggest that the microcirculatory vasodilator response to endotoxin and arachidonic acid injected locally involves both nitric oxide synthase and cyclo-oxygenase in this in vivo model.