Nitric oxide, but not interleukin-1, mediates the local blood flow response to lipopolysaccharide in rabbit skin.
Lipopolysaccharide can mimic many aspects of the inflammatory response to gram-negative bacteria. In rabbit and rat skin, lipopolysaccharide induces neutrophil accumulation and an increase in blood flow. Interleukin-1, tumor necrosis factor-alpha and the vasodilator, nitric oxide (NO) have been implicated in the biological responses to lipopolysaccharide and gram-negative bacteria. In the present study, we characterized the local vascular response to E. coli lipopolysaccharide in rabbit skin and investigated its dependence on de novo protein synthesis, NO, interleukin-1 and neutrophils. The local vascular response to the intradermal injection of lipopolysaccharide was determined by measuring changes in local blood flow with a laser-Doppler flowmeter. Injections of lipopolysaccharide (3, 10 and 30 micrograms/site) induced a dose-related increase in blood flow, with a maximum at 2 h. The response to 10 micrograms/site lipopolysaccharide was abolished by co-injection of actinomycin D (4 x 10(-9) mol/site), reduced by 60% by NG-nitro-L-arginine methyl ester (10(-7) mol/site) and suppressed by 82% in rabbits pretreated with dexamethasone (2 mg/kg, i.v.). However, the lipopolysaccharide-induced increase in blood flow was not affected by co-injection of recombinant human interleukin-1 receptor antagonist (7.0 x 10(-11) mol/site) or by systemic neutrophil depletion. These results demonstrate that lipopolysaccharide causes delayed vasodilatation of the rabbit cutaneous microvasculature which depends on protein synthesis and involves in part the release of NO. However, this response does not depend on interleukin-1 or neutrophils. The vasodilator effect of lipopolysaccharide may involve the expression of the inducible form of NO synthase in the vessel wall, through a mechanism independent of interleukin-1.
Pons
F
F
Department of Applied Pharmacology, National Heart and Lung Institute, London, UK.
Williams
T J
TJ
Warren
J B
JB
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003907:Dexamethasone