In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock.
We determined the in vivo function of LPS-induced nuclear factor-kappa B (NF-kappa B) activation in mediating inducible nitric oxide synthase (iNOS) mRNA and protein expression, and systemic arterial hypotension in a rat model of septic shock. LPS (8 mg/kg i.v.) challenge of rats activated NF-kappa B within 15 min in lung tissue, and the response persisted up to 4 h. NF-kappa B activation preceded the induction of iNOS mRNA. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappa B effective in cellular studies, prevented NF-kappa B activation in vivo and reduced iNOS mRNA expression and the increase in iNOS activity activated by LPS. At PDTC concentrations of 50, 100, and 200 mg/kg, the reductions of iNOS mRNA were 20, 46, and 48%, and the reductions in iNOS activity were 59, 66, and 75%, respectively. The PDTC concentration-dependent reductions in iNOS activity produced similar decreases in plasma nitrite/nitrate concentrations. PDTC also prevented the decrease in arterial blood pressure induced by LPS. These results demonstrate that activation of NF-kappa B is a critical in vivo regulatory mechanism mediating LPS-induced iNOS expression and the resultant systemic hypotension.
Liu
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SF
Department of Pharmacology, University of Illinois College of Medicine, Chicago 60612, USA.
Ye
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X
Malik
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D007022:Hypotension / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002118:Calcium