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 synthas e (iNOS) mRNA and protein expression, and systemic arterial hypotensio n 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 p ersisted up to 4 h. NF-kappa B activation preceded the induction of iN OS mRNA, Pyrrolidine dithiocarbamate (PDIC), an inhibitor of NF-kappa B effective in cellular studies, prevented NF-kappa B activation in vi vo and reduced iNOS mRNA expression and the increase in iNOS activity activated by LPS. At PDTC concentrations of 50, 100, and 200 mg/kg, th e reductions in iNOS mRNA were 20, 46, and 48%, and the reductions in iNOS activity were 59, 66, and 75%, respectively, The PDTC concentrati on-dependent reductions in iNOS activity produced similar decreases in plasma nitrite/nitrate concentrations, PDTC also prevented the decrea se in arterial blood pressure induced by LPS. These results demonstrat e that activation of NF-kappa B is a critical in vivo regulatory mecha nism mediating LPS-induced iNOS expression and the resultant systemic hypotension.