Activated Protein C Prevents Endotoxin-Induced Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide

Background— Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-α (TNF-α) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-α production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock. Methods and Results— Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO2−/NO3−. The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-α and expression of TNF-α mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin ge...