Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Antithrombin (AT) prevents Escherichia coli-induced hypotension in animal models of sepsis, and it further reduces the mortality of patients with septic shock. In the present study, we examined whether AT may prevent the endotoxin (ET)-induced hypotension by promoting the endothelial release of prostacyclin (PGl(2)) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO2-/ NO3- in rats given ET. Lung expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha) was transiently increased after ET administration, followed by the increases in lung tissue levels of TNF-alpha. Both the lung activity of the inducible form of nitric oxide synthase (NOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-a mRNA expression had peaked. Administration of AT significantly inhibited these Increases. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor Trp(49)-modified AT, which is not capable of promoting the endothelial release of PGl(2), showed any effects on these changes induced by ET. Administration of antirat TNF-alpha antibody produced effects similar to those Induced by AT. Indomethacin pretreatment abrogated the effects induced by AT. Iloprost, a stable derivative of PGl(2), produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of NOS through Inhibiting TNF-alpha production. These effects of AT could be mediated by the promotion of endothelial release of PGl(2) and might at least partly explain the therapeutic effects for septic shock. (C) 2002 by The American Society of Hematology.