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 (PGI(2)) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) 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 (iNOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-alpha 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 PGI(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 PGI(2), produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of iNOS through inhibiting TNF-alpha production. These effects of AT could be mediated by the promotion of endothelial release of PGI(2) and might at least partly explain the therapeutic effects for septic shock.
Isobe
Hirotaka
H
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Okajima
Kenji
K
Uchiba
Mitsuhiro
M
Harada
Naoaki
N
Okabe
Hiroaki
H
D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012772:Shock, Septic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
D004731:Endotoxins; D009566:Nitrates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000990:Antithrombin III; D011464:Epoprostenol; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat