Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide.
Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-alpha (TNF-alpha) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO2-/NO3- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-alpha production.
Enkhbaatar
P
P
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Okajima
K
K
Uchiba
M
M
Isobe
H
H
Okabe
H
H
D000818:Animals; D003619:Dansyl Compounds / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008074:Lipoproteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D012772:Shock, Septic / Q000378:metabolism / Q000517:prevention & control*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D003619:Dansyl Compounds; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009281:Naphthalenes; D009566:Nitrates; D009573:Nitrites; D011422:Propionates; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C109749:dansyl-glutamyl-glycyl-arginyl-factor VIIa; C051928:lipoprotein-associated coagulation inhibitor; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015942:Factor VIIa