Abstract
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.
MeSH terms
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Animals
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Dansyl Compounds / pharmacology
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Factor VIIa / antagonists & inhibitors
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Factor VIIa / pharmacology
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Factor Xa Inhibitors
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Gene Expression Regulation / drug effects
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Humans
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Hypotension / chemically induced
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Hypotension / metabolism
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Hypotension / prevention & control*
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Lipopolysaccharides / toxicity*
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Lipoproteins / genetics
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Lipoproteins / pharmacology
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Lipoproteins / therapeutic use*
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Lung / drug effects
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Lung / enzymology
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Male
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Naphthalenes / pharmacology
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Nitrates / blood
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Nitric Oxide / biosynthesis*
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Nitrites / blood
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Propionates / pharmacology
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RNA, Messenger / biosynthesis
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Rats
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Rats, Wistar
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Recombinant Fusion Proteins / pharmacology
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Recombinant Fusion Proteins / therapeutic use
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Respiratory Distress Syndrome / chemically induced
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Respiratory Distress Syndrome / enzymology
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Respiratory Distress Syndrome / prevention & control
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Shock, Septic / metabolism
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Shock, Septic / prevention & control*
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Specific Pathogen-Free Organisms
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology*
Substances
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(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid
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Dansyl Compounds
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Enzyme Inhibitors
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Factor Xa Inhibitors
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Lipopolysaccharides
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Lipoproteins
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Naphthalenes
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Nitrates
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Nitrites
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Propionates
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RNA, Messenger
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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dansyl-glutamyl-glycyl-arginyl-factor VIIa
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lipoprotein-associated coagulation inhibitor
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Nitric Oxide
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Factor VIIa