Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide

• Published in: Thrombosis and haemostasis Vol. 86; no. 6; p. 1573
• Main Authors: Enkhbaatar, P, Okajima, K, Uchiba, M, Isobe, H, Okabe, H
• Format: Journal Article
• Language: English
• Published: Germany 2001
• Subjects: Animals; Dansyl Compounds - pharmacology; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacology; Factor VIIa - antagonists & inhibitors; Factor VIIa - pharmacology; Factor Xa Inhibitors; Gene Expression Regulation - drug effects; Humans; Hypotension - chemically induced; Hypotension - metabolism; Hypotension - prevention & control; Lipopolysaccharides - toxicity; Lipoproteins - genetics; Lipoproteins - pharmacology; Lipoproteins - therapeutic use; Lung - drug effects; Lung - enzymology; Male; Naphthalenes - pharmacology; Nitrates - blood; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitrites - blood; Propionates - pharmacology; Rats; Rats, Wistar; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Respiratory Distress Syndrome, Adult - chemically induced; Respiratory Distress Syndrome, Adult - enzymology; Respiratory Distress Syndrome, Adult - prevention & control; RNA, Messenger - biosynthesis; Shock, Septic - metabolism; Shock, Septic - prevention & control; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0340-6245
• DOI: 10.1055/s-0037-1616764

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.