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(Circulation. 2002;106:3120.)
© 2002 American Heart Association, Inc.

Basic Science Reports

NCX-4016 (NO-Aspirin) Inhibits Lipopolysaccharide-Induced Tissue Factor Expression In Vivo

Role of Nitric Oxide

Stefano Fiorucci, MD; Andrea Mencarelli, BS; Alessandra Meneguzzi, BS; Alessandro Lechi, MD; Antonio Morelli, MD; Piero del Soldato, PhD; Pietro Minuz, MD

From Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Italy (S.F., A. Mencarelli, A. Morelli); Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Italy (A. Meneguzzi, A.L., P.M.); NicOx S.A., Sophia Antipolis, France (P.d.S.); and New York Medical College, Valhalla, NY (P.d.S.).

Correspondence to Dr Pietro Minuz, Medicina Interna C, Policlinico GB Rossi, Piazzale LA Scuro 10, 37134 Verona, Italy. E-mail pietro.minuz{at}univr.it

Background— NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a nitric oxide–releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016 might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue factor (TF).

Methods and Results— Rats were administered 90 mg/kg NCX-4016 orally for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN) were used in control groups. On day 5, rats were injected intraperitoneally with 100 µg/kg LPS and killed 6 hours later. The expression of TF in monocytes was measured by flow cytometry and Western blot analysis. Reverse transcriptase–polymerase chain reaction was performed to assess expression of TF and cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1ß and tumor necrosis factor- were measured. Urine samples were collected to evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane (TX)B₂. Gastric mucosa was inspected. LPS injection was followed by synthesis TF and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of circulating monocyte. LPS increased the excretion 11-dehydro-TXB₂, and this was prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin-1ß and tumor necrosis factor-. In addition, NCX-4016 almost completely prevented mucosal damage, whereas ASA increased the extension of gastric lesions in LPS-injected rats.

Conclusions— NCX-4016 prevents monocyte TF expression; this is accompanied by inhibition of TX and cytokine biosynthesis. These additive effects of nitric oxide release and COX inhibition may help explain efficacy and tolerability of NCX-4016.

Key Words: thromboxane • aspirin • platelets • nitric oxide

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