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ANESTHETIC PHARMACOLOGY

Peroxynitrite Decreases Rabbit Tissue Factor Activity In Vitro

Vance G. Nielsen, MD^*, and John P. Crow, PhD^*,,

Departments of *Anesthesiology, Pharmacology/Toxicology, Biochemistry and Molecular Genetics, The Center for Free Radical Biology, The University of Alabama at Birmingham

Address correspondence and reprint requests to Vance G. Nielsen, MD, Associate Professor, Department of Anesthesiology, The University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35249–6810. Address email to vance.nielsen{at}ccc.uab.edu

Tissue factor (TF) is a primary initiator of physiological coagulation in vivo. Peroxynitrite (OONO^-), a molecule formed from nitric oxide (NO) and superoxide (O₂ · ^-), decreases human TF activity in vitro. Coagulopathy has been associated with hepatoenteric ischemia-reperfusion known to involve formation of OONO^-. Further, circulating TF activity decreases in rabbits after hepatoenteric ischemia-reperfusion. We hypothesized that exposure of rabbit TF to OONO^- would result in a decrease in activity. OONO^- generation was performed with 3-morpholinosydnonimine (SIN-1), a molecule that produces both nitric oxide and superoxide. Rabbit brain TF was incubated at 37°C for 90 min with 1) 0 mM SIN-1, 2) 5 mM SIN-1, 3) 5 mM SIN-1 and 2000 U/mL recombinant human superoxide dismutase (hSOD1), or 4) 2000 U/mL hSOD1 (n = 8 per condition). TF activity was assessed by addition of TF samples to human plasma and measuring clot formation kinetics with a thrombelastograph®. TF exposure to SIN-1 resulted in a 48% decrease in activity that was significantly different from the other three conditions (P < 0.001). There were no significant differences between the other conditions. We conclude that rabbit TF is inhibited by OONO^-, and further investigation to determine the role of OONO^- in coagulopathies associated with hepatoenteric ischemia-reperfusion is warranted.

IMPLICATIONS: Tissue factor (TF) initiates physiological coagulation in vivo. Hepatoenteric ischemia-reperfusion injury is associated with peroxynitrite (OONO^-) formation, coagulopathy and decreased TF activity in rabbits. We determined that OONO^- decreased rabbit TF activity in vitro via thrombelastography®.

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