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Brisk production of nitric oxide and associated formation of S-nitrosothiols in early hemorrhage

¹Division of Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, Maryland; ²Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; and ³Department of Biochemistry and Physiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Submitted 30 August 2005 ; accepted in final form 5 December 2005

The results of previous inhibitor studies suggest that there is some increase in nitric oxide (NO) production from constitutive NO synthase in early hemorrhage (H), but the magnitude of NO production early after H has not been previously assessed. It is generally believed that only modest production rates are possible from the constitutively expressed NO synthases. To study this, anesthetized male Sprague-Dawley rats were subjected to 90 min of isobaric (40 mmHg) H. During this period of time, the dynamics of accumulation of NO intermediates in the arterial blood was assessed using electron paramagnetic resonance spectroscopy, chemiluminescence, fluorescence imaging, and mass spectrometry. Electron paramagnetic resonance-detectable NO adducts were also measured with spin traps in blood plasma and red blood cells. H led to an increase in the concentration of hemoglobin-NO from 0.9 ± 0.2 to 4.8 ± 0.7 µM. This accumulation was attenuated by a nonselective inhibitor of NO synthase, N^G-nitro-L-argininemethyl ester (L-NAME), but not by N^G-nitro-D-argininemethyl ester (D-NAME) or 1400W. Administration of L-NAME (but not 1400W or D-NAME) during H produced a short-term increase in mean arterial pressure (90%). In H, the level of N oxides in red blood cells increased sevenfold. S-nitrosylation of plasma proteins was revealed with "biotin switch" techniques. The results provide compelling evidence that there is brisk production of NO in early H. The results indicate that the initial compensatory response to H is more complicated than previously realized, and it involves an orchestrated balance between intense vasoconstrictor and vasodilatory components.

blood cells; shock; physiology

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