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Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11477-82. Epub 2004 Jul 16.

Biological activity of nitric oxide in the plasmatic compartment.

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Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1662, USA.


There exist reaction products of nitric oxide (NO) with blood that conserve its bioactivity and transduce an endocrine vasomotor function under certain conditions. Although S-nitrosated albumin has been considered the major species subserving this activity, recent data suggest that additional NO species, such as nitrite, nitrated lipids, N-nitrosamine, and iron-nitrosyl complexes, may contribute. We therefore examined the end products of NO reactions in plasma and blood in vitro and in vivo by using reductive chemiluminescent assays and electron paramagnetic resonance spectroscopy. We found that NO complexes in plasma previously considered to be S-nitrosated albumin were <10 nM after elimination of nitrite and were mercury-stable, consistent with iron-nitrosyl or N-nitrosamine complex. During clinical NO gas inhalation protocols or in vitro NO donor treatment of human plasma, S-nitroso-albumin did not form with NO exposure <2 microM, but plasma methemoglobin was detectable by paramagnetic resonance spectroscopy. Consistent with this formation of methemoglobin, human plasma was found to consume approximately 2 microM NO at a rate equivalent to that of hemoglobin. This NO consumption was mediated by the reaction of NO with plasma haptoglobin-hemoglobin complexes and limited slower reaction pathways required for S-nitrosation. These data suggest that high-affinity, metal-based reactions in plasma with the haptoglobin-hemoglobin complex modulate plasmatic NO reaction products and limit S-nitrosation at low NO flux. The studies further suggest that alternative NO reaction end products in plasma, such as nitrite, N-nitrosamines, iron-nitrosyls, and nitrated lipids, should be evaluated in blood NO transport along the vasculature.

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