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Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

Nature Medicinevolume 8pages13831389 (2002) | Download Citation



Although the deleterious vasoconstrictive effects of cell-free, hemoglobin-based blood substitutes have been appreciated, the systemic effects of chronic hemolysis on nitric oxide bioavailability have not been considered or quantified. Central to this investigation is the understanding that nitric oxide reacts at least 1,000 times more rapidly with free hemoglobin solutions than with erythrocytes. We hypothesized that decompartmentalization of hemoglobin into plasma would divert nitric oxide from homeostatic vascular function. We demonstrate here that plasma from patients with sickle-cell disease contains cell-free ferrous hemoglobin, which stoichiometrically consumes micromolar quantities of nitric oxide and abrogates forearm blood flow responses to nitric oxide donor infusions. Therapies that inactivate plasma hemoglobin by oxidation or nitric oxide ligation restore nitric oxide bioavailability. Decompartmentalization of hemoglobin and subsequent dioxygenation of nitric oxide may explain the vascular complications shared by acute and chronic hemolytic disorders.

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We thank M. Pease-Fye and B. Yang for technical assistance and B. Bennett for assistance with EPR spectroscopy. This work was supported by intramural NIH research funds, NIH grants RR01008 and GM55792 (N.H.), and International Merck Fellowship in Clinical Pharmacology (J.E.T.-S.). NO gas and delivery systems were kindly provided by INO Therapeutics.

Author information


  1. Critical Care Medicine Department of the Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

    • Christopher D. Reiter
    • , Xunde Wang
    • , Jose E. Tanus-Santos
    •  & Mark T. Gladwin
  2. Laboratory of Chemical Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    • Christopher D. Reiter
    • , Jose E. Tanus-Santos
    • , Alan N. Schechter
    •  & Mark T. Gladwin
  3. Biophysics Research Institute and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    • Neil Hogg
  4. Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

    • Richard O. Cannon III


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The authors declare no competing financial interests.

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Correspondence to Mark T. Gladwin.

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