Red blood cell storage increases hypoxia-induced nitric oxide bioavailability and methemoglobin formation in vitro and in vivo

Authors

  • Emre Almac,

    1. Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    2. Department of Anesthesiology and Intensive Care, St Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands
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  • Rick Bezemer,

    1. Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • Petra M. Hilarius-Stokman,

    1. Department of Blood Cell Research, Sanquin Research, Amsterdam, the Netherlands
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  • Peter Goedhart,

    1. Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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    • Peter Goedhart died during the writing process.
  • Dirk de Korte,

    1. Department of Blood Cell Research, Sanquin Research, Amsterdam, the Netherlands
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  • Arthur J. Verhoeven,

    1. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • Can Ince

    Corresponding author
    1. Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    • Address reprint requests to: Can Ince, Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; e-mail: c.ince@amc.uva.nl.

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  • This study was in part supported by the Landsteiner Foundation for Blood Transfusion Research (grant no. 0329).

Abstract

Background

In this study we investigated whether storage of red blood cells (RBCs) leads to alterations in nitrite reductase activity, hence in altered hypoxia-induced nitric oxide (NO) bioavailability and methemoglobin formation.

Study Design and Methods

Hypoxia-induced NO bioavailability and methemoglobin formation were measured in vitro after nitrite administration to fresh (<1 week of storage) and aged (5-6 weeks of storage) human RBC units and in blood samples of hemodiluted rats subjected to hypoxic ventilation after transfusion with fresh or aged human RBCs.

Results

In vitro, NO and methemoglobin levels 10 minutes after nitrite administration were lower in the fresh RBC samples compared to the aged RBC samples (p = 0.026 and p = 0.022, respectively). In vivo, NO bioavailability was also significantly lower in the rats receiving fresh RBCs compared to the group receiving aged RBCs (p = 0.003). In line with NO bioavailability, methemoglobin levels were higher, albeit not significantly, in the group receiving aged RBCs compared to in the group receiving fresh RBCs (p = 0.154). The difference in methemoglobin formation after nitrite administration between fresh and aged RBCs was only present under deoxygenated conditions and not under oxygenated conditions. There were no differences in methemoglobin reductase activity between fresh and aged RBCs.

Conclusions

Storage of RBCs leads to an increased rate of hypoxia-induced nitrite reduction to NO and this is associated with increased methemoglobin formation. The increased methemoglobin formation and consequent decrease in oxygen delivery capacity might contribute to the storage-related impairment of aged RBCs to oxygenate the microcirculation.

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