Sickle cell disease subjects and mouse models have elevated nitrite and cGMP levels in blood compartments

Nitric Oxide. 2020 Jan 1;94:79-91. doi: 10.1016/j.niox.2019.10.011. Epub 2019 Nov 2.


The hypothesis of decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD) proposes that multiple factors leading to decreased NO production and increased consumption contributes to vaso-occlusion, pulmonary hypertension, and pain. The anion nitrite is central to NO physiology as it is an end product of NO metabolism and serves as a reservoir for NO formation. However, there is little data on nitrite levels in SCD patients and its relationship to pain phenotype. We measured nitrite in SCD subjects and examined its relationship to SCD pain. In SCD subjects, median whole blood, red blood cell and plasma nitrite levels were higher than in controls, and were not associated with pain burden. Similarly, Townes and BERK homozygous SCD mice had elevated blood nitrite. Additionally, in red blood cells and plasma from SCD subjects and in blood and kidney from Townes homozygous mice, levels of cyclic guanosine monophosphate (cGMP) were higher compared to controls. In vitro, hemoglobin concentration, rather than sickle hemoglobin, was responsible for nitrite metabolism rate. In vivo, inhibition of NO synthases and xanthine oxidoreductase decreased nitrite levels in homozygotes but not in control mice. Long-term nitrite treatment in SCD mice further elevated blood nitrite and cGMP, worsened anemia, decreased platelets, and did not change pain response. These data suggest that SCD in humans and animals is associated with increased nitrite/NO availability, which is unrelated to pain phenotype. These findings might explain why multiple clinical trials aimed at increasing NO availability in SCD patients failed to improve pain outcomes.

Keywords: Hemoglobin; Kidney; Nitric oxide; Nitrite; Sickle cell disease; cGMP.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anemia, Sickle Cell / blood*
  • Anemia, Sickle Cell / metabolism
  • Animals
  • Biological Availability
  • Cyclic GMP / blood*
  • Cyclic GMP / metabolism
  • Disease Models, Animal*
  • Humans
  • Hypertension, Pulmonary / blood*
  • Hypertension, Pulmonary / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitrites / blood*
  • Nitrites / metabolism
  • Pain / blood*
  • Pain / metabolism
  • Young Adult


  • Nitrites
  • Cyclic GMP