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

ABSTRACT: 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.

SUBMITTER: Almeida LEF

PROVIDER: S-EPMC6911650 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Almeida Luis E F LEF Kamimura Sayuri S de Souza Batista Celia M CM Spornick Nicholas N Nettleton Margaret Y MY Walek Elizabeth E Smith Meghann L ML Finkel Julia C JC Darbari Deepika S DS Wakim Paul P Quezado Zenaide M N ZMN

Nitric oxide : biology and chemistry 20191102

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 nitri ...[more]

PMID: 31689491

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

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

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