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.

中文翻译：

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镰状细胞病受试者和小鼠模型的血室中亚硝酸盐和cGMP水平升高。

镰状细胞病（SCD）中一氧化氮（NO）生物利用度降低的假说表明，导致NO产生减少和消耗增加的多种因素有助于血管闭塞，肺动脉高压和疼痛。亚硝酸根阴离子是NO生理的核心，因为它是NO代谢的最终产物，并充当NO形成的库。但是，关于SCD患者亚硝酸盐水平及其与疼痛表型的关系的数据很少。我们在SCD受试者中测量了亚硝酸盐，并检查了其与SCD疼痛的关系。在SCD受试者中，中位数全血，红细胞和血浆亚硝酸盐水平高于对照组，并且与疼痛负担无关。同样，Townes和BERK纯合SCD小鼠的血亚硝酸盐升高。此外，在SCD受试者的红细胞和血浆中以及Townes纯合小鼠的血液和肾脏中，环鸟苷单磷酸（cGMP）的水平高于对照组。在体外，血红蛋白浓度而不是镰刀型血红蛋白是亚硝酸盐代谢速率的原因。在体内，对NO合酶和黄嘌呤氧化还原酶的抑制作用会降低纯合子中的亚硝酸盐水平，但在对照小鼠中则不会。SCD小鼠的长期亚硝酸盐治疗可进一步提高血液亚硝酸盐和cGMP含量，加重贫血，减少血小板，并且不会改变疼痛反应。这些数据表明，人和动物中的SCD与亚硝酸盐/ NO的有效性增加有关，而亚硝酸盐/ NO的有效性与疼痛表型无关。