Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Antioxid Redox Signal. 2013 May 10;18(14):1797-809. doi: 10.1089/ars.2012.4833. Epub 2012 Oct 15.
Pulmonary arterial hypertension (PAH) is a disorder characterized by increased pulmonary vascular resistance and mean pulmonary artery pressure leading to impaired function of the right ventricle, reduced cardiac output, and death. An imbalance between vasoconstrictors and vasodilators plays an important role in the pathobiology of PAH.
Nitric oxide (NO) is a potent vasodilator in the lung, whose bioavailability and signaling pathway are impaired in PAH. It is now appreciated that the oxidative product of NO metabolism, the inorganic anion nitrite (NO(2)(-)), functions as an intravascular endocrine reservoir of NO bioactivity that can be reduced back to NO under physiological and pathological hypoxia.
The conversion of nitrite to NO is controlled by coupled electron and proton transfer reactions between heme- and molybdenum-containing proteins, such as hemoglobin and xanthine oxidase, and by simple protonation and disproportionation, and possibly by catalyzed disproportionation. The two major sources of nitrite (and nitrate) are the endogenous L-arginine-NO pathway, by oxidation of NO, and the diet, with conversion of nitrate from diet into nitrite by oral commensal bacteria. In the current article, we review the enzymatic formation of nitrite and the available data regarding its use as a therapy for PAH and other cardiovascular diseases.
The successful efficacy demonstrated in several animal models and safety in early clinical trials suggest that nitrite may represent a promising new therapy for PAH.
肺动脉高压（PAH）是一种以肺血管阻力增加和肺动脉平均压升高为特征的疾病，导致右心室功能障碍、心输出量减少和死亡。血管收缩剂和血管扩张剂之间的失衡在 PAH 的病理生物学中起着重要作用。
一氧化氮（NO）是肺中的一种强效血管扩张剂，其生物利用度和信号通路在 PAH 中受损。现在人们已经认识到，NO 代谢的氧化产物无机阴离子亚硝酸盐（NO2（-））作为血管内 NO 生物活性的内分泌储存库，在生理和病理缺氧下可以还原回 NO。
亚硝酸盐转化为 NO 受血红素和钼含蛋白（如血红蛋白和黄嘌呤氧化酶）之间的电子和质子偶联转移反应以及简单的质子化和歧化以及可能的催化歧化控制。亚硝酸盐（和硝酸盐）的两个主要来源是内源性 L-精氨酸-NO 途径，通过 NO 的氧化，以及饮食，通过口腔共生细菌将饮食中的硝酸盐转化为亚硝酸盐。在本文中，我们回顾了亚硝酸盐的酶促形成以及将其用作 PAH 和其他心血管疾病治疗的现有数据。
在几种动物模型中证明的成功疗效和早期临床试验中的安全性表明，亚硝酸盐可能代表一种有前途的 PAH 新疗法。
