Nitrite as a Source of Bioactive Nitric Oxide

虽然内皮细胞的一氧化氮（NO）的局部合成有助于健康受试者的冠状动脉和体循环中的局部血管舒张张力，但是在具有冠状动脉疾病的患者中，其中NO的血管合成减少或不存在，NO的其他来源可能具有特别的重要性。在最近完成的一项研究中，我们评估了亚硝酸盐（NO和O2的反应产物）在人前臂中的血管扩张特性及其生物活化的现存机制。10将亚硝酸钠以每分钟36 imole的速度注入18名正常志愿者的前臂肱动脉，导致局部亚硝酸盐浓度为222 iM，静息前臂血流立即增加175%。在休息时，在NO合酶抑制和运动，观察到血流量增加，并导致组织灌注增加，如静脉血红蛋白氧饱和度，氧分压和pH值的增加所示。全身亚硝酸盐浓度增加到16 iM，并显着降低平均动脉血压。在另外10名受试者中，亚硝酸盐的剂量减少2个对数，导致前臂亚硝酸盐浓度为2 μ M，血流量增加22%。亚硝酸盐输注与红细胞铁-亚硝基-血红蛋白的形成有关，在较小程度上，与穿过前臂血管的S-亚硝基-血红蛋白有关。NO修饰的血红蛋白的形成似乎是由脱氧血红蛋白的亚硝酸还原酶活性引起的，其将组织缺氧和亚硝酸盐生物活化联系起来。这些结果表明，生理水平的血液和组织的亚硝酸盐代表一个主要的生物可利用池的NO，有助于血管调节，并提供了一种机制，通过反应的血管亚硝酸盐与脱氧血红素蛋白缺氧血管舒张。

Although regional synthesis of nitric oxide (NO) by the endothelium contributes to local vasodilator tone in the coronary and systemic circulations of healthy subjects, in patients with coronary artery disease, in whom vascular synthesis of NO is reduced or absent, other sources of NO may assume particular importance. In a recently completed study we evaluated the vasodilator properties of nitrite -the reactant product of NO and O2 -in the human forearm and the mechanisms extant for its bioactivation.10 Sodium nitrite was infused at 36 imoles per minute into the forearm brachial artery of 18 normal volunteers, resulting in a regional nitrite concentration of 222 iM and an immediate 175% increase in resting forearm blood flow. Increased blood flow was observed at rest, during NO synthase inhibition and with exercise, and resulted in increased tissue perfusion, as demonstrated by increases in venous hemoglobin-oxygen saturation, partial pressure of oxygen, and pH. Systemic concentrations of nitrite increased to 16 iM and significantly reduced mean arterial blood pressure. In an additional 10 subjects, the dose of nitrite was reduced 2-logs resulting in a forearm nitrite concentration of 2 iM and a 22% increase in blood flow. Nitrite infusions were associated with the formation of erythrocyte iron-nitrosyl-hemoglobin, and to a lesser extent, S-nitroso-hemoglobin across the forearm vasculature. The formation of NO-modified hemoglobin appears to result from the nitrite reductase activity of deoxyhemoglobin, linking tissue hypoxia and nitrite bioactivation. These results suggest that physiological levels of blood and tissue nitrite represent a major bioavailable pool of NO that contributes to vaso-regulation and provides a mechanism for hypoxic vasodilation via reaction of vascular nitrite with deoxygenated heme proteins.