Nitrite as a Source of Bioactive Nitric Oxide

尽管血管内皮细胞局部合成一氧化氮(NO)有助于冠脉和全身循环局部血管扩张，但在冠状动脉疾病患者中，NO的血管合成减少或缺失，其他来源的NO可能具有特别重要的作用。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-在人类前臂的血管扩张剂特性和存在的生物激活机制。10将亚硝酸钠以每分钟36毫摩尔的速度注入18名正常志愿者的前臂臂动脉，导致局部亚硝酸盐浓度达到222Im，静息前臂血流量立即增加175%。观察到静息、不抑制合酶和运动时的血流量增加，并导致组织灌注量增加，表现为静脉血氧饱和度、氧分压和pH的增加。全身亚硝酸盐浓度增加到16Im，并显著降低平均动脉压。在另外10名受试者中，亚硝酸盐的剂量减少了2个对数，导致前臂亚硝酸盐浓度增加了2Im，血流增加了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，S-亚硝基-血红蛋白横跨前臂血管。NO修饰的血红蛋白的形成似乎是脱氧血红蛋白亚硝酸还原酶活性的结果，将组织缺氧和亚硝酸盐生物激活联系在一起。这些结果表明，血液和组织亚硝酸盐的生理水平代表了一个主要的生物可利用的NO池，有助于血管调节，并通过血管亚硝酸盐与脱氧血红素蛋白的反应提供了一种缺氧血管扩张的机制。

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.