Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator
Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator
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DOI：
10.1038/nm1109
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发表时间：
2004-10-01
期刊：
影响因子：
82.9
通讯作者：
Gladwin, MT
中科院分区：
文献类型：
--
作者：
Hunter, CJ;Dejam, A;Gladwin, MT
血液阴离子亚硝酸盐通过基于血红素的一氧化氮（NO）生成反应与脱氧血红蛋白和潜在的其他血红素蛋白（1）促进缺氧血管舒张。我们假设这种生化反应可用于治疗新生儿肺动脉高压，这是一种以肺血管收缩、右向左分流病理生理学和全身性低氧血症为特征的NO缺乏状态（2）。为了验证这一点，我们通过气溶胶将吸入的亚硝酸钠输送给患有缺氧和常氧肺动脉高压的新生羔羊。吸入亚硝酸盐引起缺氧引起的肺动脉高压迅速和持续的减少（类似于65%），其幅度接近20 p. p.m.无气体吸入。这种减少与呼出气体中NO的立即出现有关。雾化亚硝酸盐引起的肺血管舒张是脱氧血红蛋白和pH值依赖性的，并与铁-亚硝基血红蛋白的血液水平增加。值得注意的是，从治疗的角度来看，通过雾化短期递送溶解在盐水中的亚硝酸盐产生选择性的、持续的肺血管舒张，而血液高铁血红蛋白水平没有临床显著增加。这些数据支持亚硝酸盐是通过转化为NO起作用的血管扩张剂的概念，该过程与血红蛋白脱氧和质子化相耦合，并表明新生儿肺动脉高压的新的、简单且廉价的潜在治疗。
The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins(1). We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia(2). To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction (similar to 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p. p. m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.