William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom.
Hypertension. 2013 May;61(5):1091-102. doi: 10.1161/HYPERTENSIONAHA.111.00933. Epub 2013 Apr 15.
Elevation of circulating nitrite (NO2(-)) levels causes vasodilatation and lowers blood pressure in healthy volunteers. Whether these effects and the underpinning mechanisms persist in hypertension is unknown. Therefore, we investigated the consequences of systemic nitrite elevation in spontaneously hypertensive rats and conducted proof-of-principle studies in patients. Nitrite caused dose-dependent blood pressure-lowering that was profoundly enhanced in spontaneously hypertensive rats versus normotensive Wistar Kyoto controls. This effect was virtually abolished by the xanthine oxidoreductase (XOR) inhibitor, allopurinol, and associated with hypertension-specific XOR-dependent nitrite reductase activity localized to the erythrocyte but not the blood vessel wall. To determine whether these pathways translate to human hypertension, we investigated the effects of elevation of circulating nitrite levels in 15 drug naïve grade 1 hypertensives. To elevate nitrite, we used a dose of dietary nitrate (≈ 3.5 mmol) that elevated nitrite levels ≈ 1.5-fold (P<0.01); a rise shown previously to exert no significant blood pressure-lowering effects in normotensives. This dose caused substantial reductions in systolic (≈ 12 mm Hg) and diastolic blood pressures (P<0.001) and pulse wave velocity (P<0.05); effects associated with elevations in erythrocytic XOR expression and XOR-dependent nitrite reductase activity. Our observations demonstrate the improved efficacy of inorganic nitrate and nitrite in hypertension as a consequence of increased erythrocytic XOR nitrite reductase activity and support the concept of dietary nitrate supplementation as an effective, but simple and inexpensive, antihypertensive strategy.
循环亚硝酸盐（NO2(-)）水平升高会导致健康志愿者血管舒张和血压降低。这些作用及其潜在机制在高血压患者中是否持续存在尚不清楚。因此，我们研究了系统性亚硝酸盐升高在自发性高血压大鼠中的后果，并在患者中进行了原理验证研究。亚硝酸盐引起剂量依赖性的降压作用，在自发性高血压大鼠中与正常血压的 Wistar Kyoto 对照相比，降压作用显著增强。这种作用几乎被黄嘌呤氧化还原酶（XOR）抑制剂别嘌呤醇所消除，并且与高血压特异性 XOR 依赖性亚硝酸盐还原酶活性相关，该活性定位于红细胞而不是血管壁。为了确定这些途径是否转化为人类高血压，我们研究了在 15 名未经药物治疗的 1 级高血压患者中循环亚硝酸盐水平升高的影响。为了升高亚硝酸盐，我们使用了约 3.5mmol 的饮食硝酸盐剂量（≈3.5mmol），该剂量使亚硝酸盐水平升高约 1.5 倍（P<0.01）；先前的研究表明，这一剂量在正常血压者中不会显著降低血压。该剂量引起收缩压（≈12mmHg）和舒张压（P<0.001）以及脉搏波速度（P<0.05）的显著降低；这些作用与红细胞 XOR 表达和 XOR 依赖性亚硝酸盐还原酶活性的升高有关。我们的观察结果表明，由于红细胞 XOR 亚硝酸盐还原酶活性的增加，无机硝酸盐和亚硝酸盐在高血压中的疗效得到改善，并支持饮食硝酸盐补充作为一种有效、简单且廉价的降压策略的概念。
