Kapil V, Weitzberg E, Lundberg J O, Ahluwalia A
William Harvey Research Institute, Centre for Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Barts Hypertension Clinic, Barts Health NHS Trust, London, United Kingdom.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Nitric Oxide. 2014 Apr 30;38:45-57. doi: 10.1016/j.niox.2014.03.162. Epub 2014 Mar 18.
The discovery of nitric oxide and its role in almost every facet of human biology opened a new avenue for treatment through manipulation of its canonical signaling and by attempts to augment endogenous nitric oxide generation through provision of substrate and co-factors to the endothelial nitric oxide synthase complex. This has been particularly so in the cardiovascular system and it is well recognized that there is reduced bioavailable nitric oxide in patients with both cardiovascular risk factors and manifest vascular disease. However, these attempts have failed to deliver the expected benefits of such an approach. Recently, an alternative pathway for nitric oxide synthesis has been elucidated that can produce authentic nitric oxide from the 1 electron reduction of inorganic nitrite. Furthermore, it has long been known that symbiotic, facultative, oral microflora can facilitate the reduction of inorganic nitrate, that is ingested in the average diet in millimolar amounts, to inorganic nitrite itself. Thus, there exists an alternative reductive pathway from nitrate, via nitrite as an intermediate, to nitric oxide that provides a novel pathway that may be amenable to therapeutic manipulation. As such, various research groups have explored the utility of manipulation of this nitrate-nitrite-nitric oxide pathway in situations in which nitric oxide is known to have a prominent role. Animal and early-phase human studies of both inorganic nitrite and nitrate supplementation have shown beneficial effects in blood pressure control, platelet function, vascular health and exercise capacity. This review considers in detail the pathways of inorganic nitrate bioactivation and the evidence of clinical utility to date on the cardiovascular system.
一氧化氮的发现及其在人类生物学几乎各个方面的作用，通过操纵其经典信号通路以及试图通过向内皮型一氧化氮合酶复合物提供底物和辅助因子来增加内源性一氧化氮的生成，开辟了一条新的治疗途径。在心血管系统中尤其如此，众所周知，患有心血管危险因素和明显血管疾病的患者体内生物可利用的一氧化氮会减少。然而，这些尝试未能带来这种方法预期的益处。最近，一种一氧化氮合成的替代途径已被阐明，该途径可以通过无机亚硝酸盐的单电子还原产生真正的一氧化氮。此外，长期以来人们就知道，共生的兼性口腔微生物群可以促进无机硝酸盐（以毫摩尔量摄入普通饮食中）还原为无机亚硝酸盐本身。因此，存在一条从硝酸盐经亚硝酸盐作为中间体到一氧化氮的替代还原途径，这提供了一条可能适合治疗性操纵的新途径。因此，各个研究小组已经探索了在已知一氧化氮起重要作用的情况下操纵这条硝酸盐 - 亚硝酸盐 - 一氧化氮途径的效用。无机亚硝酸盐和硝酸盐补充剂的动物和早期人体研究已经显示出在血压控制、血小板功能、血管健康和运动能力方面的有益效果。这篇综述详细考虑了无机硝酸盐生物活化的途径以及迄今为止在心血管系统方面临床效用的证据。
