Combating nitrate tolerance: a novel endogenous mechanism.
Combating nitrate tolerance: a novel endogenous mechanism.
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对抗硝酸盐耐受性：一种新的内源机制。
DOI：
10.1161/atvbaha.107.148023
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Gutterman,DavidD
中科院分区：
文献类型：
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作者：
Gutterman,DavidD
以硝酸甘油（GTN）为原型，硝酸盐代表了减少阻塞性冠状动脉疾病引起的心肌缺血急性症状的最安全和最快速有效的药理学手段之一。多年来，这导致了长效口服和局部制剂的开发。然而，长期给药的疗效更难实现，因为治疗耐药性的发展，通常发生在开始治疗后几天。这种现象被称为硝酸盐耐受性，它刺激了对硝酸甘油代谢命运的深入研究，并认为调节其生物转化可以提高慢性治疗的疗效。GTN诱导的扩张机制很复杂，直到发现100多年后才被确定。GTN不是一种直接的血管扩张剂，而是必须转化为二硝酸盐产物才能发挥血管活性。生物转化为活性代谢产物一氧化氮（NO）的过程与甘油-1，2-二硝酸酯的形成同时进行，并涉及二硫醇依赖性过程。1直到最近才鉴定出负责GTN生物转化的主要酶。Chen等1发现线粒体乙醛脱氢酶（ALDH-2）将GTN代谢为甘油-1，2-二硝酸酯和亚硝酸盐。Sydow等人2使用缺乏内皮细胞的培养内皮细胞证实了这一点，尽管也提出了ALDH-2的胞质来源。3线粒体酶在体内和体外将纳摩尔浓度的GTN转化为活性硝酸扩张剂代谢物，如直接测量结合使用选择性抑制剂和竞争底物所示。1，2是否代谢产物NO或相关化合物是负责随后激活鸟苷酸环化酶仍然是一个问题。4
With glycerol trinitrate (GTN) as the prototype, nitrates represent one of the safest and most rapidly effective pharmacological means to reduce acute symptoms of myocardial ischemia attributable to obstructive coronary disease. This has led, over the years, to the development of long-acting oral and topical preparations. However, efficacy with chronic administration is more difficult to achieve because of the development of therapeutic resistance, generally occurring a few days after initiating treatment. This phenomenon known as nitrate tolerance has been the stimulus for intense investigation of the metabolic fate of nitroglycerin with the idea that modulation of its biotransformation could improve efficacy of chronic treatment.The mechanism of GTN-induced dilation is complex and was not identified until more than 100 years after its discovery. GTN is not a direct vasodilator, rather it must be converted to dinitrate products for vasoactivity. Biotransformation to the active metabolite nitric oxide (NO) occurs in parallel with the formation of glycerol-1, 2-dinitrate and involves a dithiol-dependent process. 1 It was not until recently that the principal enzyme responsible for biotransformation of GTN was identified. Chen et al1 showed that mitochondrial aldehyde dehydrogenase (ALDH-2) metabolizes GTN to glycerol-1, 2-dinitrate and nitrite. This was confirmed by Sydow et al2 using mitochondrial-deficient cultured endothelial cells, although a cytosolic source of ALDH-2 has also been suggested. 3 The mitochondrial enzyme converts nanomolar concentrations of GTN to active nitrodilator metabolites in vivo and in vitro, as shown by direct measurements coupled with the use of selective inhibitors and competing substrates. 1, 2 Whether the metabolic product NO or a related compound is responsible for the subsequent activation of guanylate cyclase remains in question. 4