The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine
The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine
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DOI：
10.1016/j.amjcard.2005.07.030
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发表时间：
2005-10-10
影响因子：
2.8
通讯作者：
Münzel, T
中科院分区：
文献类型：
--
作者：
Daiber, A;Mülsch, A;Münzel, T
硝酸甘油（NTG）的血流动力学和抗缺血作用由于硝酸盐耐受性的发展而迅速减弱。随着NTG治疗的开始，有可能检测到神经激素激活和血管内容量扩张。这些所谓的假耐受机制可能损害NTG的血管舒张作用。长期硝酸盐治疗也与耐受血管系统本身内在机制的变化引起的血管反应性降低有关。根据氧化应激的概念，增加血管超氧化物（O-2）的生产和增加的敏感性，血管收缩继发于蛋白激酶C的激活有助于耐受性的发展。烟酰胺腺嘌呤二核苷酸磷酸氧化酶和非偶联内皮型一氧化氮合酶可能是O-2（-）-产生酶。一氧化氮（NO）和O-2 1都来自NTG和血管壁，形成过氧亚硝酸盐在扩散限制的快速反应。过氧亚硝酸盐、O-2 - 1或两者都可能导致对直接NO供体（如硝普钠、sydnonimines）和内皮依赖性NO还原酶激活血管扩张剂的硝酸盐耐受性和交叉耐受性的发展。肼苯哒嗪是一种有效的活性氧清除剂和O-2生成抑制剂。当与NTG同时给药时，肼苯哒嗪可防止硝酸盐耐受性的发展，并使血管O-2产生的内源性速率正常化。最近的实验工作已经定义了新的耐受机制，包括抑制生物激活NTG的酶（即线粒体醛脱氢酶亚型2 [ALDH 2]）和线粒体作为ROS的潜在来源。NTG诱导的ROS抑制ALDH 2对NTG的生物活化。这两种机制增加氧化应激和损害NTG生物活化，现在汇聚在ALDH 2水平，支持NTG耐受性和NTG诱导的内皮功能障碍的新理论。NTG下游目标（如可溶性鸟苷酸环化酶，环鸟苷一磷酸依赖性蛋白激酶），毒性作用，有助于内皮功能障碍（如前列环素合酶抑制）和肼苯哒嗪的抗氧化性能的新应用程序的这些过程的后果进行了讨论。(c)2005年爱思唯尔公司All rights reserved.
The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O-2) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C contribute to the development of tolerance. Nicotinamide adenine dinucleotide phosphate oxidase and the uncoupled endothelial nitric oxide synthase may be O-2(-)-producing enzymes. Nitric oxide (NO) and O-2 1 both derived from NTG and the vessel wall, form peroxynitrite in a diffusion-limited rapid reaction. Peroxynitrite, O-2 1 or both may be responsible for the development of nitrate tolerance and cross-tolerance to direct NO donors (eg, sodium nitroprusside, sydnonimines) and endothelium-dependent NO synthase-activating vasodilators. Hydralazine is an efficient reactive oxygen species (ROS) scavenger and an inhibitor of O-2 generation. When given concomitantly with NTG, hydralazine prevents the development of nitrate tolerance and normalizes endogenous rates of vascular O-2 production. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates NTG (ie, mitochondrial aldehyde dehydrogenase isoform 2 [ALDH2]) and mitochondria as potential sources of ROS. NTG-induced ROS inhibit the bioactivation of NTG by ALDH2. Both mechanisms increase oxidative stress and impair NTG bioactivation, and now converge at the level of ALDH2 to support a new theory for NTG tolerance and NTG-induced endothelial dysfunction. The consequences of these processes for NTG downstream targets (eg, soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase), toxic effects contributing to endothelial dysfunction (eg, prostacyclin synthase inhibition) and novel applications of the antioxidant properties of hydralazine are discussed. (c) 2005 Elsevier Inc. All rights reserved.