Daiber A, Wenzel P, Oelze M, Schuhmacher S, Jansen T, Münzel T
II Medizinische Klinik, Labor für Molekulare Kardiologie, Johannes-Gutenberg-Universität, Mainz, Germany.
Chem Biol Interact. 2009 Mar 16;178(1-3):40-7. doi: 10.1016/j.cbi.2008.09.003. Epub 2008 Sep 10.
The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. 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 and peroxynitrite production as well as an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C as well as vascular NADPH oxidases contribute to the development of tolerance. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates GTN (e.g. mitochondrial aldehyde dehydrogenase [ALDH-2]) and mitochondria as potential sources of reactive oxygen species (ROS). GTN-induced ROS inhibit the bioactivation of GTN by ALDH-2. Both mechanisms impair GTN bioactivation, and now converge at the level of ALDH-2 to support a new theory for GTN tolerance and GTN-induced endothelial dysfunction. The consequences of these processes for GTN downstream targets (e.g. soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase) and toxic effects contributing to endothelial dysfunction (e.g. prostacyclin synthase inhibition and NO synthase uncoupling) are discussed. Tolerance and endothelial dysfunction are distinct processes which rely on different sources of ROS and there is good evidence for a crosstalk between these distinct processes. Finally, we will address the question whether ALDH-2 inactivation by nitroglycerin could be a useful marker for clinical nitrate tolerance and discuss the redox-regulation of this enzyme by oxidative stress and dihydrolipoic acid.
由于硝酸酯类耐受性的发展，硝酸甘油（GTN）的血流动力学和抗缺血作用会迅速减弱。长期使用硝酸酯类药物还与耐受性血管自身内在机制改变导致的血管反应性降低有关。根据氧化应激概念，血管超氧化物和过氧亚硝酸盐生成增加，以及继发于蛋白激酶C和血管NADPH氧化酶激活后对血管收缩剂敏感性增加，都有助于耐受性的发展。最近的实验工作确定了新的耐受机制，包括抑制生物活化GTN的酶（如线粒体醛脱氢酶[ALDH-2]）以及线粒体作为活性氧（ROS）的潜在来源。GTN诱导的ROS抑制ALDH-2对GTN的生物活化。这两种机制均损害GTN的生物活化，现在在ALDH-2水平上汇聚，以支持关于GTN耐受性和GTN诱导的内皮功能障碍的新理论。讨论了这些过程对GTN下游靶点（如可溶性鸟苷酸环化酶、环磷酸鸟苷依赖性蛋白激酶）的影响以及导致内皮功能障碍的毒性作用（如前列环素合酶抑制和一氧化氮合酶解偶联）。耐受性和内皮功能障碍是不同的过程，依赖于不同的ROS来源，并且有充分证据表明这些不同过程之间存在相互作用。最后，我们将探讨硝酸甘油使ALDH-2失活是否可能是临床硝酸酯类耐受性的有用标志物，并讨论氧化应激和二氢硫辛酸对该酶的氧化还原调节。
