Simonsen Ulf, Rodriguez-Rodriguez Rosalia, Dalsgaard Thomas, Buus Niels Henrik, Stankevicius Edgaras
Department of Pharmacology, Faculty of Health Sciences, Aarhus University, Aarhus C, Denmark.
Pharmacol Rep. 2009 Jan-Feb;61(1):105-15. doi: 10.1016/s1734-1140(09)70012-x.
Endothelial dysfunction, which is defined by decreased endothelium-dependent vasodilatation, is associated with an increased number of cardiovascular events. Nitric oxide (NO) bioavailability is reduced by altered endothelial signal transduction or increased formation of radical oxygen species reacting with NO. Endothelial dysfunction is therapeutically reversible and physical exercise, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists improve flow-evoked endothelium-dependent vasodilation in patients with hypertension and diabetes. We have investigated three different approaches, with the aim of correcting endothelial dysfunction in cardiovascular disease. Thus, (1) we evaluated the effect of a cell permeable superoxide dismutase mimetic, tempol, on endothelial dysfunction in small arteries exposed to high pressure, (2) investigated the endothelial signal transduction pathways involved in vasorelaxation and NO release induced by an olive oil component, oleanolic acid, and (3) investigated the role of calcium-activated K channels in the release of NO induced by receptor activation. Tempol increases endothelium-dependent vasodilatation in arteries from hypertensive animals most likely through the lowering of radical oxygen species, but other mechanisms also appear to contribute to the effect. While oleanolic acid leads to the release of NO by calcium-independent phosphorylation of endothelial NO synthase, endothelial calcium-activated K channels and an influx of calcium play an important role in G-protein coupled receptor-evoked release of NO. Thus, all three approaches increase bioavailability of NO in the vascular wall, but it remains to be addressed whether these actions have any direct benefit at a clinical level.
内皮功能障碍定义为内皮依赖性血管舒张功能减退，与心血管事件数量增加相关。一氧化氮（NO）生物利用度因内皮信号转导改变或与NO反应的活性氧生成增加而降低。内皮功能障碍在治疗上是可逆的，体育锻炼、钙通道阻滞剂、血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂可改善高血压和糖尿病患者血流诱发的内皮依赖性血管舒张。我们研究了三种不同的方法，旨在纠正心血管疾病中的内皮功能障碍。因此，（1）我们评估了一种细胞可渗透的超氧化物歧化酶模拟物tempol对暴露于高压下的小动脉内皮功能障碍的影响，（2）研究了橄榄油成分齐墩果酸诱导血管舒张和NO释放所涉及的内皮信号转导途径，（3）研究了钙激活钾通道在受体激活诱导的NO释放中的作用。Tempol最有可能通过降低活性氧增加高血压动物动脉中的内皮依赖性血管舒张，但其他机制似乎也对此效应有贡献。虽然齐墩果酸通过内皮型一氧化氮合酶的非钙依赖性磷酸化导致NO释放，但内皮钙激活钾通道和钙内流在G蛋白偶联受体诱发的NO释放中起重要作用。因此，所有这三种方法都增加了血管壁中NO的生物利用度，但这些作用在临床水平上是否有任何直接益处仍有待探讨。
