Larsen B T, Gutterman D D, Hatoum O A
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Veterans Administration Medical Center, Milwaukee, WI 53226, USA.
Eur J Clin Invest. 2006 May;36(5):293-300. doi: 10.1111/j.1365-2362.2006.01634.x.
The importance of endothelium-derived nitric oxide in coronary vascular regulation is well-established and the loss of this vasodilator compound is associated with endothelial dysfunction, tissue hypoperfusion and atherosclerosis. Numerous studies indicate that the endothelium produces another class of compounds, the epoxyeicosatrienoic acids (EETs), which may partially compensate for the loss of nitric oxide in cardiovascular disease. The EETs are endogenous lipids which are derived through the metabolism of arachidonic acid by cytochrome P450 epoxygenase enzymes. Also, EETs hyperpolarize vascular smooth muscle and induce dilation of coronary arteries and arterioles, and therefore may be endogenous mediators of coronary vasomotor tone and myocardial perfusion. In addition, EETs have been shown to inhibit vascular smooth muscle migration, decrease inflammation, inhibit platelet aggregation and decrease adhesion molecule expression, therefore representing an endogenous protective mechanism against atherosclerosis. Endogenous EETs are degraded to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase. Pharmacological inhibition of soluble epoxide hydrolase has received considerable attention as a potential approach to enhance EET-mediated vascular protection, and several compounds have appeared promising in recent animal studies. The present review discusses the emerging role of EETs in coronary vascular function, as well as recent advancements in the development of pharmacological agents to enhance EET bioavailability.
内皮衍生的一氧化氮在冠状动脉血管调节中的重要性已得到充分证实，这种血管舒张化合物的缺失与内皮功能障碍、组织灌注不足和动脉粥样硬化有关。大量研究表明，内皮会产生另一类化合物，即环氧二十碳三烯酸（EETs），它们可能在心血管疾病中部分补偿一氧化氮的缺失。EETs是内源性脂质，由细胞色素P450环氧化酶通过花生四烯酸代谢产生。此外，EETs可使血管平滑肌超极化，并诱导冠状动脉和小动脉扩张，因此可能是冠状动脉血管舒缩张力和心肌灌注的内源性介质。此外，EETs已被证明可抑制血管平滑肌迁移、减轻炎症、抑制血小板聚集并降低黏附分子表达，因此代表了一种针对动脉粥样硬化的内源性保护机制。内源性EETs会被可溶性环氧化物水解酶降解为活性较低的二羟基二十碳三烯酸。作为增强EET介导的血管保护的一种潜在方法，可溶性环氧化物水解酶的药理学抑制已受到相当多的关注，并且在最近的动物研究中，几种化合物已显示出前景。本综述讨论了EETs在冠状动脉血管功能中的新作用，以及增强EET生物利用度的药物开发的最新进展。
