Chiamvimonvat Nipavan, Ho Chin-Min, Tsai Hsing-Ju, Hammock Bruce D
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
J Cardiovasc Pharmacol. 2007 Sep;50(3):225-37. doi: 10.1097/FJC.0b013e3181506445.
The soluble epoxide hydrolase appears to be a promising target for the development of antihypertensive therapies based on a previously unexplored mechanism of action. Epoxide hydrolases are enzymes that add water to three membered cyclic ethers known as epoxides. The soluble epoxide hydrolase in mammalian systems (sEH) is a member of the alpha/beta-hydrolase fold family of enzymes and it shows a high degree of selectivity for epoxides of fatty acids. The regioisomeric epoxides of arachidonic acid or epoxyeicosanoids (EETs) are particularly good substrates. These EETs appear to be major components of the endothelium-derived hyperpolarizing factors (EDHFs). As such, EETs cause vasodilation and reduce blood pressure. The EETs also are strongly anti-inflammatory and analgesic. By inhibiting sEH, the increase in circulating EETs leads to a reduction in blood pressure in a number of animal models. Potent transition state mimic inhibitors have been developed for the sEH. Some of these sEH inhibitors (sEHIs) show nanomolar to picomolar potency and good pharmacokinetic properties. Because of their unique mode of action they show promise in treating hypertension while reducing problems with end organ failure, vascular inflammation and diabetes. Indeed, the anti-inflammatory properties of the sEHI may make them particularly suitable for treating hypertension in patients with other concomitant metabolic syndromes. They are more potent on a molar basis than most nonsteroidal anti-inflammatory drugs (NSAIDs) in reducing PGE2 in inflammation models, they strongly synergize with NSAIDs, and appear to ameliorate apparently unfavorable eicosanoid profiles associated with some cyclo-oxygenase-2 inhibitors.
基于一种此前未被探索的作用机制，可溶性环氧化物水解酶似乎是开发抗高血压疗法的一个有前景的靶点。环氧化物水解酶是一种能将水添加到被称为环氧化物的三元环醚上的酶。哺乳动物系统中的可溶性环氧化物水解酶（sEH）是α/β-水解酶折叠家族的成员，它对脂肪酸环氧化物具有高度选择性。花生四烯酸的区域异构体环氧化物或环氧二十碳三烯酸（EETs）是特别好的底物。这些EETs似乎是内皮源性超极化因子（EDHFs）的主要成分。因此，EETs会引起血管舒张并降低血压。EETs还具有很强的抗炎和镇痛作用。通过抑制sEH，循环中EETs的增加会导致多种动物模型中的血压降低。已经开发出了针对sEH的强效过渡态模拟抑制剂。其中一些sEH抑制剂（sEHIs）表现出纳摩尔到皮摩尔的效力以及良好的药代动力学特性。由于其独特的作用方式，它们在治疗高血压的同时减少终末器官衰竭、血管炎症和糖尿病等问题方面显示出前景。事实上，sEHI的抗炎特性可能使其特别适合治疗伴有其他代谢综合征的高血压患者。在炎症模型中，它们在摩尔基础上比大多数非甾体抗炎药（NSAIDs）更有效地降低PGE2，它们与NSAIDs强烈协同作用，并且似乎能改善与某些环氧化酶-2抑制剂相关的明显不利的类花生酸谱。
