From the INSERM U644, France.
J Hypertens. 2011 Jun;29(6):1128-35. doi: 10.1097/HJH.0b013e328345ef7b.
The study addresses the hypothesis that endothelial dysfunction in experimental arterial hypertension can be related to an alteration in epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition of EETs degradation by soluble epoxide hydrolase (sEH).
Arterial hypertension was induced in FVB/N mice by renal artery stenosis ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice. Left coronary artery endothelium-dependent relaxations to acetylcholine were decreased in 2K1C mice without modification in the relaxing responses to NS309 and NS1619, the openers of calcium-activated potassium channels mediating the hyperpolarizing effect of EETs. The inhibitors of the EET-synthesizing enzymes cytochrome P450 epoxygenases, fluconazole and N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MSPPOH), reduced the coronary relaxations to acetylcholine in control but not in 2K1C mice. The sEH expression was increased in 2K1C mice. The sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid administered for 2 weeks starting 5 weeks after surgery in 2K1C mice (25 mg/l in drinking water) reduced aortic pressures and cardiac hypertrophy, improved the coronary relaxations to acetylcholine and restored the inhibitory effect of fluconazole and MSPPOH on acetylcholine-induced relaxations, without modifying the relaxations to NS309 and NS1619.
These results demonstrate that a reduced EET-mediated relaxations related to an increased degradation by sEH contributes to coronary endothelial dysfunction in 2K1C hypertensive mice. Inhibiting sEH prevents endothelial dysfunction by restoring EET-mediated relaxations and thus, could represent a promising pharmacological intervention to limit cardiovascular morbidity and mortality in arterial hypertension.
本研究旨在验证内皮功能障碍与环氧二十碳三烯酸（EETs）代谢途径改变之间的关系，并探讨可溶性环氧化物水解酶（sEH）抑制剂是否可以预防实验性动脉高血压中 EETs 代谢途径的改变。
通过肾动脉狭窄（“双肾一夹”，2K1C）诱导 FVB/N 小鼠发生动脉高血压。手术后 7 周，与对照组相比，2K1C 小鼠的主动脉压（使用 Millar 压力计测量；Millar Instruments，休斯顿，得克萨斯州，美国）和心脏肥大（超声心动图）均升高。2K1C 小鼠的左冠状动脉内皮依赖性乙酰胆碱舒张反应减弱，但对 NS309 和 NS1619（介导 EETs 产生超极化作用的钙激活钾通道开放剂）的舒张反应无改变。EET 合成酶细胞色素 P450 环氧合酶的抑制剂氟康唑和 N-甲基磺酰基-6-（2-丙炔氧基苯基）-己酰胺（MSPPOH）可降低对照组小鼠的乙酰胆碱舒张反应，但不能降低 2K1C 小鼠的乙酰胆碱舒张反应。2K1C 小鼠的 sEH 表达增加。从手术后 5 周开始，在 2K1C 小鼠中连续 2 周给予 sEH 抑制剂 12-（3-金刚烷-1-基-脲基）十二烷酸（25 mg/l 饮用水），可降低主动脉压和心脏肥大，改善乙酰胆碱引起的冠状动脉舒张反应，并恢复氟康唑和 MSPPOH 对乙酰胆碱诱导舒张反应的抑制作用，而对 NS309 和 NS1619 的舒张反应无影响。
这些结果表明，sEH 介导的 EET 降解增加导致的 EET 介导的舒张反应减少，与 2K1C 高血压小鼠的冠状动脉内皮功能障碍有关。抑制 sEH 通过恢复 EET 介导的舒张反应来预防内皮功能障碍，因此，可能是限制动脉高血压心血管发病率和死亡率的有前途的药物干预措施。
