Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula.
Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula.
复制标题
DOI：
10.33549/physiolres.932977
复制
发表时间：
2015
影响因子：
2.1
通讯作者：
Sadowski J
中科院分区：
文献类型：
--
作者：
Červenka L;Melenovský V;Husková Z;Sporková A;Bürgelová M;Škaroupková P;Hwang SH;Hammock BD;Imig JD;Sadowski J
决定充血性心力衰竭（CHF）和相关肾功能不全过程的详细机制仍不清楚。在建立汉诺威Sprague-Dawley（HanSD）大鼠下腔静脉瘘（ACF）诱导的CHF容量超负荷模型中，我们探讨了花生四烯酸代谢途径的活性产物--环氧二十碳三烯酸（Epoxyeicosatrienoic acids，ESTs）的致病作用，并将其与肾素-血管紧张素系统（RAS）的作用进行了比较。顺式-4-[4-（3-金刚烷-1-基-脲基）环己基氧基]苯甲酸（c-AUCB，3 mg/L，饮用水溶液）（一种通常降解雌二醇的可溶性环氧化物水解酶（sEH）抑制剂）的长期给药使肾内和心肌雌二醇增加至假手术HanSD大鼠中观察到的水平，但未改善存活率或肾功能损害。相反，慢性血管紧张素转换酶抑制剂（ACEi，群多普利，6 mg/L饮用水）增加肾血流量，钠排泄分数和显著改善生存，而不影响左心室结构和性能。因此，肾功能不全，而不是心脏重塑决定长期死亡率在晚期CHF由于容量超负荷。ACEi的强保护作用与循环血液和肾组织中血管收缩/钠保留轴的抑制和血管舒张/肾素-血管紧张素系统的利钠轴的激活有关。
The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/L in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.