An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats
An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats
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DOI：
10.1097/01.fjc.0000189600.74157.6d
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发表时间：
2005-12-01
影响因子：
3
通讯作者：
Imig, JD
中科院分区：
文献类型：
--
作者：
Dorrance, AM;Rupp, N;Imig, JD
可溶性环氧化物水解酶（sEH）抑制剂已被证明具有心血管保护作用。这种水解酶将脂肪酸环氧化物转化为它们相应的二醇，并且这种转化可以改变这些代谢物的生物活性。我们假设sEH抑制剂12-（3-金刚烷-1-基-脲基）十二烷酸（AUDA）可以保护易中风的自发性高血压大鼠免受脑缺血的影响。给6周龄雄性大鼠施用AUDA 6周，在此期间通过遥测测量血压。通过大脑中动脉闭塞诱导脑缺血，在缺血6小时后评估脑梗塞的大小，结果表示为半球梗塞的百分比（%HI）。使用加压动脉造影术评估血管结构和功能。治疗期结束时AUDA的血浆水平平均为5.0 +/- 0.4 ng/mL，尿排泄率为99 +/- 21 ng/d。AUDA处理的大鼠具有比对照大鼠显著更小的脑梗死（36 +/-4%vs 53 +/-4%HI，处理vs对照，P < 0.05，n = 6）。这种差异与血压的变化无关。AUDA治疗增加了脑血管的被动顺应性，但对血管结构没有影响。这项研究的结果提供了新的证据，表明sEH抑制剂AUDA是一种可能的治疗缺血性卒中的药物。
Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 +/- 0.4 ng/mL, and the urinary excretion rate was 99 +/- 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 +/- 4% vs 53 +/- 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.