An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension
An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension
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DOI：
10.1161/01.hyp.0000176237.74820.75
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发表时间：
2005-10-01
期刊：
影响因子：
8.3
通讯作者：
Hammock, BD
中科院分区：
文献类型：
--
作者：
Imig, JD;Zhao, XY;Hammock, BD
本研究验证了盐敏感型高血压患者通过抑制可溶性环氧化物水解酶(SEH)而增加环氧二十碳三烯酸可降低血压和改善肾损害的假说。大鼠静脉注射血管紧张素，分别以正常盐饮食或8%氯化钠饮食喂养14天。在14天的时间里，sEH抑制剂12-(3-金刚烷-1-基-脲)-十二酸(Auda)被口服给注射了血管紧张素的动物。测定血浆AUDA代谢物水平，给药后第14天，正常盐型血管紧张素性高血压平均为10+/-2 ng/mL，高盐型血管紧张素性高血压平均为193 ng/mL。高盐血管紧张素高血压组第14天平均动脉压为161+/-4 mm Hg，高盐血管紧张素高血压组平均动脉压为172+/-5 mm Hg。EH抑制剂治疗后，正常盐血管紧张素高血压组血压在第14天降至140+/-5 mm Hg，高盐血管紧张素高血压组在第14天降至151+/-6 mm Hg。测定尿微量白蛋白水平，并用ED-1染色检测肾损害和巨噬细胞浸润情况。奥达治疗2周后，正常盐和高盐血管紧张素高血压组尿微量白蛋白排泄量减少，高盐血管紧张素高血压组巨噬细胞数减少。这些数据表明，抑制sEH可降低血管紧张素依赖型、盐敏感型高血压患者的血压并改善肾脏损害。
The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10 +/- 2 ng/mL in normal-salt angiotensin hypertension and 19 3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161 +/- 4 mmHg in normal-salt and 172 +/- 5 mmHg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140 +/- 5 mm Hg in the normal-salt angiotensin hypertension group and to 151 +/- 6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension.