Jíchová Šárka, Kopkan Libor, Husková Zuzana, Doleželová Šárka, Neckář Jan, Kujal Petr, Vernerová Zdenka, Kramer Herbert J, Sadowski Janusz, Kompanowska-Jezierska Elzbieta, Reddy Rami N, Falck John R, Imig John D, Červenka Luděk
aCenter for Experimental Medicine, Institute for Clinical and Experimental Medicine bDepartment of Pathophysiology, 2nd Faculty of Medicine, Charles University cDepartment of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic dSection of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany eDepartment of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland fDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas gDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Hypertens. 2016 Oct;34(10):2008-25. doi: 10.1097/HJH.0000000000001029.
We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension.
Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined.
In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected.
The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.
我们评估了一种新型口服活性环氧二十碳三烯酸类似物（EET-A）对血管紧张素II（ANG II）依赖性恶性高血压大鼠的治疗效果。
使用天然外源性物质吲哚-3-甲醇（I3C）激活肾素基因，在Cyp1a1-Ren-2转基因大鼠中诱导产生恶性高血压。EET-A治疗在I3C诱导过程中同时开始（早期治疗）或在高血压形成10天后开始（晚期治疗）。测定血压（BP）（无线电遥测）、肾和心脏损伤指标以及肾素-血管紧张素系统（RAS）各组分的血浆和肾脏水平。
在I3C诱导的高血压大鼠中，与未治疗的I3C诱导大鼠相比，早期EET-A治疗减轻了血压升高（第13天为175±3 mmHg，而未治疗组为193±4 mmHg，P<0.05），降低了蛋白尿（15±1 mg/24 h，而未治疗组为28±2 mg/24 h，P<0.05）以及心脏肥大。这与血浆和肾脏ANG II水平的抑制有关（分别为48±6与106±9以及122±19与346±11 fmol/ml或g，P<0.05），并且血浆和肾脏血管紧张素（1-7）浓度升高（分别为84±9与37±6以及199±12与68±9 fmol/ml或g，P<0.05）。值得注意的是，晚期EET-A治疗并未降低血压或改善肾和心脏损伤；RAS活性指标未受影响。
新型口服活性EET-A减轻了实验性ANG II依赖性恶性高血压的发展，可能是通过抑制致高血压轴并增强RAS的血管舒张/利钠轴来实现的。
