Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established

a study in Cyp1a1-Ren-2 transgenic rats

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

doi: 10.1097/HJH.0000000000001029
ORIGINAL PAPERS: Pathophysiological aspects

Objective: 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.

Methods: 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.

Results: 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−1 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.

Conclusion: 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.

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

Correspondence to Luděk Červenka, MD, PhD, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 00 Prague 4, Czech Republic. Fax: +420 2 41721666; e-mail:

Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme type 2; ACEi, angiotensin-converting enzyme inhibitor; ANG 1–7, angiotensin-1–7; ANG I, angiotensin I; ANG II, angiotensin II; AT1, receptors for angiotensin II, type 1; BP, blood pressure; BW, body weight; CYP, cytochrome P-450; DHETEs, dihydroxyeicosatrienoic acids; EET-A, epoxyeicosatrienoic acid analog; EETs, epoxyeicosatrienoic acids; ENaC, epithelial sodium channel; GFR, glomerular filtration rate; GSI, glomerulosclerosis index; I3C, indole-3-carbinol; MAP, mean arterial pressure; NO, nitric oxide; NOS, nitric oxide synthase; NOX, nitrate/nitrite; RAS, renin–angiotensin system; RBF, renal blood flow; sEH, soluble epoxide hydrolase; UISO, 8-isoprostane

Received 24 November, 2015

Revised 2 May, 2016

Accepted 2 June, 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.