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Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

Honetschlägerová, Zuzanaa; Kitada, Kentob; Husková, Zuzanaa; Sporková, Alexandraa; Kopkan, Libora; Bürgelová, Marcelaa; Varcabová, Šárkaa; Nishiyama, Akirab; Hwang, Sung Heec; Hammock, Bruce D.c; Imig, John D.d; Kramer, Herbert J.e; Kujal, Petra,f; Vernerová, Zdenkaa,f; Červenka, Luděka,g

doi: 10.1097/HJH.0b013e32835b50aa
ORIGINAL PAPERS: Pathophysiological aspects

Objective: The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent.

Methods: ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48 h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin–angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured.

Results: Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio.

Conclusion: Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.

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aCenter for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

bDepartment of Pharmacology, Kagawa University, Kagawa, Japan

cDepartment of Entomology and UCD Cancer Center, University of California, Davis, One Shields Avenue, Davis, California

dDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Wisconsin, USA

eSection of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany

fDepartment of Pathology, 3rd Faculty of Medicine

gDepartment of Physiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

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: +4202 41721666; e-mail:

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ANG II, angiotensin II; AT1, receptors for angiotensin II, type 1; BP, blood pressure; c-AUCB, cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid; CYP, cytochrome P-450; DHETEs, dihydroxyeicosatrienoic acids; EETs, epoxyeicosatrienoic acids; GFR, glomerular filtration rate; GSI, glomerulosclerosis index; I3C, indole-3-carbinol; L-NAME, Nω-nitro-L-arginine methyl ester; 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 21 March, 2012

Revised 18 September, 2012

Accepted 9 October, 2012

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