Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME. J Hypertens 2013 Feb;31(2):321-32
Date
01/12/2013Pubmed ID
23307303Pubmed Central ID
PMC3773167DOI
10.1097/HJH.0b013e32835b50aaScopus ID
2-s2.0-84872851462 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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.
Author List
Honetschlägerová Z, Kitada K, Husková Z, Sporková A, Kopkan L, Bürgelová M, Varcabová Š, Nishiyama A, Hwang SH, Hammock BD, Imig JD, Kramer HJ, Kujal P, Vernerová Z, Červenka LMESH terms used to index this publication - Major topics in bold
Angiotensin IIAnimals
Antihypertensive Agents
Blood Pressure
Enzyme Inhibitors
Epoxide Hydrolases
Hypertension
Kidney
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase
Rats
Rats, Transgenic
Thiobarbituric Acid Reactive Substances
