Inhibition of soluble epoxide hydrolase improves the impaired pressure-natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

Zuzana Honetschlägerová, Alexandra Sporková, Libor Kopkan, Zuzana Husková, Sung H. Hwang, Bruce D. Hammock, John D. Imig, Herbert J. Kramer, Petr Kujal, Zdenka Vernerová, Věra Č Chábová, Vladimír Tesař, Luděk Červenka

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Objective: In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. Methods:Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. Results: I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. Conclusion: Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

Original languageEnglish (US)
Pages (from-to)1590-1601
Number of pages12
JournalJournal of Hypertension
Volume29
Issue number8
DOIs
StatePublished - Aug 2011

Keywords

  • AT receptor antagonist
  • cytochrome P-450 metabolites
  • epoxyeicosatrienoic acids
  • malignant hypertension
  • renal autoregulation
  • renin-angiotensin system
  • sodium excretion
  • soluble epoxide hydrolase

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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