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

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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

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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

Cite this

Honetschlägerová, Z., Sporková, A., Kopkan, L., Husková, Z., Hwang, S. H., Hammock, B. D., Imig, J. D., Kramer, H. J., Kujal, P., Vernerová, Z., Chábová, V. Č., Tesař, V., & Červenka, L. (2011). 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. Journal of Hypertension, 29(8), 1590-1601. https://doi.org/10.1097/HJH.0b013e328349062f