20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: A study in Cyp1a1-Ren-2 transgenic rats

Lenka Sedláková, Soňa Kikerlová, Zuzana Husková, Lenka Červenková, Věra Čertíková Chábová, Josef Zicha, John R. Falck, John D. Imig, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, Vojtěch Krátký, Luděk Červenka, Libor Kopkan

Research output: Contribution to journalArticle

Abstract

We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 + 3 compared with 199 + 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy (P<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 + 14 compared with 52 + 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (72 + 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 + 4 to 158 + 4 mmHg, P<0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.

LanguageEnglish (US)
Article numberBSR20171496
JournalBioscience Reports
Volume38
Issue number5
DOIs
StatePublished - Sep 12 2018

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Malignant Hypertension
Transgenic Rats
Angiotensin II
Rats
Blood Pressure
Blood pressure
Hypertension
Kidney
Cytochrome P-450 CYP4A
Chemical activation
Albuminuria
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Cardiomegaly
Xenobiotics
Renin
Cytochrome P-450 Enzyme System
Antihypertensive Agents
Transcriptional Activation
Blood Vessels
Genes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established : A study in Cyp1a1-Ren-2 transgenic rats. / Sedláková, Lenka; Kikerlová, Soňa; Husková, Zuzana; Červenková, Lenka; Chábová, Věra Čertíková; Zicha, Josef; Falck, John R.; Imig, John D.; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Krátký, Vojtěch; Červenka, Luděk; Kopkan, Libor.

In: Bioscience Reports, Vol. 38, No. 5, BSR20171496, 12.09.2018.

Research output: Contribution to journalArticle

Sedláková, L, Kikerlová, S, Husková, Z, Červenková, L, Chábová, VČ, Zicha, J, Falck, JR, Imig, JD, Kompanowska-Jezierska, E, Sadowski, J, Krátký, V, Červenka, L & Kopkan, L 2018, '20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: A study in Cyp1a1-Ren-2 transgenic rats' Bioscience Reports, vol. 38, no. 5, BSR20171496. https://doi.org/10.1042/BSR20171496
Sedláková, Lenka ; Kikerlová, Soňa ; Husková, Zuzana ; Červenková, Lenka ; Chábová, Věra Čertíková ; Zicha, Josef ; Falck, John R. ; Imig, John D. ; Kompanowska-Jezierska, Elzbieta ; Sadowski, Janusz ; Krátký, Vojtěch ; Červenka, Luděk ; Kopkan, Libor. / 20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established : A study in Cyp1a1-Ren-2 transgenic rats. In: Bioscience Reports. 2018 ; Vol. 38, No. 5.
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AU - Červenková, Lenka

AU - Chábová, Věra Čertíková

AU - Zicha, Josef

AU - Falck, John R.

AU - Imig, John D.

AU - Kompanowska-Jezierska, Elzbieta

AU - Sadowski, Janusz

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