Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: A study in Cyp1a1-Ren-2 transgenic rats

Šárka Jíchová, Libor Kopkan, Zuzana Husková, Šárka Doleželová, Jan Neckář, Petr Kujal, Zdenka Vernerová, Herbert J. Kramer, Janusz Sadowski, Elzbieta Kompanowska-Jezierska, Rami N. Reddy, J R Falck, John D. Imig, Luděk Červenka

Research output: Contribution to journalArticle

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Abstract

Objective: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. Methods: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-Angiotensin system (RAS) were determined. Results: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175±3 versus 193±4 mmHg, P<0.05, on day 13), reduced albuminuria (15±1 versus 28±2 mg/24 h, P<0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48±6 versus 106±9 and 122±19 versus 346±11 fmol ml-1or g, respectively, P<0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84±9 versus 37±6 and 199±12 versus 68±9 fmol/ml or g, respectively, P<0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. Conclusion: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

Original languageEnglish (US)
Pages (from-to)2008-2025
Number of pages18
JournalJournal of Hypertension
Volume34
Issue number10
DOIs
StatePublished - 2016

Fingerprint

Malignant Hypertension
Transgenic Rats
Kidney
Renin-Angiotensin System
Acids
Angiotensin II
Blood Pressure
Albuminuria
Wounds and Injuries
Cardiomegaly
Xenobiotics
Renin
Transcriptional Activation
Hypertension
indole-3-carbinol

Keywords

  • Epoxyeicosatrienoic acid analog
  • Malignant hypertension
  • Renal blood flow
  • Renal blood flow autoregulation
  • Renin-Angiotensin system
  • Sodium excretion

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established : A study in Cyp1a1-Ren-2 transgenic rats. / Jíchová, Šárka; Kopkan, Libor; Husková, Zuzana; Doleželová, Šárka; Neckář, Jan; Kujal, Petr; Vernerová, Zdenka; Kramer, Herbert J.; Sadowski, Janusz; Kompanowska-Jezierska, Elzbieta; Reddy, Rami N.; Falck, J R; Imig, John D.; Červenka, Luděk.

In: Journal of Hypertension, Vol. 34, No. 10, 2016, p. 2008-2025.

Research output: Contribution to journalArticle

Jíchová, Š, Kopkan, L, Husková, Z, Doleželová, Š, Neckář, J, Kujal, P, Vernerová, Z, Kramer, HJ, Sadowski, J, Kompanowska-Jezierska, E, Reddy, RN, Falck, JR, Imig, JD & Červenka, L 2016, 'Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: A study in Cyp1a1-Ren-2 transgenic rats', Journal of Hypertension, vol. 34, no. 10, pp. 2008-2025. https://doi.org/10.1097/HJH.0000000000001029
Jíchová, Šárka ; Kopkan, Libor ; Husková, Zuzana ; Doleželová, Šárka ; Neckář, Jan ; Kujal, Petr ; Vernerová, Zdenka ; Kramer, Herbert J. ; Sadowski, Janusz ; Kompanowska-Jezierska, Elzbieta ; Reddy, Rami N. ; Falck, J R ; Imig, John D. ; Červenka, Luděk. / Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established : A study in Cyp1a1-Ren-2 transgenic rats. In: Journal of Hypertension. 2016 ; Vol. 34, No. 10. pp. 2008-2025.
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abstract = "Objective: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. Methods: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-Angiotensin system (RAS) were determined. Results: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175±3 versus 193±4 mmHg, P<0.05, on day 13), reduced albuminuria (15±1 versus 28±2 mg/24 h, P<0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48±6 versus 106±9 and 122±19 versus 346±11 fmol ml-1or g, respectively, P<0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84±9 versus 37±6 and 199±12 versus 68±9 fmol/ml or g, respectively, P<0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. Conclusion: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.",
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T2 - A study in Cyp1a1-Ren-2 transgenic rats

AU - Jíchová, Šárka

AU - Kopkan, Libor

AU - Husková, Zuzana

AU - Doleželová, Šárka

AU - Neckář, Jan

AU - Kujal, Petr

AU - Vernerová, Zdenka

AU - Kramer, Herbert J.

AU - Sadowski, Janusz

AU - Kompanowska-Jezierska, Elzbieta

AU - Reddy, Rami N.

AU - Falck, J R

AU - Imig, John D.

AU - Červenka, Luděk

PY - 2016

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N2 - Objective: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. Methods: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-Angiotensin system (RAS) were determined. Results: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175±3 versus 193±4 mmHg, P<0.05, on day 13), reduced albuminuria (15±1 versus 28±2 mg/24 h, P<0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48±6 versus 106±9 and 122±19 versus 346±11 fmol ml-1or g, respectively, P<0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84±9 versus 37±6 and 199±12 versus 68±9 fmol/ml or g, respectively, P<0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. Conclusion: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

AB - Objective: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. Methods: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-Angiotensin system (RAS) were determined. Results: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175±3 versus 193±4 mmHg, P<0.05, on day 13), reduced albuminuria (15±1 versus 28±2 mg/24 h, P<0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48±6 versus 106±9 and 122±19 versus 346±11 fmol ml-1or g, respectively, P<0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84±9 versus 37±6 and 199±12 versus 68±9 fmol/ml or g, respectively, P<0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. Conclusion: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

KW - Epoxyeicosatrienoic acid analog

KW - Malignant hypertension

KW - Renal blood flow

KW - Renal blood flow autoregulation

KW - Renin-Angiotensin system

KW - Sodium excretion

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