Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

Zuzana Honetschlägerová, Kento Kitada, Zuzana Husková, Alexandra Sporková, Libor Kopkan, Marcela Bürgelová, Šárka Varcabová, Akira Nishiyama, Sung Hee Hwang, Bruce D. Hammock, John D. Imig, Herbert J. Kramer, Petr Kujal, Zdenka Vernerová, Luděk Červenka

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)321-332
Number of pages12
JournalJournal of Hypertension
Volume31
Issue number2
DOIs
StatePublished - Feb 2013

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Malignant Hypertension
Epoxide Hydrolases
NG-Nitroarginine Methyl Ester
Antihypertensive Agents
Kidney
Blood Pressure
Acids
Renin-Angiotensin System
Nitric Oxide
Transgenic Rats
Benzoic Acid
Xenobiotics
Nitric Oxide Synthase
Biological Availability
Diet
indole-3-carbinol

Keywords

  • cytochrome P-450 metabolites
  • epoxyeicosatrienoic acids
  • malignant hypertension
  • nitric oxide
  • nitric oxide synthase
  • renin-angiotensin system
  • soluble epoxide hydrolase

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME. / Honetschlägerová, Zuzana; Kitada, Kento; Husková, Zuzana; Sporková, Alexandra; Kopkan, Libor; Bürgelová, Marcela; Varcabová, Šárka; Nishiyama, Akira; Hwang, Sung Hee; Hammock, Bruce D.; Imig, John D.; Kramer, Herbert J.; Kujal, Petr; Vernerová, Zdenka; Červenka, Luděk.

In: Journal of Hypertension, Vol. 31, No. 2, 02.2013, p. 321-332.

Research output: Contribution to journalArticle

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, L 2013, 'Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME', Journal of Hypertension, vol. 31, no. 2, pp. 321-332. https://doi.org/10.1097/HJH.0b013e32835b50aa
Honetschlägerová, Zuzana ; Kitada, Kento ; Husková, Zuzana ; Sporková, Alexandra ; Kopkan, Libor ; Bürgelová, Marcela ; Varcabová, Šárka ; Nishiyama, Akira ; Hwang, Sung Hee ; Hammock, Bruce D. ; Imig, John D. ; Kramer, Herbert J. ; Kujal, Petr ; Vernerová, Zdenka ; Červenka, Luděk. / Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME. In: Journal of Hypertension. 2013 ; Vol. 31, No. 2. pp. 321-332.
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abstract = "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.",
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T1 - Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

AU - Honetschlägerová, Zuzana

AU - Kitada, Kento

AU - Husková, Zuzana

AU - Sporková, Alexandra

AU - Kopkan, Libor

AU - Bürgelová, Marcela

AU - Varcabová, Šárka

AU - Nishiyama, Akira

AU - Hwang, Sung Hee

AU - Hammock, Bruce D.

AU - Imig, John D.

AU - Kramer, Herbert J.

AU - Kujal, Petr

AU - Vernerová, Zdenka

AU - Červenka, Luděk

PY - 2013/2

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N2 - 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.

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KW - epoxyeicosatrienoic acids

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