Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1-Ren-2 transgenic rats

Alexandra Sporková, Šárka Jíchová, Zuzana Husková, Libor Kopkan, Akira Nishiyama, Sung H. Hwang, Bruce D. Hammock, John D. Imig, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, Herbert J. Kramer, Luděk Červenka

Research output: Contribution to journalArticle

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Abstract

Summary: Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.

Original languageEnglish (US)
Pages (from-to)1003-1013
Number of pages11
JournalClinical and Experimental Pharmacology and Physiology
Volume41
Issue number12
DOIs
StatePublished - Dec 1 2014

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Transgenic Rats
Epoxide Hydrolases
Angiotensin II
Antihypertensive Agents
Benzoic Acid
Blood Pressure
Acids
Kidney
Malignant Hypertension
Hypertension
Natriuresis
Xenobiotics
Renin-Angiotensin System
Renin
Drinking Water
indole-3-carbinol

Keywords

  • Angiotensin-II
  • Cytochrome P-450 epoxygenase
  • Eicosanoids
  • Epoxyeicosatrienoic acids
  • Hypertension
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Pharmacology

Cite this

Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition : Studies in Cyp1a1-Ren-2 transgenic rats. / Sporková, Alexandra; Jíchová, Šárka; Husková, Zuzana; Kopkan, Libor; Nishiyama, Akira; Hwang, Sung H.; Hammock, Bruce D.; Imig, John D.; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kramer, Herbert J.; Červenka, Luděk.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 41, No. 12, 01.12.2014, p. 1003-1013.

Research output: Contribution to journalArticle

Sporková, A, Jíchová, Š, Husková, Z, Kopkan, L, Nishiyama, A, Hwang, SH, Hammock, BD, Imig, JD, Kompanowska-Jezierska, E, Sadowski, J, Kramer, HJ & Červenka, L 2014, 'Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1-Ren-2 transgenic rats', Clinical and Experimental Pharmacology and Physiology, vol. 41, no. 12, pp. 1003-1013. https://doi.org/10.1111/1440-1681.12310
Sporková, Alexandra ; Jíchová, Šárka ; Husková, Zuzana ; Kopkan, Libor ; Nishiyama, Akira ; Hwang, Sung H. ; Hammock, Bruce D. ; Imig, John D. ; Kompanowska-Jezierska, Elzbieta ; Sadowski, Janusz ; Kramer, Herbert J. ; Červenka, Luděk. / Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition : Studies in Cyp1a1-Ren-2 transgenic rats. In: Clinical and Experimental Pharmacology and Physiology. 2014 ; Vol. 41, No. 12. pp. 1003-1013.
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AU - Husková, Zuzana

AU - Kopkan, Libor

AU - Nishiyama, Akira

AU - Hwang, Sung H.

AU - Hammock, Bruce D.

AU - Imig, John D.

AU - Kompanowska-Jezierska, Elzbieta

AU - Sadowski, Janusz

AU - Kramer, Herbert J.

AU - Červenka, Luděk

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N2 - Summary: Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.

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KW - Cytochrome P-450 epoxygenase

KW - Eicosanoids

KW - Epoxyeicosatrienoic acids

KW - Hypertension

KW - Soluble epoxide hydrolase

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