Role of cytochrome P-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats

Alexandra Sporková, Libor Kopkan, Šárka Varcabová, Zuzana Husková, Sung Hee Hwang, Bruce D. Hammock, John D. Imig, Herbert J. Kramer, Luděk Červenka

Research output: Contribution to journalArticle

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Abstract

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexy-loxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min-1·g-1). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min-1·g-1). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min-1·g-1). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

Original languageEnglish (US)
Pages (from-to)1468-1475
Number of pages8
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number6
DOIs
StatePublished - Jun 2011

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Renal Circulation
Surgical Instruments
Cytochrome P-450 Enzyme System
Blood Pressure
Kidney
Natriuresis
Glomerular Filtration Rate
Arterial Pressure
Homeostasis
Sodium
Hypertension
Natriuretic Agents
Epoxide Hydrolases
Benzoic Acid
Antihypertensive Agents
Biological Availability
N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine
Pressure
Acids

Keywords

  • Autoregulation
  • Blood pressure
  • Cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid
  • Cytochrome P-450 metabolites
  • Epoxyeicosatrienoic acids
  • Glomerular filtration rate
  • HET-0016
  • Hydroxyeicosatrienoic acids
  • Renal blood flow
  • Renal functions
  • Renovascular hypertension

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Role of cytochrome P-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats. / Sporková, Alexandra; Kopkan, Libor; Varcabová, Šárka; Husková, Zuzana; Hwang, Sung Hee; Hammock, Bruce D.; Imig, John D.; Kramer, Herbert J.; Červenka, Luděk.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 300, No. 6, 06.2011, p. 1468-1475.

Research output: Contribution to journalArticle

Sporková, Alexandra ; Kopkan, Libor ; Varcabová, Šárka ; Husková, Zuzana ; Hwang, Sung Hee ; Hammock, Bruce D. ; Imig, John D. ; Kramer, Herbert J. ; Červenka, Luděk. / Role of cytochrome P-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2011 ; Vol. 300, No. 6. pp. 1468-1475.
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AU - Sporková, Alexandra

AU - Kopkan, Libor

AU - Varcabová, Šárka

AU - Husková, Zuzana

AU - Hwang, Sung Hee

AU - Hammock, Bruce D.

AU - Imig, John D.

AU - Kramer, Herbert J.

AU - Červenka, Luděk

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N2 - Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexy-loxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min-1·g-1). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min-1·g-1). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min-1·g-1). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

AB - Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexy-loxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min-1·g-1). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min-1·g-1). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min-1·g-1). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

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KW - Blood pressure

KW - Cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid

KW - Cytochrome P-450 metabolites

KW - Epoxyeicosatrienoic acids

KW - Glomerular filtration rate

KW - HET-0016

KW - Hydroxyeicosatrienoic acids

KW - Renal blood flow

KW - Renal functions

KW - Renovascular hypertension

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