Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats

Fan Zhang, Huan Deng, Rowena Kemp, Harpreet Singh, Venkat Raj Gopal, John R. Falck, Michal Laniado-Schwartzman, Alberto Nasjletti

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Abstract

We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 μmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28±0.07 versus 0.71±0.12 μmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 μmol/L) than WKY (10 μmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.

Original languageEnglish (US)
Pages (from-to)103-108
Number of pages6
JournalHypertension
Volume45
Issue number1
DOIs
StatePublished - Jan 2005

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Cytochrome P-450 CYP2E1
Eicosanoids
Renal Artery
Inbred SHR Rats
Inbred WKY Rats
Phenylephrine
Cytochrome P-450 CYP4A
Blood Vessels
Arteries
Stereoisomerism
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Cytochrome P-450 Enzyme System
19-hydroxy-5,8,11,14-eicosatetraenoic acid
DDMS
18-hydroxy-5,8,11,14-eicosatetraenoic acid

Keywords

  • Kidney
  • Rats, spontaneously hypertensive
  • Vasoconstriction

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats. / Zhang, Fan; Deng, Huan; Kemp, Rowena; Singh, Harpreet; Gopal, Venkat Raj; Falck, John R.; Laniado-Schwartzman, Michal; Nasjletti, Alberto.

In: Hypertension, Vol. 45, No. 1, 01.2005, p. 103-108.

Research output: Contribution to journalArticle

Zhang, Fan ; Deng, Huan ; Kemp, Rowena ; Singh, Harpreet ; Gopal, Venkat Raj ; Falck, John R. ; Laniado-Schwartzman, Michal ; Nasjletti, Alberto. / Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats. In: Hypertension. 2005 ; Vol. 45, No. 1. pp. 103-108.
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abstract = "We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 μmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28±0.07 versus 0.71±0.12 μmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475{\%} and 54{\%} in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 μmol/L) than WKY (10 μmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.",
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AU - Zhang, Fan

AU - Deng, Huan

AU - Kemp, Rowena

AU - Singh, Harpreet

AU - Gopal, Venkat Raj

AU - Falck, John R.

AU - Laniado-Schwartzman, Michal

AU - Nasjletti, Alberto

PY - 2005/1

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N2 - We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 μmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28±0.07 versus 0.71±0.12 μmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 μmol/L) than WKY (10 μmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.

AB - We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 μmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28±0.07 versus 0.71±0.12 μmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 μmol/L) than WKY (10 μmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.

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