Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats

Hui Huang, Yiqiang Zhou, Venugopal T. Raju, Juan Du, Hsin Hsin Chang, Cong Yi Wang, Michael W Brands, John R. Falck, Mong-Heng Wang

Research output: Contribution to journalArticle

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Abstract

We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC50 value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg·kg-1·day-1 iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC50 = 22 μM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after NO inhibition is associated with increased MAP and RVR, whereas decreased GFR is negated by treatment of a selective and competitive CYP4A inhibitor. These results demonstrate that the interaction between renal 20-HETE and NO is important in the regulation of renal function and blood pressure in pregnant rats.

Original languageEnglish (US)
Pages (from-to)F1116-F1122
JournalAmerican Journal of Physiology - Renal Physiology
Volume289
Issue number5 58-5
DOIs
StatePublished - Nov 1 2005

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NG-Nitroarginine Methyl Ester
Hemodynamics
Kidney
Cytochrome P-450 CYP4A
Nitric Oxide
Glomerular Filtration Rate
Vascular Resistance
Renal Circulation
Blood Vessels
Arterial Pressure
Blood Pressure
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Inhibitory Concentration 50
Single Nucleotide Polymorphism
Nitric Oxide Donors
Nitroprusside
Vasoconstrictor Agents
Microsomes
Drinking Water
Up-Regulation

Keywords

  • Arachidonic acid
  • Cytochrome P-450
  • Eicosanoid
  • Hypertension
  • Kidney
  • Nitric oxide
  • Pregnancy

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats. / Huang, Hui; Zhou, Yiqiang; Raju, Venugopal T.; Du, Juan; Chang, Hsin Hsin; Wang, Cong Yi; Brands, Michael W; Falck, John R.; Wang, Mong-Heng.

In: American Journal of Physiology - Renal Physiology, Vol. 289, No. 5 58-5, 01.11.2005, p. F1116-F1122.

Research output: Contribution to journalArticle

Huang, Hui ; Zhou, Yiqiang ; Raju, Venugopal T. ; Du, Juan ; Chang, Hsin Hsin ; Wang, Cong Yi ; Brands, Michael W ; Falck, John R. ; Wang, Mong-Heng. / Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats. In: American Journal of Physiology - Renal Physiology. 2005 ; Vol. 289, No. 5 58-5. pp. F1116-F1122.
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abstract = "We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC50 value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg·kg-1·day-1 iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC50 = 22 μM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after NO inhibition is associated with increased MAP and RVR, whereas decreased GFR is negated by treatment of a selective and competitive CYP4A inhibitor. These results demonstrate that the interaction between renal 20-HETE and NO is important in the regulation of renal function and blood pressure in pregnant rats.",
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AU - Huang, Hui

AU - Zhou, Yiqiang

AU - Raju, Venugopal T.

AU - Du, Juan

AU - Chang, Hsin Hsin

AU - Wang, Cong Yi

AU - Brands, Michael W

AU - Falck, John R.

AU - Wang, Mong-Heng

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KW - Arachidonic acid

KW - Cytochrome P-450

KW - Eicosanoid

KW - Hypertension

KW - Kidney

KW - Nitric oxide

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