Oxidative stress induces BH 4 deficiency in male, but not female, SHR

Ellen E. Gillis, Krystal N. Brinson, Olga Rafikova, Wei Chen, Jacqueline B. Musall, David G. Harrison, Jennifer C Sullivan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH 4 ) is a critical cofactor required for NO generation, and decreases in BH 4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH 4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH 2 ), and BH 4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH 4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH 4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH 4 compared with females, resulting in diminished renal NOS activity in the male.

Original languageEnglish (US)
Article numberBSR20180111
JournalBioscience Reports
Volume38
Issue number4
DOIs
StatePublished - Jul 3 2018

Fingerprint

Oxidative stress
Inbred SHR Rats
Nitric Oxide Synthase
Rats
Oxidative Stress
Kidney
Nitric Oxide
Biopterin
Sex Characteristics
Peroxynitrous Acid
Blood pressure
Drinking Water
Assays
Biological Availability
tempol
Blood Pressure
Hypertension

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gillis, E. E., Brinson, K. N., Rafikova, O., Chen, W., Musall, J. B., Harrison, D. G., & Sullivan, J. C. (2018). Oxidative stress induces BH 4 deficiency in male, but not female, SHR Bioscience Reports, 38(4), [BSR20180111]. https://doi.org/10.1042/BSR20180111

Oxidative stress induces BH 4 deficiency in male, but not female, SHR . / Gillis, Ellen E.; Brinson, Krystal N.; Rafikova, Olga; Chen, Wei; Musall, Jacqueline B.; Harrison, David G.; Sullivan, Jennifer C.

In: Bioscience Reports, Vol. 38, No. 4, BSR20180111, 03.07.2018.

Research output: Contribution to journalArticle

Gillis, EE, Brinson, KN, Rafikova, O, Chen, W, Musall, JB, Harrison, DG & Sullivan, JC 2018, ' Oxidative stress induces BH 4 deficiency in male, but not female, SHR ', Bioscience Reports, vol. 38, no. 4, BSR20180111. https://doi.org/10.1042/BSR20180111
Gillis EE, Brinson KN, Rafikova O, Chen W, Musall JB, Harrison DG et al. Oxidative stress induces BH 4 deficiency in male, but not female, SHR Bioscience Reports. 2018 Jul 3;38(4). BSR20180111. https://doi.org/10.1042/BSR20180111
Gillis, Ellen E. ; Brinson, Krystal N. ; Rafikova, Olga ; Chen, Wei ; Musall, Jacqueline B. ; Harrison, David G. ; Sullivan, Jennifer C. / Oxidative stress induces BH 4 deficiency in male, but not female, SHR In: Bioscience Reports. 2018 ; Vol. 38, No. 4.
@article{6354ef5fbdd14302b982a0485733fd37,
title = "Oxidative stress induces BH 4 deficiency in male, but not female, SHR",
abstract = "We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH 4 ) is a critical cofactor required for NO generation, and decreases in BH 4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH 4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH 2 ), and BH 4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH 4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH 4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH 4 compared with females, resulting in diminished renal NOS activity in the male.",
author = "Gillis, {Ellen E.} and Brinson, {Krystal N.} and Olga Rafikova and Wei Chen and Musall, {Jacqueline B.} and Harrison, {David G.} and Sullivan, {Jennifer C}",
year = "2018",
month = "7",
day = "3",
doi = "10.1042/BSR20180111",
language = "English (US)",
volume = "38",
journal = "Bioscience Reports",
issn = "0144-8463",
publisher = "Portland Press Ltd.",
number = "4",

}

TY - JOUR

T1 - Oxidative stress induces BH 4 deficiency in male, but not female, SHR

AU - Gillis, Ellen E.

AU - Brinson, Krystal N.

AU - Rafikova, Olga

AU - Chen, Wei

AU - Musall, Jacqueline B.

AU - Harrison, David G.

AU - Sullivan, Jennifer C

PY - 2018/7/3

Y1 - 2018/7/3

N2 - We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH 4 ) is a critical cofactor required for NO generation, and decreases in BH 4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH 4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH 2 ), and BH 4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH 4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH 4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH 4 compared with females, resulting in diminished renal NOS activity in the male.

AB - We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH 4 ) is a critical cofactor required for NO generation, and decreases in BH 4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH 4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH 2 ), and BH 4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH 4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH 4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH 4 compared with females, resulting in diminished renal NOS activity in the male.

UR - http://www.scopus.com/inward/record.url?scp=85049504043&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049504043&partnerID=8YFLogxK

U2 - 10.1042/BSR20180111

DO - 10.1042/BSR20180111

M3 - Article

C2 - 29899168

AN - SCOPUS:85049504043

VL - 38

JO - Bioscience Reports

JF - Bioscience Reports

SN - 0144-8463

IS - 4

M1 - BSR20180111

ER -