Key result
Tempol treatment in male spontaneously hypertensive rats reduced peroxynitrite levels and eliminated sex differences in renal inner medulla BH4 levels and NOS activity compared to females.
Higher oxidative stress in male SHR causes a relative BH4 deficiency compared to females, leading to diminished renal NOS activity, which is reversed by the antioxidant tempol.
Supports oxidative stress as driver of sex differences in renal NOS activity in hypertensive rats; leaves open clinical relevance pending human data.
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 (BH4) is a critical cofactor required for NO generation, and decreases in BH4 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 BH4 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 (BH2), and BH4 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 BH4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH4 compared with females, resulting in diminished renal NOS activity in the male.
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Gillis et al. (2018) studied Hypertension (spontaneously hypertensive rats). Tempol vs. Vehicle was evaluated on Peroxynitrite levels, BH4 levels, and total NOS activity in the renal inner medulla. Tempol treatment in male spontaneously hypertensive rats reduced peroxynitrite levels and eliminated sex differences in renal inner medulla BH4 levels and NOS activity compared to females.
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