Dietary nitrate supplementation enhances cerebrovascular CO 2 reactivity in a sex-specific manner

J Appl Physiol (1985). 2019 Sep 1;127(3):760-769. doi: 10.1152/japplphysiol.01116.2018. Epub 2019 Jul 18.


Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day -1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% (P < 0.001) and lowered gain (d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment (d = 0.7, P = 0.043), while coherence was unaffected (P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men (d = 1.0, P = 0.014 vs. placebo), but had no effect in women (P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function.NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels' response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.

Keywords: cerebral CO2 reactivity; cerebral blood flow; cerebrovascular autoregulation; dietary nitrate supplementation; nitric oxide.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Pressure
  • Carbon Dioxide / pharmacology*
  • Cardiorespiratory Fitness
  • Cerebrovascular Circulation / drug effects*
  • Cross-Over Studies
  • Dietary Supplements
  • Female
  • Homeostasis / drug effects
  • Humans
  • Male
  • Neuroprotection
  • Nitrates / blood
  • Nitrates / pharmacology*
  • Nitrites / blood
  • Prefrontal Cortex / metabolism
  • Sex Characteristics*
  • Vascular Stiffness
  • Young Adult


  • Nitrates
  • Nitrites
  • Carbon Dioxide
  • sodium nitrate