Dietary nitrate supplementation enhances cerebrovascular CO₂ reactivity in a sex-specific manner

Abstract

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.

Cerebrovascular responses to graded exercise in young healthy males and females

“…4D-MRI analysis of the major cerebral arteries during hypercapnia has found young males to have a greater cerebral vascular reactivity than young females (Miller et al, 2019). However, this finding is not consistent especially in studies that have measured CBF with TCD (Fan et al, 2019;Madureira et al, 2017;Peltonen et al, 2015). In our study, the ΔEtCO 2 responses were similar between the sexes as exercise intensity increased (Figure 2h).…”

“…Doing this allowed for comparison of models and to aid in the explanation of cerebrovascular differences between males and females. Comparing the sex-specific model β coefficients using a Z score (Paternoster et al, 2016) (Fan et al, 2019;Kastrup et al, 1998); however, this is not universally accepted (Miller et al, 2019;Peltonen et al, 2015). This analysis is in line with the former, showing females increased MCAv to a greater extent for every change in EtCO 2 (mmHg), Table 3 and Table 4.…”

“…Additionally, females and males differentially increased MCAv in response to EtCO 2 (10.61 vs. 1.51 coefficients). Many studies demonstrate females have a greater MCAv response to P a CO 2 changes (Fan et al., 2019; Kastrup et al., 1998); however, this is not universally accepted (Miller et al., 2019; Peltonen et al., 2015). This analysis is in line with the former, showing females increased MCAv to a greater extent for every change in EtCO 2 (mmHg), Table 3 and Table 4.…”

Dietary nitrate supplementation effect on dynamic cerebral autoregulation in normoxia and acute hypoxia

“…Previous research has shown the thigh-cuff method, which imposes a large and abrupt change in blood pressure, is more sensitive to interventions, such as hypoxia, than transfer function analysis that examines spontaneous fluctuations in blood pressure. 26 The importance of using these methods is emphasised when considering the only other study to have examined dietary nitrate supplementation on dynamic CA in normoxia reported inconclusive effects 31 that may have resulted from using TCD and transfer function analysis, which is a less sensitive method to assess dynamic CA than used in the present study.…”

The Utility of Cerebrovascular Reactivity MRI in Brain Rehabilitation: A Mechanistic Perspective

“…Dietary and pharmacologic strategies that improve NO bioavailability have been shown to improve CVR. Seven days of dietary nitrate supplementation (an NO donor) improves CVR in young adults in a sex-specific manner (Fan et al, 2019). In a similar vein, statins have also improved CVR (Sander et al, 2005), likely through a NO-dependent mechanism (Yamada et al, 2000).…”