Sympathetic nerve activity and blood pressure: who leads, who follows and why sex matters

In 1972, Delius and colleagues reported a strong and inverse relationship between muscle sympathetic nerve activity (MSNA) and intra-arterial blood pressure in humans that the authors attributed to the arterial baroreflex (Delius et al. 1972). Over the years, the quantification of sympathetic baroreflex sensitivity (BRS) has undergone a number of iterations, including pharmacological (e.g. modified Oxford) and non-pharmacological (e.g. spontaneous binning/sequencing) methods using time domain analyses. These traditional sympathetic BRS approaches within the time domain assume a closed loop system in which bursts of MSNA are continuously responding to increases or decreases in beat-to-beat diastolic arterial pressure (DAP). A less common alternative approach is the utilization of frequency domain analysis to examine the low frequency coherence of MSNA and beat-to-beat DAP. Low frequency coherence analysis provides an index of the ‘strength’ of the linear relationship between two signals at specific oscillatory frequencies; in this case, oscillations of MSNA and DAP at frequencies lower than respiration. Moreover, this spectral approach provides a quantifiable measure of ‘phase angle’, which provides an unbiased estimate of which signal is leading, and which is responding. Cooke et al. (2009) demonstrated a strong DAP–MSNA coherence and positive phase angle during supine rest in a cohort of mostly young, healthy men, suggesting that under resting conditions changes in DAP were primarily responding to changes in MSNA. Interestingly, during a progressive orthostatic challenge, the DAP–MSNA coherence strengthened progressively and the phase angle shifted from positive to negative, suggesting that the relationship reversed and changes in MSNA were primarily responding to changes in DAP. These findings reaffirm a fundamental complexity regarding MSNA and blood pressure – sometimes MSNA is the leader, sometimes it is the follower; and in some cases, the association between DAP and MSNA is weak or even non-existent, and may depend importantly on sex and age. Yang et al. (2012) recently applied the DAP–MSNA coherence analysis to a cohort of young, healthy men and women, with a particular focus on sex differences. The men in the study by Yang et al. responded in agreement with Cooke et al. (2009), with a strong DAP–MSNA coherence that became progressively stronger during a graded orthostatic stress. In contrast, the DAP–MSNA coherence in the women was significantly lower than men at rest, and did not increase as aggressively during the orthostatic challenge when compared to men. The stronger DAP–MSNA coherence in men was partially explained by a higher percentage of consecutive integrated MSNA bursts, which probably enhanced the coupling of DAP and MSNA. In both sexes, the phase angles were positive at rest and negative during the orthostatic stress, suggesting MSNA is primarily a lead signal at rest and a response signal during an orthostatic challenge, irrespective of sex (Yang et al. 2012). In this issue of The Journal of Physiology, Briant and colleagues (Briant et al. 2016) propose a new method for assessing sympathetic vascular transduction, a common autonomic–vascular index that quantifies the transduction of MSNA into vascular tone. To date, the most common approach for determining sympathetic vascular transduction has been to examine the ratio of MSNA and limb vascular conductance. The current article by Briant et al. proposes a novel method that does not necessitate a measurement of limb blood flow, but instead uses DAP as the primary endpoint for the ‘vascular’ transduction. Importantly, the authors include a test–retest sub-study that demonstrates methodological reproducibility and reliability. Using their new methodology, the authors found that sympathetic vascular transduction was modulated importantly by both sex and age. Specifically, sympathetic vascular transduction was strong in young men, and decreased linearly with age. In contrast, young women demonstrated the lowest sympathetic vascular transduction, but this transduction increased during intravenous infusion of a non-selective β-adrenergic blockade, and also increased with ageing. As highlighted by the authors, these findings are consistent with a number of studies over the past decade that have reported sex differences in sympathetic–vascular coupling, including recent work from our laboratory documenting altered sympathetic vascular transduction in men and women during mental stress (Yang et al. 2013). Lastly, we point the reader to a subtle, yet important, methodological detail within the study by Briant et al.: all DAP–MSNA transduction slopes were included in the final analysis. This is a departure from most traditional baroreflex analyses, which often exclude non-significant slopes. The authors argue that non-significant slopes were included because they ‘may reflect poor transduction’ in the young women, who had a much higher number of non-significant slopes. This reminds us of some of the debates our respective laboratories have endured regarding the DAP–MSNA coherence method. Similar to Briant et al. (2016), we have argued that it is essential to include all coherence values in the low frequency, because we too believe these values represent true physiological processes and poor MSNA–DAP coordination. In conclusion, the findings of Briant et al. (2016) provide another important piece of the puzzle in understanding the complex relations between MSNA and blood pressure, and are consistent with a decade worth of data from several laboratories suggesting that sex does in fact matter.