Methodological assessment of sympathetic vascular transduction

Direct measurement of muscle sympathetic nerve activity (MSNA) originated in Sweden in the 1960s and has been used in thousands of studies (Vallbo et al. 2004). While these measures have been performed extensively to characterize resting MSNA and sympathetic responsiveness, the transduction of MSNA into changes in vascular tone is much less commonly studied. This is surprising, given that changes in MSNA must influence the peripheral vasculature in order to affect blood flow and blood pressure (BP). Indeed, the amount of MSNA is only one aspect of sympathetic control and a focus on transduction of the nerve signal into a vascular and/or BP response can provide further insight into sympathetic regulation. Transduction of an MSNA burst into a vascular response requires successful release of neurotransmitters into the synaptic cleft, receptor binding on smooth muscle, and sufficient vascular smooth muscle contraction. Several groups have used cardiovascular stressors to cause large reflex-mediated increases in sympathetic outflow and assess transduction of MSNA into a vascular or a BP response (Minson et al. 2000). While this reflects transduction of MSNA during sympathoexcitation, it does not represent sympathetic vascular transduction under resting conditions. In a recent issue of The Journal of Physiology, Briant et al. (2016) attempt to better understand resting sympathetic transduction in humans with a central goal of developing a measure of transduction for use in disease populations with elevated sympathetic nerve activity. In their study, Briant et al. (2016) utilized a technique to determine the transduction of MSNA into changes in diastolic blood pressure (DBP). Subjects were divided into four groups: young women (YW), post-menopausal women (PMW), young men (YM), and older men (OM). Subjects rested in the supine position, while DBP (finger-cuff photoplethysmography or arterial catheter) and MSNA were continuously recorded for 5 min. Linear regression of DBP to MSNA (the inverse of the relationship commonly used to investigate baroreflex sensitivity, i.e. MSNA to DBP) at a lag of 6–8 cardiac cycles was used to describe MSNA transduction. This is to say, a given DBP was traced back 6–8 cardiac cycles to investigate the influence of MSNA on DBP. MSNA burst area and burst height were normalized to the largest burst in the recording, binned into (1% × s) bins and associated with the corresponding DBP. An important question addressed in the paper was related to sex and ageing differences in the regulation of BP. The index of transduction used by Briant et al. (2016) supported differences between groups. YM had the highest transduction, with PMW and OM significantly lower than YM, but not significantly different from each other. YW had significantly lower transduction than all other groups, which may result from other vasodilatory mechanisms present in YW at rest (e.g. upregulation of nitric oxide caused by the chronic presence of oestrogen). Interestingly, this paper showed that YW had a significant increase in transduction following β-blockade while PMW and YM had no systematic changes. This evidence supports a greater role of β2-mediated sympathetic vasodilatation at rest in young women (Hart et al. 2011). In the current study, women were shown to have an increase in transduction of sympathetic nerve activity as they age, whereas men were shown to have an age-related decline in sympathetic transduction (Briant et al. 2016). Interestingly, these findings are in contrast to previous reports (Vianna et al. 2012), which found that both sexes had age-related declines in transduction of sympathetic nerve activity. This may be explained, in part, by differing methodologies, with Vianna et al. (2012) using beat-to-beat data and signal averaging of each individual burst and its ensuing blood pressure increase over a period of 10–15 cardiac cycles. Overall, the new method described by Briant et al. (2016) may offer a useful tool for estimating sympathetic transduction. There are, however, some considerations worthy of discussion. The small transduction slopes reported by Briant et al. (2016) suggest that MSNA does not have a great influence on resting DBP, whereas previous studies have suggested MSNA to be a primary effector of vascular tone at rest. This may be partly due to the methodological approach wherein all DBP values were analysed, regardless of whether or not there were any MSNA bursts at the 6–8 cardiac cycle lag for that DBP. This presents a challenge associated with the analysis and interpretation of the data because each group has very different resting MSNA, but similar heart rates, and therefore including DBP values associated with no MSNA may have altered (i.e. minimized) the slope of the relationship between MSNA and its transduction into changes in DBP. Effectively, some of the difference in transduction slopes amongst groups may be due to varying levels of resting nerve activity. Running the analysis exclusively with DBPs associated with the presence of a sympathetic burst may provide additional, important information. Interestingly, the transduction estimates using MSNA and total peripheral resistance (TPR) were not as strong as the DBP association. Although this may have been due to the small sample size included in this sub-analysis, this warrants future consideration. The use of α-receptor blockade would be important to further demonstrate the use of this measure, by providing an example of ‘minimized sympathetic transduction’. Finally, although this technique has the potential for being used to estimate transduction in various disease populations with high nerve activity, at present the studies have only been performed in healthy populations. While ageing is typically associated with higher nerve activity (OM 35 ± 3 bursts min−1; PMW 38 ± 2 bursts min−1), this activity is much less than that of disease populations (e.g. heart failure 45 ± 4 bursts min−1; Middlekauff et al., 2004). Utilization of this technique in populations with higher nerve activity will be important to test. Despite the given considerations, Briant et al. (2016) have developed a new methodology for quantifying transduction of MSNA at rest. This is important because the study of MSNA transduction