Is greater resting sympathetic nerve activity better for hypertension? Perhaps for the arterial baroreflex

The carotid and aortic baroreflexes are comprised of mechanoreceptors located at the medial-adventitial border of arteries in the carotid sinus bifurcation and aortic arch that function as the sensors in a negative feedback control system. Alterations in arterial blood pressure cause a conformational change in the baroreceptors leading to changes in afferent neuronal firing that converge centrally within the nucleus tractus solitarii of the medulla oblongata reflexively modulating parasympathetic and sympathetic efferent activity. These autonomic adjustments will affect both the heart and the blood vessels in order to return blood pressure towards its original set point. Although these pathways have been well described, the complex interactions between the multiple components of the baroreflex arc are still an ongoing area of intense investigation. Although asymmetry in arterial baroreflex-mediated heart rate responses to falling and rising blood pressure is well recognized (Eckberg & Sleight, 1992), hysteresis in the baroreflex control of muscle sympathetic nerve activity (MSNA) in humans has been less appreciated. Despite an early report by Sundlof & Wallin (1978) demonstrating that MSNA responses to spontaneous falls in pressure were greater than responses to rises in pressure, hysteresis in the baroreflex control of MSNA has been largely overlooked. Indeed, sympathetic baroreflex sensitivity (i.e. gain) has been primarily reported as a single slope derived from the linear regression analysis of the relationship between diastolic blood pressure (DBP) and MSNA without consideration for identifying separate responses to falling and rising pressures. Recent work by Studinger et al. (2009) has clearly demonstrated hysteresis in the sympathetic baroreflex using the modified Oxford technique (a bolus of sodium nitroprusside followed by phenylephrine) and in so doing has again highlighted the importance of considering MSNA baroreflex gains for falls and rises separately to yield more complete information about the baroreflex control of MSNA. These investigators also attempted to identify the underlying mechanisms that may contribute to the hysteresis in the sympathetic arm of the baroreflex. As reported, a complex interaction between mechanical (i.e. the transduction of pressure into carotid stretch) and neural (i.e. transduction of carotid stretch into MSNA) components of the baroreflex arc may help explain hysteresis in the baroreflex control of MSNA. These important mechanistic insights undoubtedly advance our overall understanding of sympathetic baroreflex hysteresis in humans; however, as with most physiological processes, multiple mechanisms are likely involved. In a recent issue of The Journal of Physiology, Hart et al. (2011) further advance our understanding of sympathetic baroreflex hysteresis using novel spontaneous baroreflex analyses to examine if resting MSNA is related to differences in sympathetic baroreflex sensitivity to rising and falling arterial pressure and whether age or sex might influence these relationships. These data are timely and build upon a strong series of experiments by these investigators examining the mechanisms underlying the wide inter-individual variability in resting MSNA in otherwise healthy men and women. Hart et al. (2011) calculated resting sympathetic baroreflex sensitivity by analysing the relationship between spontaneously occurring variations in DBP and MSNA, as previously described (Kienbaum et al. 2001; Hart et al. 2010). However, to address their primary question and differentiate slopes between falling and rising pressures, these authors also introduce a novel and creative approach of applying a methodology similar to the sequence technique, which has extensively been used for cardiac baroreflex sensitivity, to MSNA. Briefly, sympathetic baroreflex sensitivity to rising and falling arterial pressure were derived by scanning 5 min of resting DBP and MSNA data and identifying if the preceding pressure was high or low and then placing it into the falling or rising baroreflex sensitivity estimates, respectively. This analysis was also performed for runs of two and three consecutive rising or falling pressures to further validate the approach. To assess whether hysteresis was related to resting MSNA, the difference between the baroreflex slopes measured during falling and rising arterial pressures was calculated and related to resting MSNA for each participant. The findings indicate that the difference between falling and rising baroreflex sensitivity correlated with resting MSNA in young and older men and postmenopausal women. Thus, those subjects with greater baroreflex sensitivity to rising DBP had higher baseline MSNA and vice versa. Interestingly, no such relationships were found in young women. Collectively, these findings significantly advance our overall understanding of sympathetic baroreflex hysteresis in humans and further illustrate the complexity in the regulation of resting MSNA and blood pressure in young women. As noted by the authors, a potential limitation of the study is the use of the spontaneous analyses approach to assess sympathetic baroreflex sensitivity. At first glance this may be a valid criticism; however, this should not dampen enthusiasm for these findings for several reasons. First, this research group has teamed with a pioneer for the microneurography technique in humans, Dr Gunnar Wallin, and previously have validated these spontaneous measures, in particular, against the modified Oxford, the so-called ‘gold standard’ (Hart et al. 2010). Furthermore, within the current paper, multiple comparisons using a varying number of cardiac cycles have been performed to further substantiate these measures. As noted by the authors, one caveat for these spontaneous sympathetic baroreflex measures, particularly when attempting to incorporate more cardiac cycles, can be the lack of data points. This is an obvious concern in subjects with low resting MSNA and therefore, a better understanding of the amount of data and thus recording duration needed for these estimates of sympathetic baroreflex sensitivity and their reproducibility will warrant future investigation. An important consideration in the sympathetic baroreflex analyses debate is that the gain measured using bolus infusions of nitroprusside and phenylephrine (i.e. the modified Oxford technique) provides a robust loading and unloading of baroreflex neurons, whereas the sensitivity of the spontaneous baroreflex measures reflects more moderate baroreflex loading and unloading under resting conditions. Thus, some consideration should be given for these differences and perhaps the complementary nature of these measures to estimate baroreflex control rather than expecting them to provide identical information. Although as researchers we need to always strive to validate our methods and findings, we must also remember that there are no “perfect” methodologies. In summary, Hart and colleagues should be commended on providing further insight into the hysteresis in the sympathetic arm of the baroreflex, while at the same time extending the repertoire of tools available to assess sympathetic baroreflex function in humans. The finding that the sensitivity of the sympathetic baroreflex to falling and rising pressures is related to resting MSNA has important clinical implications. Indeed, these data suggest that apparently healthy individuals with high resting MSNA may be limited in their ability to respond to a hypotensive challenge, potentially contributing to orthostatic intolerance. More intriguing might be that individuals with high MSNA respond better to elevations in blood pressure. Thus, elevated resting MSNA is good for sympathetic baroreflex responses to hypertensive stimuli. This is a challenging concept that perhaps comes at a cost due to the known deleterious consequences of increased MSNA (Fisher et al. 2009). Nevertheless, the importance of evaluating sympathetic baroreflex responsiveness to hypotension and hypertension separately is becoming more and more clear.