Sympathetic Baroreflex Sensitivity Research Articles

Sublingual Nitroglycerin Acutely Alters Cardiovagal and Sympathetic Baroreflex Sensitivity in Healthy Humans

Augmented sympathetic nerve activity (SNA) and impaired baroreflex sensitivity (BRS) are important therapeutic targets in patients with cardiovascular diseases. Nitroglycerin (glyceryl trinitrate, GTN) is a vasodilator, widely used in patients with coronary artery diseases, however, the effects of GTN on SNA and BRS are incompletely understood. Importantly, the acute effects of GTN on SNA and BRS are not clear. Additionally, there are no reports evaluating both the sympathetic BRS (SBRS) and cardiovagal BRS (CBRS) responses to the administration of sublingual GTN. The purpose of this study was to assess the acute effects of GTN on muscle sympathetic nerve activity (MSNA), SBRS and CBRS in healthy subjects. We hypothesized that sublingual GTN would rapidly modulate sympathetic and cardiovagal BRS and thus increase MSNA in healthy subjects. Ten (9M, 1F) healthy subjects (60 ± 2 yrs) without medications were examined. Beat-to-beat heart rate (HR), arterial pressure (AP) and MSNA were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated by analyzing the relationship between spontaneous variations in diastolic AP and MSNA. CBRS was assessed with the sequence technique. Every 2 min HR, AP and MSNA data were recorded and compared. SBRS and CBRS were assessed during baseline, and during min 3-6 (Post A) and 7-10 min (Post B) after GTN administration. Compared to baseline, mean AP did not significantly change during Post A (baseline, 98.5 ± 1.8 to 95.6 ± 2.3 mmHg, P = 0.423) but decreased during Post B (91.9 ± 2.2 mmHg, P < 0.05). MSNA increased significantly by min 2 after GTN and remained significantly elevated during both the Post A and Post B periods (31.2 ± 4.0 to 48.2 ± 4.4, and 47.5 ± 4.2; bursts/min, both P < 0.05). Compared to baseline, during the Post A and Post B periods CBRS decreased significantly (12.9 ± 1.6 to 7.1 ± 1.0, and 6.4 ± 0.6; ms･mmHg-1, both P < 0.05), while SBRS increased significantly (0.8 ± 0.2 to 1.5 ± 0.2, and 1.8 ± 0.3; units･beat-1･mmHg-1, both P < 0.05). The SBRS operating point was also reset and shifted to upward during both the Post A and Post B periods. The results show that a clinical sublingual dose of GTN attenuated the CBRS and raised the SBRS with an upward shift of the operating point, resulting in augmented MSNA. Whether these acute changes in MSNA and BRS with GTN in the absence of changes in BP can evoke adverse sequelae in patients with atherosclerosis is unknown. These findings have never been reported before. These factors should be considered by clinicians as they use this agent.

Interaction Between Baroreflex and Venous Distension Reflex in Healthy Humans

Prior reports have shown that that venous distension induced by saline infusion into the veins of an arterially occluded forearm significantly raises muscle sympathetic nerve activity (MSNA) and blood pressure (BP) via activating afferent nerves in the forearm in healthy humans. Thus, peripheral venous distension induces a systemic sympatho-excitatory reflex (venous distension reflex, VDR). The baroreflex is an important modulator of BP via regulating sympathetic and vagal tone. However, the relationship between the VDR and the baroreflex has not been examined. Thus, the purpose of this study was to examine the relationship between VDR and the cardiovagal baroreflex sensitivity (CBRS) or sympathetic baroreflex sensitivity (SBRS). We hypothesized that VDR activation affects the CBRS and SBRS. Beat-to-beat heart rate (HR), BP and MSNA were recorded in 35 (19 M, 16 F) young healthy subjects (27 ± 1 yrs.). After a short period when a forearm was arterially occluded, 5% forearm volume normal saline (~40-60 ml) was infused into the veins of the occluded forearm at a rate of 30 ml/min. Prior studies showed that the maximal MSNA and BP responses occurred during the period of 30 seconds before and 30 seconds after the end of the saline infusion (maximal VDR responses). Thus, hemodynamic variables, MSNA, SBRS and CBRS were assessed during baseline (5 min) and the maximal VDR response period (1 min). SBRS was evaluated by analyzing the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. Mean BP, HR and MSNA during the maximal VDR response period were significantly greater than those during resting baseline (Baseline to VDR; MBP, 83.9 ± 1.8 to 98.6 ± 2.5 mmHg; HR, 65.2 ± 1.5 to 68.0 ± 1.9 bpm; MSNA, 22.8 ± 1.6 to 32.7 ± 1.7 bursts･min-1; all P < 0.05). SBRS absolute value during VDR was significantly increased (-0.66 ± 0.07 to -1.41 ± 0.10 units･beat-1･mmHg-1, P < 0.05) and SBRS operating point was reset and upward shifted. CBRS during VDR was significantly decreased (Baseline to VDR; 16.6 ± 0.9 to 13.8 ± 1.0 ms･mmHg-1, P < 0.05). These results indicate that VDR activation increased SBRS with an upward shift of the operating point and decreased CBRS, as it also evoked significant sympatho-excitation. Augmented sympathetic activity and impaired baroreflex function are important prognostic factors in patients with cardiovascular diseases. Thus, further studies are needed to examine VDR in patients with cardiovascular diseases.

Androgen Effects on Baroreflex Sensitivity in Women with AE‐PCOS

Polycystic ovary syndrome (PCOS) is a reproductive endocrinopathy affecting approximately 10% of reproductive age women. Hyperandrogenism in women may be associated with increased sympathetic activity and impaired blood pressure (BP) regulation. Women with the Androgen-Excess PCOS (AE-PCOS) phenotype can have severe clinical metabolic and cardiovascular comorbidities, including elevated BP. We tested the hypothesis that androgen exposure in AE-PCOS increases BP and impairs BP regulation, as indexed by sympathetic baroreflex sensitivity (BRS). We measured BRS in 5 women with AE-PCOS (mean±SD, age=25±5 y; BMI=40±2 kg/m2) at Baseline (BSL), after 4 days of reproductive hormone suppression with a gonadotropin-releasing hormone (GnRH) antagonist (ANT, 250 μg/day) and 4 days of GnRH ant+testosterone (T, 5 mg/day). Before participating, subjects were screened to demonstrate insulin resistance using an oral glucose tolerance test (AUC=25949±11038 IU for insulin, AUC=23385±2561 mg/dl for glucose). Muscle sympathetic nerve activity (MSNA), expressed in bursts/100 heartbeat (Hb), and diastolic BP (DBP) were measured during the Modified Oxford technique, and sympathetic BR gain (MSNA/DBP) served as an index of sympathetic BRS. We also assessed integrated BR gain with forearm vascular resistance changes as a function of lower body negative pressure (LBNP). Reproductive hormone suppression decreased resting mean arterial pressure compared to BSL (114±10 mm Hg) under both ANT (107±2 mm Hg) and T conditions (106±9 mm Hg, P=0.04). Sympathetic BR gain during ANT was greater compared to BSL (-0.922±0.506 vs. -0.800±0.542 bursts/100 Hb/mm Hg, respectively), and gain was unaffected when androgens were reintroduced (T=-0.819±0.276 bursts/100 Hb, P=0.29). Integrated BRS during LBNP was unaffected by hormone treatment (BSL=0.911±0.653; ANT=0.794±0.967; T= 1.002±0.367 units/mm Hg). In obese, insulin resistant women with AE-PCOS, suppressing testosterone and estrogen (E2) improved arterial BR control of MSNA, while testosterone administration did not restore BR control. Thus, our initial hypothesis that T impairs baroreflex control of MSNA is not supported by these data but suggests that the continued suppression of E2 during ANT and ANT+T may play a more important role. The potential impact of E2 could be a promising clinical intervention and will be directly tested in our future studies.

Eight weeks of device-guided slow breathing decreases sympathetic nervous reactivity to stress in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is characterized by increased risk for developing hypertension and cardiovascular disease. We recently showed that device-guided slow breathing (DGB) acutely lowers blood pressure (BP) and muscle sympathetic activity (MSNA) and improves baroreflex sensitivity (BRS) in PTSD. The aim of this study was to assess the long-term benefits of DGB on autonomic function at rest and during stress. We hypothesized that long-term DGB improves arterial BRS and lowers BP and MSNA in PTSD. Twenty-five veterans with PTSD were studied and randomized to either 8 wk of daily DGB (n = 12) or 8 wk of sham device (Sham; n = 13). BP, heart rate (HR), and MSNA were measured at rest and during mental math. Arterial BRS was assessed using the modified Oxford technique. Resting MSNA, BP, and heart rate (HR) remained comparable before and after 8 wk in both groups (DGB and Sham). Likewise, the change in sympathetic and cardiovagal BRS was not different between the groups. Interestingly, DGB significantly decreased MSNA reactivity to mental math when expressed as burst frequency (P = 0.012) or burst incidence (P = 0.008) compared with Sham, suggesting a sustained effect of DGB on sympathetic reactivity to stress in PTSD. Contrary to our hypothesis, long-term DGB did not lower systolic BP, diastolic BP, or HR responses to stress compared with Sham. Likewise, pulse pressure reactivity after 8 wk (P = 0.121) was also comparable. In summary, these data suggest that long-term use of DGB may lead to a sustained dampening of sympathetic reactivity to mental stress in PTSD.

Reply from Paul J. Fadel

I appreciate the Letter by Dr Akshay Pendyal (2020) regarding our recent publication in Experimental Physiology reporting an augmented resting beat-to-beat blood pressure (BP) variability in young non-Hispanic black men compared to white men (Young et al., 2020). We further observed that this enhanced BP variability was associated with greater fluctuations in systemic vascular resistance and reduced sympathetic baroreflex sensitivity. Notably, this heightened BP variability occurred despite a normal, and similar, resting BP between groups. We proposed that these swings in BP over time may contribute to the enhanced cardiovascular risk profile in black individuals. Dr Pendyal raises an important and timely point about a potential underlying factor that may contribute to the observed differences, namely the unequal societal conditions and enhanced environmental stress (i.e. racism) that many black individuals encounter on a regular basis, particularly black men. We completely agree with Dr Pendyal and our intention was not to disregard or downplay this factor as an underlying contributor. However, we are physiologists by training and our study was designed to investigate neural cardiovascular mechanisms as presented in the paper, and not psycho-social factors. Thus, the intent was not to overlook this factor, but with no measures made in our volunteer participants to directly assess and speak to these factors, we were careful not to comment. In fact, quantifying such experiences can be challenging, particularly considering the varying backgrounds, societal conditions and exposures to enhanced environmental stress (i.e. cultural, socioeconomic, and psychosocial factors) among our participants. As such, we cannot comment in any meaningful way on these factors as we can for measures of endothelium-dependent vasodilatation and sympathetically mediated vasoconstriction. Nevertheless, we recognize that differences in environmental factors between black and white individuals, and in the case of our study men, undoubtedly impact cardiovascular physiology and in no way are we pinning these differences solely on genetics, per Dr Pendyal's concern. This is just not a factor we have reported on in our studies as assessing these environmental stress factors is not trivial and requires a dedicated approach in and of itself. Similarly, papers on socio-economic and cultural factors in society rarely mention physiological mechanisms. In short, we agree with Dr Pendyal and in no way were we suggesting these were ‘purely’ intrinsic physiological differences between black and white men. The enhanced environmental stressors that most black individuals have to deal with on a regular basis should not be overlooked as contributory factors for the heightened cardiovascular risk in this population (Brownlow et al., 2019; Clark, Anderson, Clark, & Williams, 1999; Frierson, Howard, DeFina, Powell-Wiley, & Willis, 2013). Clearly these interactions are important and are worthy of future investigation, particularly studies using interdisciplinary approaches merging physiological and psychosocial factors. We thank Dr Pendyal for the reminder of the complexities of studying racial differences and the importance of considering the stress of racism and socioeconomic deprivation on cardiovascular physiology in black individuals. None declared.

Broader adaptive range of sympathetic burst size in response to blood pressure change in older women with greater arterial stiffness.

In this study, we focused on muscle sympathetic nerve activity (MSNA) burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men. Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes. Sympathetic baroreflex sensitivity assessed with burst incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men. These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similar to that in older men. There are sex differences in arterial stiffness and neural control of blood pressure (BP) among older adults. We examined whether the sympathetic response to BP is greater in older women than men in burst size but not burst occurrence. Burst occurrence and size were assessed with burst interval and area of muscle sympathetic nerve activity, respectively, and the distributions of these indices were evaluated by range during supine rest in 61 healthy older subjects (30 men (69±6years) and 31 women (68±6years); means±SD). Also, we analysed sympathetic baroreflex sensitivity (BRS) with burst occurrence and area simultaneously. Carotid β-stiffness was measured with B-mode ultrasonic image and carotid BP. The range of burst interval was smaller in older women than men (P=0.002), while there was no difference in the range of burst area. Carotid β-stiffness was greater in older women than men (6.7±2.7 vs. 5.1±2.7, P=0.027). Sympathetic BRS assessed with burst incidence was lower in older women than men (-2.3±1.4 vs. -3.3±1.4 bursts·100beats-1 mmHg-1 , P=0.007), while this sex difference was observed when assessed with burst area after adjusting for carotid β-stiffness (-116.1±135.0 vs. -185.9±148.2a.u. burst-1 mmHg-1 , P=0.040), but not before. Sympathetic BRS assessed with burst area was negatively (more sensitive) correlated with carotid β-stiffness in older women (r=-0.53, P=0.002) but not men. These data suggest that the response of burst size within each burst is augmented for the baroreflex BP control despite the impaired response of burst occurrence in older women with greater carotid stiffness.

Within-breath sympathetic baroreflex sensitivity is modulated by lung volume but unaffected by acute intermittent hypercapnic hypoxia in men.

Muscle sympathetic nerve activity (MSNA) exhibits well-described within-breath respiratory modulation, but the interactive contributions of the arterial baroreflex remain unclear. The present study assessed 1) within-breath modulation of sympathetic baroreflex sensitivity (BRS) and 2) the effect of acute intermittent hypercapnic hypoxia (IHH) on within-breath sympathetic BRS and respiratory-sympathetic entrainment. Seventeen men (24 ± 4 yr) underwent an 8- to 10-min spontaneously breathing baseline while continuous measures of blood pressure (BP), heart rate, MSNA, ventilation, and end-tidal gases were collected. A subset of 12 participants subsequently underwent a 40-min IHH exposure composed of 40 consecutive 1-min breathing cycles: 40 s of hypercapnic hypoxia and 20 s of normoxia. Data were compared between inspiration and expiration and low and high lung volume (calculated from the integral of spirometry-derived flow). Sympathetic BRS was determined by the slope of the weighted linear regression between diastolic BP and MSNA burst incidence. Respiratory-sympathetic entrainment was quantified as percentage of MSNA bursts during each respiratory epoch relative to the total burst count. Sympathetic BRS was similar between inspiration and expiration (-3.9 ± 2.0 vs. -3.6 ± 1.8 bursts·100 heartbeats-1·mmHg-1; P = 0.61) but greater during low versus high lung volumes (-4.6 ± 2.3 vs. -2.1 ± 1.6 bursts·100 heartbeats-1·mmHg-1; P < 0.01). High (r = -0.64; P < 0.01)- but not low (r = -0.24; P = 0.35)-lung volume sympathetic BRS was associated with resting MSNA. IHH increased resting MSNA burst frequency (15 ± 7 vs. 20 ± 7 bursts/min; P < 0.01) and diastolic BP (68 ± 5 vs. 77 ± 9 mmHg; P = 0.02), without altering resting or within-breath sympathetic BRS or respiratory-sympathetic entrainment (all P > 0.05). These findings provide novel insight into the mechanisms controlling within-breath modulation of sympathetic outflow in humans.NEW & NOTEWORTHY In resting spontaneously breathing men, the present study observed that sympathetic baroreflex sensitivity (BRS) was higher during low versus high lung volumes but not different between inspiration and expiration. High- but not low-lung volume BRS was negatively associated with resting muscle sympathetic nerve activity (MSNA). Acute intermittent hypercapnic hypoxia increased resting MSNA and diastolic blood pressure, without altering within-breath BRS. These findings provide novel insight into mechanisms controlling within-breath modulation of MSNA in humans.

Augmented resting beat-to-beat blood pressure variability in young, healthy, non-Hispanic black men.

What is the central question of this study? The prevalence of hypertension in black individuals exceeds that in other racial groups. Despite this well-known heightened risk, the underlying contributory factors remain incompletely understood. We hypothesized that young black men would exhibit augmented beat-to-beat blood pressure variability compared with white men and that black men would exhibit augmented total peripheral resistance variability. What is the main finding and its importance? We demonstrate that young, healthy black men exhibit greater resting beat-to-beat blood pressure variability compared with their white counterparts, which is accompanied by greater variability in total peripheral resistance. These swings in blood pressure over time might contribute to the enhanced cardiovascular risk profile in black individuals. The prevalence of hypertension in black (BL) individuals exceeds that in other racial groups. Recently, resting beat-to-beat blood pressure (BP) variability has been shown to predict cardiovascular risk and detect target organ damage better than ambulatory BP monitoring. Given the heightened risk in BL individuals, we hypothesized young BL men would exhibit augmented beat-to-beat BP variability compared with white (WH) men. Furthermore, given studies reporting reduced vasodilatation and augmented vasoconstriction in BL individuals, we hypothesized that BL men would exhibit augmented variability in total peripheral resistance (TPR). In 45 normotensive men (24 BL), beat-to-beat BP (Finometer) was measured during 10-20min of quiet rest. Cardiac output and TPR were estimated (Modelflow method). Despite similar resting BP, BL men exhibited greater BP standard deviation (e.g. systolic BP SD; BL, 7.1±2.2mmHg; WH, 5.4±1.5mmHg; P=0.006) compared with WH men, which was accompanied by a greater TPR SD (P=0.003), but not cardiac output SD (P=0.390). Other traditional measures of variability provided similar results. Histogram analysis indicated that BL men exhibited a greater percentage of cardiac cycles with BPs higher(> +10mmHg higher) and lower (< -8mmHg lower) than mean systolic BP compared with WH men (interaction, P<0.001), which was accompanied by a greater percentage of cardiac cycles with high/low TPR (P<0.001). In a subset of subjects (n=30), reduced sympathetic baroreflex sensitivity was associated with augmented BP variability (r=-0.638, P<0.001), whereas cardiac baroreflex sensitivity had no relationship (P=0.447). Herein, we document an augmented beat-to-beat BP variability in young BL men, which coincided with fluctuations in vascular resistance and reduced sympathetic BRS.

Acute Intermittent Hypoxia Results in Baroreflex Resetting to Higher Blood Pressures in Young Men but Not Young Women

BackgroundRepetitive hypoxic apneas, similar to what is observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP) in humans. This resetting of the baroreflex is associated with increased BP in preclinical models of sleep apnea (chronic intermittent hypoxia, CIH); however, the majority of our understanding comes from men. There are data to suggest female rats exposed to CIH do not develop high BP. With this, we sought to examine potential sex‐related differences in the effect of intermittent hypoxia (IH) on the sympathetic baroreflex. We hypothesized young men would exhibit resetting of the baroreflex to higher BP following IH, with no change in young women.MethodsBP and muscle sympathetic nerve activity (MSNA) were assessed in 17 men (30±1 yrs) and 10 women (28±1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic exposures (0.05 FiO2) alternating with 90‐s room air breathing] resulting in 15 hypoxic events (91.7±0.5 % SpO2). Sympathetic baroreflex sensitivity was evaluated using the modified Oxford technique before and after 30‐min of IH.ResultsDiastolic BP increased in men following IH (71±2 to 74±2 mmHg; p&lt;0.01) with no change in women (75±3 to 75±3 mmHg; p=0.97). Sympathetic baroreflex sensitivity did not change following IH in either group (Men: −1.8±0.2 to −1.9±0.3; Women: −1.6±0.3 to −2.1± 0.5 bursts/100 heart beats/mmHg; Main effect of IH, p=0.14; Interaction of group and IH, p=0.28).ConclusionAcute IH resets the sympathetic baroreflex to higher BP in young men, with no change in young women. Baroreflex sensitivity slopes were unchanged in either group following IH. Our results support sex differences in the effect of IH on sympathetic control of BP and show that young women are protected from the BP‐raising effects of IH. These data enhance our understanding of sex‐specific mechanisms that may contribute to the development of hypertension in sleep apnea.Support or Funding InformationNIH HL130339, Mayo Clinic Center for Biomedical Discovery

Long‐term Device Guided Slow Breathing Decreases Sympathetic Nervous Reactivity to Stress in Post‐Traumatic Stress Disorder

Posttraumatic stress disorder is characterized by augmented sympathetic reactivity, impaired baroreflex sensitivity, and an increased risk for developing hypertension and cardiovascular disease. We recently showed that device‐guided slow breathing (DGB), in which breathing rates are lowered to subphysiologic levels using a biofeedback device, acutely lowers blood pressure (BP) and muscle sympathetic activity (MSNA) and improves sympathetic baroreflex sensitivity (BRS) in post‐traumatic stress disorder (PTSD). The aim of this study was to assess the potential long‐term benefits of DGB on MSNA, hemodynamics, and BRS in patients with PTSD at rest and during stress. We hypothesized that long‐term DGB will further improve sympathetic BRS, lower BP and MSNA in PTSD. Twenty five young adults, clinically diagnosed with PTSD, were studied and randomized to either 8 weeks of DGB (n=12; age, 36±2 years; BMI, 30±2 Kg/m2) or 8 weeks of an identically looking Sham device (n=13; age, 34±2 years; BMI, 28±2 Kg/m2). DGB guided the participants to a breathing rate of 5–6 breaths/min while Sham guided breathing to 14 breaths/min. BP, heart rate (HR) and MSNA was measured at rest and during 3 min of mental arithmetic. Sympathetic and cardiovagal BRS were assessed using the modified oxford technique. Measurements were done during two laboratory visits, before and after 8 weeks of 15 min of at‐home breathing daily. Both groups (DGB and Sham) were matched for age, BMI, resting MSNA, BP and heart rate (HR). Resting MSNA, BP and HR remain comparable (condition*device, p&gt;0.05) before and after the 8 weeks (condition effect) in both breathing groups. Likewise, the change in sympathetic and cardiovagal BRS was not different between the two groups (condition*device, p&gt;0.05). Interestingly, 8 weeks of DGB significantly decreased minute by minute (time effect) MSNA reactivity to mental arithmetic when expressed as burst frequency (time*condition*device, p= 0.006) or burst incidence (time*condition*device, p= 0.004) compared to 8 weeks of sham, suggesting a sustained effect of chronic DGB on sympathetic reactivity to mental stress in PTSD. Contrary to our hypothesis, long term DGB did not lower (time*condition*device, p&gt;0.05) systolic BP, diastolic BP or HR responses to stress compared to sham. However, DGB but not sham tended to decrease pulse pressure reactivity after 8 weeks of intervention (time*condition*device, p= 0.06), due to the tendency for low systolic BP reactivity post DBG. In summary, our data suggest that the long‐term use of DGB leads to a sustained dampening of sympathetic reactivity and trend towards improved pulse pressure reactivity to mental stress. Taken together, these results suggest that long term use of DGB may have beneficial effects on neurocardiovascular reactivity in individuals with PTSD.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grant R01 HL135183; NIH R61 AT010457, VA Merit I01CX001065, the Department of Veterans Affairs, Veterans Health Administration and the Office of Research and Development, Decatur, Georgia.

Reduced sympathetic baroreflex sensitivity in individuals with multiple sclerosis during the Valsalva maneuver

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease characterized by demyelination in central nervous system leading to potential impairments in the autonomic control of cardiovascular function. We have previously demonstrated individuals with MS exhibit a diminished ability to increase blood pressure in response to a simulated hypotensive stimulus (carotid neck pressure) compared with healthy controls likely due to impaired sympathetic modulation of the vasculature. The aim of the current investigation was to test the hypothesis that individuals with MS have a blunted muscle sympathetic nerve response (MSNA) to drops in arterial blood pressure induced via a Valsalva maneuver compared to matched healthy controls. Four patients with relapsing‐remitting MS (2 females/2 males, EDSS &lt; 4) and 4 sex‐, age‐ and mass‐matched healthy controls were instrumented for MSNA (peroneal nerve), arterial blood pressure (Finometer), and heart rate. Participants performed a Valsalva maneuver (VM) at 40 mmHg for a 15 s after a normal inspiration. Sympathetic baroreflex function was assessed by relating all sympathetic burst occurring during the 15 s straining period of the VM to the maximum fall in DBP measured from highest values (Phase I) to the nadir prior to the end of the VM (Phase III). Drops in diastolic pressure during the Valsalva were similar between groups (MS: −31 ± 10 mmHg: CON: −25 ± 15 mmHg; P = 0.30). Individuals with MS produced less total MSNA bursts during the 15 s VM compared to healthy controls (MS: 8.3 ± 4.1 bursts/15 s; CON: 15.0 ± 4.1 bursts/15 s; P = 0.003). Sympathetic baroreflex sensitivity was reduced in individuals with MS (MS: −0.32 ± 0.25 bursts/15 s/mmHg) vs. CON: −0.77 ± 0.43 bursts/15 s/mmHg; P = 0.048). Individuals with MS have a reduced ability to increase MSNA in response to decreases in blood pressure during the VM confirming previous speculations of abnormal sympathetic baroreflex control of arterial blood pressure in this clinical population.Support or Funding InformationNIH R15HL117224; National MS Society RG4696A3

Oral Contraceptives Do Not Alter Sympathetic Neural Control of Blood Pressure in Young, Healthy Women

BackgroundSympathetic nerve activity and its effect on blood pressure are altered by female sex hormones; however, this effect differs between exogenous and endogenous hormones. With oral contraceptive (OC) use, cross‐sectional data has demonstrated higher blood pressure (BP) with no corresponding change in muscle sympathetic nerve activity (MSNA). This results in a higher BP/MSNA ratio with OC use although contributing mechanisms are unclear. The higher BP/MSNA ratio in women on OC suggests OC use may limit the ability of sympathetic baroreflex (sBRS) to suppress MSNA. Alternatively, a “burst” of MSNA could result in a greater change in BP (augmented neurovascular transduction).ObjectiveThe goal of this study was to determine if OCs alter blood pressure control through autonomic mechanisms in young women.HypothesesWe hypothesized (1) sympathetic baroreflex sensitivity would be decreased and (2) neurovascular transduction would be augmented in women on OCs compared to naturally cycling women.MethodsWe conducted a retrospective analysis of data from healthy young women taking OCs (n=30, 25±4yrs) and with natural menstrual cycles (n=23, 27±4yrs). Women were studied during the placebo phase of OC use or early follicular phase of the menstrual cycle. Heart rate (HR, 3‐lead ECG), BP (arterial line or photoplethysmography for both groups), and MSNA (peroneal nerve microneurography) were measured over 5 min of quiet rest and data were analyzed for measures of sBRS and neurovascular transduction (Ensemble, Elucimed Inc., Dunedin, New Zealand).ResultsGroups did not differ in mean BP (Control: 94±9, OC:92±8mmHg, p=0.60), or HR (Control: 61±8, OC: 62±9 bpm, p=0.57), but women on OCs had lower MSNA than controls (Control: 16±6, OC: 12±5 bursts/min, p=0.006). There were no significant differences in TPR (Control: 0.022±0.005, OC: 0.020±0.005 mmHg min/L, p=0.12), however there was a trend toward increased cardiac output in women on OCs (Control: 4.45±0.86, OC: 4.94±1.02 L/min, p=.068). There were no significant group differences in sBRS (Control: −4.3±2.1, OC: −4.0±2.6 bursts ·100 heartbeats−1 ·mmHg−1, p=0.79), or neurovascular transduction (Control: 0.093±0.042, OC: 0.091±0.058 ΔmmHg/% burst area, p=0.87). Furthermore, there were no significant correlations between BP and BRS, MSNA, or transduction in either group.ConclusionsOur data strengthen previous findings which have shown women taking OCs have higher BP for a given MSNA. The analysis we performed build on these results and demonstrate that the increase in BP for a given MSNA in women taking OCs is not due to attenuated sBRS or augmented neurovascular transduction. This work has advanced our understanding of the alteration of blood pressure with OC use in young women.Support or Funding InformationNIH HL083947

Attenuated Sympathetic Baroreflex Sensitivity Evoked by Acute Mental Stress but not Prolonged Sleep Restriction in Healthy Adults

BackgroundPsychological stress and insufficient sleep are both associated with an increased risk of developing hypertension. While the underlying mechanisms are not well defined, it has been postulated that this may be facilitated by modulation of baroreflex control of sympathetic activity. Short periods (&lt;5 min) of mental stress attenuate sympathetic baroreflex sensitivity (sBRS), but it is currently unclear whether this holds true for longer bouts of stress. As such, we sought to examine the effect of 10 min of mental stress on sBRS. Additionally, we evaluated the impact of experimental sleep restriction on baroreflex control of blood pressure during mental stress. We hypothesized that mental stress would attenuate sBRS, and that prolonged exposure to restricted sleep would result in a greater reduction in sBRS during mental stress.MethodsFourteen healthy adults (10M/4F, 25±1 yrs) underwent 10 min of mental stress consisting of a 5‐min mental arithmetic task, followed immediately by a 5‐min Stroop color‐word conflict test. Heart rate (electrocardiography), blood pressure (finger photoplethysmography), and muscle sympathetic nerve activity (microneurography of the common peroneal nerve) were continuously measured to determine sBRS at baseline and during mental stress. A subset of participants (n=9) completed the mental stress protocol under both experimental sleep restriction (4 hr/night) and control sleep conditions (8–9 hr/night) while inpatient at a hospital‐based clinical research unit. Subjects underwent a 3‐night acclimation period, followed by 9 or 14 nights of either sleep restriction or control sleep. Data from Day 2/1 or Day 13/15 (during control sleep only) were used to assess the effect of mental stress alone, and data from Day 13/15 (under both conditions) were used to assess the effect of sleep restriction.ResultsAcute mental stress resulted in a marked blunting of sBRS from baseline (−2.7±0.5 to −1.5±0.4 bursts·100hb−1·mmHg−1, p=0.04). Examining the mental stress interventions individually revealed a significant decrease in sBRS during the initial 5 min of stress (mental arithmetic, p=0.03), but not during the subsequent 5 min of testing (Stroop test, p=0.75). Mental stress also reduced baroreflex function following sleep restriction (main effect of condition, p&lt;0.01); however, the reduction in sBRS was not significantly different in restricted sleep compared to control (main effect of visit, p=0.78). There was no significant interaction effect between sleep restriction and mental stress (p=0.81).ConclusionsThese data provide further support that, in young healthy individuals, sBRS is attenuated early in mental stress but quickly returns to baseline values. In contrast, prolonged sleep restriction does not appear to alter sympathetic control of blood pressure.Support or Funding InformationNIH HL114024 (VKS), NIH HL114676 (VKS), NIH HL083947 (MJJ), FAER Medical Student Anesthesia Research Fellowship (NMP)

Influence of multiparity on sympathetic nerve activity during normal pregnancy.

Recent evidence suggests an elevated risk of cardiovascular disease development in multiparous women. Therefore, we investigated the effects of multiparity on within-pregnancy sympathetic neural regulation in normotensive, pregnant women. We retrospectively analyzed heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA; n = 8) data from 10 women whom participated in microneurographic research studies during two sequential pregnancies (i.e., PREG1 and PREG2). There was no difference in resting BP between pregnancies (P > 0.05), whereas HR trended higher in PREG2 versus PREG1 (P = 0.06). MSNA burst frequency was greater in PREG2 versus PREG1 after adjusting for age (32 ± 12 vs. 22 ± 12 bursts/min; P = 0.049), whereas burst incidence did not differ (40 ± 16 vs. 34 ± 17 bursts/100 heartbeats; P = 0.21). Sympathetic baroreflex sensitivity was not different between PREG1 and PREG2 (P > 0.05). Our results may highlight a possible role of altered within-pregnancy sympathetic neural regulation in the observed relationship in women between parity and future cardiovascular disease risk.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the effects of multiparity on within-pregnancy sympathetic neural regulation. We observed augmented muscle sympathetic nerve activity in women's second studied pregnancy versus their first. Conversely, blood pressure and sympathetic baroreflex sensitivity did not differ, whereas a trend for increased heart rate was observed. Our results highlight a possible role of altered within-pregnancy sympathetic neural regulation in the relationship between increased parity and cardiovascular disease development.

Arterial baroreflex regulation of muscle sympathetic single-unit activity in men: influence of resting blood pressure.

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships (r ≥ -0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (-2.27 ± 1.27%·cardiac cycle-1·mmHg-1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (-0.13 ± 0.18 spikes·cardiac cycle-1·mmHg-1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, -2.08 ± 1.08 vs. -2.46 ± 1.42%·cardiac cycle-1·mmHg-1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension.NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.

Sympathetic baroreflex sensitivity is inversely related to vascular transduction in men but not women.

Sympathetic baroreflex sensitivity (BRS) is a measure of how effectively the baroreflex buffers beat-to-beat changes in blood pressure through the modulation of muscle sympathetic nerve activity (MSNA). However, current methods of assessment do not take into account the transduction of sympathetic nerve activity at the level of the vasculature, which is known to vary between individuals. In this study we tested the hypothesis that there is an inverse relationship between sympathetic BRS and vascular transduction. In 38 (18 men) healthy adults, continuous measurements of blood pressure, MSNA and superficial femoral artery diameter and blood flow (Doppler ultrasound) were recorded during 10 min of rest. Spontaneous sympathetic BRS was quantified as the relationship between diastolic pressure and MSNA burst incidence. Vascular transduction was quantified by plotting the changes in leg vascular conductance for 10 cardiac cycles following each burst of MSNA, and taking the nadir. In men, sympathetic BRS was inversely related to vascular transduction (r = -0.49; P = 0.04). However, this relationship was not present in women (r = -0.17; P = 0.47). To conclude, an interaction exists between sympathetic BRS and vascular transduction in healthy men, such that men with high sympathetic BRS have low vascular transduction and vice versa. This may be to ensure that blood pressure is regulated effectively, although further research is needed to explore what mechanisms are involved and examine why this relationship was not apparent in women.NEW & NOTEWORTHY Evidence suggests that compensatory interactions exist between factors involved in cardiovascular control. This study was the first to demonstrate an inverse relationship between sympathetic BRS and beat-to-beat vascular transduction. Those with low sympathetic BRS had high vascular transduction and vice versa. However, this interaction was present in young men but not women.

Sex differences in baroreflex function in health and disease.

This brief review summarizes the current knowledge on sex differences in baroreflex function, with a major focus on studies in humans. It has been demonstrated that healthy women have blunted cardiovagal baroreflx sensitivity during a rapid (i.e., within seconds) hypertensive stimulus, but baroreflex sensitivity is similar between the sexes during a hypotensive stimulus. Normal aging decreases cardiovagal baroreflex sensitivity and the rate of decline is similar in men and women. Cardiovagal baroreflex sensitivity is reduced in pathological conditions such as hypertension and type II diabetes, and the reduction is greater in female patients than male patients. There is no clear sex difference in sympathetic baroreflex sensitivity among young individuals, however, with women of more advanced age, sympathetic baroreflex sensitivity decreases, which appears to be associated with greater arterial stiffness compared with similarly aged men. The blunted sympathetic baroreflex sensitivity in older women may predispose them to an increased prevalence of hypertension and cardiovascular disease.

Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults.

High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents and is thought to result from elevated plasma [Na+] sensitizing central sympathetic networks. Our purpose was to test the hypothesis that water deprivation (WD)-induced elevations in serum [Na+] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans. In a randomized crossover fashion, 35 adults [17 female/18 male, age: 25 ± 4 yr, systolic/diastolic blood pressure (BP): 107 ± 11/60 ± 7 mmHg, body mass index: 23 ± 3 kg/m2] completed two hydration protocols: a euhydration control condition (CON) and a stepwise reduction in water intake over 3 days, concluding with 16 h of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants (n = 25) underwent ambulatory BP monitoring during day 3 of each protocol. We calculated average real variability as an index of BPV. WD increased serum [Na+] (141.0 ± 2.3 vs. 142.1 ± 1.7 mmol/L, P < 0.01) and plasma osmolality (288 ± 4 vs. 292 ± 5 mosmol/kg H2O, P < 0.01). However, WD did not increase beat-to-beat (1.9 ± 0.4 vs. 1.8 ± 0.4 mmHg, P = 0.24) or ambulatory daytime (9.6 ± 2.1 vs. 9.4 ± 3.3 mmHg, P = 0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity (P = 0.20) and sympathetic vascular transduction were not different after WD (P = 0.17 for peak Δmean BP following spontaneous MSNA bursts). These findings suggest that, despite modestly increasing serum [Na+], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults.

Cardiac and Vascular Sympathetic Baroreflex Control during Orthostatic Pre-Syncope.

We hypothesized that sympathetic baroreflex mediated uncoupling between neural sympathetic discharge pattern and arterial pressure (AP) fluctuations at 0.1 Hz during baroreceptor unloading might promote orthostatic pre-syncope. Ten volunteers (32 ± 6 years) underwent electrocardiogram, beat-to-beat AP, respiratory activity and muscle sympathetic nerve activity (MSNA) recordings while supine (REST) and during 80° head-up tilt (HUT) followed by −10 mmHg stepwise increase of lower body negative pressure until pre-syncope. Cardiac and sympathetic baroreflex sensitivity were quantified. Spectrum analysis of systolic and diastolic AP (SAP and DAP) and calibrated MSNA (cMSNA) variability assessed the low frequency fluctuations (LF, ~0.1 Hz) of SAP, DAP and cMSNA variability. The squared coherence function (K2) quantified the coupling between cMSNA and DAP in the LF band. Analyses were performed while supine, during asymptomatic HUT (T1) and at pre-syncope onset (T2). During T2 we found that: (1) sympathetic baroreceptor modulation was virtually abolished compared to T1; (2) a progressive decrease in AP was accompanied by a persistent but chaotic sympathetic firing; (3) coupling between cMSNA and AP series at 0.1 Hz was reduced compared to T1. A negligible sympathetic baroreceptor modulation during pre-syncope might disrupt sympathetic discharge pattern impairing the capability of vessels to constrict and promote pre-syncope.

Arterial baroreflex regulation of muscle sympathetic nerve activity at rest and during stress.

The arterial baroreflex controls vasoconstrictor muscle sympathetic nerve activity (MSNA) in a negative feedback manner by increasing or decreasing activity during spontaneous blood pressure falls or elevations, respectively. Spontaneous sympathetic baroreflex sensitivity is commonly quantified as the slope of the relationship between MSNA burst incidence or strength and beat-to-beat variations in absolute diastolic blood pressure. We assessed the relationships between blood pressure inputs related to beat-to-beat blood pressure change or blood pressure rate-of-change (variables largely independent of absolute pressure) and MSNA at rest and during exercise and mental stress. The number of participants with strong linear relationships between MSNA and beat-to-beat diastolic blood pressure change variables or absolute diastolic blood pressure were similar at rest, although during stress the beat-to-beat diastolic blood pressure change variables were superior. Current methods may not fully characterize the capacity of the arterial baroreflex to regulate MSNA. Spontaneous sympathetic baroreflex sensitivity (sBRS) is commonly quantified as the slope of the relationship between variations in absolute diastolic blood pressure (DBP) and muscle sympathetic nerve activity (MSNA) burst incidence or strength. This relationship is well maintained at rest but not during stress. We assessed whether sBRS could be calculated at rest and during stress (static handgrip, rhythmic handgrip, mental stress) using blood pressure variables that quantify relative change: beat-to-beat DBP change (ΔDBP), ΔDBP rate-of-change (ΔDBP rate), pulse pressure (PP) and PP rate-of-change (PP rate). Sixty-six healthy participants underwent continuous measures of blood pressure (finger photoplethysmography) and multi-unit MSNA (microneurography). At rest, absolute DBP (91%), ΔDBP (97%) and ΔDBP rate (97%) each yielded higher proportions of participants with strong linear relationships (r≥0.6) with MSNA burst incidence compared to PP (57%) and PP rate (56%) and produced similar sBRS slopes (DBP: -4.5±2.0 bursts100heartbeats-1 /mmHg; ΔDBP: -5.0±2.1 bursts100heartbeats-1 /ΔmmHg; ΔDBP rate: -4.9±2.2 bursts100heartbeats-1 /ΔmmHgs-1 ; P>0.05). During stress, ΔDBP (74%) and ΔDBP rate (74%) yielded higher proportions of strong linear relationships with MSNA burst incidence than absolute DBP (43%), PP (46%) and PP rate (49%) (all P<0.05). The absolute DBP associated with a 50% chance of a MSNA burst (T50 ) was shifted rightward during static handgrip (Δ+15±11mmHg, P<0.001) and mental stress (Δ+11±7mmHg, P<0.001); however, the ΔDBP T50 was shifted rightward during static handgrip (Δ+2.5±3.7mmHg, P=0.009) but not mental stress (Δ0.0±4.4mmHg, P=0.99). These findings suggest that calculating sBRS using absolute DBP alone may not adequately characterize arterial baroreflex regulation of MSNA, particularly during stress.