Changes In Muscle Sympathetic Nerve Activity Research Articles

The interactive effects of posture and biological sex on the control of muscle sympathetic nerve activity during rhythmic handgrip exercise.

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions, and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise, remain unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared with supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] yr; means [SD]) individuals (9 males, 11 females) underwent 6 min of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography), and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency (P < 0.001), amplitude (P = 0.009), and total MSNA (P < 0.001) were higher during upright compared with supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P = 0.063-0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise (P = 0.006) and was not impacted by posture (P = 0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude (P = 0.002) and total MSNA (P = 0.001) compared with females, which coincided with greater reductions in sympathetic baroreflex gain among males (P = 0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females.NEW & NOTEWORTHY The impact of posture and sex on cardiovascular control during rhythmic handgrip (RHG) exercise is unknown. We show that increases in muscle sympathetic nerve activity (MSNA) during RHG are partly mediated by a reduction in sympathetic baroreflex gain. In addition, males demonstrate larger increases in total MSNA during upright RHG than females. These data indicate that the baroreflex partly mediates increases in MSNA during RHG and that males have a greater sympathetic vasoconstrictor reserve than females.

Randomized Trial Comparing SGLT2 Inhibition and Hydrochlorothiazide on Sympathetic Traffic in Type 2 Diabetes

Reductions in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibition on cardiovascular outcomes. Therefore, we tested the hypothesis that SGLT2 inhibition with empagliflozin (Empa) lowers muscle sympathetic nerve activity (MSNA) in patients with type 2 diabetes mellitus (T2DM) compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from responses to increased natriuresis. We randomized patients with T2DM on metformin monotherapy to either 25 mg/d Empa (n= 20) or 25 mg/d HCT (n= 21) for 6 weeks in a parallel, double-blind fashion. We assessed MSNA by peroneal microneurography, blood pressure, cardiovascular and metabolic biomarkers at baseline and at the end of treatment. Both drugs elicited volume depletion, as indicated by increased thoracic impedance. Compared with HCT, Empa caused 1.23 kg more body weight loss (P= 0.011) and improved glycemic control. Seated systolic blood pressure decreased with both treatments (P< 0.002). MSNA did not change significantly with either treatment; however, MSNA changes were negatively correlated with changes in body weight on Empa (P= 0.042) and on HCT(P= 0.001). The relationship was shifted to lower MSNA on Empa compared with HCT (P= 0.002). Increased renal sodium excretion eliciting body weight loss may promote sympathetic activation. However, sympathetic excitation in the face of increased sodium loss may be attenuated by SGLT2 inhibitor-specific actions.

Effect of adaptive servo-ventilation for central sleep apnoea in systolic heart failure on muscle sympathetic nerve activity: a SERVE-HF randomised ancillary study.

Adaptive servo-ventilation (ASV) effectively suppresses central sleep apnoea (CSA) but has been associated with increased all-cause and cardiovascular mortality in chronic heart failure patients with reduced ventricular ejection fraction (HFrEF). All-cause and, especially, cardiovascular mortality in chronic heart failure is highly correlated with sympathetic tone. This analysis of SERVE-HF data investigated the effect of ASV on sympathetic tone in patients with HFrEF and CSA. HFrEF patients in the SERVE-HF trial (left ventricular ejection fraction (LVEF) ≤45%, apnoea-hypopnoea index (AHI) ≥15 events·h-1 with predominant CSA) were randomly assigned to receive guideline-based heart failure treatment alone (controls) or plus ASV. For this analysis, the primary outcome was change in muscle sympathetic nerve activity (MSNA) at 3-month follow-up. The effects of baseline MSNA and change in MSNA over time on mortality in the main study were also assessed. 40 patients with HFrEF were included in this analysis (age 71.3±11.7 years, LVEF 34.2±7.7%, 57.5% in New York Heart Association (NYHA) Functional Class II, 42.5% in NYHA Functional Class III, AHI 35.2±11 events·h-1). Sympathetic tone evolution during follow-up did not differ between groups (controls: 47.6±8.3 bursts·min-1 at baseline to 44.6±11.2 bursts·min-1; ASV group: 43.0±9.0 bursts·min-1 at baseline to 42.74±9.45 bursts·min-1). The reduction in sympathetic tone was associated with significantly increased cardiovascular mortality in the ASV group, whereas in the control group reduced sympathetic tone appeared to be protective. Suppression of CSA with ASV did not seem to have a significant effect on chronic heart failure-related sympathetic activation. Simultaneous suppression of CSA and reduction in MSNA was associated with increased cardiovascular mortality.

Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection.

Cross‐sectional data indicate that acute SARS‐CoV‐2 infection increases resting muscle sympathetic nerve activity (MSNA) and alters hemodynamic responses to orthostasis in young adults. However, the longitudinal impact of contracting SARS‐CoV‐2 on autonomic function remains unclear. The aim of this study was to longitudinally track MSNA, sympathetic transduction to blood pressure (BP), and hemodynamics over 6 months following SARS‐CoV‐2 infection. Young adults positive with SARS‐CoV‐2 reported to the laboratory three times over 6 months (V1:41 ± 17, V2:108 ± 21, V3:173 ± 16 days post‐infection). MSNA, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured at rest, during a cold pressor test (CPT), and at 30° head‐up tilt (HUT). Basal SBP (p = 0.019) and DBP (p < 0.001) decreased throughout the 6 months, whereas basal MSNA and HR were not different. Basal sympathetic transduction to BP and estimates of baroreflex sensitivity did not change over time. SBP and DBP were lower during CPT (SBP: p = 0.016, DBP: p = 0.007) and HUT at V3 compared with V1 (SBP: p = 0.041, DBP: p = 0.017), with largely no changes in MSNA. There was a trend toward a visit‐by‐time interaction for burst incidence (p = 0.055) during HUT, wherein at baseline immediately prior to tilting, burst incidence was lower at V3 compared with V1 (p = 0.014), but there were no differences between visits in the 30 HUT position. These results support impairments to cardiovascular health, and potentially autonomic function, which may improve over time. However, the improvements in BP over 6 months recovery from mild SARS‐CoV‐2 infection are likely not a direct result of changes in sympathetic activity.

Effect of pulmonary vein isolation on the relationship between left atrial reverse remodeling and sympathetic nerve activity in patients with atrial fibrillation.

Catheter ablation (CA) to isolate the pulmonary vein, which is an established treatment for atrial fibrillation (AF), is associated with left atrium reverse remodeling (LARR). The intrinsic cardiac autonomic nervous system includes the ganglion plexi adjacent to the pulmonary vein in the left atrium (LA). However, little is known about the effect of CA on the relationship between LARR and sympathetic nerve activity in patients with AF. This study enrolled 22 AF patients with a normal left ventricular ejection fraction (LVEF) aged 64.6 ± 12.9years who were scheduled for CA. Sympathetic nerve activity was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) before and 12weeks after CA. Blood pressure, heart rate (HR), HR variability, and echocardiography were also measured. The heart rate increased significantly after CA (63 ± 10.9 vs. 70.6 ± 7.7 beats/min, p < 0.01), but blood pressure did not change. A high frequency (HF) and low frequency (LF) of HR variability decreased significantly after ablation, but no significant change in LF/HF was observed. CA significantly decreased MSNA (38.9 ± 9.9 vs. 28 ± 9.1 bursts/min, p < 0.01). Moreover, regression analysis revealed a positive correlation between the percentage change in MSNA and the LA volume index (r = 0.442, p < 0.05). Our results show that CA for AF reduced MSNA and the decrease was associated with the LA volume index in AF patients with a normal LVEF. These findings suggest that LARR induced by CA for AF decrease sympathetic nerve activity.

Muscle Sympathetic Nerve Activity and Cerebrovascular Responses to Mental Stress

Mental stress has been shown to elicit increases in arterial blood pressure, heart rate and cerebral blood flow, whereas the degree of sympathoexcitation induced by mental stress has been shown to be inconsistent. Previous studies have examined the relationship between limb vascular responsiveness and muscle sympathetic nerve activity (MSNA) during mental stress; however, this has not been studied in relation to the cerebral vasculature. The purpose of this study was to examine concurrent neural and cerebrovascular responses to mental stress. Thirteen healthy adults (men/women: 7/6; age = 28 ± 5 years; BMI = 25 ± 2 kg/m2) completed the Stroop Color Word Test. Beat‐to‐beat mean arterial pressure (MAP) using finger photoplethysmograpy, heart rate (HR) using a 3‐lead ECG, middle cerebral artery velocity (MCAv) using transcranial doppler ultrasound, and MSNA using microneurography were continuously recorded at baseline and in response to the Stroop Color Word Test. The response to the mental stress was recorded as the change from baseline. Linear regression was used to assess the influence of MSNA on cerebrovascular and hemodynamic variables. As expected, there were increases in HR (baseline = 58 ± 8 bpm vs. Stroop = 66 ± 10 bpm; p = 0.045) and MCAv (baseline = 58 ± 8 cm/s vs. Stroop = 69 ± 13 cm/s; p = 0.016) from baseline during the Stroop test. However, there was no change in MAP (baseline = 96 ± 16 mmHg vs. Stroop = 99 ± 17 mmHg; p &gt; 0.05) or MSNA (baseline = 16 ± 6 bursts/min vs. Stroop = 17 ± 7 bursts/min; p &gt; 0.05) from baseline during the Stroop test. Although the change in MAP was positively associated with the change in MCAv (r = 0.46, p = 0.025), there were no associations between the change in MSNA and the increase in MCAv, MAP, or HR in response to the Stroop test. In conclusion, our results demonstrate a disassociation between the MSNA, MAP and MCAv responses to mental stress. It is also possible that the temporal response to mental stress is different and future studies could examine the time course of the sympathetic and cerebrovascular responses.

Mental Stress Pressor Response and Post‐Stress Aortic Wave Reflection

Reactivity to mental stress has been linked to cardiovascular risk, and is shown to negatively influence aortic wave reflection for up to an hour after acute mental arithmetic. It has been postulated that sympathetic catecholamine release during the stressful task drives the sustained elevation in wave reflection. In the present study we sought to determine how muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) reactivity influence post mental stress aortic augmentation index (AIx). Twenty‐seven volunteers (25±1 years) with resting blood pressure ≥120/80 mmHg participated in the present study. Baseline pulse wave analysis and pulse wave velocity recordings were assessed on participants after 10 minutes of supine rest. Participants were then instrumented for measurements of MSNA (microneurography), beat‐to‐beat blood pressure (finger plethysmography), and heart rate (3‐lead ECG). Subsequently MSNA, blood pressure, and heart rate were measured during a 5‐minute baseline, 5‐minute mental stress task (serial subtraction), and 5‐minute recovery. Finally, aortic wave reflection (i.e. AIx) was reassessed 10 minutes after completion of mental stress. Statistical analyses included paired t‐tests to compare MSNA, MAP, heart rate (HR), and perceived stress during baseline and mental stress. We used standard multiple regression with change in AIx as the dependent variable and changes in MSNA, MAP, and perceived stress as the independent variables. Means were considered significantly different when p&lt;0.05. The mental stress task significantly increased HR (Δ15±2 beats/minute), MAP (Δ14±1 mmHg), and perceived stress (Δ1.9±0.1 a.u.), while MSNA was not significantly increased. There was however a range of changes in MSNA from ‐13 to +20 bursts/minute. The change in MAP during mental stress was a significant predictor (ꞵ=0.47; p=0.03) of the change in AIx (post‐stress vs. baseline). Changes in MSNA and perceived stress were not predictors of mental stress‐related changes in AIx. Our results indicate that the aortic wave reflection responses to mental stress appear to be linked to the pressor response, but not sympathetic or perceived stress responses. This is novel preliminary data that suggests there may not be a direct link between sympathetic activation and aortic wave reflection following cognitive stress.

Sex Differences in Muscle Metaboreflex Activation after Static Handgrip Exercise.

Larger blood pressure (BP) responses to relative-intensity static exercise in men versus women are thought to involve altered muscle metaboreflex activation, but whether this is because of an intrinsic sex difference in metabolite production or differences in muscle strength and absolute load is unknown. Continuous BP and heart rate were recorded in 200 healthy young men and women (women: n = 109) during 2 min of static handgrip exercise at 30% of maximal voluntary contraction (MVC), followed by 2 min of postexercise circulatory occlusion (PECO). Muscle sympathetic nerve activity (MSNA) was recorded in a subset of participants (n = 39; women, n = 21), permitting calculation of signal-averaged resting sympathetic transduction (MSNA-diastolic BP). Sex differences were examined with and without statistical adjustment for MVC. Multivariate regression analyses were performed to identify predictors of BP responses. Men had larger systolic BP responses (interactions, P < 0.0001) to static handgrip exercise (24 ± 10 vs 17 ± 9 mm Hg [mean ± SD], P < 0.0001) and PECO (20 ± 11 vs 16 ± 9 mm Hg, P < 0.0001). Adjustment for MVC abolished these sex differences in BP (interactions, P > 0.7). In the subset with MSNA, neither burst frequency or incidence responses to static handgrip exercise or PECO differed between men and women (interactions, P > 0.2). Resting sympathetic transduction was also similar (P = 0.8). Multiple linear regression analysis showed that MVC or the change in MSNA, were predictors of BP responses to static handgrip, but only MVC was associated with BP responses during PECO. Sex differences in absolute contraction load contribute to differences in BP responses during muscle metaboreflex isolation using PECO. These data do not support an intrinsic effect of sex as being responsible for exercise BP differences between men and women.

Muscle Metaboreflex Control of Sympathetic Activity Is Preserved after Acute Intermittent Hypercapnic Hypoxia.

In normotensive patients with obstructive sleep apnea (OSA), the muscle sympathetic nerve activity (MSNA) response to exercise is increased while metaboreflex control of MSNA is decreased. We tested the hypotheses that acute intermittent hypercapnic hypoxia (IHH) in males free from OSA and associated comorbidities would augment the MSNA response to exercise but attenuate the change in MSNA during metaboreflex activation. Thirteen healthy males (age = 24 ± 4 yr) were exposed to 40 min of IHH. Before and after IHH, the pressor response to exercise was studied during 2 min of isometric handgrip exercise (at 30% maximal voluntary contraction), whereas the metaboreflex was studied during 4 min of postexercise circulatory occlusion (PECO). Mean arterial pressure (MAP), heart rate (HR), and fibular MSNA were recorded continuously. MSNA was quantified as burst frequency (BF) and total activity (TA). Mixed effects linear models were used to compare the exercise pressor and metaboreflex before and after IHH. As expected, IHH led to significant increases in MSNA BF, TA, and MAP at baseline and throughout exercise and PECO. However, during handgrip exercise, the change from baseline in MAP, HR, MSNA BF, and TA was similar before and after IHH (All P > 0.31). During PECO, the change from baseline in MSNA BF and TA was similar after IHH, whereas the change from baseline in MAP (Δ14 mm Hg, 95% CI = 7-19, vs Δ16 mm Hg, 95% CI = 10-21; P < 0.01) was modestly increased. After acute IHH, MSNA response to handgrip exercise and metaboreflex activation were preserved in healthy young males despite overall increases in resting MSNA and MAP. Chronic IHH and comorbidities often associated with OSA may be required to modulate the exercise pressor reflex and metaboreflex.

Sympathetic activation due to limb venous distension is preserved during muscle metaboreceptor stimulation

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e. muscle metaboreflex) would modify venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A, saline (5% forearm volume) was infused into the veins of an arterially occluded arm (non-handgrip trial). In trial B, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial A, the infusion increased MSNA and BP as expected (both P < 0.001). In trial B, handgrip significantly raised MSNA, BP and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (D8.6 ± 1.5 to D10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure (P = 0.844) evoked by the infusion during PECO were not significantly different from those in the non-handgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.

Habitual Exercise Training on Muscle Sympathetic Nerve Activity Responses to Hypercapnia in Older Adults

Elevated activity of the sympathetic nervous system at rest and sympathetic hyperreactivity to stress have been shown to be predictors of cardiovascular diseases. The effect of habitual exercise training on muscle sympathetic reactivity to a stressor is unclear, with some studies demonstrating blunted muscle sympathetic nerve activity (MSNA) reactivity following training and others demonstrating no change in MSNA reactivity; however, many of these studies have not been performed in older adults. The purpose of this study was to compare MSNA responses to hypercapnia in older exercise trained and sedentary adults. Twenty-five older healthy adults were evaluated including 14 exercise trained (EX: age = 63 ± 4 years; BMI = 23 ± 3 kg/m2) and 11 sedentary controls (CON: age = 62 ± 6 years; BMI = 23 ± 2 kg/m2). Participants underwent a maximal exercise test to exhaustion on a cycle ergometer to measure VO2max. On a separate day, mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants underwent stepped increases in hypercapnia, stabilizing at 6% CO2. Results are reported as mean ± SE. MAP was not different between groups at baseline (EX: 96 ± 2 mmHg vs. CON: 102 ± 5 mmHg; p>0.05) and during 6% CO2 (EX: 104 ± 4 mmHg vs. CON: 107 ± 5 mmHg; p>0.05). Both the change in MAP (EX: 8 ± 2 mmHg vs. CON: 5 ± 2 mmHg; p>0.05) and % change in MAP (EX: 8 ± 2 % vs. CON: 4 ± 2 %; p>0.05) were not different between groups. HR was not significantly different, but tended to be higher in the CON group at baseline (EX: 53 ± 2 bpm vs. CON: 57 ± 1 mmHg; p=0.09) and during 6% CO2 (EX: 57 ± 2 bpm vs. CON: 62 ± 2 bpm; p=0.09). Both the change in HR (EX: 4 ± 1 bpm vs. CON: 5 ± 1 mmHg; p>0.05) and % change in HR (EX: 8 ± 2 % vs. CON: 8 ± 2 %; p>0.05) were not different between groups. MSNA was not different between groups at baseline (EX: 32 ± 3 bursts/min vs. CON: 34 ± 3 bursts/min; p>0.05) and during 6% CO2 (EX: 35 ± 3 bursts/min vs. CON: 35 ± 3 bursts/min; p>0.05). Similarly, the change in MSNA (EX: 3 ± 1 bursts/min vs. CON: 1 ± 2 bursts/min; p>0.05) and the % change in MSNA (EX: 10 ± 5 % vs. CON: 5 ± 5 %; p>0.05) were not different between groups. The sympathetic response to hypercapnia was not different in older exercise-trained adults compared with sedentary adults. Taken together, these results suggest that hypercapnia-induced sympathoexcitation may not be altered with habitual exercise training in older healthy adults. Future studies could assess sympathoexcitation to other physiological stressors to further explore the effects of exercise on sympathetic reactivity in older adults.

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.

Heart failure-specific inverse relationship between the muscle sympathetic response to dynamic leg exercise and V̇O2peak

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (V̇O2peak) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇O2peak: 78 ± 23 percent age-predicted (%V̇O2peak); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29%V̇O2peak) performed 2min of mild- ("loadless") and moderate-intensity ("loaded") 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher (p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min-1). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of "loadless" and "loaded" cycling, group mean BF fell from baseline values in controls (-5 ± 6 and -7 ± 7 bursts·min-1, respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min-1). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to "loaded" cycling and %V̇O2peak was present in patients (r = -0.43, p < 0.05) but absent in controls (r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in %V̇O2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake (V̇O2peak) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.

Sex differences in vascular transduction of sympathetic nerve activity.

Sympathetic vasoconstriction plays a major role in the beat-to-beat control of blood pressure. To be effective and thus avoid dangerously high or low blood pressures, this mechanism relies upon transduction of sympathetic nerve activity at the level of the vasculature. However, recent evidence suggests that considerable variability exists in beat-to-beat vascular transduction, particularly between the sexes. We reviewed the methods available for quantifying beat-to-beat transduction of muscle sympathetic nerve activity (MSNA) and explored the recent evidence for sex differences in vascular transduction. We paid specific attention to relationships between vascular transduction and factors such as resting levels of sympathetic nerve activity and baroreflex sensitivity. There are two dominant methods now available for the quantification of beat-to-beat transduction of muscle sympathetic nerve activity at rest. Whilst there is some evidence to suggest that young females exhibit lower levels of vascular transduction, results vary depending on the method used and the direction of change in MSNA. Evidence suggests that compensatory relationships may exist between key components of neurovascular control, such as vascular transduction and resting levels of MSNA. Also consistent is the presence of such relationships in young males but not young females. The lack of significant relationships in young females may reflect the influence of vasodilator mechanisms that counteract sympathetic vasoconstriction. The assessment of vascular transduction following MSNA bursts and non-bursts in males and females, both young and older, may help to gain a mechanistic understanding of the prevalence of hypotensive and hypertensive disorders across the lifespan.

Influence of Sex and Age on Muscle Sympathetic Nerve Activity of Healthy Normotensive Adults.

As with blood pressure, age-related changes in muscle sympathetic nerve activity (MSNA) may differ nonlinearly between sexes. Data acquired from 398 male (age: 39±17; range: 18-78 years [mean±SD]) and 260 female (age: 37±18; range: 18-81 years) normotensive healthy nonmedicated volunteers were analyzed using linear regression models with resting MSNA burst frequency as the outcome and the predictors sex, age, MSNA, blood pressure, and body mass index modelled with natural cubic splines. Age and body mass index contributed 41% and 11%, respectively, of MSNA variance in females and 23% and 1% in males. Overall, changes in MSNA with age were sigmoidal. At age 20, mean MSNA of males and females were similar, then diverged significantly, reaching in women a nadir at age 30. After 30, MSNA increased nonlinearly in both sexes. Both MSNA discharge and blood pressure were lower in females until age 50 (17±9 versus 25±10 bursts·min-1; P<1×10-19; 106±11/66±8 versus 116±7/68±9 mm Hg; P<0.01) but converged thereafter (38±11 versus 35±12 bursts·min-1; P=0.17; 119±15/71±13 versus 120±13/72±9 mm Hg; P>0.56). Compared with age 30, MSNA burst frequency at age 70 was 57% higher in males but 3-fold greater in females; corresponding increases in systolic blood pressure were 1 (95% CI, -4 to 5) and 12 (95% CI, 6-16) mm Hg. Except for concordance in females beyond age 40, there was no systematic change with age in any resting MSNA-blood pressure relationship. In normotensive adults, MSNA increases after age 30, with ascendance steeper in women.

High‐intensity interval training decreases muscle sympathetic nerve activity and improves peripheral vascular function in patients with heart failure with reduced ejection fraction

BackgroundModerate intensity continuous exercise (MICT) has been shown to reduce muscle sympathetic nerve activity (MSNA) in heart failure patients with reduced ejection fraction (HFrEF). However, the effects of high‐intensity interval training (HIIT) on MSNA in HFrEF patients are unknown. We hypothesized that reductions in MSNA would be greater following HIIT than MICT and correspond with improvements in peripheral vascular function.MethodsHFrEF patients (30 ‐ 65 years), left ventricular ejection fraction ≤ 40%, Functional Classes II–III, were randomized into HIIT, MICT or no training (NT) three times/week for 12 weeks. MSNA was assessed by microneurography. Brachial artery flow‐mediated dilation (FMD), blood flow and vascular conductance were assessed by ultrasonography, blood pressure (BP) and heart rate (HR) by plethysmography and peak oxygen uptake (V̇O2peak) by a cardiopulmonary exercise test.ResultsBoth, HIIT and MICT, led to reductions in MSNA (frequency and incidence burst) relative to NT (p&lt;0.05). However, the reduction in MSNA was more pronounced following HIIT than MICT (p&lt;0.05). Increases in brachial artery FMD, resting blood flow and conductance were also greater following HIIT than MICT (p&lt;0.05), while V̇O2peak increased similarly following HIIT and MICT relative to NT. No changes in BP or HR were observed in either exercise condition. Further analysis showed a negative correlation between changes in MSNA and FMD following the interventions (r=−0.60, p=0.005).ConclusionOur findings indicate that 12 weeks of HIIT is superior to MICT in reducing sympathetic overactivity and improving vascular function in patients with HFrEF, despite similar increases in exercise capacity.Support or Funding InformationFAPESP Grants (2014/11671‐6 and 2017/25613‐6)

Sympathetic Activation to Limb Venous Distension is Preserved during Muscle Metaboreceptor Stimulation

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). Animal studies suggest that venous distension increases the discharge of Group III and IV afferent nerve endings in peripheral veins. Exercise also activates the Group III and IV afferent nerves in exercising muscles. It is unclear if the venous distension reflex contributes to BP regulation during exercise. We hypothesized that muscle metaboreceptor stimulation might alter the venous distension reflex response. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects (13 M, 5 F, 26 ± 1 yrs). In trial 1, saline (5% forearm volume) was infused into veins of an arterially occluded arm (non‐handgrip trial). In the second experiment, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial 1, infusion increased MSNA (18.5 ± 1.6 to 29.1 ± 2.4 bursts/min, P &lt; 0.001) and BP (P &lt;0.001) as expected. Handgrip significantly raised MSNA (19.8 ± 1.6 to 28.0 ± 1.8 bursts/min, P &lt; 0.001), BP (P &lt; 0.001) and venous lactic acid (1.0 ± 0.1 to 3.1 ± 0.4, mmol/L, P &lt; 0.001). Venous saline infusion during PECO further raised MSNA (prior infusion vs. end of infusion, 29.0 ± 2.4 to 37.7±2.7 bursts/min, P= 0.001) and BP (P &lt; 0.001). The changes in MSNA evoked by infusion during PECO were not significantly different from the rises in the non‐handgrip trial (delta 8.6 ± 1.5 to delta 10.6 ± 1.8 bursts/min, P = 0.258). The BP responses to the infusion were not different in the two trials. These observations indicate that venous distension reflex responses are preserved during the sympathetic activation mediated by the muscle metaboreceptor stimulation. These data may suggest that venous distension reflex contributes to the BP regulation during exercise.Support or Funding InformationSupported by NIH R01 HL144781 (Cui and Sinoway) and UL1 TR002014 (Sinoway), and Pennsylvania Department of Health Tobacco CURE Funds SAP#4100079742 (Cui).

Increase in diastolic blood pressure induced by fragrance inhalation of grapefruit essential oil is positively correlated with muscle sympathetic nerve activity

Fragrance inhalation of essential oils is widely used in aromatherapy, and it is known to affect blood pressure (BP) and heart rate (HR) via autonomic control of circulation. In this study, we aimed to test the hypothesis that the changes in hemodynamics with fragrance inhalation were observed along with changes in muscle sympathetic nerve activity (MSNA). In study 1, thirteen healthy men were exposed to fragrance stimulation of grapefruit essential oil for 10 min, and BP, HR, and MSNA were continuously measured. In study 2, another nine healthy men were exposed to the same fragrance stimulation; responses in BP and HR were continuously measured, and plasma noradrenaline and cortisol concentrations were determined. We found that diastolic BP increased significantly during fragrance inhalation, while the other variables remained unchanged in both studies. Although MSNA burst frequency, burst incidence, and total activity remained unchanged during fragrance inhalation, we found a significant linear correlation between changes in diastolic BP in the last 5 min of fragrance inhalation and changes in MSNA burst frequency. The plasma cortisol concentration decreased significantly at 10 min of fragrance inhalation, though the noradrenaline concentration remained unchanged. These results suggest, for the first time, that changes in BP with fragrance inhalation of essential oil are associated with changes in MSNA even with decreased stress hormone.

Effects of dynamic arm and leg exercise on muscle sympathetic nerve activity and vascular conductance in the inactive leg.

The influence of muscle sympathetic nerve activity (MSNA) responses on local vascular conductance during exercise are not well established. Variations in exercise mode and active muscle mass can produce divergent MSNA responses. Therefore, we sought to examine the effects of small- versus large-muscle mass dynamic exercise on vascular conductance and MSNA responses in the inactive limb. Thirty-five participants completed two study visits in a randomized order. During visit 1, superficial femoral artery (SFA) blood flow (Doppler ultrasound) was assessed at rest and during steady-state rhythmic handgrip (RHG; 1:1 duty cycle, 40% maximal voluntary contraction), one-leg cycling (17 ± 3% peak power output), and concurrent exercise at the same intensities. During visit 2, MSNA (contralateral fibular nerve microneurography) was acquired successfully in 12/35 participants during the same exercise modes. SFA blood flow increased during RHG (P < 0.0001) and concurrent exercise (P = 0.03) but not cycling (P = 0.91). SFA vascular conductance was unchanged during RHG (P = 0.88) but reduced similarly during concurrent and cycling exercise (both P < 0.003). RHG increased MSNA burst frequency (P = 0.04) without altering burst amplitude (P = 0.69) or total MSNA (P = 0.26). In contrast, cycling and concurrent exercise had no effects on MSNA burst frequency (both P ≥ 0.10) but increased burst amplitude (both P ≤ 0.001) and total MSNA (both P ≤ 0.007). Across all exercise modes, the changes in MSNA burst amplitude and SFA vascular conductance were correlated negatively (r = -0.43, P = 0.02). In summary, the functional vascular consequences of alterations in sympathetic outflow to skeletal muscle are most closely associated with changes in MSNA burst amplitude, but not frequency, during low-intensity dynamic exercise.NEW & NOTEWORTHY Low-intensity small- versus large-muscle mass exercise can elicit divergent effects on muscle sympathetic nerve activity (MSNA). We examined the relationships between changes in MSNA (burst frequency and amplitude) and superficial femoral artery (SFA) vascular conductance during rhythmic handgrip, one-leg cycling, and concurrent exercise in the inactive leg. Only changes in MSNA burst amplitude were inversely associated with SFA vascular conductance responses. This result highlights the functional importance of measuring MSNA burst amplitude during exercise.

Muscle Sympathetic Nerve Activity Responses to Hypercapnia in Exercise Trained and Sedentary Adults

Elevated activity of the sympathetic nervous system at rest and sympathetic hyperreactivity to stress have been shown to be predictors for the development of cardiovascular diseases, such as hypertension. Previous studies have shown that there is no difference in resting muscle sympathetic nerve activity (MSNA) with exercise in young adults; however, the effects of exercise on the sympathoexcitatory response to chemical stimuli, such as hypercapnia, have not been studied. The purpose of this study was to compare MSNA responses to hypercapnia in young exercise trained and sedentary adults. Twenty‐nine young healthy adults were evaluated including 16 exercise trained (EX: M/F = 7/9; age = 27 ± 5 years; BMI = 23 ± 2 kg/m2) and 13 sedentary controls (CON: M/F = 7/6; age = 28 ± 4 years; BMI = 25 ± 2 kg/m2). Mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants underwent a stepped hypercapnic protocol increasing to 6% CO2. Results are reported as mean ± SE. MAP was not different between groups at baseline (EX: 95 ± 4 mmHg vs. CON: 91 ± 5 mmHg; p&gt;0.05) and during 6% CO2 (EX: 96 ± 4 mmHg vs. CON: 101 ± 5 mmHg; p&gt;0.05). Both the change in MAP (EX: 1 ± 4 mmHg vs. CON: 11 ± 5 mmHg; p&lt;0.05) and % change in MAP (EX: 2 ± 4 % vs. CON: 13 ± 5 %; p&lt;0.05) were greater in the CON group compared with the EX group. HR was greater in the CON group compared with the EX group at baseline (EX: 50 ± 1 bpm vs. CON: 59 ± 3 mmHg; p&lt;0.05) and during 6% CO2 (EX: 57 ± 2 bpm vs. CON: 68 ± 3 bpm; p&lt;0.05). Both the change in HR (EX: 8 ± 1 bpm vs. CON: 9 ± 2 mmHg; p&gt;0.05) and % change in HR (EX: 16 ± 3 % vs. CON: 16 ± 4 %; p&gt;0.05) were not different between groups. MSNA was not different at baseline (EX: 16 ± 1 bursts/min vs. CON: 18 ± 2 bursts/min; p&gt;0.05) and during 6% CO2 (EX: 17 ± 2 bursts/min vs. CON: 20 ± 2 bursts/min; p&gt;0.05). The change in MSNA was greater in the CON group compared with the EX group (EX: 0.5 ± 0.4 bursts/min vs. CON: 2.4 ± 0.9 bursts/min; p&lt;0.05) and the percent change in MSNA was non‐significant but tended to be higher in the CON group compared with the EX group (EX: 4 ± 2 % vs. CON: 16 ± 6 %; p=0.057). The sympathetic response to hypercapnia was lower in young exercise‐trained adults compared with sedentary adults. Taken together, these results suggest that hypercapnia‐induced sympathoexcitation may be altered with exercise training status, even in young healthy adults.Support or Funding InformationNIH HL118154This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.