Total Muscle Sympathetic Nerve Activity Research Articles

Regional cerebral perfusion and sympathetic activation during exercise in hypoxia and hypercapnia: preliminary insight into'Cushing's mechanism'.

We examined the interactive influence of hypoxia and exercise, and hypercapnia and exercise,on regional cerebral perfusion and sympathetic activation. Twenty healthy young adults (seven women) completed study trials including (1) rest in normoxia ( : ∼96%, : ∼36mmHg), normocapnic hypoxia ( : ∼84%, : ∼36mmHg), and normoxic hypercapnia ( : ∼98%, : ∼46mmHg) and (2) unilateral rhythmic handgrip exercise (45% of maximal voluntary contraction at 1Hz for 3min) under the same gas conditions. Based on the exercising arm, blood flow in the contralateral internal carotid (ICABF) and ipsilateral vertebral (VABF) arteries, anterior and posterior cerebral O2 delivery ( ), and muscle sympathetic nerve activity (MSNA) were measured in each trial. During exercise in hypoxia, ICABF, VABF, anterior and posterior were significantly lower, whereas total MSNA was significantly greater, than the sum of the responses evoked by either hypoxia or exercise alone. During exercise in hypercapnia, ICABF and anterior were significantly greater, whereas MSNA was lower, than the sum of the responses evoked by either hypercapnia or exercise alone. The VABF and posterior responses to hypercapnic exercise were not different from the summated responses. These findings suggest that the brain is hypoperfused and sympathetic outflow potentiated during hypoxic exercise, and that the brain is hyperperfused and sympathetic discharge constrained during hypercapnic exercise. The contrasting consequences for cerebral perfusion and sympathetic activation indicate a potential involvement of Cushing's mechanism in the autonomic control during exercise in healthy humans. KEY POINTS: Brain O2-demand and -supply are mismatched, and muscle sympathetic nerve activity (MSNA) is enhanced in humans exercising at high altitude; the link between the two phenomena remains elusive. We evaluated the isolated and interactive effects of exercise, hypoxia, and hypercapnia on blood flow in the internal carotid (ICABF) and vertebral (VABF) arteries, and MSNA. The interaction of hypoxia and exercise was hypo-additive for ICABF and VABF and anterior and posterior cerebral O2 delivery ( ), but hyper-additive for MSNA. The interaction of hypercapnia and exercise was hyper-additive for ICABF and anterior , additive for VABF and posterior , and hypo-additive for MSNA. These observations indicate that a suboptimal brain perfusion during hypoxic exercise coincides with a potentiated sympathetic outflow, while a (supra-)optimal brain perfusion during hypercapnic exercise coincides with a suppressed sympathetic outflow. Our findings suggest that Cushing's mechanism may play a role in the autonomic control in exercising humans.

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.

Effect of Sex on Sympatho-inhibitors and Non-inhibitor Phenotypes during Acute Hyperoxia

Acute hyperoxia (i.e., breathing air consisting of 100% oxygen, O2) reduces muscle sympathetic nerve activity (MSNA), positioning hyperoxia as a potential anti-hypertensive therapeutic. However, the link between hyperoxia and MSNA has not been established in females. We tested the hypothesis that males would exhibit greater reductions in MSNA during hyperoxia than females. We tested healthy females (n=18, 27±5yr, body mass index [BMI] 23±3kg/m2) and males (n=13, 27±5yr, 25±3kg/m2) of similar age (P=0.99) and BMI (P=0.08). Integrated MSNA, blood pressure, and end-tidal O2 (ETO2) and CO2 (ETCO2) were measured during normal room air breathing (BSL; 3-min) and hyperoxic breathing (100% O2; 3-min). Integrated MSNA was quantified as burst frequency (BF; bursts/min), amplitude (BA; a.u.), and total MSNA (a.u.); blood pressure was quantified as mean arterial pressure (MAP). Baseline MSNA BF was not different between females and males (24±7 vs 23±8 bursts/min, respectively, P=0.68); MAP was lower in females than males (85±7 vs 93±7 mmHg; p&lt;0.01). Hyperoxia increased ETO2 (effect of cond: p&lt;0.01) and reduced ETCO2 (effect of cond: p&lt;0.01) in a manner similar between sexes for ETO2 (sex*cond: P=0.56) whereas ETCO2 decreased more in females than males (sex*cond: P=0.01). Overall, hyperoxia evoked reductions in MSNA BF (effect of cond: P=0.02) but not BA (effect of cond: P=0.80) or total MSNA (effect of cond: P=0.26). Nadir MSNA responses during hyperoxia unveiled sex differences insofar as total MSNA was reduced consistently only in males (sex*cond: P=0.04); within the females we observed the presence of sympatho-inhibitors and non-inhibitors. Whereas female and male inhibitors reduced total MSNA via substantial reductions in BF and non-significant reductions in BA, female non-inhibitors demonstrated limited reductions in BF (P=0.11 vs inhibitors) coupled with increases in BA (p&lt;0.01 vs inhibitors), resulting in no net change in total MSNA (p&lt;0.01 vs inhibitors). Overall, these findings indicate sex differences exist in the sympathetic response to hyperoxia, in marked variability in the female sympathetic response to acute hyperoxia. The Women and Children's Health Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Habitual Sleep and Muscle Sympathetic Nerve Activity in Humans

Short habitual sleep duration and inadequate sleep effciency are associated with poor cardiovascular health. Although a potential mediator of this relationship is augmented sympathetic activity, only one study to date has assessed the relationship between objectively measured habitual sleep duration and direct muscle sympathetic nerve activity (MSNA) in humans. Moreover, the proportion of resting MSNA that can be independently explained by habitual sleep while controlling for other key variables remains unknown. The purpose of the present study was to assess the independent relationship between total sleep time (TST), sleep effciency (SE), and MSNA in a large population of young males and females. We hypothesized that short TST and low SE would be associated with elevated MSNA and blood pressure. A minimum 7 days of at-home, objective actigraphy sleep monitoring was collected in 66 healthy young adults (35 males, 31 females; 24±1 years; 26±1 kg/m2). In each participant, the average of three seated brachial blood pressures was recorded and used to determine resting mean arterial blood pressure (MAP). All participants underwent an autonomic function test that simultaneously assessed heart rate (HR, electrocardiogram), beat-to-beat blood pressure (finger plethysmography) and MSNA (microneurography) during 10 minutes of quiet rest. Resting MAP (83±1 mmHg), HR (64±1 beats/min) and MSNA (19±1 bursts/min) were normally distributed. Habitual TST was significantly correlated with MSNA (r=-0.265, p=0.032), but was not associated with resting MAP (r=-0.153, p=0.219) or HR (r=-0.205, p=0.098). SE was not associated with any of the outcome variables (all p&gt;0.25). Multiple regression was used to test the independent relationship between TST, MAP, HR, and MSNA while accounting for effects of age, sex, and body mass index (BMI). The regression model significantly predicted MAP (R2=0.253, p=0.001) and MSNA (R2=.211, p=0.005), but not HR (R2=.047, p=0.560). TST did not independently explain any additional variance in MAP (ΔR2=0.004, p=0.562) beyond that ascribed to the effects of age, sex, and BMI. In contrast, TST independently explained an additional 5% of the variance in MSNA (ΔR2=0.053, p=0.048). In a large sample of healthy young males and females, our results indicate that habitual TST explains only a minor proportion of the observed variance in resting MSNA between participants. NIH (AA-024892). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Young Trauma-Exposed Women with Low Sleep Effciency have Blunted Sympathetic Baroreflex Sensitivity and Higher Muscle Sympathetic Nerve Activity

Introduction: Poor sleep, a known risk factor for cardiovascular disease (CVD) and one of the American Heart Association’s essential 8th, is common after trauma-exposure. Although premenopausal women are thought to be protected from CVD, trauma exposure might increase their CVD risk. In a recent large epidemiological study examining sleep-related CVD comorbidities, the empirical cut off point for optimal sleep effciency (SE) was set at 83%, distinguishing between good and poor sleep effciency. Studies have suggested an overactive sympathetic nervous system and an impaired baroreflex sensitivity (BRS) as potential mechanisms of increased CVD risk. However, the impact of poor sleep effciency on muscle sympathetic nerve activity (MSNA) and BRS in young trauma-exposed women is unknown. We hypothesized that young trauma-exposed women with poor sleep effciency will present with impaired BRS and increased MSNA at rest. Methods: We collected data on 30 women (18 – 40 years) from diverse backgrounds who had been exposed to trauma. Sleep data was acquired via ActiWatch for 7 days and used to categorize our participants into two groups: good effciency (SE &gt; 83%, n=17) and poor effciency (SE &lt; 83%, n=13), with SE calculated as the percentage of time spent asleep while in bed. Additionally, we collected continuous noninvasive blood pressure (BP), heart rate (HR), and MSNA (burst frequency, incidence, and total activity) during 10 minutes of quiet rest. Sympathetic BRS was determined as the slope of the regression between individual sympathetic bursts and diastolic BP bins (3 mmHg), weighted against the number of cardiac cycles, utilizing an automated program (Ensemble, NZ). Results: There were no significant differences in trauma symptom severity, resting BP and HR between the two groups (p&gt;0.05 for all). However, resting sympathetic BRS was blunted in the poor SE (-0.10±0.88 bursts/100hb/mmHg) compared to the good SE (-1.44±1.58 bursts/100hb/mmHg, p=0.006) group, even after adjusting for age (p=0.009). Likewise, resting total MSNA was higher in the poor SE compared to the good SE after adjusting for age (p=0.028). MSNA burst frequency and burst incidence were comparable between the groups (p&gt;0.05). Conclusion: Our analyses revealed that poor sleep effciency is associated with decreased sympathetic baroreflex sensitivity and higher total muscle sympathetic activity at rest, regardless of age. Blunted sympathetic BRS may contribute to increased sympathetic activity in young women with poor sleep effciency. Future studies testing strategies to improve sleep effciency in this population could provide potential long-term cardiovascular benefits. UL1TR002494 and NIH K01HL161027 No disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The interactive effects of age and sex on the neuro-cardiovascular responses during fatiguing rhythmic handgrip exercise.

The impact of age on exercise pressor responses is equivocal, likely because of sex-specific neuro-cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty-five young (25 (2) years; mean (SD)) males (YM; n=12) and females (YF; n=13) and 23 older (71 (5) years) males (OM; n=11) and females (OF; n=12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post-exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P=0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P=0.75-0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P=0.08-0.94). Altogether, age-related changes in neuro-cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex-specific impact of age underscores the importance of considering biological sex when assessing age-related changes in neuro-cardiovascular control during exercise. KEY POINTS: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise. Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise. Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post-exercise circulatory occlusion (i.e. independent effect of age). Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise. Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise.

Muscle Sympathetic Nerve Reactivity to Trier Social Stress Test

Muscle sympathetic nerve activity (MSNA) responses to laboratory mental stress are highly variable, making characterization of the sympathoneural response difficult to infer. However, most commonly used mental stress tasks (i.e., mental arithmetic, Stroop Color Word Task, etc.) are primarily cognitive tasks. Further, interpretation of MSNA reactivity to these stressors can be challenging due to irregular breathing patterns, limb movement, etc. The current study assesses MSNA reactivity to the Trier Social Stress Test (TSST), an ecologically valid evaluative social stress task that utilizes an anticipatory stress period free of confounds such as irregular breathing and movement found in other mental stress tasks. The primary purpose of the present study was to assess MSNA during the stress‐anticipation period, as well as during the socially evaluated portion of the task. We hypothesized that MSNA would be elevated during both phases of the task. Sixteen healthy adults (12 female, 26 ± 1 years, 24 ± 1 kg/m2) participated in a morning autonomic function test consisting of simultaneous recordings of heart rate (HR, electrocardiogram), beat‐to‐beat blood pressure (finger plethysmography), and MSNA (microneurography) during a 10‐minute resting baseline followed by the TSST. The TSST consists of a speech preparation period (5 min), a public speech (5 min), and mental arithmetic task (5 min) in front of two laboratory judges and video recording. After completion of the TSST, participants were assessed throughout a 5‐minute recovery. MSNA was obtained throughout all tasks in 12 individuals. Compared to baseline, mean arterial pressure (MAP) significantly increased during the anticipatory phase (Δ8 ± 2 mmHg, p&lt;.001), increased further during the speech (Δ25 ± 3 mmHg, p&lt;.001) and arithmetic (Δ23 ± 3 mmHg, p&lt;.001), and returned to anticipatory levels during recovery (Δ10 ± 1 mmHg, p&lt;.001). Similarly, HR was elevated during the anticipatory (Δ8 ± 2 bpm, p=.002), and increased further during the speech (Δ24 ± 5 bpm, p&lt;.001) and arithmetic (Δ19 ± 4 bpm, p&lt;.001) phases, but fully returned to baseline levels during recovery (Δ2 ± 1 bpm p=.232). MSNA burst frequency was significantly reduced during the anticipatory phase (Δ‐5 ± 2 bursts/min, p=.014) and tended to be reduced during mental arithmetic (Δ‐5 ± 2 bursts/min, p=.058), while MSNA burst incidence was reduced during the anticipatory (Δ‐9 ± 3 bursts/100hb, p=.008) and arithmetic (Δ‐11 ± 4 bursts/100hb, p=.016) phases. In 7 individuals, MSNA signal quality allowed assessment of MSNA total area. While total MSNA appeared to increase during the speech portion of the TSST, this effect did not reach significance (Δ8906 ± 4547 arbitrary units, p=.098). Contrary to our hypothesis, while blood pressure and HR were significantly elevated, MSNA was reduced in response to social stress, likely due to baroreflex inhibition. Further, our findings exhibit previously observed inter‐individual variability in MSNA responsiveness to mental stress, even during anticipatory stress, suggesting that this variability is conserved between various laboratory stressors.

Acute changes in forearm vascular compliance during transient sympatho-excitation.

The study of vascular regulation often omits important information about the elastic properties of arteries under conditions of pulsatile flow. The purpose of this study was to examine the relationship between muscle sympathetic nerve activity (MSNA), vascular bed compliance, and peripheral blood flow responses in humans. We hypothesized that increases in MSNA would correlate with reductions in vascular compliance, and that changes in compliance would correspond with changes in peripheral blood flow during sympatho‐excitation. MSNA (microneurography), blood pressure (Finopres), and brachial artery blood flow (Doppler ultrasound), were monitored in six healthy males at baseline and during the last 15 s of voluntary end‐inspiratory, expiratory apneas and 5 min of static handgrip exercise (SHG; 20% maximum voluntary contraction) and 3 min of post‐exercise circulatory occlusion (SHG + PECO; measured in the non‐exercising arm). A lumped Windkessel model was employed to examine vascular bed compliance. During apnea, indices of MSNA were inversely related with vascular compliance, and reductions in compliance correlated with decreased brachial blood flow rate. During SHG, despite increased MSNA, compliance also increased, but was unrelated to increases in blood flow. Neither during SHG nor PECO did indices of MSNA correlate with forearm vascular compliance nor did vascular compliance correlate with brachial flow. However, during PECO, a linear combination of blood pressure and total MSNA was correlated with vascular compliance. These data indicate the elastic components of the forearm vasculature are regulated by adrenergic and myogenic mechanisms during sympatho‐excitation, but in a reflex‐dependent manner.

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude.

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy young males at baseline and during 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 47 ± 3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA [Δ273 ± 208 vs. Δ254 ± 193 arbitrary units (AU), P = 0.84] and single-unit spike frequency (Δ8 ± 10 vs. Δ12 ± 13 spikes/min, P = 0.12). Among 19 identified single units, the proportions of activated (47% vs. 68%), nonresponsive (32% vs. 16%), and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P = 0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 nonresponsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (Δ595 ± 282 AU, P < 0.01) only one single unit was inhibited. These findings suggest that the proportions of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.NEW & NOTEWORTHY Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.

Muscle sympathetic single‐unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: The role of sympathoexcitation magnitude

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy, young males at baseline and during: 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 of 47±3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA (delta 273±208 vs. 254±193 AU, P=0.84) and single-unit spike frequency (delta 7±9 vs. 11±15 spikes/min, P=0.29). Among 19 identified single units, the proportion of activated (58% vs. 74%) non-responsive (21% vs. 16%) and inhibited (21% vs. 10%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P=0.57). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (8 activated and 1 non-responsive during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (delta 595±282 AU, P<0.01) none of the single units were inhibited. These findings suggest that the proportion of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Countdown before voluntary exercise induces muscle vasodilation with baroreflex-mediated decrease in muscle sympathetic nerve activity in humans.

We examined whether a countdown (CD) before voluntary cycling exercise induced prospective vascular adjustment for the exercise and, if so, whether and how muscle sympathetic nerve activity (MSNA) was involved in the responses. Young men performed voluntary cycling in a semirecumbent position (n = 14) while middle cerebral artery blood flow velocity (VMCA; Doppler ultrasonography), heart rate (HR), arterial pressure (AP; finger photoplethysmography), oxygen consumption rate (V̇o2), oxygen saturation in the thigh muscle (; near-infrared spectrometry), cardiac output (CO; Modelflow method), and total peripheral resistance (TPR) were measured (experiment 1). Another group underwent the same exercise protocol but used only the right leg (n = 10) while MSNA (microneurography) was measured in the peroneal nerve of the left leg (experiment 2). All subjects performed eight trials with a ≥5-min rest between trials. In four trials randomly selected from the eight trials, exercise onset was signaled by a 30-s CD, whereas in the remaining four trials, exercise was started without CD. We found that CD first increased VMCA, HR, CO, and mean AP, and then decreased TPR and increased and V̇o2 (experiment 1; all P < 0.021). Furthermore, the CD-induced increase in mean AP decreased total MSNA and burst frequency (experiment 2; both P < 0.048) through the baroreflex, with decreased TPR and increased (experiment 2; both P < 0.001). The vasodilation and increased V̇o2 continued after the start of exercise. Thus CD before starting exercise induced the muscle vasodilatory response with a concomitant reduction in MSNA through the baroreflex to accelerate aerobic energy production after the start of exercise.NEW & NOTEWORTHY Prospective cardiovascular adjustment occurs before starting voluntary exercise, increasing heart rate and arterial pressure followed by muscle vasodilation; however, the precise mechanisms and significance for this vasodilation remain unknown. We found that during the countdown before starting exercise cerebral blood flow velocity increased, followed by increases in heart rate and arterial pressure, which suppressed MSNA through baroreflex, resulting in thigh muscle vasodilation to increase oxygen consumption rate, which might make it easier to start exercise.

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.

Simultaneous assessment of central and peripheral chemoreflex regulation of muscle sympathetic nerve activity and ventilation in healthy young men.

Central chemoreceptor stimulation, by hypercapnia (acidosis), and peripheral, by hypoxia plus hypercapnia, evoke reflex increases in ventilation and sympathetic outflow. The assumption that central or peripheral chemoreceptor-mediated sympathetic activation elicited when increases parallels concurrent ventilatory responses is unproven. Applying a modified rebreathing protocol that equilibrates central and peripheral chemoreceptor whilst clamping O2 tension at either hypoxic or hyperoxic concentrations, the independent ventilatory and muscle sympathetic stimulus-response properties of the central and peripheral chemoreflexes were quantified and compared in young men. The novel findings were that ventilatory and sympathetic responses to central and peripheral chemoreflex stimulation are initiated at similar recruitment thresholds but individual specific sympathetic responsiveness cannot be predicted from the ventilatory sensitivities of either chemoreceptor reflex. Such findings in young men, if replicated in heart failure or hypertension, should temper present enthusiasm for trials targeting the peripheral chemoreflex based solely on ventilatory responsiveness to non-specific chemoreceptor stimulation. In humans, stimulation of peripheral or central chemoreceptor reflexes is assumed to evoke equivalent ventilatory and sympathetic responses. We evaluated whether central or peripheral chemoreceptor-mediated sympathetic activation elicited by increases in CO2 tension ( ) parallels concurrent ventilatory responses. Twelve healthy young men performed a modified rebreathing protocol designed to equilibrate central and peripheral chemoreceptor tensions with end-tidal ( ) at two isoxic end-tidal ( ) such that central responses can be segregated, by hyperoxia, from the net response (hypoxia minus hyperoxia). Ventilation and muscle sympathetic nerve activity (MSNA) were recorded continuously during rebreathing at isoxic of 150 and 50mmHg. During rebreathing, the values at which ventilation (Lmin-1 ) and total MSNA (units) began to rise were identified ( recruitment thresholds) and their slopes above the recruitment threshold were determined (sensitivity). The central chemoreflex recruitment threshold for ventilation (46±3mmHg) and MSNA (45±4mmHg) did not differ (P=0.55) and slopes were 2.3±0.9Lmin-1 mmHg-1 and 2.1±1.5unitsmmHg-1 , respectively. The peripheral chemoreflex recruitment thresholds, at 41±3mmHg for both ventilation and MSNA were lower (P<0.05) compared to the central chemoreflex recruitment thresholds. Peripheral chemoreflex sensitivity was 1.7±0.1Lmin-1 mmHg-1 for ventilation and 2.9±2.6unitsmmHg-1 for MSNA. There was no relationship between the ventilatory and MSNA sensitivity for either the central (r2 =0.01, P=0.76) or peripheral (r2 =0.01, P=0.73) chemoreflex. In healthy young men, ventilatory and sympathetic responses to central and peripheral chemoreceptor reflex stimulation are initiated at similar recruitment thresholds but individual ventilatory responsiveness does not predict sympathetic sensitivities of either chemoreflex.

Effects of Dynamic Arm and Leg Exercise on Muscle Sympathetic Nerve Activity and Vascular Conductance in the Inactive Leg

The aim of this study was to comprehensively assess the effects of rhythmic handgrip (RHG), one‐leg cycling, and concurrent arm and leg exercise on muscle sympathetic nerve activity (MSNA) and vascular conductance responses in the inactive leg. Thirty‐five participants completed two study visits in a randomized order. During visit 1, hemodynamic (Finometer) and superficial femoral artery (SFA) blood flow (Doppler ultrasound) measurements were assessed at rest and during 3 min of RHG (1:1 duty cycle; 40% MVC), one‐leg cycling (17 ± 3% peak power output), and concurrent exercise at the same intensities. During visit 2, hemodynamic and MSNA (fibular nerve microneurography) measurements were acquired during the same exercise modes (MSNA; n=12). SFA blood flow and MSNA were both acquired in the inactive leg. Heart rate, blood pressure, cardiac output, and respiration rate increased during each exercise mode (all, P&lt;0.0001), with the largest increases during concurrent exercise (all, P&lt;0.006); no differences were detected between visit 1 and 2 (all, P&gt;0.05). SFA mean blood flow increased during RHG (Δ24 ± 30 ml/min, P&lt;0.0001) and concurrent exercise (Δ10 ± 38 ml/min, P=0.03) but not cycling (Δ2.3 ± 30 ml/min, P=0.9). SFA vascular conductance was unchanged during RHG (Δ0.02 ± 0.29 ml·min−1·mmHg−1, P=0.9) but reduced similarly during concurrent and cycling exercise (Δ−0.14 ± 0.33 ml·min−1·mmHg−1; Δ−0.14 ± 0.38 ml·min−1·mmHg−1, P&lt;0.003). RHG increased MSNA burst frequency (Δ4 ± 8 burst/min, P=0.04) without altering burst amplitude (Δ7 ± 14 %, P=0.7) or total MSNA (Δ40 ± 40 %, P=0.07). In contrast, cycling and concurrent exercise had no effects on MSNA burst frequency (Δ−3 ± 6 burst/min and Δ4 ± 6 burst/min, P≥0.1) but increased burst amplitude (Δ34 ± 30 %; Δ31 ± 31 %, P≤0.001) and total MSNA (Δ59 ± 63 %; Δ94 ± 100 %, P≤0.007). In conclusion, during one‐leg cycling or concurrent exercise, reductions in inactive leg SFA vascular conductance occurred in parallel with increases in burst amplitude and total MSNA but not burst frequency. Exercise studies relying solely on measures of MSNA burst occurrence may not accurately reflect the corresponding changes in vascular conductance.Support or Funding InformationResearch was supported by a Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M; #06019), the Canada Foundation for Innovation (P.J.M.; #34379), and the Ontario Ministry of Research, Innovation, and Science (P.J.M. #34379).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of Resting Differences in Muscle Sympathetic Nerve Activity on Hemodynamic and Neural Responses to Exercise

Resting muscle sympathetic nerve activity (MSNA) displays high inter‐individual variability, yet the neural characteristics of those with high vs. low MSNA and resultant cardiovascular consequences are largely unclear. The purpose of this study was to examine blood pressure (BP) variability at rest and during exercise in individuals with high vs. low resting MSNA, and to characterize differences in resting sympathetic and cardiac baroreflex sensitivity (cBRS), in order to understand the accompanying neural characteristics and cardiovascular consequences of different levels of vasoconstrictor outflow. We retrospectively analyzed MSNA (microneurography) and continuous BP (Finometer) obtained at rest and during 2 minutes of static handgrip exercise at 30% maximal voluntary contraction from 60 young healthy men (n=30) and women (n=30). Within each sex, data was split into tertiles based on resting MSNA burst frequency and a comparative analysis was performed on the highest vs. lowest MSNA groups. BP variability was calculated as the beat‐to‐beat standard deviation. Spontaneous sympathetic baroreflex sensitivity (sBRS) was calculated using a weighted linear regression between diastolic blood pressure (DBP) and MSNA burst incidence. Threshold values (T50) were obtained by calculating the resting DBP associated with 50% of the MSNA bursts. cBRS was determined using the sequence technique. As expected, resting MSNA burst frequency was different between high and low groups (30±4 vs. 14±6 bursts/min [mean±SD], p&lt;0.01), however, baseline anthropometrics, BP, heart rate, and cBRS sensitivity were not different (all, p&gt;0.05). Resting DBP variability was lower in the high group (4±1 vs. 5±2 mmHg, p=0.05). sBRS was higher in the high group (−5.4±1.9 vs. −4.6±1.6 bursts/100 heartbeats/mmHg, p&lt;0.01), and was correlated with resting MSNA (r=−0.46, p&lt;0.01). T50 did not differ between the groups (60 vs. 55 mmHg, p&gt;0.05), however, the prevailing mean DBP was above the T50 DBP to a lower extent in the high group (mean DBP – T50 DBP: 10±3 vs. 18±7 mmHg, p&lt;0.01), and this value was negatively correlated with resting MSNA burst incidence (r=−0.76, p&lt;0.01). During static handgrip exercise, BP and heart rate increased similarly in both groups (all, p&gt;0.05), yet the increase in MSNA burst frequency was smaller in the high group (Δ 4±7 vs 10±6 bursts/min, p&lt;0.01); similar results were obtained using MSNA burst incidence and total MSNA (both p&lt;0.01). The change in burst frequency was unrelated to resting sBRS (r=0.23, p&gt;0.05). Systolic BP variability was lower in the high group during exercise (7±3 vs 10±5 mmHg, p&lt;0.05), but DBP variability was not different. In conclusion, differences in resting MSNA are unrelated to resting and exercising BP, but are likely associated with inter‐individual differences in the degree of BP variability and arterial baroreflex‐mediated suppression of MSNA. Further, baseline MSNA was found to influence the magnitude of the change during static handgrip exercise, though the hemodynamic consequences of these differences, and mechanisms responsible warrant further research.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant; Canada Foundation for InnovationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of Corin in Blood Pressure Regulation in Normotensive and Hypertensive Pregnancy

Corin (an atrial natriuretic peptide-converting enzyme) represents a potential biomarker for gestational hypertensive disorders; yet, its role in blood pressure (BP) regulation throughout pregnancy remains unclear. We investigated the time course of change in blood corin content in relation to BP and sympathetic nerve activity throughout pregnancy. Forty-four women (29±0.9 years) participated. Following-term, 23 had low-risk (no personal history of gestational hypertensive disorders) normal pregnancies, 13 had high-risk (personal history of gestational hypertensive disorders) normal pregnancies, and 8 developed gestational hypertension. BP, heart rate, muscle sympathetic nerve activity, and serum corin were measured before pregnancy, during early (4-8 weeks) and late pregnancy (32-36 weeks), and postpartum (6-10 weeks). Overall, compared with prepregnancy, corin remained unchanged during early pregnancy, increased markedly during late pregnancy ( P<0.001), and returned to prepregnancy levels postpartum. In women who developed gestational hypertension, the change in corin from early to late pregnancy was greater than those with low-risk normal pregnancies (Δ971±134 versus Δ486±79 pg/mL; P<0.05). Throughout pregnancy, BP and muscle sympathetic nerve activity were augmented in women with gestational hypertension (all P<0.05). Finally, changes in corin from early to late pregnancy were related to all indices of BP ( R=0.454-0.551; all P<0.01) in late pregnancy, whereas burst frequency, burst incidence, and total muscle sympathetic nerve activity ( R=0.576-0.614; all P<0.001) in early pregnancy were related to changes in corin from early to late pregnancy. Corin plays a unique role in BP regulation throughout normotensive and, especially, hypertensive pregnancy and may represent a promising biomarker for determining women at high risk of adverse pregnancy outcome.

Evidence for differential control of muscle sympathetic single units during mild sympathoexcitation in young, healthy humans.

Two subpopulations of muscle sympathetic single units with opposite discharge characteristics have been identified during low-level cardiopulmonary baroreflex loading and unloading in middle-aged adults and patients with heart failure. The present study sought to determine whether similar subpopulations are present in young healthy adults during cardiopulmonary baroreflex unloading ( study 1) and rhythmic handgrip exercise ( study 2). Continuous hemodynamic and multiunit and single unit muscle sympathetic nerve activity (MSNA) data were collected at baseline and during nonhypotensive lower body negative pressure (LBNP; n = 12) and 40% maximal voluntary contraction rhythmic handgrip exercise (RHG; n = 24). Single unit MSNA responses were classified as anticipated or paradoxical based on whether changes were concordant or discordant with the multiunit MSNA response, respectively. LBNP and RHG both increased multiunit MSNA burst frequency (∆5 ± 3 bursts/min, P < 0.001; ∆5 ± 8 bursts/min, P = 0.005), burst amplitude (∆5 ± 7%, P = 0.04; ∆13 ± 14%, P < 0.001), and total MSNA (∆302 ± 191 AU/min, P = 0.001; ∆585 ± 556 AU/min, P < 0.001). During LBNP and RHG, 43 and 64 muscle single units were identified, respectively, which increased spike frequency (∆9 ± 11 spikes/min, P < 0.001; ∆10 ± 19 spikes/min, P < 0.001) and the probability of multiple spike firing (∆10 ± 12%, P < 0.001; ∆11 ± 26%, P = 0.001). During LBNP and RHG, 36 (84%) and 39 (61%) single units possessed anticipated firing responses (∆12 ± 10 spikes/min, P < 0.001; ∆19 ± 19 spikes/min, P < 0.001), whereas 7 (16%) and 25 (39%) single units exhibited paradoxical reductions (∆-3 ± 1 spikes/min, P = 0.003; ∆-4 ± 5 spikes/min, P < 0.001). The observation of divergent subpopulations of muscle sympathetic single units in healthy young humans during two mild sympathoexcitatory stressors supports differential control at the fiber level as a fundamental characteristic of human sympathetic regulation. NEW & NOTEWORTHY The activity of muscle sympathetic single units was recorded during cardiopulmonary baroreceptor unloading and rhythmic handgrip exercise in young healthy humans. During both stressors, the majority of single units (84% and 61%) exhibited anticipated behavior concordant with the integrated muscle sympathetic response, whereas a smaller proportion (16% and 39%) exhibited paradoxical sympathoinhibition. These results support differential control of postganglionic muscle sympathetic fibers as a characteristic of human sympathetic regulation during mild sympathoexcitatory stress. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/differential-control-of-sympathetic-outflow-in-young-humans/ .

Peripheral chemoreceptor deactivation attenuates the sympathetic response to glucose ingestion.

Acute increases in blood glucose are associated with heightened muscle sympathetic nerve activity (MSNA). Animal studies have implicated a role for peripheral chemoreceptors in this response, but this has not been examined in humans. Heart rate, cardiac output (CO), mean arterial pressure, total peripheral conductance, and blood glucose concentrations were collected in 11 participants. MSNA was recorded in a subset of 5 participants via microneurography. Participants came to the lab on 2 separate days (i.e., 1 control and 1 experimental day). On both days, participants ingested 75 g of glucose following baseline measurements. On the experimental day, participants breathed 100% oxygen for 3 min at baseline and again at 20, 40, and 60 min after glucose ingestion to deactivate peripheral chemoreceptors. Supplemental oxygen was not given to participants on the control day. There was a main effect of time on blood glucose (P < 0.001), heart rate (P < 0.001), CO (P < 0.001), sympathetic burst frequency (P < 0.001), burst incidence (P = 0.01), and total MSNA (P = 0.001) for both days. Blood glucose concentrations and burst frequency were positively correlated on the control day (r = 0.42; P = 0.03) and experimental day (r = 0.62; P = 0.003). There was a time × condition interaction (i.e., normoxia vs. hyperoxia) on burst frequency, in which hyperoxia significantly blunted burst frequency at 20 and 60 min after glucose ingestion only. Given that hyperoxia blunted burst frequency only during hyperglycemia, our results suggest that the peripheral chemoreceptors are involved in activating MSNA after glucose ingestion.