Spontaneous Bursts Of Muscle Sympathetic Nerve Activity Research Articles

Sympathetic baroreflex sensitivity is enhanced in postmenopausal women.

The sympathetic nervous system is critical for regulating blood pressure (BP) via the arterial baroreflex and sympathetic transduction in the peripheral vasculature. These mechanisms interact, and both may be altered with aging and impacted by menopause. Although age-related decreases in sympathetic transduction have been demonstrated in women, it remains unclear whether sympathetic baroreflex sensitivity (BRS) is impaired in postmenopausal women (POST). We tested the hypothesis that sympathetic BRS would be enhanced in POST compared with premenopausal women (PRE). We examined beat-by-beat BP and muscle sympathetic nerve activity (MSNA) in 19 PRE (22 ± 2 yr, 22 ± 3 kg/m2) and 12 POST (57 ± 5 yr, 24 ± 2 kg/m2) during 10 min of rest. Spontaneous sympathetic BRS was quantified as the slope of a linear regression between MSNA burst incidence and diastolic BP. Sympathetic transduction to mean arterial pressure (MAP) for the 10 cardiac cycles following spontaneous MSNA bursts was assessed via signal averaging method. Resting MAP was similar (PRE: 82 ± 8 vs. POST: 85 ± 8 mmHg, P = 0.43), whereas resting MSNA was elevated in POST (PRE: 10 ± 6 vs. POST: 45 ± 16 bursts/100 heart beats, P < 0.0001). Spontaneous sympathetic BRS was enhanced in POST (PRE: -2.0 ± 1.2 vs. POST: -5.2 ± 1.9 bursts/beat/mmHg, P < 0.0005). Sympathetic transduction to MAP was attenuated in POST (time: P < 0.001, group: P < 0.001, interaction: P < 0.01). These data suggest that sympathetic BRS may be enhanced in POST. Consistent with recent hypotheses, enhanced sensitivity of the arterial baroreflex's neural arc may signify a compensatory response to reduced efficiency of the peripheral arterial baroreflex arc (i.e., sympathetic transduction) to preserve BP buffering capacity.NEW & NOTEWORTHY Studies examining sympathetic baroreflex function with aging remain equivocal, with some studies showing an increase, decrease, or no change in sympathetic baroreflex sensitivity (BRS) in older adults compared with younger adults. With aging, women experience unique physiological changes due to menopause that influence autonomic function. For the first time, we show that postmenopausal women exhibit a greater sympathetic BRS compared with young premenopausal women.

A comparison of wavelet-based action potential detection from the NeuroAmp and the Iowa Bioengineering Nerve Traffic Analysis system.

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) reflect postganglionic sympathetic axonal activity directed toward the skeletal muscle vasculature. Recordings are typically evaluated for spontaneous bursts of MSNA; however, the filtering and integration of raw neurograms to obtain multiunit bursts conceals the underlying c-fiber discharge behavior. The continuous wavelet transform with matched mother wavelet has permitted the assessment of action potential discharge patterns, but this approach uses a mother wavelet optimized for an amplifier that is no longer commercially available (University of Iowa Bioengineering Nerve Traffic Analysis System; Iowa NTA). The aim of this project was to determine the morphology and action potential detection performance of mother wavelets created from the commercially available NeuroAmp (ADinstruments), from distinct laboratories, compared with a mother wavelet generated from the Iowa NTA. Four optimized mother wavelets were generated in a two-phase iterative process from independent datasets, collected by separate laboratories (one Iowa NTA, three NeuroAmp). Action potential extraction performance of each mother wavelet was compared for each of the NeuroAmp-based datasets. The total number of detected action potentials was not significantly different across wavelets. However, the predictive value of action potential detection was reduced when the Iowa NTA wavelet was used to detect action potentials in NeuroAmp data, but not different across NeuroAmp wavelets. To standardize approaches, we recommend a NeuroAmp-optimized mother wavelet be used for the evaluation of sympathetic action potential discharge behavior when microneurographic data are collected with this system.NEW & NOTEWORTHY The morphology of custom mother wavelets produced across laboratories using the NeuroAmp was highly similar, but distinct from the University of Iowa Bioengineering Nerve Traffic Analysis System. Although the number of action potentials detected was similar between collection systems and mother wavelets, the predictive value differed. Our data suggest action potential analysis using the continuous wavelet transform requires a mother wavelet optimized for the collection system.

Spontaneous Bursts of Muscle Sympathetic Nerve Activity Reduce Femoral Arterial Compliance in Humans

Previous studies in rodents have demonstrated tonic sympathetic restraint of arterial compliance. To date, studies in humans have examined sympathetic restraint of compliance via either reflexively or pharmacologically manipulating sympathetic vasoconstriction and measuring resultant changes in compliance. The extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) dynamically regulate arterial compliance in humans on a beat-by-beat basis remains unknown. Herein, we hypothesized that femoral arterial compliance would be transiently reduced following spontaneous bursts of MSNA. Further, we hypothesized that the magnitude of reduction in arterial compliance would be graded to the MSNA burst amplitude (index of net neural outflow). Beat-to-beat blood pressure (BP; Finometer), heart rate (ECG), MSNA (peroneal microneurography), and femoral artery blood flow (duplex Doppler ultrasound) were continuously measured over 10-20 minutes of quiet supine rest in 27 young, healthy men (age: 22 ± 1 years, resting MSNA burst frequency: 11 ± 5 bursts/minute). Customized labview programs were used to time-align neural cardiovascular variables with ultrasound data sampled at 30Hz, enabling the quantification of arterial compliance on a beat-by-beat basis defined as the change in arterial cross-sectional area divided by the change in blood pressure over the cardiac cycle. Bursts of MSNA were tracked for 10 cardiac cycles and changes in arterial compliance were quantified using signal-averaging for all bursts, and subsequently, for bursts of MSNA when sub-classified based on amplitude into quartiles (Q1= smallest 25% of bursts, Q4= largest 25% of bursts). Reductions in arterial compliance were significantly greater following cardiac cycles with bursts of MSNA compared to cardiac cycles without bursts of MSNA (bursts: -5.1 ± 0.6% vs. non-bursts: -0.8 ± 0.2%, p&lt;0.001). Further, reductions in compliance appeared to be graded to MSNA burst amplitude (Q1: -6.5 ± 0.8%; Q4: -9.1 ± 1.3%, P=0.051). The latency (i.e., number of heartbeats) to nadir arterial compliance following bursts of MSNA was 4.2 ± 0.6 cardiac cycles. Collectively, these findings suggest that the sympathetic nervous system dynamically regulates femoral arterial compliance on a beat-to-beat basis. College of Nursing and Health Innovation, University of Texas at Arlington. 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.

Blunted sympathetic transduction to blood pressure in females with relapsing-remitting multiple sclerosis

Approximately 1 million people in the United States are living with multiple sclerosis (MS) with nearly 75% of those being female. MS is a progressive demyelinating neurological disease of the central nervous system associated with a high prevalence of orthostatic hypotension. Our laboratory has previously shown that individuals with MS have a reduced ability to increase mean arterial pressure during simulated hypotension which was attributed to a blunted vascular response. The purpose of this project was to investigate how spontaneous bursts of muscle sympathetic nerve activity (MSNA) induce end-organ response(s) and ultimately evoke a change in blood pressure (BP) on a heartbeat-to-heartbeat basis in females with MS, a process known as sympathetic transduction to BP. We tested the hypothesis that females with MS have reduced resting sympathetic transduction to BP compared to sex-, height-, weight-, age- and race-matched healthy controls. Beat-to-beat BP (Finometer) and MSNA (peroneal microneurography) were continuously recorded during 10 minutes of quiet supine rest in 9 females with relapsing-remitting MS (age: 39.6 ± 3.3 years; Expanded Disability Status Scale &lt; 6.0) and 10 healthy female controls (age: 35.4 ± 2.1 years). Total vascular conductance (TVC) was estimated using modelflow. Sympathetic transduction was determined by identifying the peak change in diastolic BP and the nadir reduction of TVC over 10 cardiac cycles following spontaneous MSNA bursts using signal averaging. No differences were detected in resting mean arterial pressure (MS: 88 ± 3 mmHg; controls: 85 ± 2; P = 0.42) or MSNA burst frequency (MS: 26 ± 3 bursts/min; controls: 19 ± 3 bursts/min; P = 0.11) between groups. Peak increases in diastolic BP following MSNA bursts were lower in females with MS (1.2 ± 0.2 mmHg) compared to controls (2.5 ± 0.6 mmHg; P = 0.039). Whereas no differences were observed in nadir reductions in TVC (MS: -1.7 ± 0.5 ml/min/mmHg; controls: -3.0 ± 0.8 ml/min/mmHg; P = 0.11). These preliminary data suggest that sympathetic transduction to BP is blunted in females with MS. Reduced sympathetic transduction to BP may contribute to the high occurrence of orthostatic hypotension in this clinical population. Further investigation is warranted to help better understand the potential mechanism(s) underlying lower sympathetic transduction in females with MS. This work was supported by American Heart Association Predoctoral Fellowship (Award #915655, Trotter) and American College of Sports Medicine Doctoral Research Grant (Award # 19-01141, Trotter) This is the full abstract presented at the American Physiology Summit 2023 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.

Sympathetic transduction to blood pressure during euglycemic-hyperinsulinemia in young healthy adults: role of burst amplitude.

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the "net effect" of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC (P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts (P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.

Sympathetic Transduction During Euglycemic‐Hyperinsulinemia in Humans

Insulin plays an important role in post-prandial blood pressure (BP) regulation. Within the central nervous system insulin acts to stimulate sympathetic outflow to skeletal muscle. Concurrently, insulin acts locally in the periphery to promote vasodilation and is suggested to also attenuate sympathetically-mediated vasoconstriction. Given these divergent actions, the ‘net effect’ of insulin on the sympathetic control of BP remains incompletely understood. Therefore, the purpose of this study was to examine the effect of hyperinsulinemia on sympathetic transduction to BP. To accomplish this, in 10 young healthy men, heart rate (ECG), BP (finometer or brachial arterial line) and muscle sympathetic nerve activity (MSNA) were measured at rest and during euglycemic-hyperinsulinemia. Signal-averaging was used to characterize the changes in mean arterial pressure (MAP) and total vascular conductance (TVC; derived from ModelFlow) over 10 cardiac cycles following spontaneous bursts of MSNA at rest and during hyperinsulinemia. No significant differences were found in the peak MAP (Rest: ∆2.8 ± 0.3; Insulin: ∆2.4 ± 0.2 mmHg, P=0.15) or TVC (Rest: ∆-3.0 ± 0.4; Insulin: ∆-2.7 ± 0.5 mL/min/mmHg, P=0.38) responses following bursts of MSNA between rest and hyperinsulinemia (i.e., ‘net’ sympathetic transduction was unchanged). Notably, the average size of normalized MSNA bursts was increased during hyperinsulinemia (Rest: 45.6 ± 1.8; Insulin 65.3 ± 5.0 Au, P<0.01). To take into account changes in burst height, MSNA bursts were divided into amplitude-matched bins. When MSNA burst amplitude bins were matched between rest and hyperinsulinemia, sympathetic transduction for a given burst amplitude was blunted during insulin infusion (e.g., largest resting bursts: MAP, Rest: ∆4.4 ± 0.5; Insulin: ∆3.0 ± 0.3 mmHg, P=0.02; TVC, Rest: ∆-5.2 ± 0.8; Insulin: ∆-3.1 ± 0.7 mL/min/mmHg, P=0.05). However, it is important to note that 15 ± 5% of MSNA bursts exhibited amplitudes greater than that which existed at rest and overall during hyperinsulinemia ~50% of all MSNA bursts were comparable or greater in amplitude to the largest bursts present at rest. Collectively, these preliminary findings suggest that during hyperinsulinemia, sympathetic transduction for a given burst amplitude is attenuated while ‘net’ sympathetic transduction remains unchanged due to the generation of larger MSNA bursts.

An open-source program to analyze spontaneous sympathetic neurohemodynamic transduction.

The sympathetic nervous system is important for the beat-by-beat regulation of arterial blood pressure and the control of blood flow to various organs. Microneurographic recordings of pulse-synchronous muscle sympathetic nerve activity (MSNA) are used by numerous laboratories worldwide. The transduction of hemodynamic and vascular responses elicited by spontaneous bursts of MSNA provides novel, mechanistic insight into sympathetic neural control of the circulation. Although some of these laboratories have developed in-house software programs to analyze these sympathetic transduction responses, they are not openly available and most require higher level programming skills and/or costly platforms. In the present paper, we present an open-source, Microsoft Excel-based analysis program designed to examine the pressor and/or vascular responses to spontaneous resting bursts of MSNA, including across longer, continuous MSNA burst sequences, as well as following heartbeats not associated with MSNA bursts. An Excel template with embedded formulas is provided. Detailed written and video-recorded instructions are provided to help facilitate the user and promote its implementation among the research community. Open science activities such as the dissemination of analytical programs and instructions may assist other laboratories in their pursuit to answer novel and impactful research questions regarding sympathetic neural control strategies in human health and disease.NEW & NOTEWORTHY The pressor responses to spontaneous bursts of muscle sympathetic nerve activity provide important information regarding sympathetic regulation of the circulation. Many laboratories worldwide quantify sympathetic neurohemodynamic transduction using in-house, customized software requiring high-level programming skills and/or costly computer programs. To overcome these barriers, this study presents a simple, open-source, Microsoft Excel-based analysis program along with video instructions to assist researchers without the necessary resources to quantify sympathetic neurohemodynamic transduction.

Aerobic fitness and sympathetic responses to spontaneous muscle sympathetic nerve activity in young males

Lower aerobic fitness increases the risk of developing hypertension. Muscle sympathetic nerve activity (MSNA) is important for the beat-by-beat regulation of blood pressure. Whether the cardiovascular consequences of lower aerobic fitness are due to augmented transduction of MSNA into vascular responses is unclear. We tested the hypothesis that aerobic fitness is inversely related to peak increases in total peripheral resistance (TPR) and mean arterial pressure (MAP) in response to spontaneous MSNA bursts in young males. Relative peak oxygen consumption (VO2peak, indirect calorimetry) was assessed in 18 young males (23 ± 3years; 41 ± 8ml/kg/min). MSNA (microneurography), cardiac intervals (electrocardiogram) and arterial pressure (finger photoplethysmography) were recorded continuously during supine rest. Stroke volume and cardiac output (CO) were estimated via the ModelFlow method. TPR was calculated as MAP/CO. Changes in TPR and MAP were tracked for 12 cardiac cycles following heartbeats associated with or without spontaneous bursts of MSNA. Overall, aerobic fitness was inversely correlated to the peak ΔTPR (0.8 ± 0.7mmHg/l/min; R = -0.61, P = 0.007) and ΔMAP (2.3 ± 0.8mmHg; R = -0.69, P < 0.001), but not with the peak ΔCO (0.2 ± 0.1l/min; P = 0.50), MSNA burst frequency (14 ± 5 bursts/min; P = 0.43) or MSNA relative burst amplitude (65 ± 12%; P = 0.13). Heartbeats without an associated burst of MSNA did not increase TPR, MAP or CO. Although unrelated to traditional MSNA characteristics, aerobic fitness was inversely associated with spontaneous sympathetic neurovascular transduction in young males. This may be a potential mechanism by which aerobic fitness modulates the regulation of arterial blood pressure through the sympathetic nervous system.

The Potential Impact of Discrete Action Potentials on Resting Sympathetic Vascular Transduction in Humans

The sympathetic nervous system dynamically regulates blood pressure (BP), primarily through the modification of peripheral vascular tone. Our lab has developed a methodology for quantifying resting sympathetic vascular transduction wherein bursts of muscle sympathetic nerve activity (MSNA) act as a trigger and ensuing changes in BP and vascular conductance are signal‐averaged over the subsequent 15 cardiac cycles to produce characteristic (mean) responses. These previous investigations have focused on the effect of net sympathetic outflow (e.g, burst sequences and burst amplitudes) on the pressor and vascular conductance responses to spontaneous bursts of MSNA. The recent development of methods to identify sympathetic action potentials (APs) to obtain further information regarding sympathetic control of the circulation has led us to begin to examine the potential role that discrete sympathetic APs may play in determining the BP and vascular responses following spontaneous bursts of MSNA. Herein, we compared BP and leg vascular conductance responses between MSNA bursts containing small (i.e., common) or large (i.e., uncommon) APs within quartiles of MSNA normalized to burst amplitude. We hypothesized the presence of large APs in a burst of MSNA would elicit a greater pressor response and a larger decrease in leg vascular conductance. Resting MSNA (microneurography), beat‐to‐beat BP (finger photoplethysmography), and femoral artery blood velocity (Doppler ultrasound) were collected for 10–20 minutes in 5 young healthy adults. Leg vascular conductance index was calculated (LVCi=femoral artery blood velocity/mean arterial pressure). MSNA bursts were sorted into normalized amplitude quartiles (Q1=smallest 25% of bursts; Q4=largest 25% of bursts), and APs were extracted using a matched wavelet methodology. Within Q4, there was no difference in the peak BP or LVCi responses to bursts containing small APs when compared to bursts containing large APs (Δ6±3 small vs. Δ6±2 large mmHg, p=0.74; Δ0.95±2.0 small vs. Δ0.87±1.7 large ml·min−1·mmHg−1, p=0.59). To account for the potential contribution of MSNA bursts occurring in consecutive sequence, we next isolated singlet bursts (separated by ≥1 cardiac cycle lacking MSNA bursts). Within Q4, there was again no difference in the peak BP or LVCi response to singlet bursts containing small APs compared to singlet bursts containing large APs (Q4: Δ7±3 small vs. Δ6±2 large mmHg, p=0.42; Δ0.05±0.07 small vs. Δ0.17±0.11 large ml·min−1·mmHg−1, p=0.08). These preliminary data suggest that the presence of large APs does not appear to translate to greater pressor or decreased leg vascular conductance responses following a spontaneous burst of resting MSNA.Support or Funding InformationFunded by the UTA College of Nursing and Health Innovation and Natural Sciences and Engineering Research Council of Canada

Identifying Increases in Activity of the Human RVLM Through MSNA-Coupled fMRI

AimWe initially developed concurrent recording of muscle sympathetic nerve activity (MSNA) and functional magnetic resonance imaging (fMRI) of the brain to functionally identify the human homolog of the rostral ventrolateral medulla (RVLM). Here we summarize the cortical and subcortical connections to the RVLM, as identified using MSNA-coupled fMRI.MethodsMSNA was recorded via tungsten microelectrodes inserted into the peroneal nerve. Gradient echo, echo-planar fMRI was performed at 3T (Philips Achieva). 200 volumes (46 axial slices (TR = 8 s, TE = 4 s, flip angle = 90°, raw voxel size = 1.5 × 1.5 × 2.75 mm) were collected in a 4 s-ON, 4 s-OFF sparse sampling protocol and MSNA measured in each 1 s epoch in the 4-s period between scans. Blood oxygen level dependent (BOLD) signal intensity was measured in the corresponding 1 s epoch 4 s later to account for peripheral neural conduction and central neurovascular coupling delays.ResultsBOLD signal intensity was positively related to bursts of MSNA in the RVLM, dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), insula, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex (PCC), and precuneus, and negatively related in the caudal ventrolateral medulla (CVLM), nucleus tractus solitarius (NTS), and the midbrain periaqueductal gray (PAG). During physiological increases in MSNA (tonic muscle pain), MSNA-coupled BOLD signal intensity was greater in RVLM, NTS, PAG, DMH, dlPFC, medial prefrontal cortex (mPFC), precuneus, and anterior cingulate cortex (ACC) than at rest. During pathophysiological increases in MSNA [obstructive sleep apnoea (OSA)] signal intensity was also higher in dlPFC, mPFC, ACC, and precuneus than in controls. Conversely, signal intensity was lower in RVLM in OSA than in controls, which we interpret as reflecting a withdrawal of active inhibition of the RVLM.ConclusionThese results suggest that multiple cortical and subcortical areas are functionally coupled to the RVLM, which in turn is functionally coupled to the generation of spontaneous bursts of MSNA and their augmentation during physiological and pathophysiological increase in vasoconstrictor drive.

Sympathetic Transduction in Type 2 Diabetes Mellitus.

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index-matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both P>0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D -statin), indicated that T2D -statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg, P=0.01) and control (control: 2.8±0.3 mm Hg, P=0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D -statin patients (T2D -statin: -3.3±0.6 mL/(min·mm Hg), T2D +statin: -1.6±0.3 mL/(min·mm Hg), P=0.03; control -2.2±0.3 mL/(min·mm Hg), P=0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.

Influence of fitness on the pressor response following spontaneous bursts of muscle sympathetic nerve activity (1172.6)

Previous studies suggest that high fit (HF) subjects may exhibit altered vascular responses to reflex mediated increases in muscle sympathetic nerve activity (MSNA). Whether the ability of MSNA to modulate arterial blood pressure (BP) on a beat‐to‐beat basis is affected by fitness is unknown. In 7 HF (VO2 max=67±2 ml/kg/min) and 7 average fit (AF; VO2=44±2 ml/kg/min) young men, MSNA (microneurography) and blood pressure (Finapres) were continuously measured at rest for 10 minutes. Signal averaging was used to characterize beat‐by‐beat changes in mean arterial pressure (MAP) for 10 cardiac cycles following each individual MSNA burst and a peak response calculated. Variations in MSNA burst pattern were considered by comparing single (bordered by &gt;1 heartbeat lacking MSNA) vs. multiple bursts. Changes in MAP were also calculated following heartbeats without MSNA (i.e., non‐bursts). In response to single MSNA bursts, no significant difference was noted in MAP (HF: +2.8±1.2 vs. AF: +1.8±0.34 mmHg, P&gt;0.05); however, multiple bursts produced a significantly greater increase in MAP in HF subjects (HF: +4.8±0.5 vs. AF: +3.4±0.3 mmHg, P&lt;0.05). Also, following non‐bursts, HF subjects tended to have a greater reduction in MAP (HF: ‐1.3±0.3 vs. AF: ‐0.7±0.1, P=0.053). These preliminary findings suggest a greater role for spontaneous MSNA bursts in modulating BP on a beat‐to‐beat basis in HF compared to AF subjects.Grant Funding Source: Supported by NIH Grant RO1 HL093167 (PJF)

The role of α‐adrenergic receptors in mediating beat‐by‐beat sympathetic vascular transduction in the forearm of resting man

Sympathetic vascular transduction is commonly understood to act as a basic relay mechanism, but under basal conditions, competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC) and the contribution of local α-adrenergic receptor-mediated pathways to the observed FVC responses. In 19 young men, MSNA (microneurography), arterial blood pressure and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during supine rest. These measures were also recorded in seven men during intra-arterial infusions of normal saline, phentolamine (PHEN) and PHEN with angiotensin II (PHEN+ANG). The latter was used to control for increases in resting blood flow with α-adrenergic blockade. Spike-triggered averaging was used to characterize beat-by-beat changes in FVC for 15 cardiac cycles following each MSNA burst and a peak response was calculated. Following MSNA bursts, FVC initially increased by +3.3 ± 0.3% (P = 0.016) and then robustly decreased to a nadir of -5.8 ± 1.6% (P < 0.001). The magnitude of vasoconstriction appeared graded with the number of consecutive MSNA bursts; while individual burst size only had a mild influence. Neither PHEN nor PHEN+ANG infusions affected the initial rise in FVC, but both infusions significantly attenuated the subsequent decrease in FVC (-2.1 ± 0.7% and -0.7 ± 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via α-adrenergic receptors.

Cardiorespiratory coupling of sympathetic outflow in humans: a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle

What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 ± 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 ± 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 ± 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 ± 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors.

The role of α‐adrenergic receptors in mediating beat‐by‐beat sympathetic vascular transduction in resting humans

Sympathetic vascular transduction is commonly understood to act as a basic relay, but under basal conditions competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC). In 7 young men, MSNA (microneurography) and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during 20 minute infusions of intra‐arterial saline (control), phentolamine (PHEN), and PHEN with angiotensin II (PHEN‐ANG). The latter was used to control for increases in resting blood flow with a‐adrenergic blockade. Signal averaging was used to characterize beat‐by‐beat changes in FVC for 15 cardiac cycles following each individual MSNA burst and a peak response was calculated. During saline, FVC initially increased by +3.3±0.3% following MSNA bursts (P=0.016) and then robustly decreased to a nadir of −5.8±1.5% (P&lt;0.001). PHEN and PHEN+ANG infusion did not alter the initial rise in FVC, but significantly attenuated the ensuing decrease in FVC (−2.1±0.7% and −0.7±0.8%, respectively; P&lt;0.001 vs. saline). These findings indicate that spontaneous MSNA bursts are capable of evoking robust decreases in FVC that are exclusively mediated via α‐adrenergic receptors. Supported by RO1 HL093167

Cardiac‐locked bursts of muscle sympathetic nerve activity are absent in familial dysautonomia

Familial dysautonomia (Riley-Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement.

Spontaneous bursts of muscle sympathetic nerve activity decrease leg vascular conductance in resting humans

Previous studies in humans attempting to assess sympathetic vascular transduction have related large reflex-mediated increases in muscle sympathetic nerve activity (MSNA) to associated changes in limb vascular resistance. However, such procedures do not provide insight into the ability of MSNA to dynamically control vascular tone on a beat-by-beat basis. Thus we examined the influence of spontaneous MSNA bursts on leg vascular conductance (LVC) and how variations in MSNA burst pattern (single vs. multiple bursts) and burst size may affect the magnitude of the LVC response. In 11 young men, arterial blood pressure, common femoral artery blood flow, and MSNA were continuously recorded during 20 min of supine rest. Signal averaging was used to characterize percent changes in LVC for 15 cardiac cycles following heartbeats associated with and without MSNA bursts. LVC significantly decreased following MSNA bursts, reaching a nadir during the 6th cardiac cycle (single bursts, -2.9 ± 1.1%; and multiple bursts, -11.0 ± 1.4%; both, P < 0.001). Individual MSNA burst amplitudes and the total amplitude of consecutive bursts were related to the magnitude of peak decreases in LVC. In contrast, cardiac cycles without MSNA bursts were associated with a significant increase in LVC (+3.1 ± 0.5%; P < 0.001). Total vascular conductance decreased in parallel with LVC also reaching a nadir around the peak rise in arterial blood pressure following an MSNA burst. Collectively, these data are the first to assess beat-by-beat sympathetic vascular transduction in resting humans, demonstrating robust and dynamic decreases in LVC following MSNA bursts, an effect that was absent for cardiac cycles without MSNA bursts.

Real-time imaging of cortical and subcortical control of muscle sympathetic nerve activity in awake human subjects

Blood pressure is controlled on a beat-to-beat basis through fluctuations in heart rate and the degree of sympathetically-mediated vasoconstriction in skeletal muscles. By recording muscle sympathetic nerve activity (MSNA) at the same time as performing functional magnetic resonance imaging (fMRI) of the brain, we aimed to identify cortical structures involved in central cardiovascular control in awake human subjects. Spontaneous bursts of MSNA were recorded via a tungsten microelectrode inserted percutaneously into the peroneal nerve of 14 healthy subjects in a 3T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast - gradient echo, echo-planar - images were continuously collected in a 4s ON, 4s OFF sampling protocol. MSNA burst amplitudes were measured during the OFF periods and BOLD signal intensity was measured during the subsequent 4s period to allow for neurovascular coupling and nerve conduction delays. Group analysis demonstrated regions showing fluctuations in BOLD signal intensity that covaried with the intensity of the concurrently recorded bursts of MSNA. Signal intensity and MSNA were positively correlated in the left mid-insula, bilateral dorsolateral prefrontal cortex, bilateral posterior cingulate cortex and bilateral precuneus. In addition, MSNA covaried with signal intensity in the left dorsomedial hypothalamus and bilateral ventromedial hypothalamus (VMH). Construction of a functional connectivity map revealed coupling between activity in VMH and the insula, dorsolateral prefrontal cortex, precuneus, and in the region of the left and right rostroventrolateral medulla (RVLM). This suggests that activity within suprabulbar regions may regulate resting MSNA by projections to the premotor sympathetic neurons in the rostroventrolateral medulla.

Heterogeneity in arm and leg vasoconstrictor responses to spontaneous bursts of resting muscle sympathetic nerve activity in humans

Sympathetic vascular regulation depends on the effectiveness of peripheral vessels to respond to muscle sympathetic nerve activity (MSNA). Greater α1‐adrenoceptor responsiveness has been reported in the human leg compared to the arm. However, whether these underlying receptor differences alter limb vascular responsiveness to MSNA is unknown. To begin to address this, we examined arm and leg vascular conductance responses to spontaneous MSNA bursts. Arterial pressure (Finapres), MSNA (microneurography) and simultaneous blood flows in the brachial (BA) and common femoral (CFA) arteries (duplex Doppler ultrasound) were continuously measured during 20 minutes of supine rest in 8 young men. Beat‐by‐beat changes in conductance for each vessel were characterized for 15 cardiac cycles following each individual MSNA burst using signal averaging to identify the temporal conductance pattern and a peak response was calculated. CFA conductance significantly decreased following MSNA bursts, reaching a nadir (−7.6±1.7%, p&lt;0.05 vs. baseline) in ~8 cardiac cycles. In contrast, BA conductance initially increased (peak: +7.0±1%, p&lt;0.05) and subsequently decreased (nadir: −1.4±1.3%, p&gt;0.05) after ~8 cardiac cycles. These preliminary findings suggest heterogeneity between the arm and leg in the acute vascular responses following individual bursts of MSNA. Supported by RO1 HL093167

Transient Increases In Blood Pressure After Spontaneous Bursts Of Muscle Sympathetic Nerve Activity: Contributions Of Cardiac Output And Systemic Vascular Conductance

Previously, a latency of 5.5 seconds between the occurrence of a burst of muscle sympathetic nerve activity (MSNA) and the subsequent peak arterial blood pressure (BP) response was reported. Although this BP increase was thought to be primarily due to peripheral vasoconstriction, beat-to-beat vascular conductance measures were not made. Furthermore, a transient cardio-acceleration was observed following MSNA bursts. However, whether an increase in cardiac output contributes to the BP response is unknown. PURPOSE: To assess the beat-to-beat fluctuations in cardiac output (CO) and systemic vascular conductance (SVC) following a spontaneous burst of MSNA. METHODS: In 7 young men, BP (finger photoplethysmography), stroke volume (SV; Modelflow), heart rate (HR; ECG) and MSNA (microneurography) were continuously measured during 30 minutes of supine rest. Beat-to-beat fluctuations in BP, CO (HR × SV) and systemic vascular conductance (SVC; CO/MAP) were characterized for 15 cardiac cycles following each individual MSNA burst using signal averaging to identify the temporal pattern for each variable and a peak response was calculated. RESULTS: A significant rise in diastolic BP was observed following each burst of MSNA with a peak increase of 4.35 ± 0.5 mmHg (+6.6 ± 0.7%; p<0.05) occurring at a latency of 5.4 ± 0.2 s. Within the first 2 cardiac cycles following an MSNA burst, the immediate (1.7 ± 0.05 s) increase in BP was associated with a 0.49 ± 0.10 L (+10 ± 0.03%; p<0.05) increase in CO. SVC was also transiently increased with CO during this initial period but then subsequently decreased by -0.005 ml·min-1mmHg-1 (-8.1 ± 0.4%; p<0.05), reaching a maximum reduction around the time of the peak increase in BP. CONCLUSIONS: These preliminary findings indicate that spontaneous bursts of MSNA consistently produce elevations in BP that appear to be mediated by alterations in both CO and SVC. The initial rise in BP is associated with an increase in CO that transitions to peripheral vasoconstriction, noted by the significant fall in SVC at the time of the peak BP response. Thus, it appears that both central and peripheral adjustments contribute to the transient rise in BP following a spontaneous burst of MSNA.