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Cited by 68Heart Rate Variability and Autonomic ControlBlood Pressure and Hypertension StudiesCardiovascular and exercise physiology

Single‐unit muscle sympathetic nervous activity and its relation to cardiac noradrenaline spillover

Open access
Lambert, Elisabeth A., Schlaich, Markus P., Dawood, Tye, Sari, Carolina, Chopra, Reena, Barton, David A., Kaye, David M., Elam, Mikael +2 more·2011·The Journal of Physiology
DOI 10.1113/jphysiol.2011.205351PMC PMC3115828
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Abstract

Non‐technical summary Recent work has demonstrated differences in the firing pattern of sympathetic nerves in a variety of patient groups. The significance or consequences of this firing pattern remain unknown. We examined whether the nerve firing pattern was associated with increased noradrenaline release from the heart. The activity and pattern of the nerve firing was recorded in the peroneal nerve and subjects were divided into two groups according to the firing pattern as ‘low firing rate’ or ‘high firing rate’. In those with a high firing rate, the noradrenaline released by the heart was two times higher than that of subjects with a low firing rate. This study indicates that the nerve firing pattern may dictate the amount of noradrenaline released by the heart.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with hypertension, major depressive disorder, or panic disorder, a more irregular single-unit muscle sympathetic firing pattern (high incidence of multiple spikes per cardiac cycle) was associated with roughly twofold higher cardiac noradrenaline spillover. This relationship was not seen for multi-unit MSNA or whole-body noradrenaline spillover.

Key findings

  • Subjects with a high incidence of multiple spikes had higher single-unit firing probability (65 ± 4 vs. 39 ± 2%, P < 0.05) and firing rate (74 ± 12 vs. 27 ± 2 spikes per 100 heart beats, P < 0.05) than those with low incidence.
  • Cardiac noradrenaline spillover was significantly higher in the high-incidence group (22.0 ± 4.9 vs. 11.0 ± 1.5 ng min⁻¹, P < 0.05).
  • Whole-body noradrenaline spillover did not differ between groups, and multi-unit MSNA was not different between the low- and high-incidence groups.
  • The median incidence of multiple spikes across all subjects was 9%, and the dichotomous split was made around this value.

Methods

  • Participants were drawn from prior investigations in hypertension (n = 6), major depressive disorder (n = 7), and panic disorder (n = 9); all underwent same-day cardiac catheterisation followed by microneurography and were medication-free at testing.
  • Multi-unit and single-unit muscle sympathetic nerve activity were recorded from the peroneal nerve; single-unit parameters included firing rate, probability of firing, and incidence of multiple firing.
  • Cardiac and whole-body noradrenaline spillover were measured by isotope dilution with ³H-labelled noradrenaline and coronary sinus sampling; groups were split by median incidence of multiple spikes and compared with Student’s t test, with significance at P < 0.05.

Limitations

  • The paper states that the precision and demanding nature of the techniques dictated a low number of successful observations and required reliance across different patient groups.
  • The paper states that direct recording of cardiac sympathetic nerve activity combined with cardiac noradrenaline spillover would be more conclusive but is not possible in conscious humans.
  • Evident from the text: the sample is small (11 per group), drawn from mixed clinical populations, and the design is cross-sectional, so it cannot establish causality or whether skeletal muscle single-unit firing patterns mirror cardiac sympathetic firing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1113/jphysiol.2011.205351

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 33 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Multi-unit MSNA was not different between the low and high incidence of multiple spikes groups.

    “Multi-unit MSNA was not different between the two groups.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the present analysis, ectopic beats were a relatively rare event.

    “In the present analysis ectopic beats were a relatively rare event.”
    Quote in the paperSubstantial claim
  • Findingown data

    Subjects with a high incidence of multiple spikes had a higher probability of firing per heart beat than subjects with a low incidence (65 ± 4 vs. 39 ± 2%, P < 0.05).

    “Those with 'high incidence of multiple spikes' were also characterised by a higher probability of firing per heart beat (65 ± 4 vs. 39 ± 2%, P < 0.05) and higher firing rates (74 ± 12 vs.27 ± 2 spikes per 100 heart beats, P < 0.05) compared with the subjects with 'low incidence of multiple spikes' (Fig. 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Subjects with a high incidence of multiple spikes had higher firing rates than subjects with a low incidence (74 ± 12 vs. 27 ± 2 spikes per 100 heart beats, P < 0.05).

    “Those with 'high incidence of multiple spikes' were also characterised by a higher probability of firing per heart beat (65 ± 4 vs. 39 ± 2%, P < 0.05) and higher firing rates (74 ± 12 vs.27 ± 2 spikes per 100 heart beats, P < 0.05) compared with the subjects with 'low incidence of multiple spikes' (Fig. 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In all subjects combined, the median incidence of multiple spikes (the percentage of heart beats with at least 2 spikes) was 9%.

    “In all subjects combined the incidence of multiple spikes (i.e. the percentage of heart beats where at least 2 spikes occurred) was 9% (median value).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    The firing pattern of single-unit muscle vasoconstrictor fibres is associated with the rate of spillover of noradrenaline from the heart, with an irregular firing pattern (high incidence of multiple spikes within a cardiac cycle) linked with more pronounced cardiac noradrenaline spillover to plasma.

    “The major finding of the present analysis is that the firing pattern of single-unit muscle vasoconstrictor fibres is associated with the rate of spillover of noradrenaline from the heart, with an irregular firing pattern, as indicated by high incidence of multiple spikes within a cardiac cycle, being linked with a more pronounced cardiac noradrenaline spillover to plasma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In healthy subjects, muscle vasoconstrictor single units usually fire as a solitary spike during a sympathetic burst regardless of the burst rate, indicating that the sympathetic firing pattern is not related to the overall sympathetic neural drive.

    “In healthy subjects, muscle vasoconstrictor single units usually fire as a solitary spike during a sympathetic burst regardless of the burst rate (Macefield & Wallin, 1999), thereby indicating that the sympathetic firing pattern is not related to the overall sympathetic neural drive.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Macefield & Wallin, 1999

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier work indicated that skeletal muscle (and skin) contributed no more than 20% of whole body noradrenaline spillover.

    “Earlier work, based on blood sampling from the forearm, with blood flow estimated from the fraction of cardiac output directed towards the skeletal muscle compartment, indicated that skeletal muscle (and skin) contributed no more than 20% of whole body noradrenaline spillover (Esler et al. 1984).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Esler et al. 1984

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In an anaesthetised rabbit model, MSNA parallels renal and cardiac sympathetic activity in response to a forced baroreceptor pressure change.

    “A correlation between multi-unit MSNA and cardiac noradrenaline spillover has previously been demonstrated in healthy subjects (Wallin et al. 1992), and more recently Kamiya and colleagues observed in an anaesthetised rabbit model that MSNA parallels renal and cardiac sympathetic activity in response to a forced baroreceptor pressure change (Kamiya et al. 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kamiya et al. 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The association between sympathetic nerve firing pattern (multiple single fibre salvos) and cardiac noradrenaline release is specific, in that it is not explained by overall sympathetic drive (multi-unit MSNA) or whole body noradrenaline spillover.

    “Interestingly the pattern of sympathetic firing bore no association to multi-unit MSNA or to whole body noradrenaline spillover, suggesting a specificity linking a sympathetic nerve firing pattern with multiple single fibre salvos to cardiac noradrenaline release.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In normotensive obese individuals, there is no evidence of a disturbed firing pattern, and even though mMSNA is elevated, cardiac noradrenaline spillover is normal.

    “Interestingly, and adding further indirect support to this proposal, in obesity there is no evidence of a disturbed firing pattern (Lambert et al. 2007) and even though mMSNA is elevated, cardiac noradrenaline spillover is normal in normotensive obese individuals (Vaz et al. 1997).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lambert et al. 2007

      Not checked in the free run.

    • cites Vaz et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A shift towards increased frequency of multiple spikes within a cardiac cycle has been demonstrated in pathological conditions such as heart failure, obstructive sleep apnoea syndrome and panic disorder, as well as in response to acute sympatho-excitatory stimuli such as maximal inspiratory breath-hold.

    “A shift towards increased frequency of multiple spikes within a cardiac cycle has been demonstrated in pathological conditions such as heart failure, obstructive sleep apnoea syndrome and panic disorder (Macefield et al. 1999;Elam et al. 2002;Lambert et al. 2006;Murai et al. 2009), as well as in response to acute sympatho-excitatory stimuli such as maximal inspiratory breath-hold (Macefield & Wall”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Macefield et al. 1999

      Not checked in the free run.

    • cites Elam et al. 2002

      Not checked in the free run.

    • cites Lambert et al. 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A number of studies have demonstrated that increased irregularity of the firing pattern may influence effector organ responses.

    “A number of studies have demonstrated that increased irregularity of the firing pattern may influence effector organ responses.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Andersson et al. 1983

      Not checked in the free run.

    • cites Nilsson et al. 1985

      Not checked in the free run.

    • cites Ando et al. 1993

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The pattern of renal sympathetic nerve stimulation in rats significantly influenced the rapidity, magnitude, and selectivity of the renal vascular and tubular responses.

    “Dibona and colleagues observed that the pattern of renal sympathetic nerve stimulation in rats significantly influenced the rapidity, magnitude, and selectivity of the renal vascular and tubular responses (DiBona & Sawin, 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DiBona & Sawin, 1999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A similar observation to the effect of irregular stimulation on effector responses was made in skin resistance responses in humans.

    “A similar observation was made in skin resistance responses in humans (Kunimoto et al. 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kunimoto et al. 1992

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The groups did not differ in terms of gender, BMI, blood pressure or in terms of distribution of subjects with hypertension, panic disorder or depression.

    “The groups did not differ in terms of gender, BMI, blood pressure or in terms of distribution of subjects with hypertension, panic disorder or depression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Left ventricular hypertrophy impacts unfavourably on cardiovascular morbidity and mortality and predicts future cardiovascular complications in patients who develop hypertension.

    “Importantly, LVH impacts unfavourably on cardiovascular morbidity and mortality (Levy et al. 1990) and LVH predicts future cardiovascular complications in patients who develop hypertension (Casale et al. 1986).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Levy et al. 1990

      Not checked in the free run.

    • cites Casale et al. 1986

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The precision and demanding nature of the techniques used dictated that the number of successful observations was low and reliance across different patient groups was required.

    “The precision and demanding nature of the techniques used dictated that the number of successful observations was low and reliance across different patient groups was required.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    For the analysis of single-unit recordings, the authors applied similar methods as those developed by Macefield et al. (1994), which use very stringent criteria for the acceptance of a recording as being truly unitary.

    “For the analysis of single-unit recordings, we applied similar methods as those developed by Macefield et al. (1994) which use very stringent criteria for the acceptance of a recording as being truly unitary.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Macefield et al. (1994)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the association between the pattern of sympathetic nerve firing and the rate of spillover of noradrenaline from the heart, and previous work documenting the detrimental effect of elevated cardiac noradrenaline spillover, targeting the firing pattern of sympathetic nerves may offer some therapeutic benefit.

    “Taken together, given our observations of an association between the pattern of sympathetic nerve firing and the rate of spilover of noradrenaline from the heart, and previous work documenting the detrimental effect of elevated cardiac noradrenaline spillover, it would seem that targeting the firing pattern of sympathetic nerves may offer some therapeutic benefit.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The analysis of all microneurography recordings was performed without knowledge of the participant's identity.

    “The analysis of all microneurography recordings was performed without knowledge of the participant's identity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The degree of left ventricular hypertrophy was not proportional to the degree of blood pressure elevation but rather was directly associated with the magnitude of cardiac sympathetic activation.

    “Interestingly, the degree of LVH was not proportional to the degree of blood pressure elevation but rather was directly associated with the magnitude of cardiac sympathetic activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schlaich et al. 2003

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Patients with hypertension were slightly older than those with panic disorder and had higher systolic and diastolic blood pressure compared with the other groups.

    “Patients with hypertension were slightly older that those with panic disorder and had higher systolic and diastolic blood pressure compared with the other groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Subjects and data were drawn from previous investigations examining the role of the sympathetic nervous system in hypertension, major depressive disorder and panic disorder, conditions which share the common characteristic of being associated with disturbances in noradrenaline release and/or disposition.

    “Subjects and data were drawn from our previous investigations examining the role of the sympathetic nervous system in hypertension (Schlaich et al. 2004) (n = 6), major depressive disorder (Barton et al. 2007) (n = 7) and panic disorder (Lambert et al. 2006) (n = 9), conditions which share the common characteristic of being associated with a disturbances in noradrenaline release and/or disposition”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Schlaich et al. 2004

      Not checked in the free run.

    • cites Barton et al. 2007

      Not checked in the free run.

    • cites Lambert et al. 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study protocols were approved by the Alfred Hospital Human Research Ethics Committee and all participants provided written informed consent.

    “The study protocols were approved by the Alfred Hospital Human Research Ethics Committee and all participants provided written informed consent.”
    Quote in the paperNot a substantial claim
20 of 20

  • The paper relies on this without support.

    Whole body noradrenaline spillover reflects overflow of noradrenaline from many vascular beds including the lungs, splanchnic and renal vasculatures.

    “Whole body noradrenaline spillover reflects overflow of noradrenaline from many vascular beds including the lungs, splanchnic and renal vasculatures.”

  • The paper relies on this without support.

    The disturbed sympathetic firing pattern observed in skeletal muscle also occurs in the sympathetic nerves to the heart.

    “Whether the disturbed sympathetic firing pattern that we observe in the skeletal muscle also occurs in the sympathetic nerves to the heart is not known.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The presence of multiple firing salvos in the human heart is probable, because patients who have nerve firing salvos recorded at microneurography have, in parallel, the highest levels of cardiac norepinephrine spillover.

    “Direct recording from the human cardiac sympathetic nerves is not possible, but the presence there of multiple firing salvos is probable, as patients who have nerve firing salvos recorded at microneurography have, in parallel, the highest levels of cardiac norepinephrine spillover.51”

    From Obesity Paradox in Hypertension: Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form? (2018) · cites this paper as [51]

  • With the coexistence of impaired norepinephrine reuptake with firing salvos in normal-weight essential hypertension and in depressive illness and panic disorder, there is evidence of cardiac risk, even in panic disorder.

    “Conversely, with the coexistence of impaired norepinephrine reuptake with firing salvos in normal-weight essential hypertension 31,[33][34][35][36] and in depressive illness 42,51,79 and panic disorder, 51,79,80 there is evidence of cardiac risk, 84 even in panic disorder.[85][86][87]”

    From Obesity Paradox in Hypertension: Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form? (2018) · cites this paper as [51]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Low-incidence group has fewer reported spikes than firing heartbeats

    Major

    For the low-incidence group, the reported firing probability is 39% of heartbeats, but the firing rate is only 27 spikes per 100 heartbeats. Under the paper's definitions, every heartbeat counted in the firing probability must contain at least one spike, so the firing rate cannot be lower than 39 spikes per 100 heartbeats.

1 of 1

The citation lists haven’t been fetched yet

References 46 · Cited by 68

Authors
Lambert, E. A., Schlaich, M. P., Dawood, T., Sari, C., Chopra, R., Barton, D. A., Kaye, D. M., Elam, M., Esler, M. D., & Lambert, G. W.
Affiliations
  • Baker Heart and Diabetes Institute (AU)
  • University of Gothenburg (SE)
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2011-05-13
Volume
589
Issue
10
Pages
2597-2605
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jphysiol.2011.205351
PMC
PMC3115828
OpenAlex
W1729896994
Semantic Scholar
62343509301ba4155e0b1118df43598a8a04a15d
Cited by
68
References
46
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 3 · 2021: 8 · 2020: 4 · 2019: 3 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 6 · 2014: 4 · 2013: 4 · 2012: 6
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Swinburne figshare (Swinburne University of Technology) (submittedVersion)
Funders
  • National Heart Foundation of Australia
  • Baker Heart and Diabetes Institute
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
muscle sympathetic nerve activity, hypertension, depression, panic disorder, noradrenaline release, sympathetic nervous system
MeSH terms
Action Potentials, Adult, Blood Pressure, Depression, Female, Heart, Heart Rate, Humans, Male, Middle Aged, Norepinephrine, Sympathetic Nervous System, Panic Disorder, Myocytes, Cardiac

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