Sympathetic neural activity to the cardiovascular system: integrator of systemic physiology and interindividual characteristics.

The sympathetic nervous system is a ubiquitous, integrating controller of myriad physiological functions. In the present article, we review the physiology of sympathetic neural control of cardiovascular function with a focus on integrative mechanisms in humans. Direct measurement of sympathetic neural activity (SNA) in humans can be accomplished using microneurography, most commonly performed in the peroneal (fibular) nerve. In humans, muscle SNA (MSNA) is composed of vasoconstrictor fibers; its best-recognized characteristic is its participation in transient, moment-to-moment control of arterial blood pressure via the arterial baroreflex. This property of MSNA contributes to its typical "bursting" pattern which is strongly linked to the cardiac cycle. Recent evidence suggests that sympathetic neural mechanisms and the baroreflex have important roles in the long term control of blood pressure as well. One of the striking characteristics of MSNA is its large interindividual variability. However, in young, normotensive humans, higher MSNA is not linked to higher blood pressure due to balancing influences of other cardiovascular variables. In men, an inverse relationship between MSNA and cardiac output is a major factor in this balance, whereas in women, beta-adrenergic vasodilation offsets the vasoconstrictor/pressor effects of higher MSNA. As people get older (and in people with hypertension) higher MSNA is more likely to be linked to higher blood pressure. Skin SNA (SSNA) can also be measured in humans, although interpretation of SSNA signals is complicated by multiple types of neurons involved (vasoconstrictor, vasodilator, sudomotor and pilomotor). In addition to blood pressure regulation, the sympathetic nervous system contributes to cardiovascular regulation during numerous other reflexes, including those involved in exercise, thermoregulation, chemoreflex regulation, and responses to mental stress.

Sympathetic single axonal discharge after spinal cord injury in humans: activity at rest and after bladder stimulation.

STUDY DESIGN: Clinical experimental mechanistic study. OBJECTIVES: (1) To determine in three spinal cord-injured patients whether individual muscle sympathetic nerve fibres below the level of the spinal lesion display spontaneous activity. (2) To determine in these patients if individual sympathetic vasoconstrictor fibres show a prolonged discharge following a bladder stimulus. SETTING: University hospital in Gothenburg, Sweden. METHODS: Microneurographic recordings of action potentials from individual muscle nerve sympathetic fibres in a peroneal nerve. Recordings of skin blood flow and electrodermal responses in a foot. RESULTS: In all patients, there was sparse ongoing spontaneous impulse traffic in individual sympathetic fibres. Brisk mechanical pressure over the urinary bladder evoked a varying number of action potentials in individual fibres, but the activity was brief and did not continue after the end of the evoked multiunit burst. CONCLUSION: Prolonged discharges in individual sympathetic fibres are unlikely to contribute to a long duration of blood pressure increases induced by brief bladder stimuli.

Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress.

Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus and mental stress evoked by a 3 min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33 ± 10 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P = 0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r = 0.80, P < 0.001) between MSNA responses induced by arousal and by mental stress but not between responses evoked by arousal and the cold test (r < 0.1, P > 0.6). Additionally arousal-induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r = 0.48; P < 0.01; diastolic BP: r = 0.42; P < 0.05) but not with blood pressure changes during CT. We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress.

Relationship between breathing and cardiovascular function at rest: sex-related differences.

AIM: to compare relationships at rest between breathing rate, levels of muscle sympathetic nerve activity, total peripheral resistance and cardiac output among young men and women. METHODS: recordings were made of respiratory movements, sympathetic nerve activity (peroneal microneurography), intra-arterial blood pressure, electrocardiogram, cardiac output (open-circuit acetylene uptake technique) in 19 healthy men (age 27 (+/-) 2years, mean (+/-) SEM) and 17 healthy women (age 25 (+/-) 1years). Total peripheral resistance and stroke volume were calculated. Four minutes epochs of data were analysed. RESULTS: breathing rates and sympathetic activity were similar in men and women but compared to men, women had significantly lower blood pressures, cardiac output and stroke volume. In men breathing rate correlated positively with sympathetic activity (r = 0.58, P < 0.05) but not in women (r = 0.12, P > 0.05). Furthermore, in men, respiratory rate correlated positively with total peripheral resistance (r = 0.65, P < 0.05) and inversely with cardiac output (r =-0.84, P < 0.05) and heart rate (r = -0.60, P < 0.05) but there were no such relationships in women (P > 0.05 for all). CONCLUSIONS: the positive relationship between breathing and sympathetic activity in men, and the inverse coupling of breathing to cardiac output and heart rate suggest that influences of respiration may be important not only for dynamic but also for 'tonic' cardiovascular function. The lack of relationships among these variables in women shows that there are fundamental differences in basic blood pressure regulation between the sexes.

Integrative mechanisms of blood pressure regulation in humans and rats: cross-species similarities.

As our understanding of the importance of individualized medicine continues to grow, the clinical relevance of interindividual variability in hemodynamic variables is receiving increasing attention. However, it is not known whether the rat, which is often used for studies of cardiovascular regulation, exhibits similar interindividual variability. In the present study, we evaluated whether the magnitude of interindividual variability in cardiac output (CO) and total peripheral resistance (TPR) was similar in humans and in rats. We assessed interindividual variability of mean arterial pressure (MAP), CO, and TPR during control conditions in normotensive humans (n = 40) and during normotension and deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats (n = 16). Humans and rats showed marked interindividual variability in CO and TPR but low variability in MAP. During deoxycorticosterone acetate-salt hypertension, CO was maintained, but TPR was elevated compared with the baseline period. We conclude that the magnitudes of interindividual variability of MAP, CO, and TPR are quantitatively similar in humans and rats, providing support for the relevance of this variability in both species and suggesting that studies in rats could be designed to address questions specific to individualized medicine in hypertension.

Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans.

Large interindividual differences exist in resting sympathetic nerve activity (SNA) among normotensive humans with similar arterial pressure (AP). We recently showed inverse relationships of resting SNA with cardiac output (CO) and vascular adrenergic responsiveness that appear to balance the influence of differences in SNA on blood pressure. In the present study, we tested whether nitric oxide (NO)-mediated vasodilation has a role in this balance by evaluating hemodynamic responses to systemic NO synthase (NOS) inhibition in individuals with low and high resting muscle SNA (MSNA). We measured MSNA via peroneal microneurography, CO via acetylene uptake and AP directly, at baseline and during increasing systemic doses of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). Baseline MSNA ranged from 9 to 38 bursts/min (13 to 68 bursts/100 heartbeats). L-NMMA caused dose-dependent increases in AP and total peripheral resistance and reflex decreases in CO and MSNA. Increases in AP with L-NMMA were greater in individuals with high baseline MSNA (PANOVA<0.05). For example, after 8.5 mg/kg of L-NMMA, in the low MSNA subgroup (n=6, 28+/-4 bursts/100 heartbeats), AP increased 9+/-1 mmHg, whereas in the high-MSNA subgroup (n=6, 58+/-3 bursts/100 heartbeats), AP increased 15+/-2 mmHg (P<0.01). The high-MSNA subgroup had lower baseline CO and smaller decreases in CO with L-NMMA, but changes in total peripheral resistance were not different between groups. We conclude that differences in CO among individuals with varying sympathetic traffic have important hemodynamic implications during disruption of NO-mediated vasodilation.

Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans.

In humans, sympathetic nerve activity (SNA) at rest can vary several-fold among normotensive individuals with similar blood pressures. We recently showed that a balance exists between SNA and cardiac output, which may contribute to the maintenance of normal blood pressures over the range of resting SNA levels. In the present studies, we assessed whether variability in vascular adrenergic responsiveness has a role in this balance. We tested the hypothesis that forearm vascular responses to noradrenaline (NA) and tyramine (TYR) are related to SNA such that individuals with lower resting SNA have greater adrenergic responsiveness, and vice-versa. We measured multifibre muscle SNA (MSNA; microneurography), arterial pressure (brachial catheter) and forearm blood flow (plethysmography) in 19 healthy subjects at baseline and during intrabrachial infusions of NA and TYR. Resting MSNA ranged from 6 to 34 bursts min(-1), and was inversely related to vasoconstrictor responsiveness to both NA (r = 0.61, P = 0.01) and TYR (r = 0.52, P = 0.02), such that subjects with lower resting MSNA were more responsive to NA and TYR. We conclude that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity. Further understanding of this balance may have important implications for our understanding of the pathophysiology of hypertension.

Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation.

Large, reproducible interindividual differences exist in resting sympathetic nerve activity among normotensive humans with similar arterial pressures, resulting in a lack of correlation between muscle sympathetic nerve activity (MSNA) and arterial pressure among individuals. Although it is known that the arterial pressure is the main short-term determinant of MSNA in humans via the arterial baroreflex, the lack of correlation among individuals suggests that the level of arterial pressure is not the only important input in regulation of MSNA in humans. We studied the relationship between cardiac output (CO) and baroreflex control of sympathetic activity by measuring MSNA (peroneal microneurography), arterial pressure (arterial catheter), CO (acetylene uptake technique) and heart rate (HR; electrocardiogram) in 17 healthy young men during 20 min of supine rest. Across individuals, MSNA did not correlate with mean or diastolic blood pressure (r<0.01 for both), but displayed a significant negative correlation with CO (r=-0.71, P=0.001). To assess whether CO is related to arterial baroreflex control of MSNA, we constructed a baroreflex threshold diagram for each individual by plotting the percentage occurrence of a sympathetic burst against diastolic pressure. The mid-point of the diagram (T50) at which 50% of cardiac cycles are associated with bursts, was inversely related to CO (r=-0.75, P<0.001) and stroke volume (SV) (r=-0.57, P=0.015). We conclude that dynamic inputs from CO and SV are important in regulation of baroreflex control of MSNA in healthy, normotensive humans. This results in a balance between CO and sympathetically mediated vasoconstriction that may contribute importantly to normal regulation of arterial pressure in humans.

No compensatory sweating after botulinum toxin treatment of palmar hyperhidrosis.

BACKGROUND: Primary focal hyperhidrosis is caused by excessive secretion by eccrine sweat glands, usually at the palms, soles and axillae. The underlying mechanism is unclear. In recent years botulinum toxin A has emerged as a useful treatment. Compensatory sweating, which is a major problem in many patients who have undergone transthoracic endoscopic sympathectomy for hyperhidrosis, has only rarely been reported after botulinum toxin. However, this potential side-effect of botulinum toxin treatment has not been systematically examined. OBJECTIVES: To investigate if treatment with botulinum toxin A in hyperhidrotic hands may cause compensatory sweating at other skin locations. METHODS: In 17 patients with a history of palmar hyperhidrosis repeated measurements of evaporation were made before and up to 6 months after treatment of the hands with botulinum toxin A. Recordings were made at 16 skin areas and compared with subjective estimates of sweating. RESULTS: Following treatment, palmar evaporation decreased markedly and then returned slowly towards pretreatment values, but was still significantly reduced 6 months after treatment. No significant increase of sweating was found after treatment in any nontreated skin area. CONCLUSIONS: Successful treatment of palmar hyperhidrosis with botulinum toxin does not evoke compensatory hyperhidrosis in nontreated skin territories.

Spectral analysis of burst periods in EEG from healthy and post-asphyctic full-term neonates.

OBJECTIVE: To investigate whether the periodic EEG patterns seen in healthy and sick full term neonates (trace alternant and burst suppression, respectively) have different frequency characteristics. METHODS: Burst episodes were selected from the EEGs of 9 healthy and 9 post-asphyctic full-term neonates and subjected to power spectrum analysis. Powers in two bands were estimated; 0-4 and 4-30 Hz, designated low- and high-frequency activity, respectively (LFA, HFA). The spectral edge frequency (SEF) was also assessed. RESULTS: In bursts, the LFA power was lower in periods of burst suppression as compared to those of trace alternant. The parameter that best discriminated between the groups was the relative amount of low- and high-frequency activity. The SEF parameter had a low sensitivity to the group differences. In healthy neonates, the LFA power was higher over the posterior right as compared to the posterior left region. CONCLUSIONS: Spectral power of low frequencies differs significantly between the burst episodes of healthy and sick neonates. SIGNIFICANCE: These results can be used when monitoring cerebral function in neonates.

Unmyelinated tactile afferents signal touch and project to insular cortex.

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

Tactile directional sensibility and diabetic neuropathy.

Five different procedures used to diagnose neuropathy were compared in a "blind" study with diabetic patients. The aim was to evaluate tests of tactile directional sensibility. Three matched groups were examined, two groups with type I diabetes, either with or without suspected neuropathy, and one of healthy controls. Testing consisted of: (1) examination by a specialist in neurology, (2) electrophysiologic measurement of nerve conduction velocity and determination of cool sensitivity, and (3) determination of directional sensibility in two stages, with categorical and quantitative techniques. Abnormal test results were obtained for both groups of diabetic patients. Quantitatively measured directional sensibility had the highest sensitivity (89%) and specificity (85%) when calculated for patients who had received a diagnosis of neuropathy from the neurologist, despite one case of abnormal directional sensibility among the healthy controls. Conduction velocity testing was almost comparably sensitive (80%) and cool sensitivity, comparably specific (85%) when calculated in the same manner.

Is the somatotropic axis related to sympathetic nerve activity in healthy ageing men?

OBJECTIVE: The mechanisms underlying the age-related increase in blood pressure and sympathetic nerve activity remain largely unknown. The decline in growth hormone (GH) secretion and insulin-like growth factor-I (IGF-I) with age has been related to several cardiovascular risk factors. Low serum IGF-I levels in severe adult GH deficiency is associated with markedly increased sympathetic nerve activity. This study evaluates whether a relationship between serum IGF-I and sympathetic nerve traffic exists in healthy aging men. DESIGN AND METHODS: Sympathetic nerve activity to the muscle vascular bed (MSA) was recorded in 56 healthy normotensive males, and related to age (range 21-71 years), body mass index (BMI, range 18.4-32.2), serum IGF-I and plasma nitrate levels. Blood pressure, BMI and MSA increased with age, whereas IGF-I and plasma nitrate decreased. In a forward stepwise multiple regression analysis, age explained 40% of the variability in MSA and excluded other variables. Omitting age, IGF-I became the strongest independent predictor, explaining 23% of the variability in MSA. MSA was an independent predictor of diastolic blood pressure, but its influence (10%) was less than that of BMI (28%). BMI was not related to MSA or IGF-I. CONCLUSIONS: Decreased serum IGF-I levels are coupled to increased MSA during ageing, an effect independent from the impact of increased body weight. Although MSA is a weak predictor of rising blood pressure with age, it constitutes one possible pathway for the somatotropic axis to affect cardiovascular function in ageing.

Thin fibre territories of nerves innervating hairs in the human forearm estimated from axon reflex vasodilatations.

1. To study the territories of thin nerve fibres innervating hair follicles, we extracted single hairs from forearm skin. Scanning laser Doppler methodology was used to measure the evoked local increase of skin perfusion, the underlying assumption being that axon reflex vasodilatation would be evoked within the territory of extraction-activated thin nerve fibres. Ninety-two single hairs were extracted in 14 healthy males. 2. In 93 % of the cases perfusion increased transiently near the site of the extracted hair. No responses occurred when arm blood flow was occluded. In support of an underlying axon reflex mechanism the intensity of hair extraction-evoked pain correlated with the peak area of the response. In addition, after pre-extraction local anaesthesia, response components were seen in only 50 % of the cases and when they occurred they were very small. 3. The response had two components which could occur independently of each other. An early short-lasting component consisted of one or several separate areas with a peak total extension of 176 +/- 176 mm(2) (mean +/- S.D.), a peak maximal intensity (in percentage of pre-extraction perfusion) of 484 +/- 272 %, and a duration of 6-8 min. A later long-lasting component consisted of a single area of 51 +/- 107 mm(2), an intensity of 342 +/- 301 % and a duration of up to approximately 60 min. Perfusion could be influenced from a single hair in an asymmetrical skin area with diameters at right angles of 23 +/- 9 and 16 +/- 9 mm, respectively. 4. We suggest that the responses were evoked by two sets of thin nerve fibres, one at a superficial level with fairly large innervation territories, and the other located more deeply close to the hair follicle and with smaller innervation territories.

Two sites for modulation of human sympathetic activity by arterial baroreceptors?

1. Peroneal muscle sympathetic nerve activity (MSA), finger blood pressure and cardiac intervals were recorded at rest in 60 healthy subjects, aged 18-71 years. Arterial baroreflex control of MSA was analysed by relating each spontaneous sympathetic burst to the diastolic blood pressure and the cardiac interval of the heart beat during which the burst was generated. The results were expressed as blood pressure/cardiac interval threshold for occurrence of bursts, and as baroreflex sensitivity (i.e. the relationship between diastolic pressure/cardiac interval and burst strength). 2. Significant blood pressure/cardiac interval thresholds were present in all subjects and old subjects had less variability of thresholds than young subjects. In contrast, significant baroreflex sensitivity for diastolic pressure and cardiac interval was present in only 55 and 73 % of the subjects, respectively. There was no age-related difference in sensitivity. 3. In 40 subjects, two 5 min periods from the same recording were analysed. The number of sympathetic bursts and the threshold for occurrence of bursts were reproducible in all subjects. In contrast, significant baroreflex sensitivity in both periods was present in only 30 % (diastolic pressure) and 40 % (cardiac interval) of the subjects. 4. The results show that the baroreflex mechanisms regulating the occurrence and strength of sympathetic bursts are not identical. We suggest that the modulation occurs at two sites, one which determines whether or not a burst will occur, and another at which the strength of the discharge is determined.

Does sympathetic nerve discharge affect the firing of polymodal C-fibre afferents in humans?

Experimental and clinical studies in animals and humans have indicated that nociceptive nerve fibres can acquire sensitivity to norepinephrine after injury or chemical sensitization. To evaluate the functional relevance of such sensitization, we recorded the activity of single polymodal C-fibre afferents in healthy human volunteers and investigated whether intense physiological sympatho-excitation could affect their firing properties. This was studied before and after chemical sensitization of receptive fields by topical application of mustard oil. All afferent C fibres investigated (11 units in 10 subjects) were mechano-heat-sensitive, and four of seven fibres subjected to mustard oil were also chemosensitive. Putative sensitivity to sympathetic stimulation was investigated during low-frequency (0.25 Hz) electrical stimulation of the unit receptive field at a threshold intensity sufficient to evoke an action potential in the afferent fibre after every second to third stimulus. Following a prolonged period of silent rest, sympathoexcitation was elicited by forced mental arithmetic for 60 s, again followed by a long silent rest period. During stress, sympathetic nerve traffic increased to 625 +/- 146% of the control level, while firing of the afferent units remained unchanged. There was no sign of sympathetically mediated direct activation of afferent units and no change in the relative amounts of afferent activations caused by the background electrical stimulation. Results were similar for all units, both before (seven units in six subjects) and after (seven units in seven subjects) chemical sensitization of their cutaneous receptive field. The results suggest that if chemical sensitization of nociceptive C afferent neurons with mustard oil does induce sensitivity to noradrenaline in humans, it is not sufficient to make C nociceptive fibres respond to short-lasting physiological variations in sympathetic outflow.

Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA. METHODS AND RESULTS: Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29+/-5%, mean+/-SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88+/-5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5+/-5.2% (range, 21 to 89%), and mean firing frequency was 0.98+/-0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (P<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects. CONCLUSIONS: An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.

Capsaicin treatment induces histamine release and perfusion changes in psoriatic skin.

To determine whether neurogenic factors may be of importance in the regulation of histamine release and blood flow in psoriatic plaque, the effect of capsaicin was studied in 22 psoriatic patients with active, untreated psoriatic lesions. In each of 12 patients, one microdialysis fibre was placed in non-lesional skin and one was placed in lesional skin at depths of 0.7 and 0.9 mm, respectively. Dialysates were collected for the analysis of histamine in the resting state and after 60 min of repetitive epicutaneous application of 1% capsaicin above the microdialysis catheter. In 10 patients, topical capsaicin and placebo were applied for 24 h to lesional/lesion-free skin. Skin blood flow and perfusion (evaluated using the 133xenon clearance technique and scanning laser Doppler, respectively) were measured before the application of capsaicin and after removal. After 60 min of capsaicin treatment, both the perfusion and interstitial concentration of histamine, as well as the net release of histamine, were significantly increased in affected (from 38 +/- 6 to 45 +/- 6 nmol/L, mean +/- SEM) and unaffected (from 15 +/- 2 to 19 +/- 2 nmol/L) skin. Compared with placebo, 24 h of treatment with capsaicin caused a 15% decrease in perfusion in lesional skin. The results are compatible with the hypothesis that capsaicin-sensitive nerves may induce histamine release in non-lesional and lesional skin and that afferent unmyelinated nerve fibres may contribute to the high blood flow in psoriatic plaques.

Cardiac- and noncardiac-related coherence between sympathetic drives to muscles of different human limbs.

Partial coherence analysis was used to evaluate the extent to which coherence between resting muscle sympathetic activity (MSA) in different pairs of limbs in humans is explained by the common baroreceptor input and by other noncardiac-related factors. Multiunit MSA in two or three nerves, arterial blood pressure, and electrocardiogram were recorded simultaneously. Correlated MSA consisted of a sharp periodic component at the heart rate and a wideband component of relatively low power distributed between 0 and 2-2.5 Hz. Quantitative analysis revealed stronger coupling between MSAs in close limbs than in distant limbs (peak coherence leg-leg, 0. 94 +/- 0.03; arm-leg, 0.76 +/- 0.11). Furthermore, the wideband component, unaffected by partialization with circulatory signals, was significantly stronger between leg-leg (0.67 +/- 0.10) than between arm-leg pairs (0.29 +/- 0.10), i.e., noncardiac-related components explained 71% of leg-leg and 38% of arm-leg coherences at the frequency of the heart. Our results indicate that nonuniform relationship exists between resting sympathetic outflow to muscles in close and distant extremities which is, however, partially masked by the effect of the common rhythmic baroreceptor input.