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(Circulation. 2004;110:2786-2791.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Acute ß-Blockade Increases Muscle Sympathetic Activity and Modifies Its Frequency Distribution

Chiara Cogliati, MD; Simona Colombo, MD; Tomaso Gnecchi Ruscone, MD; Domenico Gruosso, MD; Alberto Porta, PhD; Nicola Montano, MD, PhD; Alberto Malliani, MD; Raffaello Furlan, MD

From Medicina Interna II, Ospedale L. Sacco, Milano (C.C., N.M., A.M., R.F.); Dipartimento Scienze Precliniche LITA di Vialba (A.P.); Università degli Studi di Milano, Divisioni di Cardiologia, Ospedali di Rho (S.C.) e Merate (T.G.R.), Milano; and Medicina Interna, Università Seconda, Napoli (D.G.), Italy.

Correspondence to Dr Raffaello Furlan, Unità Sincopi e Disturbi della Postura, Medicina Interna II, Ospedale L. Sacco, Università di Milano, Via G.B. Grassi 74, 20157 Milano, Italy. E-mail raffaellof{at}fisiopat.sacco.unimi.it

Received February 27, 2003; de novo received December 16, 2003; revision received March 30, 2004; accepted April 2, 2004.

	Abstract

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Background— The possible mechanisms by which ß-adrenergic antagonists may act on the neural regulation of the cardiovascular system are still elusive. Recent studies reported a marked increase of postganglionic muscle sympathetic nerve activity (MSNA) after acute ß-blockade associated with unchanged values of arterial blood pressure and baroreflex sensitivity. We tested the hypothesis that acute ß-blockade might also alter the oscillatory characteristics of MSNA, thus decreasing its effectiveness on peripheral vasoconstriction.

Methods and Results— In 11 healthy volunteers, ECG, MSNA, arterial pressure, and respiration were recorded before and after atenolol (0.05 mg/kg IV bolus) administration. The frequency distribution of RR interval, MSNA, systolic arterial pressure (SAP), and respiratory variability was assessed by spectrum and cross-spectrum analysis. Spontaneous baroreflex sensitivity (-index) and plasma catecholamines (high-performance liquid chromatography) were measured. Atenolol induced a significant increase in RR interval (14.3±1.6%) with no changes in systolic and diastolic arterial pressure. MSNA increased (42±13% from 18±2 bursts per minute). The low-frequency (LF) component of RR and MSNA variability decreased (–44±7% and –24±5%, respectively), whereas the high-frequency (HF) component increased (163±55% and 34±11%, respectively), expressed in normalized units. Spectral coherence, an index of oscillatory coupling, decreased between LF_RR and LF_MSNA, whereas it increased between HF_MSNA and HF_Resp. SAP variability, -index, and plasma catecholamines remained unchanged.

Conclusions— Atenolol induced a change in MSNA frequency distribution reflecting a stronger respiratory coupling. This shift toward high frequency, despite an increase in MSNA, may lead to a less efficient sympathetic vasomotor modulation.

Key Words: adrenergic ß-antagonists • nervous system, sympathetic • nervous system, autonomic • baroreceptors

	Introduction

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Both animal¹ and clinical studies^2–4 suggest that sympathetic overactivity is a major determinant of pathophysiological conditions, including myocardial infarction¹ and sudden cardiac death.³ ß-Adrenergic antagonists are largely used in acute myocardial infarction and appear to reduce mortality and morbidity.^2,3 However, the complexity of the influence of ß-blockade on autonomic and cardiovascular function is still largely elusive.

Spectral analysis of heart rate variability is a widely used tool to assess cardiac neural regulation. Indeed, the low-frequency (LF) (0.1 Hz) and the high-frequency (HF) (synchronous with respiratory rate) components detectable in heart rate variability provide information about the state of the cardiac sympathovagal balance.^5–7 In healthy subjects, acute administration of ß-blockers, such as atenolol, propranolol, and metoprolol, has been found to induce either no changes in spectral indices of cardiac autonomic modulation⁵ or a remarkable increase in the HF component,^8–10 a spectral component predominantly due to vagal modulation.

Conflicting results have also been reported by studies using direct recordings of postganglionic sympathetic neural discharge (muscle sympathetic nerve activity [MSNA]), which was found to be increased^11,12 or unchanged¹³ after acute ß-blockade.

Recent application of spectral techniques to the study of MSNA variability enabled the addition of important information to the quantification of sympathetic discharge. Two main oscillatory components similar to those observed in RR variability are detectable in MSNA variability. The increase of sympathetic activity, such as that induced by sodium nitroprusside administration¹⁴ or gravitational stress,¹⁵ is associated with a shift in MSNA spectral profile toward a predominant LF component. However, modifications in MSNA frequency distribution were observed even in the absence of changes of mean neural activity, such as during low-dose atropine administration.¹⁶ On the other hand, MSNA levels similar to those observed in advanced heart failure,¹⁷ obstructive sleep apnea,¹⁸ and baroreflex failure¹⁹ were attended by a markedly different distribution of spectral power. This suggests that information obtained from MSNA changes may be at least partially different from that provided by MSNA variability.

On the basis of these considerations, it is plausible to speculate that the unchanged levels of arterial pressure recently reported after ß-blockade, concomitant with increased mean values of MSNA,¹² may depend on the frequency distribution of sympathetic discharge.

In the present study, despite unaltered arterial pressure, we observed an increase in MSNA values induced by acute ß-blockade and a simultaneous partial shift of the discharge toward the HF range, suggesting, as a hypothesis, a less efficient sympathetic vasomotor modulation.

	Methods

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Experiments were conducted on 11 healthy human volunteers (9 men) aged 29±2 years. All were nonsmokers without medications.

Two intravenous lines were placed in antecubital veins for blood drawing and drug administration. We recorded ECG, plethysmographic beat-to-beat arterial pressure (Finapres), respiratory activity (by a pneumatic chest belt), and efferent sympathetic nerve activity to muscular vessels measured directly by microneurography from the right peroneal nerve, as previously described.^20,21 Briefly, multiunit recordings of postganglionic sympathetic activity were obtained by placing a tungsten electrode in a fascicle of the right peroneal nerve, posterior to the fibular head. A reference electrode was inserted subcutaneously, close to the recording needle. The neural signals were amplified, filtered, rectified, and integrated by a nerve traffic analyzer system (Bioengineering Department, University of Iowa). Integrated neural sympathetic activity, ECG, arterial blood pressure, and respiratory activity were continuously recorded on the paper of an optic chart recorder, simultaneously digitized at 300 samples per second, and stored on the hard disk of a PC.

High-performance liquid chromatography with electrochemical detection²² was used to measure plasma epinephrine and norepinephrine levels on venous blood samples.

Protocol
After instrumentation, subjects were allowed to rest for at least 30 minutes; measurements were obtained over the following 30 minutes.

Thereafter, a blood sample was withdrawn for plasma catecholamine evaluation, and baseline data acquisition was initiated while subjects were breathing spontaneously.

Atenolol was given intravenously over 10 minutes to all the subjects in the supine position. The dose of the drug (average 0.05 mg/kg) was tailored to reach a decrease in heart rate of 10% to 15% in every subject. Fifteen minutes later, a second blood sample was withdrawn for catecholamine evaluation, and recordings were performed for 30 minutes.

In a placebo-treated control group of 5 subjects, the same recording settings and duration were performed before and after an intravenous bolus of saline to exclude possible effects on MSNA of both the infusion procedure and the time.

Our institutional review board approved the study protocol. Written informed consent was provided by all subjects.

Analysis
Data were analyzed offline after analog-to-digital conversion at 300 Hz. Microneurography was considered to reflect MSNA when previously established criteria were fulfilled.²⁰ The principles of the software for automatic evaluation of data and for autoregressive spectral and cross-spectral analyses have been described elsewhere.^14,23 Briefly, a digital algorithm was used to automatically detect MSNA bursts. For each individual sympathetic burst, the computer program provided the time of occurrence and its amplitude (timexvoltage area). The neurogram was provided through integration of the continuous MSNA signal, according to the following equation

where each integral was performed over the time window between 2 consecutive diastolic values delimiting the i-th cardiac cycle of period t(i). Accordingly, this new series of variability measures of MSNA is synchronous with the other variability signals, such as tachogram and systogram on a beat-by-beat basis. Time series length used for the analysis ranged from 200 to 400 beats; the number of parameters for autoregressive modeling was between 6 and 14. The program automatically calculated the best order of the model on the basis of Akaike’s test.

The power of LF and HF components of RR, systolic arterial pressure (SAP), and MSNA variabilities were measured in absolute and normalized units; LF range was considered between 0.03 and 0.15 Hz, and the power of the HF component was calculated as the power of the oscillation coherent with respiratory spectrum¹⁴; normalization is obtained by dividing the absolute power of each component by total variance (minus the power of the very-low-frequency component) and subsequently multiplying by 100.^5,6

The peak coherence function (K²) quantified the amount of linear coupling between oscillatory components centered at the same frequency in different signal variabilities. In particular, we considered as HF component of MSNA variability only the HF oscillation coherent with respiration. Other possible HF components (noise) were not taken into account. A K² value >0.5 was considered significant.

The spectral measure of baroreflex sensitivity, -index, was calculated as the square root of the ratio between the power of LF oscillations of RR interval and SAP variability.²⁴

Statistical Analysis
Data are expressed as mean±SE. Student t test for paired observations was used to evaluate differences induced by atenolol administration. P<0.05 was considered significant.

	Results

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Figure 1 illustrates an analog recording of various signals; their average values, together with biochemical estimates, are listed in Table 1. Atenolol induced a significant increase in RR interval, as expected, with no changes in systolic and diastolic arterial pressure. MSNA increased significantly. Respiratory activity and plasma catecholamine values were unchanged.

View larger version (34K): [in this window] [in a new window]   Figure 1. Example of recorded signals in a healthy volunteer. After atenolol administration (right), bradycardia and increased MSNA are clearly detectable. BP indicates arterial blood pressure; Resp, respiration.

View this table: [in this window] [in a new window]   TABLE 1. Hemodynamic, Neurophysiological, and Neurohormonal Parameters Before and After Atenolol Administration

Spectral analysis results are reported in Table 2. MSNA variability was obtained in 10 of the 11 subjects because of the presence of artifacts in 1 recording. Atenolol administration was accompanied by a significant decrease of LF_RR normalized units and increase of HF_RR normalized units. Accordingly, LF/HF_RR decreased significantly. Parallel changes were observed for MSNA oscillations, namely, a significant decrease in LF_MSNA and an increase in HF_MSNA components in normalized units. SAP variability remained substantially unchanged (Figure 2). No differences in the center frequency of spectral components were observed after ß-blockade.

View this table: [in this window] [in a new window]   TABLE 2. Spectral Analysis of RR Interval, SAP, and MSNA Variability Before and After Atenolol Administration

View larger version (28K): [in this window] [in a new window]   Figure 2. Spectral analysis of RR interval (RR), SAP, MSNA variability, and respiration (Resp) in the same subject presented in Figure 1. Notice the reduction of LF and the increase of HF spectral components in the variability spectrum of RR and MSNA after atenolol. SAP variability remains unaffected.

View larger version (25K): [in this window] [in a new window]   Figure 3. Values of LF and HF spectral components in normalized units (nu) of RR (left) and MSNA (right) variability. For each subject, data are shown during control conditions and after atenolol administration. *P <0.05 vs control.

Figure 4 illustrates the linear relationship among the oscillatory components of RR, SAP, and MSNA variability as assessed by the coherence values (K²) in the LF and HF bands. In control conditions, K² between LF_MSNA and LF_RR and between LF_MSNA and LF_SAP was >0.5 in all subjects. K² between HF_MSNA and respiration was >0.5 in 4 subjects. After administration of atenolol, K² between LF_MSNA and LF_RR decreased significantly, whereas it markedly increased between HF_MSNA and respiration, becoming >0.5 in all subjects. Coherence between LF_MSNA and LF_SAP was unchanged.

View larger version (17K): [in this window] [in a new window]   Figure 4. Coherence values between LF components of MSNA and RR (top) and of MSNA and SAP (middle) and between HF components of MSNA and respiration (bottom) before and after atenolol administration. *P<0.05 vs control.

The spectral -index of baroreflex sensitivity was unaffected by atenolol administration (20.8±4 from 18.8±3 ms/mm Hg).

Results of the placebo-treated group are reported in Table 3; intravenous injection of saline did not determine any modification in the considered variables, nor was a time effect of the procedure on neural sympathetic discharge observed.

View this table: [in this window] [in a new window]   TABLE 3. Spectral Analysis of RR Interval, SAP, and MSNA Variability in 5 Control Subjects Before and After Placebo Administration

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
We found that in healthy humans, (1) intravenous administration of atenolol was followed by an increase in MSNA occurring in the absence of changes in blood pressure and in the -index of baroreflex control of heart rate; (2) the enhancement of postganglionic neural sympathetic firing was associated with a remarkable modification in the pattern of its frequency distribution, consisting of reduced LF_MSNA and increased HF_MSNA spontaneous fluctuations; (3) an increase in the coherence function between HF_MSNA and respiration was present after ß-blockade, suggesting an augmented coupling between respiratory activity and MSNA; and (4) atenolol induced a marked bradycardia and a shift in sympathovagal balance toward a vagal predominance, as indicated by a reduced LF_RR and an increased HF_RR normalized power.

Previous studies in humans have reported an increased MSNA after acute metoprolol¹¹ or propranolol¹² administration, in keeping with our findings. In regard to the mechanism that may account for the remarkable increase of MSNA observed in the present study after atenolol administration, the lack of changes in both arterial pressure values and in the -index of cardiac baroreflex control seems to reasonably exclude a role played by arterial baroreceptor unloading. As an alternative mechanism, a direct effect of the drug at the central nervous system level must be considered. Although only low concentrations of atenolol are likely to be achieved in the brain because of its hydrophilicity, the presence, in treated patients, of central nervous system side effects suggests a possible concomitant action of the drug at this level as well.²⁵ However, because ß-blockers have been shown to act on different areas within the central nervous system, the stimulation of which may result in either a reduction²⁶ or an increase²⁷ in sympathetic activity, such a central action is still largely undetermined. Moreover, we cannot rule out a possible action of the drug at the ganglionic level and at the prejunctional ß₂-adrenergic receptors,²⁸ although the ß₁ selectivity of atenolol should limit this effect.

In healthy subjects, increased sympathetic activity, induced by a vasodilating drug¹⁴ or by orthostatic position,¹⁵ is associated with enhanced MSNA values and a LF predominance in the spectral profile of MSNA. In contrast, in the present study, after administration of atenolol an increase in MSNA was associated with enhanced HF and reduced LF components of MSNA variability, reflecting a burst distribution predominantly clustered around the respiratory frequency. Similar behavior has been observed previously in healthy humans during hyperventilation,²⁹ indicating that respiration may affect the oscillatory pattern of MSNA independently of its average level. Evidence from animal experiments has suggested the concept of a common pool of "cardiorespiratory interneurons" within the medulla impinging on peripheral sympathetic nerve discharge through rostral ventrolateral medulla presympathetic neurons.³⁰ In healthy humans, a clear respiratory modulation of MSNA has been observed.³¹ This modulation increases (1) with increasing tidal volume, (2) when a chemoreceptor stimulus is used to drive ventilation, and (3) during activation of respiratory muscle metaboreflexes, although it remains unclear whether in humans central respiratory motor output affects sympathetic nerve discharge significantly.³² Even though we did not detect significant changes in respiratory frequency after administration of atenolol, coherence analysis indicated an augmented coupling between MSNA and respiration. We hypothesize that the increased coupling between respiration and sympathetic activity at the central level, by inducing a prevailing HF_MSNA oscillatory pattern, might overwhelm the expected increase in LF_MSNA oscillation usually associated with sympathetic excitation.^14,15

Interestingly, despite the marked increase in MSNA, no significant changes in systemic arterial pressure were detected in the present study, as described by Tank et al.¹² A plausible explanation of this finding may be provided by the peculiar frequency distribution of the neural sympathetic discharge activity, characterized in our study by reduced LF_MSNA and prevailing HF_MSNA component. A similar sympathetic spectral pattern has been observed during hyperventilation,²⁹ when increased sympathetic activity is associated with unchanged blood pressure values. Such a pattern of neural discharge activity does not correspond with the optimal frequency characteristics of sympathetic neural transmission to the vasculature. Indeed, it has been reported recently in humans that the gain of the transfer function between sympathetic activity and skin arterial blood vessels reaches its maximum at 0.1 Hz, ie, in the LF range, with progressive decay.^33,34 Thus, a relative shift of spectral power toward a HF predominance might imply reduced effectiveness of neural vasoconstrictor activity. Of course, we cannot rule out that other peripheral or central mechanisms may be responsible for these findings. In addition, our data were obtained from integrated microneurography signals, which might underestimate the information provided by single-unit discharge.

An ancillary observation of the present investigation deals with the changes in heart rate variability after atenolol, which, to some extent, were expected. Previous studies have shown an increase in the HF power of RR variability after chronic^5,35–38 or acute^8–10 ß-blockade in healthy subjects, although not consistently.¹² In the present study, we report a shift of cardiac sympathovagal balance toward a parasympathetic predominance, as indicated by increased HF_RR and decreased LF_RR spectral components, expressed in normalized units. Different mechanisms may underlie and possibly coexist in determining such a modification in neural regulation of heart rate after ß-blockade. Among these, we consider the following possibilities: a peripheral action of the drug at the sinus node level determining a reduced sympathetic modulation; an inhibitory effect of atenolol on presynaptic sympathetically mediated vagal inhibition; and a central effect on vagal outflow.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
The present study provides evidence that the information content of frequency domain and time domain approaches is complementary³⁹ to address the complexity of cardiovascular neural regulation. We can hypothesize that despite an increased sympathetic discharge that follows atenolol administration, changes in the frequency distribution of MSNA, reflecting a stronger respiratory coupling, may lead to less efficient sympathetic vasoconstriction. This mechanism might be "beneficial" in conditions characterized by sympathetic overactivity, such as the acute phase of myocardial infarction.

	Acknowledgments

 
This work was supported in part by Italian Space Agency grant 336/2000 to Dr Malliani and by University of Milan FIRST grant 2002 to Drs Malliani and Montano.

	References

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