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1 Sections of Cardiology and
2 Pulmonary, We examined muscle sympathetic nerve activity (MSNA) in the
nonexercising lower limb during repetitive static quadriceps
contraction paradigm at 25% maximal voluntary contraction in eight
men. Subjects performed 20-s contractions with 5-s rest periods for up
to 12 contractions. Although the workload was constant, we found that MSNA amplitude rose as a function of contraction number [0.6 ln (amplitude/min)/contraction]; this suggests chemical
sensitization of the muscle reflex response. We employed
signal-averaging techniques and then integrated the data to examine the
onset latency of the MSNA response as a function of the 25-s
contraction-rest period. We observed an onset latency of ~4-6 s.
Moreover, although the onset latency did not appear to vary as a
function of contraction number, the rate of MSNA increase took
approximately four contractions to reach a steady-state rate of rise;
this suggests contraction-induced sensitization. The onset latency
reported here is similar to findings in recent animal studies, but it
is at odds with latencies determined in prior human handgrip
contraction studies. We believe our data suggest that
1) mechanically sensitive afferents
contribute importantly to the MSNA response to the paradigm employed
and 2) these afferents may be
sensitized by the chemical products of muscle contraction.
sympathetic nerve activity; autonomic reflexes; exercise; muscle
reflexes
DURING EXERCISE the sympathetic nervous system is
activated. Two systems have been suggested to contribute to this
response. The first, central command, is a feed-forward central neural
system thought to play an important role in the regulation of heart
rate (HR) (31), skin sympathetic activity (33), and muscle sympathetic nerve activity (MSNA) during high levels of work (32). The second system, termed the exercise pressor reflex, is thought to be engaged during bouts of muscle contraction (3, 11, 15, 17). This system
potently increases MSNA in human subjects, and, in the process, blood
pressure increases during contraction (14, 26, 30). A large body of
work in both animal and human models suggests that this reflex is
activated by both mechanical deformation of the afferents' receptive
field as well as by the chemical stimulation of group III and IV
afferents, the free nerve endings of which reside within the
interstitium of the exercising muscle (4, 12, 13, 16, 25).
A problem in interpreting physiological data from humans and animals is
that the results obtained from these different models often yield
surprisingly different conclusions. For example, recent animal work suggests that contraction-sensitive group III and IV muscle
afferents increase their discharge within 2 s of the onset of
locomotion (1, 2). This onset latency is consistent with other work in
a cat model (10), which demonstrated that single-fiber skeletal muscle
sympathetic efferent discharge increases with an onset latency of
7 ± 2 s (range, 2-20 s). These data suggest that the
mechanically sensitive muscle afferents play an important role in
mediating the exercise pressor reflex.
Human experiments, on the other hand, suggest that, from the onset of
static contraction to the increase in MSNA, there is an onset latency
in the range of 60 s (6, 8, 14, 20, 26, 30). These data suggest that
the afferents that evoke the exercise pressor reflex are not
particularly mechanically sensitive.
In this report, our goal was to employ signal-averaging techniques
during a repetitive static-contraction paradigm to gain further insight
into the timing characteristics of sympathetic outflow in human
subjects. The results of our report demonstrate that static quadriceps
contractions (QC) at 25% maximal voluntary contraction (MVC) evoked
a MSNA response with an onset latency of between 4 and 6 s.
Subjects.
Eight healthy men (mean age, 28 ± 2 yr) participated in the study.
The subjects were normotensive and were not taking any medications.
Each subject gave written informed consent, and the procedures used in
the study were approved by the Institutional Review Board of The Milton
S. Hershey Medical Center.
HR and blood pressure.
HR was monitored by standard electrocardiogram methods, and systemic
blood pressure was measured continuously by using the volume-clamp
method (Finapres; Ohmeda, Madison, WI). Resting blood pressure was
determined by using an automated sphygmomanometer (Dinamap; Critikon,
Tampa, FL).
Microneurography.
The microneurographic technique provides direct recordings of
sympathetic nerve traffic directed to blood vessels in skeletal muscle
by causing an increase in vascular smooth muscle tone and vasoconstriction (9, 19, 24, 30). The method, as used in our
laboratory, has been described previously (5, 22, 27).
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
The static QC paradigm. A custom-made device for quadriceps exercise was utilized for this paradigm. Subjects were placed in a supine position. The thigh was supported at an angle of 45° by an adjustable, padded, triangular wooden support. A precalibrated, universal, flat, load cell (Strainsert, West Conshohocken, PA) was mounted directly beneath and attached to the left ankle with nylon strapping. The device was calibrated before each study by using 22.7- and 45.5-kg weights. Three MVCs were performed, and the largest value was used to determine the 25% MVC value. The subjects received visual feedback, via an analog meter, of the amount of tension generated.
Baseline data were collected for 5 min, and the volunteers performed static QC (left leg). Each contraction lasted 20 s and was followed by 5 s of rest. This paradigm was continued for a total of 12 contractions. Measurements of blood pressure, HR, and MSNA were made continuously throughout the protocol. MSNA was expressed in bursts per minute, and amplitude was expressed in arbitrary units (AU) per minute.General signal averaging of MSNA. Traditional methods for visually identifying and quantifying MSNA could have been used to determine the time course of MSNA changes and the onset latency for MSNA responses during a given contraction. However, signal averaging of the MSNA data affords several distinct advantages over the traditional methods. In a paradigm in which a repetitive stimulus (i.e., QC) evokes a response (i.e., MSNA), the signal-averaging process uses signal summation to progressively increase signal events correlated with the stimulus while decreasing the amplitude of random background noise and uncorrelated "stray" events. The improved signal-to-noise ratio offered by signal averaging permits the detection of small, correlated MSNA bursts that would be overlooked by traditional visual analysis. Signal averaging also eliminates the subjectivity involved in deciding what is and is not an MSNA burst, a decision potentially having an impact on both MSNA quantification and the determination of latency times.
Initially, two segments of MSNA and isometric exerciser load cell data were selected from each subject for analysis. One segment contained data from the preexercise baseline and the other from the 12 cycles of QC. These data were processed into an averaged MSNA cycle for the contraction data or an equivalent 25-s period of averaged baseline data (7, 18, 23).Signal averaging by subject. In seven subjects, data were digitally recorded with a MacLab data-acquisition system (ADInstruments, Castle Hill, NSW, Australia). From each subject's raw data, selected segments of MSNA and load cell data were smoothed, decimated, and saved with time-base data in text format. These text files were brought into a Microsoft Excel processing template developed for signal averaging. Two 200-sample data-averaging buffers were initialized, one for MSNA data and one for load cell data. Each buffer held a 25-s sequence of data, the nominal duration of the contraction period. Initially, the load cell data were quantized so that, for each portion of the paradigm, the 20-s QC and 5-s relaxation signals were represented by sequences of 1 and 0 s, respectively. This provided easy identification of the initial time point of each QC cycle and its corresponding initial MSNA data point. These initial MSNA data points, typically 12, were averaged and saved in the MSNA-averaging buffer. Similarly, MSNA data points were averaged and saved for each of the remaining time points in the QC cycle. The identical process was used to produce an averaged load cell signal. To produce an averaged baseline MSNA signal, a sequence of 25-s MSNA data segments were identified, then averaged, and saved in a similar 200-point buffer.
For the remaining subject, from whom data were recorded only on paper, 12 QC cycles of MSNA and corresponding load cell data were identified and marked by hand to indicate time end points and signal-amplitude limits. Equivalent 25-s segments of baseline MSNA data were then identified and marked. Digital images of each QC cycle or baseline segment were obtained from the paper recordings via optical scanning. Numerical values for MSNA, load cell signals, and the corresponding time base were obtained from these digital images and were stored by using Un-Scan-It (Silk Scientific, Orem, UT), a waveform tracing and digitizing program. The load cell data were quantized into sequences of 1 s and 0 s, which, in turn, were used to locate the starting point of each QC cycle. Because the scanning process, in effect, sampled the signals at a much higher rate than those sampled by MacLab, these scanned signals were digitally resampled to match the MacLab sampling rate. This resampling process employed digital smoothing, followed by interpolation between samples, and produced 12 QC cycles each of MSNA and load cell signals, which were averaged (as described above). Similarly, the scanned MSNA baseline data segments were also resampled and averaged.Signal averaging by cycle. An alternative method of processing the data was to compute a group average MSNA signal for each of the 12 QC cycles to investigate whether MSNA during QC changes as a function of exercise duration. Using the database described above, we extracted baseline and exercise values for MSNA and load cell data for all subjects and computed averaged waveforms for each cycle. The averaged cycle data were inserted into a new spreadsheet in which the cycle averages were combined. In one analysis, the temporal progression of MSNA was examined by generating four time points during the exercise sequence, comprising data from cycles 1-3, 4-6, 7-9, and 10-12. In a second analysis, averaged data from all 12 QC cycles were combined to produce overall averaged baseline and exercise values for MSNA signals and load cell signals. The arbitrary minimum background level of each composite MSNA waveform was adjusted to zero to simplify the subsequent computation and interpretation of numerical integrals.
MSNA signal integration.
Numerical integration of the averaged and background-adjusted MSNA
signals was used to examine the synchronization characteristics of the
MSNA signal. A simple trapezoidal integration algorithm was employed.
This algorithm was programmed into Excel to compute a MSNA integral
over the 25 s of the contraction-rest cycles for any individual or
composite MSNA waveform (29). Figure
1 summarizes the analytic approach used in
this report.
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Statistical analysis. To determine whether MSNA, HR, or mean arterial blood pressure (MAP) rose as the number of contractions increased, mixed-effects, linear-regression models were employed to determine whether the slope from each model was significantly different from zero. To meet modeling assumptions, such as normality and homogeneous variance from assessment of residual diagnostics, the natural logarithm (ln) of the response (amplitude/minute) was taken. It was not necessary to transform the MAP or HR responses. All analyses were performed by using the SAS statistical package (SAS Institute, Cary, NC). A P value of <0.05 was considered statistically significant.
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RESULTS |
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Abstract
Introduction
Methods
Results
Discussion
References
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MAP, HR, and MSNA (Fig. 2).
We were able to obtain adequate MSNA recordings for at least 8 contractions in all subjects, 9 contractions in seven subjects, 11 contractions in five subjects, and 12 contractions in four subjects.
Baseline HR and MAP were 64 ± 3 beats/min and 92 ± 2 mmHg,
respectively. There was a statistically significant increase in MAP as
a function of contraction number [slope = 1.79 mmHg/contraction; 95% confidence interval (CI), 1.08 to 2.50;
P < 0.001]. Thus the MAP
increased ~1.8 mmHg per contraction. In addition, there was a
statistically significant increase in HR (slope = 1.2 beats · min
1 · contraction1;
95% CI, 1.1-1.3; P < 0.001).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The purpose of this study was to characterize the sympathetic nerve response to intermittent QC in humans. Our study demonstrates that the intermittent static paradigm employed did evoke an increase in sympathetic discharge and that the response was quite variable from subject to subject (Fig. 2). We also employed signal averaging, followed by integration of the MSNA signal across the repetitive 25-s contraction-rest paradigm, to determine whether the integrated signal-averaged nerve tracing had distinctive inflection points. We speculated that, if a distinctive inflection point(s) was present, we would gain insight into the potential reflex systems responsible for the increase in sympathetic discharge.
Prior work in humans has suggested that the latency from the onset of voluntary static contraction to the increase in MSNA is in the range of ~60 s (8, 14, 20, 26, 30). However, recent work from Hill et al. (10), in a cat model, suggests that the latency from the onset of muscle contraction to the increase in firing of single-unit muscle sympathetic efferents (in the tibial nerve) was on the order of 7 s (range, 2-20 s). This discrepancy in onset latencies between the human studies and recent animal studies is of more than passing curiosity, because the prior human experiments described above have been cited as providing important evidence in favor of the concept that mechanically insensitive and/or metabolically sensitive muscle afferents are the primary mediators of the exercise pressor reflex (14, 24, 30). On the other hand, the recent work by Hill et al. (10), demonstrating an onset latency of ~7 s in the walking cat model, suggests that the discharges of mechanically sensitive group III and IV afferents are the primary mediators of the exercise pressor reflex. The recent work of Adreani and Kaufman (2) also is important because it suggests that the mechanically sensitive group III afferent discharge can be augmented by arterial occlusion, a stimulus likely to increase the interstitial concentration of a number of metabolites. Thus the present report would suggest that the afferents mediating the exercise pressor reflex are mechanically sensitive and that these afferents can be chemically sensitized. Accordingly, these reports challenge our basic understanding of the muscle reflex (28).
The data presented in Fig. 4 demonstrate that the inflection point for the increase in MSNA was between 4 and 6 s and, therefore, similar to the recent animal work. Moreover, the onset latency for contractions 1-3 is approximately the same as for later contractions, but a steady-state slope for the increase in MSNA during a contraction was not achieved until contractions 4-6 (Fig. 5). We interpret these results as suggesting that the specific mechanism for sympathoexcitation was the same for early and late contractions but that afferent responsiveness became enhanced as the repetitive-contraction paradigm continued. Specifically, we would speculate that mechanically sensitive muscle afferents were responsible for the observed responses and, furthermore, that they were chemically sensitized, leading to enhanced sympathoexcitation directed to skeletal muscle. We believe that the data shown in Fig. 3 support this hypothesis as well.
We doubt that the sympathetic responses we observed in the present study were due to central command, although we can not exclude this possibility. However, recent animal and human work suggests that central sympathoexcitatory stimuli generally engage the autonomic nervous system with a shorter onset latency than reported in the present study or in the prior animal studies mentioned above (10, 21, 32). Additionally, central command is thought to be engaged at relatively high levels of work (i.e., 75% MVC), and it is unlikely that repetitive QC at 25% MVC would be a sufficient stimulus (32). One potential approach to evaluate central command would have been to electrically stimulate the quadriceps muscle as we measured MSNA and examined onset latencies. Unfortunately, involuntary QCs of this magnitude of MVC are painful; additionally, it would be exceedingly difficult to generate muscle tension in a sufficiently rapid fashion that we could make meaningful statements regarding the onset latency of the responses.
In summary, we believe this report provides data that challenge the commonly held view that the sympathetic response to exercise in human subjects is always associated with a long onset latency. The short onset latency described in this report is consistent with recent animal studies and with the hypothesis that mechanically sensitive afferents engaged during quadriceps work are an important determinant of the MSNA response to leg exercise in humans. Our report is also consistent with the hypothesis that these afferents become sensitized by one or more of the by-products of muscle contraction.
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ACKNOWLEDGEMENTS |
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The nursing care supplied by the staff of the Pennsylvania State General Clinical Research Center at The Milton S. Hershey Medical Center is appreciated. We also thank Kristen Gray for technical support and Jennie Stoner for expert typing.
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FOOTNOTES |
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This work was supported by National Institute on Aging Grant R01-AG-12227 (to L. I. Sinoway) and by Division of Research Resources General Clinical Research Center Grant M01-RR-0732.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: L. I. Sinoway, Sect. of Cardiology, MC H047, Pennsylvania State Univ. College of Medicine, The Milton S. Hershey Medical Center, PO Box 850, Hershey, PA 17033 (E-mail: lsinoway{at}med.hmc.psghs.edu).
Received 18 August 1998; accepted in final form 11 November 1998.
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J. P. Fisher, M. Sander, I. MacDonald, and M. J. White Decreased muscle sympathetic nerve activity does not explain increased vascular conductance during contralateral isometric exercise in humans Exp Physiol, May 1, 2005; 90(3): 377 - 382. [Abstract] [Full Text] [PDF]
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A. Momen, D. Bower, J. Boehmer, A. R. Kunselman, U. A. Leuenberger, and L. I. Sinoway Renal blood flow in heart failure patients during exercise Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2834 - H2839. [Abstract] [Full Text] [PDF]
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K. Tokizawa, M. Mizuno, Y. Nakamura, and I. Muraoka Passive triceps surae stretch inhibits vasoconstriction in the nonexercised limb during posthandgrip muscle ischemia J Appl Physiol, November 1, 2004; 97(5): 1681 - 1685. [Abstract] [Full Text] [PDF]
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H. R. Middlekauff, J. Chiu, M. A. Hamilton, G. C. Fonarow, W. R. MacLellan, A. Hage, J. Moriguchi, and J. Patel Muscle mechanoreceptor sensitivity in heart failure Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1937 - H1943. [Abstract] [Full Text] [PDF]
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H. R. Middlekauff and J. Chiu Cyclooxygenase products sensitize muscle mechanoreceptors in healthy humans Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1944 - H1949. [Abstract] [Full Text] [PDF]
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A. Momen, U. A. Leuenberger, B. Handly, and L. I. Sinoway Effect of aging on renal blood flow velocity during static exercise Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H735 - H740. [Abstract] [Full Text] [PDF]
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 U. A. Leuenberger, S. Mostoufi-Moab, M. Herr, K. Gray, A. Kunselman, and L. I. Sinoway Control of Skin Sympathetic Nerve Activity During Intermittent Static Handgrip Exercise Circulation, November 11, 2003; 108(19): 2329 - 2335. [Abstract] [Full Text] [PDF]
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A. Momen, U. A. Leuenberger, C. A. Ray, S. Cha, B. Handly, and L. I. Sinoway Renal vascular responses to static handgrip: role of muscle mechanoreflex Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1247 - H1253. [Abstract] [Full Text] [PDF]
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T. A. Markel, J. C. Daley III, C. S. Hogeman, M. D. Herr, M. H. Khan, K. S. Gray, A. R. Kunselman, and L. I. Sinoway Aging and the Exercise Pressor Reflex in Humans Circulation, February 11, 2003; 107(5): 675 - 678. [Abstract] [Full Text] [PDF]
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J. C. Daley III, C. S. Hogeman, and L. I. Sinoway Venous plasma potassium is not associated with maintenance of the exercise pressor reflex in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1608 - R1612. [Abstract] [Full Text] [PDF]
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Q. Fu, S. Iwase, Y. Niimi, A. Kamiya, J. Kawanokuchi, J. Cui, T. Mano, and A. Suzumura Effects of lower body positive pressure on muscle sympathetic nerve activity response to head-up tilt Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R778 - R785. [Abstract] [Full Text] [PDF]
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H. R. Middlekauff, E. U. Nitzsche, C. K. Hoh, M. A. Hamilton, G. C. Fonarow, A. Hage, and J. D. Moriguchi Exaggerated muscle mechanoreflex control of reflex renal vasoconstriction in heart failure J Appl Physiol, May 1, 2001; 90(5): 1714 - 1719. [Abstract] [Full Text] [PDF]
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K. J. Doerzbacher and C. A. Ray Muscle sympathetic nerve responses to physiological changes in prostaglandin production in humans J Appl Physiol, February 1, 2001; 90(2): 624 - 629. [Abstract] [Full Text] [PDF]
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J. A. Cornett, M. D. Herr, K. S. Gray, M. B. Smith, Q. X. Yang, and L. I. Sinoway Ischemic exercise and the muscle metaboreflex J Appl Physiol, October 1, 2000; 89(4): 1432 - 1436. [Abstract] [Full Text] [PDF]
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J. K. Shoemaker, M. D. Herr, and L. I. Sinoway Dissociation of muscle sympathetic nerve activity and leg vascular resistance in humans Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1215 - H1219. [Abstract] [Full Text] [PDF]
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S. Mostoufi-Moab, M. D. Herr, D. H. Silber, K. S. Gray, U. A. Leuenberger, and L. I. Sinoway Limb congestion enhances the synchronization of sympathetic outflow with muscle contraction Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R478 - R483. [Abstract] [Full Text] [PDF]
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D. A. MacLean, V. A. Imadojemu, a |
