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1 Division of Cardiology, ABSTRACT Shoemaker, J. Kevin, Prasant Pandey, Michael D. Herr, David
H. Silber, Qing X. Yang, Michael B. Smith, Kristen Gray, and Lawrence
I. Sinoway. Augmented sympathetic tone alters muscle metabolism
with exercise: lack of evidence for functional sympatholysis. J. Appl. Physiol. 82(6):
1932-1938, 1997.
sympathetic nervous system; handgrip exercise; phosphocreatine; phosporous-31-nuclear magnetic spectroscopy; pH; Doppler ultrasound
INTRODUCTION BLOOD FLOW to resting skeletal muscle is constrained by
a high level of sympathetic tone (17). With contractions, vasodilation occurs within the active muscle to augment flow and oxygen transport. This vasodilation is caused, in part, by metabolites released from
muscle after contraction (1, 18). Additionally, several mechanisms are
activated during exercise that initiate a sympathetic vasoconstrictor
response during ischemic or heavy work (8). A number of investigators
have suggested that this heightened vasoconstrictor response actively
opposes local vasodilatory stimuli, resulting in a reduction in muscle
perfusion (10, 23).
In contrast, other studies suggest that the accumulation of metabolites
from active skeletal muscle during heavy work inhibits adrenergic
effects on vascular smooth muscle (18) and opposes the vasoconstrictor
influences of the elevated sympathetic tone (5, 9, 15, 21). For
example, Kjellmer (9) and Remensnyder et al. (15) concluded that even
maximal sympathetic nerve activation, which resulted in small
reductions in blood flow, cannot oppose the vasodilatory stimuli caused
by local metabolic changes in active skeletal muscle. These results
have prompted investigators to hypothesize that such a functional
sympatholysis develops so that muscle perfusion is matched to the
metabolic demand (5, 9, 21).
If flow to the working skeletal muscle is preserved by local
vasodilatory metabolites, even during heavy exercise, then muscle glycolytic metabolism should be altered minimally in the face of an
elevated sympathetic tone. Indeed, Strandell and Shepherd (21) have
argued, on the basis of measured forearm blood flow (FBF) and deep
venous hemoglobin (Hb) saturation levels during and after exercise,
that the reduced oxygen transport with elevated sympathetic tone had
minimal metabolic consequences. It was argued that the augmented oxygen
extraction compensated for any reductions in flow so that tissue
metabolism was unchanged. However, important experiments examining
canine limb blood flow have demonstrated that sympathetic activation
reduced oxygen uptake in the contracting muscle (23). These findings
strongly suggest that heightened sympathetic tone reduces nutritive
flow and increases cellular reliance on anaerobic glycolysis.
To date, the effects of elevated sympathetic tone on tissue metabolism
during rhythmic exercise have not been assessed. Therefore, the purpose
of the present study was to examine the effects of an elevated level of
sympathetic tone, evoked by METHODS Subjects
Experimental Design
It is unclear whether sympathetic tone opposes
dilator influences in exercising skeletal muscle. We examined high
levels of sympathetic tone, evoked by lower body negative pressure
(LBNP, 
60 mmHg) on intramuscular pH and phosphocreatine (PCr)
levels (31P-nuclear magnetic resonance spectroscopy) during
graded rhythmic handgrip (30 contractions/min; ~17, 34, 52 and 69%
maximal voluntary contraction). Exercise was performed
with LBNP and without LBNP (Control). At the end of exercise, LBNP
caused lower levels of muscle pH (6.59 ± 0.09) compared
with Control (6.78 ± 0.05; P < 0.05). PCr recovery, an index of mitochondrial respiration, was less
during the recovery phase of the LBNP trial. Exercise mean arterial
pressure was not altered by LBNP. The protocols were repeated with
measurements of forearm blood flow velocity and deep venous samples
(active forearm) of hemoglobin (Hb) saturation, pH, and lactate. With
LBNP, mean blood velocity was reduced at rest, during exercise, and
during recovery compared with Control (P < 0.05). Also, venous Hb
saturation and pH levels during exercise and recovery were lower with
LBNP and lactate was higher compared with Control
(P < 0.05). We conclude
that LBNP enhanced sympathetic tone and reduced oxygen transport. At
high workloads, there was a greater reliance on nonoxidative
metabolism. In other words, sympatholysis did not occur.
60 mmHg lower body negative pressure
(LBNP), on the metabolic responses of active skeletal muscle during
rhythmic handgrip exercise. We hypothesized that the reductions in
muscle blood flow accompanying the elevated sympathetic tone would
result in a greater reliance on nonoxidative fuel sources and more
cellular acidosis. Accordingly, we measured intracellular pH, and
phosphocreatine (PCr) with 31P-nuclear magnetic resonance
(NMR) spectroscopy during exercise under conditions of normal and
elevated sympathetic tone (LBNP). The results indicated that, although
resting muscle metabolism was not affected by the heightened
sympathetic tone, intracellular pH during both exercise and recovery
was lower with LBNP, an effect that was associated with reductions in
FBF and mitochondrial respiration.
60 mmHg).
For investigation of the role of an elevated level of sympathetic tone on the metabolic responses to rhythmic handgrip contractions, the exercise was performed without (Control) and with LBNP to
60
mmHg. LBNP was chosen for the present studies because it elevates the
level of sympathetic nervous system (SNS) outflow (5)
without altering mean arterial pressure (MAP) (21). This was important because a change in arterial pressure could alter limb blood flow in a
manner independent of changes in vascular resistance. The effect of the
progressive exercise paradigm was then superimposed on the elevated SNS
tone during LBNP. The order of the Control and LBNP trials was varied
among subjects. At least 20 min of rest occurred between each trial.
LBNP was begun during baseline and continued for 2 min before the
handgrip exercise was initiated.
With this design, our goal was to alter muscular metabolism in a graded
fashion and thereby grade the amount of metabolite-induced vasodilation. In this manner, we could determine whether heightened sympathetic activation had a greater effect on metabolism at low or
high workloads.
Data collection and analysis.
The metabolic profile of the contracting forearm skeletal muscle was
assessed by using 31P-NMR
spectroscopy for analysis of muscle PCr and pH. Measures of the
high-energy phosphate content of the exercising flexor digitorum
superficialis were obtained with a 1.9-T 26-cm-bore superconducting
magnet (Oxford Instruments, Abbington, UK) interfaced with a
radio-frequency transmitter/receiver (Nicolet Instrument, Madison, WI).
A coil 2.5 cm in diameter was placed over the flexor digitorum
superficialis muscle. The obtained spectra were collected at 32.5 MHz
and represented the Fourier transformation of 32 transients averaged
over 60 s at rest, at each exercise workload, and for each
minute of recovery. The relative concentrations of PCr were calculated
from the area under the resonance curve and are expressed in arbitrary
units. Intracellular pH was calculated from the shift of the
Pi resonance relative to PCr. The NMR technique has been described previously (3).
Intravenous studies and FBF.
To further investigate the possibility that oxygen transport was
limited with LBNP, thereby providing a mechanism for the altered tissue
metabolism, we carried out additional experiments in four of the
original and four additional subjects.
In these experiments, the subjects performed the same exercise protocol
as shown in Fig. 1, and deep venous blood samples were withdrawn to
assess venous blood gases, Hb saturation, pH (model 510 radiometer;
ABL, Copenhagen, Denmark), and lactate (model 23L lactate analyzer;
Yellow Springs Instruments, Yellow Springs, OH) levels. Hb saturation
was calculated and corrected to 37°C. If FBF was reduced with LBNP
due to vasoconstriction, then a reduction in Hb saturation and pH,
together with increases in venous lactate, should have been apparent
during exercise.
A 20-gauge Teflon catheter was inserted in a retrograde fashion into a
deep vein in the antecubital fossa that drains the exercising muscle of
the forearm. Blood samples were withdrawn at rest, at the end of each
minute of exercise, and at the end of minutes
1, 3, and
5 of recovery. In the LBNP trial,
blood samples at rest were obtained before the application of LBNP.
Blood was collected into heparinized syringes and stored in an ice
bath. No more than 45 min passed before these samples were analyzed.
In a subset of subjects, brachial artery diameter
(n = 4) and mean blood velocity (MBV;
n = 6) data were collected to directly assess the effect of an elevated sympathetic tone on FBF at rest, at
each level of exercise, and at each minute of recovery. Brachial artery
diameters were measured by using an echo Doppler ultrasound-imaging system (Philips SD-800) and a handheld 7.5-MHz linear probe. Measures were obtained during the last 10 s of each measurement period. MBV was
collected by using a 5-MHz continuous-wave Doppler probe (Hokanson
CW-1A) that was fixed to the skin over the brachial artery just
proximal to the medial epicondyle, where the artery runs parallel to
the skin. The continuous MBV data during the last 10 s of each
measurement period were averaged to reduce variability associated with
muscular contractions and relaxation (16, 20).
Statistics
The effects of LBNP on the metabolic and hemodynamic variables over the course of the exercise trials were assessed by using a repeated-measures two-way analysis of variance. The differences were considered statistically significant if P < 0.05. When a significant interaction was observed, point-wise comparisons were assessed by using the Student-Newman-Keuls post hoc test. All values are presented as means ± SE.RESULTS
Intramuscular Metabolism
Significant statistical interactions occurred for both intramuscular PCr and pH across the exercise workload and recovery time points. Intramuscular PCr levels, as a percentage of baseline, were reduced during the exercise (P < 0.05; Fig. 2). In addition, post hoc analysis showed that at the second and third workloads, as well as at all recovery time points, PCr levels were lower with LBNP compared with Control (P < 0.05; Fig. 2). Post hoc analysis of cellular pH showed that, compared with the Control trials, exercise with LBNP caused a greater acidosis in the working muscle during the fourth exercise load and throughout the first 4 min of recovery (P < 0.05; Fig. 2).
) and without LBNP
(Control; 
). LBNP resulted in greater reductions in both PCr and pH,
compared with Control. * Significant difference between groups,
P < 0.05.
Deep Venous Blood Sample Measurements
In the Control trial, Hb saturation was reduced from a rest level of 82.9 ± 3.6 to 52.1 ± 2.6% in the first exercise load (P < 0.05) and was maintained at this lower level until the end of exercise (Fig. 3). With LBNP, the exercise Hb-saturation levels were significantly reduced from Control at all workloads (P < 0.05). During recovery, Control Hb saturation returned quickly to rest levels. With LBNP, Hb saturation was not different from Control during the first minute after the cessation of exercise. However, LBNP resulted in a reduction in recovery Hb saturation by 5 min after exercise (P < 0.05).
);
control (); n = 8 subjects.
* Significant difference between groups,
P < 0.05.
In both the Control and LBNP trials, venous pH was reduced from 7.38 ± 0.01 at rest to ~7.33 at the end of the second work period (P < 0.05 compared with rest). With LBNP, the venous pH was lower than Control at the end of the fourth workload (P < 0.05). With LBNP, venous pH remained below Control levels for the duration of recovery (P < 0.05; Fig. 3).
In conjunction with the venous pH response, blood lactate levels were increased over rest, beginning with the second workload and continuing for the duration of recovery (P < 0.05; Table 1). LBNP produced an additional increase in blood lactate levels, which were greater than Control for the final exercise workload and for the duration of recovery (P < 0.05). Blood-gas analysis showed reductions in venous oxygen pressure (PvO2) with exercise which were greater during LBNP for the first exercise workload as well as for minutes 3 and 5 of recovery (P < 0.05; Table 1). Otherwise, PvO2 was similar between Control and LBNP. PvCO2 levels were increased during exercise, relative to rest and recovery (P < 0.05), but were unchanged by LBNP (Table 1).
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Hemodynamic Responses
The HR and MAP responses, obtained during the venous blood sampling and Doppler studies, were qualitatively and statistically similar to the tests conducted during the NMR experiments. By the first measured time point, after 2 min of LBNP, baseline MAP (92.8 ± 3.2) was unchanged from Control (91.7 ± 3.8). Also, the increase in MAP with exercise was not altered by LBNP (Table 2). The hypotensive effect of60 mmHg lower body suction was partially offset by heart rate, which increased from 62 ± 3 beats/min before LBNP to 80 ± 4 beats/min after 2 min of lower body suction
(P < 0.001; Table 2). The increase
in heart rate with LBNP was maintained for the duration of the test.
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In the Control trial, brachial artery diameter increased from 3.8 ± 0.1 mm at rest to 4.3 ± 0.2 mm at the end of exercise (P < 0.05; Table 2). During LBNP, diameters were 3.6 ± 0.3 and 4.0 ± 0.2 mm at rest and end exercise, respectively, but these were not significantly different from Control (P = 0.07). Compared with Control, MBV was reduced during the LBNP portion of the test (P < 0.001; see Main Effect, Table 2).
DISCUSSION
We have shown that, for the conditions studied, an increase in sympathetic tone was associated with alterations in muscle metabolism during moderate and heavy exercise intensities and during recovery from the exercise. Specifically, intramuscular levels of PCr and pH were reduced, and venous lactate concentrations were increased with exercise during LBNP compared with Control. These data indicate a greater reliance on nonoxidative metabolism during exercise in the presence of heightened sympathetic tone. In addition, the blood pressure response to the exercise and during recovery was not altered by the elevated sympathetic tone so that the reduced Hb saturation, lower recovery PCr levels, and diminished brachial artery MBV with LBNP reflected a reduction in FBF due to sympathetic constriction, rather than a direct effect of LBNP on perfusion pressure or myogenic tone. It appears, therefore, that sympathetic vasoconstriction was not overridden by metabolic vasodilation. Thus, with augmented sympathetic tone, the sympatholytic effects of muscle metabolism did not adjust oxygen transport to match the metabolic demand.
There is a controversy regarding the ability of an augmented sympathetic outflow to vasoconstrict a metabolically active muscle bed, with evidence provided both for (5, 9, 21) and against (6, 14, 19, 24) the hypothesis of sympatholysis. Part of this controversy may be due to differences in the methods used to report muscle perfusion data. The effect of sympathetic activation under conditions of high blood flow is relatively small if expressed in terms of vascular resistance or blood flow but is much greater if expressed in terms of conductance (13). For example, Kjellmer (9) observed that steady-state changes in vascular resistance with direct sympathetic nerve stimulation became smaller and smaller as blood flow increased in response to electrically induced contractions; Kjellmer concluded that functional sympatholysis had occurred. Rowell (16) expressed the vascular resistance data of Kjellmer (9) to reflect changes in vascular conductance and concluded that sympatholysis had not occurred. Also, other investigators have concluded that sympathetic nervous system retains the ability to reduce vascular conductance in skeletal muscle during sustained exercise (6, 14, 19, 24).
Differences in the magnitude of sympathetic activation may also
contribute to the controversy of sympatholysis. As opposed to the
60 mmHg LBNP used in the present study, Hansen et al. (5) used
20 mmHg LBNP and near infrared spectroscopy measures of Hb and
myoglobin oxygen saturation in the exercising forearm. They concluded
that tissue oxygenation is sustained during even mild intensity
handgrip exercise. Finally, an important factor to consider in this
controversy may be the baseline level of sympathetic tone. Previous
proponents of sympatholysis activated LBNP after steady-state exercise
had been achieved (5, 21), whereas, in the present study, exercise was
superimposed on a higher level of sympathetic tone induced by LBNP.
Whether or not these findings suggest that the total number of
microvascular units recruited for a given vasodilatory signal is
attenuated with augmented baseline sympathetic tone will require
further investigation.
The critical issue regarding the role of sympathetic tone in producing a change in blood flow, vascular conductance, or vascular resistance is the effect on muscle metabolism. Joyner et al. (7) and Thompson and Mohrman (23) have shown that sympathetic activation results in reductions in exercise muscle oxygen uptake at a given workload. These data suggested that enhanced sympathetic tone increased the reliance on nonaerobic sources of energy.
In the present study, venous lactate and pH levels were altered by LBNP, suggesting that skeletal muscle metabolism was altered by the heightened sympathetic tone. However, venous lactate and pH can also be affected by the rate of washout and concentration gradients. Hb saturation data also indicated a reduced flow with LBNP. However, Hb saturation may also be altered by differences in muscle temperature and pH (i.e., the Bohr effect). Accordingly, NMR measures of intramuscular PCr and pH were obtained as direct measures of tissue metabolism. Together, the results of the present study are consistent in showing that, for the conditions studied, sympathetic activation does alter muscle metabolism. Thus the present data support the postulate of previous studies (6, 19, 23) that metabolic vasodilation cannot adequately override sympathetic vasoconstrictor influences during rhythmic exercise. The NMR and venous effluent data suggest that the metabolic impact of enhanced sympathetic tone was greatest at the highest workload when the balance between flow delivery and muscle metabolism would be presumed to be most tenuous.
Although brachial artery diameters were not altered with LBNP, MBV was reduced, indicating a reduction in limb blood flow. Because brachial artery diameters were obtained from a small number of subjects, we did not calculate FBF. However, given the small effect of LBNP on the conduit artery dimensions, it can be expected that the ~12% reduction in velocity at end exercise would translate into a similar effect of LBNP on FBF. Because MAP was constant between Control and LBNP trials, the reduction in FBF was due to an increase in downstream resistance, likely secondary to increased sympathetic tone (4). When the velocity data are viewed in conjunction with the Hb saturation data, it can be estimated that muscle oxygen uptake was reduced ~20% at end exercise with LBNP. This estimate assumes that LBNP did not change arterial Hb saturation. An important consideration in estimating the reduction in muscle oxygen uptake with LBNP is that our measures of blood gases and Hb saturation were obtained from mixed venous blood representing contributions from active and inactive skeletal muscle as well as from forearm skin with relatively low metabolic activity. Therefore, the oxygen uptake by active muscle may be greater than estimated. How increased sympathetic tone alters flow distribution in the human forearm muscle is unknown. Overall, the altered levels of PCr, the reductions in intramuscular pH, and the venous pH and lactate values are all in line with the measured reductions in tissue perfusion. Therefore, the present data provide both hemodynamic and metabolic evidence that flow to the exercising muscle during and after exercise was reduced by LBNP.
Recovery
During recovery, brachial artery MBV continued to be attenuated by LBNP, although Hb saturation levels were similar during the two trials. These results suggest that during recovery, oxygen consumption was lower during LBNP. This may explain, in part, the lower PCr and hydrogen ion concentrations observed during recovery in the LBNP trial. Parenthetically, it could be argued that an elevated hydrogen ion concentration during recovery with LBNP could have slowed PCr recovery (2, 22). However, the time course of change in PCr, with respect to intramuscular pH, does not support this explanation. The differences in PCr between the Control and LBNP trials became progressively larger as recovery continued, whereas differences in intramuscular pH were greatest early in the recovery phase. PCr recovery depends largely on the oxidative capacity of muscle (11) and has been used to estimate the rate of oxidative metabolism after exercise (22). Therefore, the attenuated levels of PCr during the entire recovery period of the present study suggest that oxygen utilization was diminished after the cessation of contractions, as well as during exercise.Clinical Implications
Our report demonstrates that the ability to vasodilate a metabolically active muscle bed is attenuated by an augmented sympathetic tone leading to marked alterations in muscle metabolism. It has been hypothesized that blood flow to active skeletal muscle is reduced by vasoconstriction when the individual's cardiac output has been exceeded by the flow requirements of large muscle mass exercise (16). The present data support this hypothesis and, by inference, suggest that oxygen extraction may not compensate for the reduced flow so that muscle metabolism is altered. From a clinical standpoint, patients with congestive heart failure are known to have elevated sympathetic tone at rest. Concurrently, exercise tolerance is attenuated in these individuals due to premature fatigue relative to normal controls. It is not known whether the decreased exercise tolerance is due to alterations in skeletal muscle function (12), to limitations in cardiac output, to reductions in limb perfusion, or to a combination of these effects. Based on the results of the present study, it is hypothesized that the elevated sympathetic tone associated with heart failure may evoke prominent vasoconstriction in active muscle beds, thereby further impeding vasodilation and leading to premature cellular acidosis and fatigue.ACKNOWLEDGEMENTS
We are grateful for the technical assistance of M. Bodenstein and for the help of S. Ward, M. Gerberich, and J. Stoner in preparation of the manuscript. The nursing care provided by the staff of the Penn State General Clinical Research Center at The Milton S. Hershey Medical Center is appreciated. We are grateful to Philips Medical Systems for the use of the echo Doppler imaging system.
FOOTNOTES
Address for reprint requests: L. I. Sinoway, Div. of Cardiology, The Milton S. Hershey Medical Center, PO Box 850, Hershey, PA 17033.
Received 21 January 1997; accepted in final form 10 February 1997.
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F. Lee, J. K. Shoemaker, P. M. McQuillan, A. R. Kunselman, M. B. Smith, Q. X. Yang, H. Smith, K. Gray, and L. I. Sinoway Effects of forearm bier block with bretylium on the hemodynamic and metabolic responses to handgrip Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H586 - H593. [Abstract] [Full Text] [PDF]
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 C.F. Notarius, S. Ando, G.A. Rongen, and J.S. Floras Resting muscle sympathetic nerve activity and peak oxygen uptake in heart failure and normal subjects Eur. Heart J., June 2, 1999; 20(12): 880 - 887. [Abstract] [PDF]
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 J. K. Shoemaker, P. M. McQuillan, and L. I. Sinoway Upright posture reduces forearm blood flow early in exercise Am J Physiol Regulatory Integrative Comp Physiol, May 1, 1999; 276(5): R1434 - R1442. [Abstract] [Full Text] [PDF]
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J. K. Shoemaker, A. R. Kunselman, D. H. Silber, and L. I. Sinoway Maintained exercise pressor response in heart failure J Appl Physiol, November 1, 1998; 85(5): 1793 - 1799. [Abstract] [Full Text] [PDF]
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J. K. Shoemaker, C. S. Hogeman, D. H. Silber, K. Gray, M. Herr, and L. I. Sinoway Head-down-tilt bed rest alters forearm vasodilator and vasoconstrictor responses J Appl Physiol, May 1, 1998; 84(5): 1756 - 1762. [Abstract] [Full Text] [PDF]
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