Sympathetic vasoconstrictor responses are blunted in the vascular beds of contracting muscle (functional sympatholysis), but the mechanism(s) have been difficult to elucidate. We tested the hypothesis that the mechanical effects of muscle contraction blunt sympathetic vasoconstriction in human muscle. We measured forearm blood flow (Doppler ultrasound) and calculated the reductions in forearm vascular conductance (FVC) in response to reflex increases in sympathetic activity evoked via lower body negative pressure (LBNP). In protocol 1, eight young adults were studied under control resting conditions and during simulated muscle contractions using rhythmic forearm cuff inflations (20 inflations/min) with cuff pressures of 50 and 100 mmHg with the arm below heart level (BH), as well as 100 mmHg with the arm at heart level (HL). Forearm vasoconstrictor responses (%ΔFVC) during LBNP were −26 ± 2% during control conditions and were not blunted by simulated contractions (range = −31 ± 3% to −43 ± 6%). In protocol 2, eight subjects were studied under control conditions and during rhythmic handgrip exercise (20 contractions/min) using workloads of 15% maximum voluntary contraction (MVC) at HL and BH (similar metabolic demand, greater mechanical muscle pump effect for the latter) and 5% MVC BH alone and in combination with superimposed forearm compressions of 100 mmHg (similar metabolic demand, greater mechanical component of contractions for the latter). The forearm vasoconstrictor responses during LBNP were blunted during 15% MVC exercise with the arm at HL (−1 ± 3%) and BH (−2 ± 3%) compared with control (−25 ± 3%; both P < 0.005) but were intact during both 5% MVC alone (−24 ± 4%) and with superimposed compressions (−23 ± 4%). We conclude that mechanical effects of contraction per se do not cause functional sympatholysis in the human forearm and that this phenomenon appears to be coupled with the metabolic demand of contracting skeletal muscle.
- blood flow
- sympathetic nervous system
during dynamic exercise, blood flow increases substantially to exercising muscle in proportion to the metabolic demand of the tissue (19, 28). Because the ability of the skeletal muscle vasculature to vasodilate is quite remarkable (2), large muscle mass dynamic exercise imposes a significant challenge to blood pressure regulation, resulting in the need for sympathetic nervous system restraint of active muscle blood flow (18, 26). However, although sympathetic vasoconstriction persists in active skeletal muscle under these conditions, the vasoconstrictor responses to acute sympathetic stimulation are blunted in the vascular beds of contracting muscle (functional sympatholysis) (1, 4, 7, 25, 33, 38). Thus there is a unique interplay between local events in skeletal muscle and the sympathetic nervous system that act in concert to preserve adequate blood flow and oxygen delivery to active muscle in the face of elevated sympathetic vasoconstrictor tone (1, 39).
Although functional sympatholysis has been clearly demonstrated in experimental animals and humans, the mechanism(s) underlying this phenomenon have been difficult to elucidate. Studies employing pharmacological inhibition of substances during exercise such as nitric oxide and prostaglandins (alone or in combination) (5–8, 34), as well as inhibition of ATP-sensitive potassium channels (15, 32), have demonstrated that these factors might be involved in functional sympatholysis. However, an important and often overlooked observation is that inhibition of these substances typically does not completely explain this phenomenon (5, 7, 8, 15, 32, 34). In other words, in most studies, there is still a significant attenuation of the vasoconstrictor response in contracting muscle compared with the responses observed in normal resting or passively vasodilated skeletal muscle (5, 8, 15, 34).
Although the efforts of our laboratory and others have been focused on determining what substance(s) can explain this unique ability of muscle contractions to blunt sympathetic vasoconstriction, the potential role for the basic mechanical effects of muscle contractions has been largely ignored. During muscular contraction, intramuscular pressure increases in proportion to the intensity of contraction (27, 31), the volume of blood in the veins is expelled subsequently reducing venous pressure (16, 36), and compression or distortion of resistance vessels occurs (10, 36). Under certain experimental conditions, the reductions in venous pressure increases the arteriovenous pressure gradient, thereby increasing the driving force for muscle blood flow (i.e., muscle pump effect) (30, 37). Additionally, the mechanical compression or distortion of resistance vessels has been suggested to evoke a rapid vasodilation that is graded with the intensity of contractions via the potential release of substances from the endothelium or via a direct effect on vascular smooth muscle membrane potential (11, 12, 35). Given that functional sympatholysis is specific to muscle contractions (i.e., this is not due to a generalized “high-flow” condition) (7, 33, 38) and is also graded with the level of exercise intensity (4, 38), we reasoned that perhaps the mechanical effects of muscle contraction could play a role in this phenomenon in humans.
Therefore, the purpose of the present investigation was to test the hypothesis that the mechanical effects of muscle contraction blunt sympathetic vasoconstriction in humans. To do so, we measured forearm hemodynamics (Doppler ultrasound) and calculated the vasoconstrictor responses to reflex increases in sympathetic vasoconstrictor activity during 1) simulated mechanical effects of rhythmic muscle contraction and 2) rhythmic handgrip exercise under various conditions to manipulate the mechanical effects associated with contractions. Our findings indicate that the mechanical effects of contraction per se do not cause functional sympatholysis and that this phenomenon appears to be tightly regulated to the underlying metabolic demand of the contracting muscle.
A total of 11 young healthy adults (8 men, 3 women; age = 24 ± 2 yr; weight = 68.5 ± 2.3 kg; height = 175 ± 2 cm; body mass index = 22.4 ± 0.5 kg/m2; means ± SE) participated in the present study. Five of the 11 subjects participated in both experimental protocols (see below). All were nonsmokers, nonobese, normotensive, and not taking any medications. All female subjects were studied in the early phase of their menstrual cycle or placebo phase of oral contraceptives. Studies were performed in a temperature-controlled environment after a minimum of a 4-h fast, the subjects abstained from caffeine and exercise the day of the study, and all studies were performed with the subjects in the supine position. This research was approved by the Human Research Committee of Colorado State University, and all subjects gave their written informed consent to participate.
Arterial Blood Pressure and Heart Rate
Resting arterial blood pressure was measured noninvasively over the brachial artery of the control arm after 30 min of supine rest before any experimental trials, and just before each experimental trial thereafter (Cardiocap/5, Datex-Ohmeda, Louisville, CO). Beat-by-beat arterial blood pressure was measured at heart level by finger photoplethysmography (Finapres, Ohmeda) on the middle finger of the control hand during all experimental trials. Heart rate was determined using a three-lead ECG.
Forearm Blood Flow and Vascular Conductance
A 4-MHz pulsed Doppler probe (model 500V, Multigon Industries, Mt. Vernon, NY) was used to measure brachial artery mean blood velocity (MBV) with the probe securely fixed to the skin over the brachial artery as previously described by our laboratory (7, 8). The probe insonation angle was 45 degrees. A linear 7.0-MHz echo Doppler ultrasound probe (Hewlett-Packard Sonos 4500, Andover, MA) was placed in a holder securely fixed to the skin immediately proximal to the velocity probe to measure brachial artery diameter. Forearm blood flow was calculated as FBF = MBV × π (brachial artery diameter/2)2 × 60, where FBF is in millimeters per minute, MBV is in centimeters per second, brachial diameter is in centimeters, and 60 is used to convert from milliliters per second to milliliters per minute.
Forearm vascular conductance (FVC) was calculated as (FBF/MAP) × 100 and expressed as milliliters per minute per 100 mmHg, where MAP is mean arterial pressure. FVC for the trials with the experimental arm below heart level was calculated using MAP values adjusted for the hydrostatic distance from the level of the heart to the midforearm (29, 35).
Lower Body Negative Pressure
Subjects lay supine and were sealed at the iliac crests in a chamber designed for administering lower body negative pressure (LBNP). LBNP was administered at −20 mmHg to unload cardiopulmonary and arterial baroreceptors and evoke reflex increases in muscle sympathetic nerve activity (23). This degree of LBNP was administered for 2 min and was chosen because it typically does not alter arterial blood pressure or heart rate (23), it evokes reproducible increases in sympathetic vasoconstrictor activity (14), and the vasoconstrictor responses are eliminated by acute forearm sympathectomy (14, 24). Pilot studies in our laboratory indicate that, when separated by 15 min of rest, the forearm vasoconstrictor response to LBNP under resting conditions is repeatable over time.
Rhythmic Handgrip Exercise
Maximum voluntary contraction (MVC) for each subject was determined for the nondominant arm as the average of three maximal squeezes of a handgrip dynamometer (Stoelting, Chicago, IL) that were within 3% of each other. Rhythmic handgrip exercise was performed using a load that corresponded to either 5 or 15% of the subjects' MVC. The weight was lifted 4–5 cm over a pulley at a duty cycle of 1-s contraction/2-s relaxation (20 contractions/min) using audio and visual signals to ensure the correct timing (7, 8). These workloads were chosen because sympathetic vasoconstrictor responses have been shown to be preserved during 5% MVC, whereas 15% MVC clearly blunts sympathetic vasoconstriction (i.e., causes functional sympatholysis) (7, 13). Additionally, rhythmic handgrip exercise at these intensities can be performed in the absence of increases in sympathetic activity (14, 40).
Rhythmic Forearm Cuff Inflations
Subjects were instrumented with a custom-designed tapered blood pressure cuff that was wrapped around the entire nondominant forearm. Rhythmic cuff inflations were performed with an inflation/deflation cycle of 1 s/2 s (20 inflations/min) to mimic the duty cycle used for the exercise trials in the present study and in our previous studies on functional sympatholysis in the human forearm (7, 8). The cuff was inflated within 0.5 s using a rapid cuff inflation unit (Hokanson E20, Bellevue, WA) to pressures of 50 or 100 mmHg. Cuff pressures of 50 mmHg were used in an attempt to isolate the effects of venous emptying with minimal distortion of resistance vessels, whereas cuff pressures of 100 mmHg were used to mimic the net effect of venous emptying and the mechanical distortion of resistance vessels observed during moderate-intensity contractions. From the available data derived from studies measuring intramuscular pressure during exercise in humans, we believe that utilizing a cuff pressure of 100 mmHg is (at a minimum) comparable to the pressures observed during exercise performed at 15% MVC (27, 31) and causes functional sympatholysis.
Protocol 1: effects of simulated muscle contractions on forearm sympathetic vasoconstrictor responses.
In the first group of subjects (n = 8; 7 men, 1 woman), the forearm vasoconstrictor responses to reflex increases in sympathetic activity evoked via LBNP were determined under the following conditions: 1) during control resting conditions with the arm at heart level; 2) during control resting conditions with the arm below heart level (midforearm ∼20 cm below heart); 3) during rhythmic cuff inflations of 50 mmHg with the arm below heart level; 4) during rhythmic cuff inflations of 100 mmHg with the arm below heart level; and 5) during rhythmic cuff inflations of 100 mmHg with the arm at heart level. We are unaware of any studies comparing the forearm vasoconstrictor effects to sympathetic stimulation under control (resting) conditions with the arm at or below heart level; therefore, we felt it was necessary to perform the control trials in both arm positions to accurately quantify the effects of rhythmic cuff inflations on sympathetic vasoconstriction.
To determine whether the simulated mechanical effects of muscle contraction blunt sympathetic vasoconstriction, the trials below heart level (50 and 100 mmHg cuff inflations) were performed to maximize the effectiveness of the muscle pump on forearm hemodynamics. The trial at heart level was performed to determine whether the rhythmic cuff inflations at 100 mmHg were capable of blunting sympathetic vasoconstriction in a similar manner to what we have observed previously during rhythmic handgrip exercise with the arm at heart level (7, 8). Although our pilot data demonstrate repeatable forearm vasoconstrictor responses to LBNP over time, the order of experimental trials was randomized and counterbalanced across subjects to eliminate any potential order effect. All trials were separated by 15 min of rest. The timelines for the experimental trials in protocol 1 are shown in Fig. 1, A and B.
Protocol 2: effects of rhythmic handgrip exercise with varying mechanical influences on forearm sympathetic vasoconstrictor responses.
In the second group of subjects (n = 8; 5 men, 3 women), the vasoconstrictor responses to reflex increases in sympathetic activity evoked via LBNP were determined under the following conditions: 1) during control resting conditions; 2) during 15% MVC rhythmic handgrip exercise with the arm at heart level; 3) during 15% MVC rhythmic handgrip exercise below heart level; 4) during 5% MVC rhythmic handgrip exercise below heart level; and 5) during 5% MVC rhythmic handgrip exercise below heart level with simultaneous 100-mmHg cuff inflations superimposed on the muscle contractions. Because the forearm vasoconstrictor responses under control resting conditions were not different with the arm at or below heart level in protocol 1 (see results), half of the control trials were performed at heart level, the other half were performed below heart level, and these control trials were randomized across subjects.
The rationale for the various exercise trials follows: the 15% MVC trial at heart level was performed to establish functional sympatholysis under conditions previously used for studying this phenomenon in humans (7, 8). The 15% MVC trial below heart level was performed to match the muscle metabolic demand of the previously described trial while maximizing any potential mechanical effect of the muscle pump on forearm hemodynamics. The 5% MVC trial below heart level was performed because this exercise intensity does not appear to blunt sympathetic vasoconstriction. Finally, the 5% MVC plus 100 mmHg cuff inflation trial was performed to match the muscle metabolic demand in the previously described trial but with the addition of a mechanical component that more closely resembles the higher-exercise-intensity trials (27, 31). As in protocol 1, all trials were separated by 15 min of rest and were randomized and counterbalanced across subjects. The timelines for the experimental trials in protocol 2 are shown in Fig. 1, C and D.
Data Acquisition and Analysis
Data were collected and stored on a computer at 250 Hz and analyzed off-line with signal-processing software (WinDaq, DATAQ Instruments, Akron, OH). Baseline FBF and MAP represent an average of the last 30 s of the resting time period, the hyperemic values represent an average of the last 30 s of steady-state rhythmic cuff inflations (protocol 1) or rhythmic handgrip exercise (protocol 2) before LBNP, and the sympathetic vasoconstrictor effects represent an average of the final 30 s of LBNP (see Fig. 1). The percent reduction in FVC during LBNP was calculated as [(FVC post-LBNP − FVC pre-LBNP)/(FVC pre-LBNP)] × 100.
We used percent reduction in FVC to compare vasoconstrictor responses to LBNP across conditions, because we believe this is the most appropriate way to compare vascular responses under conditions where there might be marked differences in baseline blood flow and vascular tone (3, 17, 20, 33, 38). However, because MAP was not directly measured at the midforearm for the trials with the arm below heart level, we chose to also present percent reduction in FBF. Finally, we have presented the absolute levels of forearm hemodynamics during all conditions in tabular form in an effort to be comprehensive.
All values are reported as means ± SE. Specific hypothesis testing within each of the conditions (control, rhythmic cuff inflations, or exercise) and comparison of the vasoconstrictor responses across conditions were performed using repeated-measures ANOVA. In the case of a significant F value, Newman-Keuls method for multiple comparisons was used to determine where differences occurred. Comparisons of the hemodynamic values at specific time points between the conditions within each protocol were made with paired t-tests. Significance was set at P < 0.05.
Protocol 1: Effects of Simulated Muscle Contractions on Forearm Sympathetic Vasoconstrictor Responses
Forearm hemodynamic responses to rhythmic cuff inflations.
Forearm hemodynamics and MAP for the experimental trials are presented in Table 1. Baseline FBF (∼20%) and FVC (∼30%) were slightly lower in the below-heart-level position compared with heart level, and MAP was elevated due to a greater hydrostatic component of arterial pressure (all P < 0.05 vs. heart level). In general, rhythmic cuff inflations significantly increased FBF and FVC from baseline to steady state before LBNP (all P < 0.05 vs. baseline). Cuff inflations with the arm below heart at 50 mmHg resulted in an increase in FBF and FVC of ∼30%. FBF and FVC increased ∼20% during cuff inflations at 100 mmHg with the arm at heart level, whereas 100-mmHg cuff inflations below the heart resulted in the largest increase in FBF and FVC of the three conditions (∼80%; P < 0.05 vs. other 2 trials). MAP did not change from baseline to steady state during any of the rhythmic cuff inflations trials. Heart rate was not significantly influenced by any experimental manipulation in either protocol 1 or protocol 2 (data not shown).
Forearm vasoconstrictor responses to LBNP during rhythmic cuff inflations.
As expected, LBNP evoked significant forearm vasoconstriction during control conditions with the arm at heart level (ΔFBF = −26 ± 2% and ΔFVC = −26 ± 2%; Fig. 2), and these responses were similar when the arm was below the heart (ΔFBF = −25 ± 3% and ΔFVC = −26 ± 2%). In general, the vasoconstrictor responses to LBNP were not blunted in any of the three rhythmic cuff inflation trials. During 50- and 100-mmHg cuff inflations below heart level, LBNP reduced FBF and FVC by ∼30%. Interestingly, the vasoconstrictor responses during 100-mmHg rhythmic cuff inflations at heart level were greater than control conditions (ΔFBF = 43 ± 5% and ΔFVC = 43 ± 6%; P < 0.05) but not significantly greater than 50 or 100 mmHg below-heart level trials. MAP was unaffected by LBNP.
Protocol 2: Effects of Rhythmic Handgrip Exercise With Varying Mechanical Influences on Forearm Sympathetic Vasoconstrictor Responses
Forearm hemodynamic responses to rhythmic handgrip exercise.
Forearm hemodynamics and MAP for the experimental trials are presented in Table 2. Similar to protocol 1, baseline FBF (∼20%) and FVC (∼30%) were slightly lower and MAP elevated when the arm was below heart level (all P < 0.05 vs. heart level). Both 15% MVC exercise trials significantly increased FBF, and the increases were greater below heart level than at heart level (∼700% and ∼500%, respectively; P < 0.05). However, absolute levels of calculated FVC were similar, indicating that the greater FBF responses below heart level were due to greater muscle pump effectiveness (not greater vasodilation). Rhythmic handgrip exercise at 5% MVC below heart level resulted in ∼225% increase in FBF and FVC. Interestingly, contractions at 5% MVC with superimposed cuff inflations resulted in a larger increase in FBF and FVC than 5% exercise alone (∼315%; P < 0.05). MAP for all trials was not significantly different between baseline and steady-state exercise.
Forearm vasoconstrictor responses to LBNP during rhythmic handgrip exercise.
Forearm vasoconstrictor responses to LBNP under control conditions were similar in magnitude to those observed in protocol 1 (ΔFBF = −24 ± 2%; ΔFVC = −25 ± 3%; Fig. 3). Rhythmic handgrip exercise at 15% MVC with the arm at heart level significantly blunted LBNP-induced vasoconstriction compared with control conditions (ΔFBF = −2 ± 4%; ΔFVC = −1 ± 3%). Additionally, 15% MVC exercise below heart level significantly blunted the vasoconstrictor responses, and these responses were similar to those during 15% MVC exercise at heart level (ΔFBF = −4 ± 2%; ΔFVC = −2 ± 3%). In contrast, rhythmic handgrip exercise at 5% MVC did not impact on LBNP-induced vasoconstriction (ΔFBF = −25 ± 4%; ΔFVC = −24 ± 4%). When 5% MVC was performed with superimposed cuff inflations, the vasoconstrictor responses to LBNP were similar to those observed under control conditions and 5% exercise alone (ΔFBF = −24 ± 4%; ΔFVC = −23 ± 4%). MAP was similar from steady-state exercise to the end of LBNP in all trials.
To the best of our knowledge, this is the first study performed to determine whether the mechanical effects of muscle contraction play a role in functional sympatholysis in humans. The primary findings from the present investigation are as follows. First, simulation of the mechanical effect of muscle contraction via rhythmic forearm cuff inflations does not blunt sympathetic vasoconstriction in humans (protocol 1). Second, the addition of a greater mechanical effect of the muscle pump and/or greater mechanical distortion of resistance vessels to voluntary muscle contractions does not impact on functional sympatholysis during rhythmic handgrip exercise (protocol 2). Finally, the findings of intact sympathetic vasoconstriction during low exercise intensities and blunted sympathetic vasoconstriction during higher exercise intensities, with and without augmented mechanical effects, strongly indicate that functional sympatholysis is coupled with the underlying metabolic demand of contracting skeletal muscle.
Simulation of Muscle Contractions via Rhythmic Forearm Cuff Inflations
In the present study, we employed a technique previously used by Tschakovsky and colleagues (37) to mimic the mechanical effects of muscle contraction in the human forearm. Accordingly, several observations deserve comment. First, similar to this previous study, rhythmic cuff inflations using pressures of 100 mmHg with the arm below heart level resulted in a significant increase in FBF (37). Second, although the magnitude of increase was less than during the 100-mmHg trials, increases in FBF were also observed using pressures of 50 mmHg with the arm below heart level. The finding that the magnitude of blood flow responses were greater with higher levels of cuff pressures could indicate either 1) more effective emptying of forearm veins or 2) greater distortion of resistance vessels and subsequent vasodilation.
Interestingly, rhythmic cuff inflations using 100 mmHg with the arm at heart level also resulted in an increase in FBF similar in magnitude to the 50-mmHg below-heart trial. Because the effectiveness of the muscle pump with the arm at heart level should be minimal (i.e., minimal gain of the arteriovenous pressure gradient due to low levels of venous pressure), this latter observation could possibly be explained by the distortion of resistance vessels during mechanical compression and the subsequent release of vasodilators or direct effects on vascular smooth muscle membrane potential (11, 12, 35). Although we cannot determine the mechanisms involved in this simulated mechanical effect of contraction, the primary purpose of the present investigation was to determine whether the net effect of the mechanical component of muscle contractions can blunt sympathetic vasoconstriction in humans.
Effects of Simulated Muscle Contractions on Sympathetic Vasoconstriction: Evidence Against a Role for the Mechanical Effects of Contraction
The data from protocol 1 indicate that simulation of muscle contractions via rhythmic forearm cuff inflations does not blunt sympathetic vasoconstriction (i.e., does not cause functional sympatholysis). Despite the ability of rhythmic mechanical compressions of the forearm to augment blood flow in each of the respective experimental trials (Table 1), the ability of the sympathetic nerves to evoke vasoconstriction was clearly intact (Fig. 2). Interestingly, the forearm vasoconstrictor responses during cuff inflations with the arm at heart level actually resulted in a greater vasoconstrictor response compared with control conditions. During simulated contractions with greater cuff pressure, brachial artery blood velocity becomes negative on the rapid inflation of the cuff due to the compression of resistance vessels and subsequent elevated resistance to flow, similar to the retrograde flow during the contraction phase of higher-intensity exercise (22, 41). However, with the arm at heart level, the magnitude of the increase in blood velocity on the release of cuff pressure is less than when the arm is in the dependent position or when active muscle contractions are performed. Because mean FBF reflects both anterograde (arterial inflow) and retrograde blood velocity, we believe that the greater calculated vasoconstrictor response reflects the sympathetic nerves constricting forearm muscle arterioles and reducing arterial inflow but not affecting the retrograde flow evoked via simulated muscle contractions. Nevertheless, we interpret the collective data from this protocol as clearly indicating that the mechanical effects of contraction per se do not blunt sympathetic vasoconstriction in the human forearm.
Effects of Rhythmic Handgrip Exercise on Sympathetic Vasoconstriction: Uncoupling of the Mechanical and Metabolic Effects of Muscle Contraction
In protocol 2, we sought to determine whether the manipulation of the mechanical effects of contractions during exercise further blunts the forearm vasoconstrictor responses to reflex increases in sympathetic outflow via LBNP. Consistent with previous studies from our laboratory (7, 8), rhythmic handgrip exercise performed at 15% MVC (heart level condition) significantly attenuated the vasoconstrictor responses to sympathetic activation (Fig. 3). When exercise at 15% MVC was performed below heart level, FBF was ∼15% greater than that during the same workload with the arm at heart level, which is consistent with greater muscle pump effectiveness when the limb is in the dependent position (9). However, despite an augmented muscle pump (mechanical) effect, the vasoconstrictor responses were similar to the responses observed during the exercise trial at heart level.
Because we hypothesized that the mechanical effects of muscle contraction blunts sympathetic vasoconstriction and that the vasoconstrictor responses were nearly abolished during 15% MVC exercise at heart level (Fig. 3), one could question why we would expect that the responses would be more attenuated when performed below heart level. The finding that the vasoconstrictor responses were nearly abolished during 15% MVC at heart level was somewhat surprising based on our previous studies. However, in these studies (7, 8), vasoconstrictor drugs were infused into the forearm during control (nonexercise) vasodilator conditions evoking substantially greater vasoconstriction than that observed during control conditions of the present study (∼50 vs. 25%). Thus, although this was somewhat unexpected, it most likely can be explained by the moderate level of vasoconstriction evoked via LBNP under resting conditions. In an attempt to address this issue, we performed a subgroup analysis of four subjects who demonstrated the most vasoconstriction during LBNP when performing 15% MVC exercise at heart level and compared their responses to the exercise trial below heart level. When this analysis was performed, the vasoconstrictor responses were identical (%ΔFVC below heart = −7 ± 3%; heart level = −8 ± 2%). Thus we interpret these data to indicate that augmented mechanical effects of the muscle pump do not further impact on sympathetic vasoconstriction when rhythmic exercise is performed with similar metabolic demands.
During lower-intensity exercise of 5% MVC, muscle contractions did not impact on sympathetic vasoconstriction (i.e., vasoconstrictor responses were intact). When exercise at 5% MVC was performed below heart level with an additional mechanical component achieved via superimposed cuff inflations, FBF was significantly greater when compared with the 5% MVC trial alone. Whether this reflects greater emptying of forearm veins during the superimposed cuff inflations or greater distortion of resistance vessels and subsequent vasodilation is unknown. Nevertheless, despite the ability of superimposed mechanical compressions to augment FBF during low levels of exercise, this had no impact on the ability of sympathetic nerves to evoke vasoconstriction (Fig. 3). We believe that this finding is strong evidence for uncoupling the mechanical and metabolic effects of muscle contraction on sympathetic vasoconstrictor responses during exercise. Therefore, the collective data from this protocol indicate that the ability of muscle contractions to blunt sympathetic vasoconstriction in humans appears independent of the mechanical effects of contractions and is likely coupled to the underlying metabolic demand of the exercising muscle.
The experimental limitations with the present study are as follows. First, it is possible that rhythmic, external forearm cuff inflations do not perfectly mimic the mechanical effects of active muscle contractions. However, in an effort to simulate the nature of rhythmic forearm muscle contractions used in the present study and in our previous studies on functional sympatholysis, we used an identical duty cycle for the cuff inflation and exercise trials. In this context, it should be noted that in all experimental trials (cuff inflations alone and superimposed on 5% MVC), rhythmic cuff inflations did evoke an increase in forearm hemodynamics, indicating a clear mechanical effect of the cuff inflations. Additionally, studies employing the measurement of intramuscular pressure during cuff inflations indicate that cuff pressure is well transmitted to the underlying tissue (27). Therefore, although we recognize that this is a limitation, we do not feel that this influences the interpretation of our data as it pertains to the inability of the mechanical effects of muscle contraction per se to blunt sympathetic vasoconstriction.
Recent evidence indicates that there might be differences in sympathetic α-adrenergic vasoconstrictor responsiveness at rest and during exercise in the forearm compared with the leg vasculature in humans (21, 42). Thus a second limitation is that our findings should only be interpreted with respect to the upper limb (forearm). Whether the mechanical effects of muscle contractions play a role in functional sympatholysis in the lower limbs of humans remains to be determined.
A third limitation relates to the extrapolation of our findings to maximal exercise, where muscle blood flow can be high, the amount of active muscle mass can be large, and intramuscular pressure can exceed 200 mmHg (16). However, the purpose of this study was to determine whether the mechanical effects of contraction, similar to that observed during exercise intensities that clearly cause functional sympatholysis (e.g., 15% MVC), were capable of blunting sympathetic vasoconstriction. From the available data, we believe that cuff inflations of 100 mmHg increased intramuscular pressure (and therefore empties veins and distorts resistance vessels) at a minimum to that observed during 15% MVC and most likely mimics exercise intensities up to ∼50% MVC (27, 31). Thus, although we cannot conclude that the mechanical effects of contraction do not play a role in functional sympatholysis during maximal exercise, we are confident that this does not impact on sympathetic vasoconstriction during moderate intensities of submaximal exercise.
In conclusion, the findings from the present investigation demonstrate that the mechanical effects of muscle contraction per se do not impact on sympathetic vasoconstriction in the human forearm (i.e., do not cause functional sympatholysis). Furthermore, our data indicate that the ability of muscle contractions to blunt sympathetic vasoconstriction is coupled with the underlying metabolic demand of the tissue, indicating that this phenomenon is tightly regulated and acts to maintain adequate oxygen delivery to the exercising muscle in the face of sympathetic vasoconstriction.
This research was supported by National Institute of Health Grant AG-22337 (to F. A. Dinenno).
We thank Molly White for technical assistance, and we thank the subjects who volunteered for this study.
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. Section 1734 solely to indicate this fact.
- Copyright © 2005 by the American Physiological Society