Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response.
- neural cardiovascular regulation
- peripheral reflexes
- integrated circulatory regulation
when oxygen delivery to active skeletal muscle is insufficient to meet the metabolic demands during dynamic exercise, metabolites (e.g., lactic acid, adenosine, potassium, diprotonated phosphate, H+, and arachidonic acid products, among others) accumulate within the active muscle and stimulate group III and IV afferent neurons. These sensory neurons project to the medulla oblongata, and their activity elicits reflex increases in sympathetic nerve activity and systemic blood pressure in an effort to enhance blood flow to the ischemic muscle (1, 11, 14, 27, 29, 31, 41). Termed the muscle metaboreflex, this response is thought to provide important functional links between metabolism in active muscles and central hemodynamics during exercise.
The function of the muscle metaboreflex during dynamic exercise has been investigated in dogs through examination of the cardiovascular responses to graded reductions of hindlimb blood flow (11, 15, 34, 36, 41). In this experimental model, hindlimb blood flow is maintained at a constant level using an occluder placed at the terminal aorta, despite the evoked systemic presser response and/or local vasodilation in the ischemic muscles. This model thus creates an open-loop relationship between active skeletal muscle blood flow and both systemic and local cardiovascular responses, which enables experimental control of the hemodynamic changes that would otherwise influence the activation level of the muscle metaboreflex (4, 7, 32, 36, 41). Using this approach, it was shown that, during mild treadmill running, marked reductions in hindlimb blood flow (∼50% of free-flow exercise condition) were required before the muscle metaboreflex was activated; that is, an increase in arterial blood pressure only occurred after blood flow fell below an apparent threshold (2, 11, 34, 36, 41). In addition, increases in workload shifted the muscle metaboreflex threshold toward higher blood flow levels and reduced the change in blood flow necessary to elicit the reflex pressor response. Indeed, at workloads greater than moderate, the pressor response occurred as soon as any reduction in blood flow occurred, effectively eliminating the threshold and making the muscle metaboreflex tonically active; alternatively, muscle blood flow may be right at the threshold so that any reduction causes activation of the reflex (2, 11, 34, 36, 41). The strength or “gain” of the reflex could be estimated as the slope of the relationship between hindlimb blood flow (below the threshold for the reflex) and the cardiovascular response [e.g., arterial pressure, heart rate (HR), cardiac output (CO), or peripheral vascular responses] (2, 34, 36).
In humans, there is evidence that restricting blood flow to rhythmically contracting muscles elicits a similar reflex increase in blood pressure (7, 8, 17, 25, 26, 32, 37). In these studies, perfusion of the exercising limb was reduced by applying positive pressure to the limb. The positive pressure was increased in several steps, and the relationship between the applied pressure and the systemic cardiovascular response was assessed (7, 17, 25, 32). However, a limitation of this approach was that blood flow to the exercising skeletal muscle could not be sustained at a constant level because of the reflex presser response and the local vasodilation (7, 32). Consequently, this experimental model did not provide the open-loop relationship between active skeletal muscle blood flow and systemic cardiovascular responses that was established in dogs. To the best of our knowledge, the open-loop active muscle blood flow-systemic arterial pressure relationship had never been examined in humans. In the present study, therefore, we investigated the muscle metaboreflex threshold and gain during dynamic handgrip exercise in humans using a newly developed experimental model that created an open-loop relationship between active skeletal muscle blood flow and systemic cardiovascular responses. Next, using this model, we assessed the effect of exercise workload on muscle metaboreflex function. We hypothesized that, in humans, there is a threshold blood flow level needed to engage the muscle metaboreflex during rhythmic handgrip exercise and that increasing exercise intensity shifts that threshold to higher blood flow levels and reduces the change in flow necessary to elicit a reflex pressor response in a manner similar to that previously seen in dogs.
We studied 11 healthy volunteers (9 men and 2 women), with a mean age of 25 ± 1 yr, a body weight of 63.0 ± 2.0 kg, and a height of 170.9 ± 2.0 cm. None of the subjects was receiving medication and none smoked. The study was carried out in accordance with the Declaration of Helsinki and code of research activities of Meiji University and was approved by the Human Subjects Committee of the University of Tsukuba. Each subject gave informed written consent.
After entering the test room, which was maintained at 25°C, each subject adopted a supine position, then performed a maximum voluntary contraction (MVC) using a handgrip dynamometer held in the right hand, from which we determined the 5 and 15% MVC. Thereafter, a rapidly inflatable cuff for occlusion was placed on the upper arm, and the subject was allowed to rest for at least 15 min before data collection was begun.
The subjects performed three exercise protocols in random order. In protocol 1 (free-flow exercise), baseline data were acquired for 3 min before the start of the handgrip exercise, after which the subject performed rhythmic handgrip exercise for 18 min at 15% MVC (30 contractions/min with a duty cycle of 1-s contraction and 1-s relaxation). Visual feedback showing the achieved force was provided by an oscilloscope display, and a metronome was used to ensure correct timing. Five seconds before cessation of the exercise, the occlusion cuff at the upper arm was inflated to supersystolic pressure (>240 mmHg). The cuff remained inflated to produce a 2-min period of postexercise muscle ischemia (PEMI). Protocol 1 was designed to determine the responses during nonischemic exercise. In protocol 2 (ischemic exercise at 15% MVC), baseline data were acquired for 3 min, after which the subjects performed the rhythmic handgrip exercise for 18 min at 15% MVC. Beginning 3 min after the start of the exercise, forearm blood flow (FBF) was reduced in five steps by manipulating the inner pressure of the occlusion cuff. The FBF was continuously measured using Doppler ultrasound, and real-time beat-to-beat values were shown on a computer display. One experimenter used those FBF values as feedback while continuously manipulating the cuff pressure to clamp FBF at each step. The FBF was maintained for 3 min at each level. Protocol 3 (ischemic exercise at 5% MVC) was the same as protocol 2, except the exercise intensity was set at 5% MVC. Protocols 2 and 3 were designed to examine responses during ischemic exercise and to create an open-loop relationship between active muscle blood flow and hemodynamic responses at two exercise workloads. In protocol 2, we manipulated the occlusion cuff pressure so that FBF was reduced to ∼80% of the free-flow exercise level at the first occlusion. Thereafter, the cuff pressure was progressively increased, and FBF was reduced to ∼30% of the free-flow exercise level by the fifth occlusion. In protocol 3, the cuff pressure was manipulated so that FBF was reduced to ∼75% of the free-flow exercise level at first occlusion and to ∼15% of the free-flow level at the fifth occlusion. The target FBF levels at each occlusion in each protocol were fixed based on the results of our pilot studies such that the relationship between FBF and the selected hemodynamic parameters could be examined during exercise at two different workloads. The mean cuff pressures for the first occlusion in protocols 2 and 3 were set at 48 ± 2 and 44 ± 3 mmHg, respectively, and were progressively increased to 162 ± 4 and 151 ± 4 mmHg, respectively, by the fifth occlusion. The cuff pressure was regulated to never exceed the systolic arterial pressure (173 ± 7 and 161 ± 5 mmHg during fifth occlusion in protocols 2 and 3, respectively), thereby maintaining some level of FBF.
HR was monitored using a three-lead electrocardiogram (ECG). Beat-to-beat changes in blood pressure were assessed by finger photoplethysmography (Finometer; Finapres Medical Systems); the monitoring cuff was placed around the middle finger of the left hand, with the forearm and hand supported so that the cuff was aligned at the level of the heart. Stroke volume (SV) was measured by using a Minnesota impedance plethysmograph (20. Total vascular conductance (TVC) was calculated as TVC = CO/MAP, where MAP is mean arterial pressure.
We measured FBF using Doppler ultrasound as previously described (12, 19, 24). Briefly, a Doppler ultrasound system (HDI 5000; ATL Ultrasound) equipped with a hand-held transducer probe (model L12–5) with an operating frequency of 6 MHz was used to simultaneously measure two-dimensional brachial artery diameter and mean blood velocity (MBV). Figure 1 shows a schematic of FBF measurement during the rhythmic handgrip exercise. The measurement position was distal to the occlusion cuff in the upper arm. All Doppler data were recorded continuously on S-VHS videotape (ST-120; Maxell). The videotape record of the vessel image was digitized using a digital video board (PCI-1411; National Instruments) and stored on a personal computer equipped with software for measuring vessel diameter. The brachial artery diameters related to systole (Ds; mm) and diastole (Dd; mm) were taken as the largest and smallest diameter within each cardiac cycle, respectively. The mean diameter (Dm; mm) was calculated as Dm = Ds/3 + 2·Dd/3. We calculated Dm for each minute as the mean Dm value from 20 consecutive beats during the previous 30 s. The cross-sectional area of the brachial artery (CSA) was estimated using the representative Dm as CSA = (Dm/10/2)2·π. MBV was continuously estimated by means of a computer program developed with the aid of LabVIEW (version 6.0; National Instruments), as described in detail elsewhere (12, 24). Our system collects MBV at 100 Hz together with the analog signals representing the ECG and blood pressure waveform. Beat-to-beat MBV was calculated using an off-line data-analysis program. FBF was calculated as the product of MBV (cm/s) and brachial artery CSA (cm2) and was multiplied by 60 to obtain values expressed in terms of milliliters per minute. During the exercise protocol, our system calculated the FBF in real time and showed the beat-to-beat values on a computer display. Individual ratings of perceived exertion (based on the 6–20 Borg scale) were obtained at the end of each 3 min of handgrip exercise (3).
All data were averaged over each minute. In protocols 2 and 3, the initial reductions in forearm perfusion did not elicit any cardiovascular responses; however, once forearm perfusion fell below a threshold level, a pressor response occurred. This nonlinear pattern of cardiovascular responses to graded reductions in FBF was assessed using procedures described in previous studies in dogs (2, 11, 34, 36, 41). Hemodynamic variables (e.g., MAP) were plotted against FBFs measured during the last minute of the free-flow exercise and each partial occlusion, and the two resultant regression lines were fitted to the data as shown in Fig. 2B. The initial response line shows that no reflex responses occurred during the initial reductions in forearm perfusion while the pressor response line shows that further reductions in forearm perfusion elicited a reflex pressor response (muscle metaboreflex). The threshold for the muscle metaboreflex was approximated as the intersection between these two regression lines. The gain of the reflex was then estimated as the slope of the relationship between the cardiovascular responses and FBF below the reflex threshold (e.g., during muscle metaboreflex activation). Because there was no significant relationship between SV and FBF or between CO and FBF, we did not calculate the threshold or gain of the SV and CO responses.
Data are presented as means ± SE. Two-way repeated-measures ANOVA with post hoc Tukey's test was performed to compare the cardiovascular responses between protocol 1 (nonischemic exercise at 15% MVC) and protocol 2 (ischemic exercise at 15% MVC) and between protocol 2 and protocol 3 (ischemic exercise at 5% MVC). Student's paired t-test was used to compare FBFs at the muscle metaboreflex threshold or the gains of the reflex between the 5 and 15% MVC trials. The characteristics of the relationship between FBF and cardiovascular responses were determined using least-squares linear regression analysis. Values of P < 0.05 were considered significant.
Table 1 shows the cardiovascular responses during the free-flow and ischemic exercises. Representative data illustrating the pressor responses to graded reductions in FBF during exercise at 15% MVC are shown in Fig. 2. In addition, Fig. 3 shows the average values for MAP, HR, SV, CO, and TVC during exercise at 5 and 15% MVC at the following three FBF levels: 1) with no imposed reductions in FBF (free flow), 2) at the threshold FBF for the muscle metaboreflex, and 3) at the minimum FBF. All of the hemodynamic parameters except SV increased and then plateaued during free-flow exercise at 15% MVC. MAP, HR, CO, and TVC then returned to their resting levels during the PEMI, indicating that the muscle metaboreflex was not activated during free-flow exercise. During the free-flow phase of the 5% MVC exercise, MAP and SV did not change significantly, but we observed increases in HR, CO, TVC, and FBF. In both the 5 and 15% MVC trials during the ischemic exercise, the initial occlusion period had no marked effect on any of the cardiovascular parameters. However, once FBF reached the threshold for the muscle metaboreflex, further reductions in FBF caused marked increases in MAP and HR and a decrease in TVC. The reductions in FBF did not affect SV in the 5% MVC trial, but SV slightly but significantly declined in the 15% MVC trial. CO was not significantly affected by the reductions in FBF at either workload. MAP and HR during the fourth and fifth occlusions were higher, and SV during the fourth occlusion was lower, in the 15% MVC trial than the 5% MVC trial. Brachial artery diameter did not change from the resting diameter at any setting across all conditions (0.44 ± 0.02 vs. 0.44 ± 0.02 vs. 0.43 ± 0.02 cm in free-flow exercise at 15% MVC, ischemic exercise at 5% MVC, and ischemic exercise at 15% MVC, respectively).
Figure 4 shows the FBFs at the muscle metaboreflex thresholds for the MAP, HR, and TVC responses expressed as absolute values and as percentages of free-flow exercise levels. The threshold was calculated separately for each parameter at both workloads. At both workloads, there was no significant difference in the calculated muscle metaboreflex thresholds for MAP, HR, and TVC, indicating the reflex modulates these three parameters in concert. When we compared the 5 and 15% MVC trials, we found that the reflex threshold in the 15% MVC trial was at a significantly higher FBF level than in the 5% MVC trial. The threshold was ∼65% of the FBF during free-flow exercise in the 15% MVC trial and was ∼45% of the free-flow exercise level in the 5% MVC trial. Thus a significantly smaller reduction in FBF from the free-flow level was needed to activate the muscle metaboreflex at the higher workload.
Figure 5 shows the muscle metaboreflex gains for MAP, HR, and TVC. The gains for the MAP response (−0.45 ± 0.07 vs. −0.49 ± 0.05 mmHg·(ml·min−1)−1 at the 5 and 15% MVC trials, respectively) and the TVC response (0.35 ± 0.09 vs. 0.26 ± 0.07 ml·min−1·mmHg−1·(ml·min−1)−1 at the 5 and 15% MVC trials, respectively) did not differ between the two workloads. On the other hand, the gain of the HR response was significantly greater in the 15% MVC trial than the 5% MVC trial (−0.11 ± 0.04 vs. −0.26 ± 0.04 beats·min−1·(ml·min−1)−1 at the 5 and 15% MVC trials, respectively).
Although we could not make a reliable statistical comparison between the responses of the female and male subjects because we had only two female subjects, we did not see any important gender differences in the results. We also had one left-handed subject who performed the rhythmic handgrip exercise in the nondominant hand. The cardiovascular responses of this subject were not importantly different from those of the right-handed subjects.
To the best of our knowledge, this is the first study to characterize muscle metaboreflex function in humans by creating an open-loop relationship between active skeletal muscle blood flow and systemic hemodynamic responses. Our experimental model revealed the threshold blood flow level needed to engage the muscle metaboreflex during a rhythmic handgrip exercise as well as the gain of the reflex expressed as the slope of the reflex response vs. blood flow. We found that increasing exercise intensity shifted the threshold of the muscle metaboreflex to higher blood flow levels, thereby reducing the change in blood flow necessary to elicit a reflex pressor response in a manner similar to that previously seen in dogs. In addition, the exercise level did not influence the gain of the reflex for the MAP and TVC responses, but the gain of the HR response was enhanced at higher workloads.
Wyss et al. (41) established an experimental model to investigate muscle metaboreflex function in dogs by creating an open-loop relationship between active muscle blood flow and systemic hemodynamic responses during dynamic exercise. They showed that, at low workloads, a substantial reduction in active muscle blood flow (∼50% of free-flow exercise condition) is needed to evoke a pressor response. They also showed that increases in the workload shift the muscle metaboreflex threshold to higher blood flow levels and reduce the change in blood flow necessary to evoke the reflex pressor responses. In the present study, we made similar observations in humans. In the 5% MVC trial, active muscle blood flow had to be reduced by ∼60% from that in the free-flow exercising situation to activate the muscle metaboreflex. In the 15% MVC trial, by contrast, a significantly smaller reduction in active muscle blood flow (∼40% from the free-flow level) elicited the reflex. There was thus a substantial shift in the threshold to higher blood flow levels compared with the 5% MVC trial. These results imply that regulation of the balance between blood supply to and metabolic demand within exercising muscle is an important determinant of exercise performance, since accumulation of metabolites causes muscle fatigue. Apparently, the contribution to cardiovascular control made by metabolic feedback from an exercising muscle is dependent on both the adequacy of the muscle perfusion and the work performed by the muscle. In both the 5 and 15% MVC trials, unrestricted forearm perfusion was well above the threshold for any substantial ischemic pressor reflex, so that the muscle metaboreflex was not tonically active.
In both the 5 and 15% MVC trials, the gain of the muscle metaboreflex expressed as the ratio of the pressor response to the reduction in blood flow was approximately −0.45 mmHg·(ml·min−1)−1. The gains for the HR responses were approximately −0.11 and ∼−0.26 beats·min−1·(ml·min−1)−1 in the 5 and 15% MVC trials, respectively. These values are substantially greater than the gains of the MAP [−0.18 to −0.065 mmHg·(ml·min−1)−1] and HR [approximately −0.06 beats·min−1·(ml·min−1)−1] responses seen in dogs performing a mild treadmill exercise (2, 36). One possible physiological explanation for the apparent difference between the gains of the reflex in dogs and humans is that human skeletal muscle has a lower oxidative capacity than that of dogs (10), and that metabolites associated with anerobic metabolism accumulate at a greater rate in humans, once blood flow falls below the threshold of the muscle metaboreflex. In addition, the difference in the type of exercise could also account for these differences. For example, oxygen delivery (or blood flow) relative to the metabolic demand of the active skeletal muscles during treadmill exercise (i.e., hindlimb muscles) and rhythmic handgrip (i.e., forearm muscles) may differ, which would influence gain. Furthermore, in contrast to the whole body dynamic exercise employed in the dog studies, very little muscle mass is activated during rhythmic handgrip. This difference in the muscle mass activated during exercise could affect cardiovascular responses during exercise and during muscle metaboreflex activation. Moreover, the ischemic exercise was performed using different limbs (i.e., upper limb in this study vs. hindlimb in the dog studies), and this also might contribute to the observed differences between the results of the present study and the earlier dog studies.
Another plausible explanation for the observed differences in metaboreflex gain is that different procedures for reducing blood flow were employed in the present study in humans and the earlier studies in dogs. In dogs, hindlimb blood flow was reduced through partial occlusion of the terminal aorta using a vascular occluder (2, 41). We reduced flow both into and out of the forearm through arteriovenous occlusion using a cuff. Once the metabolites started to accumulate in the muscle, their rate of accumulation would be greater with arteriovenous occlusion than with only arterial occlusion given the same reduction in active muscle blood flow (i.e., inflow), since the reduction in outflow would hinder their washout. Nonetheless, the open-loop active skeletal muscle blood flow-systemic pressor response relationship observed in the present study appears very similar to that characterized in earlier studies in dogs (2, 34, 36, 41), although careful consideration of the differences in species, type of exercise, and methodology used for reducing blood flow is needed when comparing results from dogs and humans.
Activation of the muscle metaboreflex during submaximal treadmill exercise in dogs reportedly elicits a pressor response primarily by increasing CO, without significantly affecting vascular conductance in the nonischemic area (2, 11, 41). The rise in CO reflects increases in HR, ventricular contractility, and central blood volume mobilization (5, 16, 28, 33, 35). By contrast, we did not find an important increase in CO during activation of the muscle metaboreflex in humans. However, we did observe significant tachycardia, and the lack of an increase in CO was due to a small reduction in SV, which was most likely caused by an increase in left ventricular afterload. Interestingly, Nishiyasu et al. (27) found that, upon activation of the muscle metaboreflex during PEMI in humans, SV and CO declined slightly, despite an increase in left ventricular contractility. It is therefore likely that, during activation of the muscle metaboreflex in humans, the increase in left ventricular contractility is not enough to sustain SV in the face of a substantial increase in afterload. The tachycardia observed during muscle metaboreflex could also contribute to the decrease in SV by shortening the left ventricular filling time (21, 40). In addition, subjects adopted a supine posture in this study, which would increase left ventricular preload both at rest and during the rhythmic handgrip exercise, even before the muscle metaboreflex was engaged. Hence, muscle metaboreflex activation might not cause a further increase in preload. Another possibility is that, in the dog studies, the hindlimbs account for only a fraction of the active muscle, the rest of which (as well as the hindlimbs) continued to pump blood back to the heart to maintain, or even increase, preload, despite the rise in CO during activation of the muscle metaboreflex (35). Our model lacks this locomotor muscle function of a large muscle mass to act as a “skeletal muscle pump.” Consequently, preload might not have been maintained during activation of the muscle metaboreflex, resulting in a reduction in SV. Further studies are clearly needed to better understand the muscle metaboreflex control of cardiac function during dynamic exercise in humans.
We found that, in humans performing a rhythmic handgrip exercise, activation of the muscle metaboreflex elicits a pressor response primarily through peripheral vasoconstriction, without a significant rise in CO. Our results are consistent with earlier studies showing that, in humans, activation of chemosensitive afferents causes a marked increase in vasoconstrictor efferent muscle sympathetic nerve activity, leading to peripheral vasoconstriction (7, 12–14, 17, 18, 27, 37). It has been suggested that, during ischemic exercise in humans, sympathetic vasoconstriction occurs within the exercising muscle, which may prevent restoration of blood flow to ischemic active muscle because of the rise in pressure (7, 17, 18). However, other studies have reported an increase in CO during muscle metaboreflex activation (6, 8, 25, 32). Although we cannot provide a definitive explanation for this inconsistency, differences in the experimental model used, the type of exercise employed, the amount of muscle mass used in the exercise, and the intensity of the exercise (i.e., activation level of the muscle metaboreflex) could lead to different results.
We do not know the precise mechanism underlying the increase in the gain of the HR response in the 15% MVC trial compared with the 5% MVC trial. It has been shown, however, that muscle metaboreflex-induced tachycardia is primarily due to increased sympathetic activity (29). Therefore, the observed increase in the gain of the HR response might reflect control of cardiac sympathetic activity by the muscle metaboreflex. On the other hand, there was no change in the gain of the TVC response, suggesting no alteration of sympathetic activity to resistance vessels. This suggests that different workloads may have different effects on muscle metaboreflex control of sympathetic activity affecting the heart and resistance vessels. Another possibility is that the altered HR gain might be a consequence of the interaction between the muscle metaboreflex and the baroreflex in the control of cardiac autonomic nervous activity. It has been reported that, during PEMI-induced muscle metaboreflex activation, the pressor response leads to baroreceptor activation and, in turn, an increase in cardiac parasympathetic activity (9, 13, 27, 39). If this baroreflex engagement occurred during the graded FBF reductions, it could have affected the HR response to changes in flow. By inducing sympathetic and parasympathetic blockade, Fisher et al. (9) recently showed that muscle metaboreflex activation following handgrip exercises of different intensities increases cardiac sympathetic nerve activity during PEMI in humans and affects HR control when the metabolic stimulus is strong enough to overcome the increased cardiac parasympathetic activation resulting from baroreflex engagement. Those findings suggest that, in the present study, the graded reductions in FBF at higher exercise workloads could provide a metabolic stimulus strong enough for cardiac sympathetic nerve activity to prevail over the baroreflex-mediated increase in cardiac parasympathetic nerve activity, resulting in an increase in HR gain.
An alternative explanation for part of the pressor response during graded reduction of FBF is that muscle fatigue would require recruitment of more motor units to maintain force, and thus central command would be increased. In fact, ischemic exercise was clearly perceived as more fatiguing than free-flow exercise (Table 1). During small muscle mass exercise in an earlier study, central command did not increase sympathetic outflow to muscles until effort was nearly maximal (38). In the present study, effort was nearly maximal at the end of the 15% MVC trial, so central command may have contributed to the increased sympathetic activity to the resistance vessels during this period. In addition, HR is known to rise with increased central command, which may have contributed via cardiac vagal inhibition to the increased HR gain seen during the 15% MVC trial. Another possibility is that the venous occlusion caused blood pooling in the forearm, leading to increased intramuscle pressure, which would then be further increased by muscle contraction, thereby increasing activation of sympathoexcitatory group III mechanosensitive afferents (22, 23, 30). The blood pooling would have almost certainly occurred at all occlusion levels, since the applied cuff pressure was higher than the venous pressure from the first occlusion. That we observed no significant cardiovascular responses at the initial occlusion levels suggests the effect of blood pooling on the systemic hemodynamics under these conditions was marginal. However, because blood volume in the forearm would have continued to increase for as long as the occlusion remained, the muscle mechanoreflex may have been enhanced at later occlusions and contributed to the pressor responses seen during the graded FBF reductions. Metaboreflex activation techniques such as arterial vascular occluders (11, 15, 34, 36, 41), intra-arterial balloon catheters (4), and external positive pressure box (7, 8, 17, 25, 26, 32) generate little if any venous blood flow stasis; thus, the potential influences from venous blood pooling-congestion are not considered when employing these techniques.
In conclusion, our experimental model demonstrated the threshold and gain of the muscle metaboreflex in humans by creating an open-loop relationship between active muscle blood flow and the hemodynamic responses to dynamic handgrip exercise. Our results show that increasing workload shifts the muscle metaboreflex threshold to higher blood flow levels and therefore reduces the change in blood flow necessary to elicit a reflex pressor response. In addition, we found that the exercise level does not influence the gain of the reflex for the MAP and TVC responses, but the gain of the HR response was enhanced at higher workloads.
This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Overseas Outreach Program of Meiji University.
No conflicts of interest are declared by the authors.
We thank the volunteer subjects.
- Copyright © 2011 the American Physiological Society