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J Appl Physiol 104: 716-723, 2008. First published December 13, 2007; doi:10.1152/japplphysiol.00956.2007
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Modulation of spontaneous baroreflex control of heart rate and indexes of vagal tone by passive calf muscle stretch during graded metaboreflex activation in humans

Rachel C. Drew, Martin P. D. Bell, and Michael J. White

School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

Submitted 11 September 2007 ; accepted in final form 12 December 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
We examined whether spontaneous baroreflex modulation of heart rate and other indexes of cardiac vagal tone could be altered by passive stretch of the human calf muscle during graded concurrent activation of the muscle metaboreflex. Ten healthy subjects performed four trials: a control trial, resting for 1.5 min (0% trial); or 1.5 min of one-legged isometric plantar flexor exercise at 30, 50, and 70% maximal voluntary contraction. The incremental increases in blood pressure (BP) caused were then partially sustained by subsequent local circulatory occlusion (CO). After 3.5 min of CO alone, sustained calf stretch and CO were applied for 3 min. Spontaneous baroreflex sensitivity (SBRS) was progressively decreased with increasing exercise intensity (P < 0.05). During CO, stretch decreased SBRS and increased BP similarly in all trials (P < 0.05). Within 15 s of stretch onset, heart rate (HR) increased by 6 ± 1, 6 ± 1, 8 ± 1, and 6 ± 2 beats/min in the 0, 30, 50, and 70% trials, respectively (P < 0.05), and root mean square of successive differences was decreased from CO-alone levels (P < 0.05). During the second and third minutes of stretch, HR fell back but remained significantly above CO levels, and common coefficient of variance of R-R interval decreased progressively with increasing prior exercise intensity (P < 0.05; 70% trial). This suggests that passive stretch of the human calf muscles decreases cardiac vagal outflow irrespective of the levels of BP increase caused by muscle metaboreflex activation and implies that central modulation of baroreceptor input, mediated by the actions of stretch-activated mechanoreceptive muscle afferent fibers, continues.

spontaneous baroreflex sensitivity; muscle afferent

IT IS NOW WELL ESTABLISHED that mechanoreceptive muscle afferents contribute a significant proportion of the drive controlling the cardiovascular system during exercise (1, 2, 11, 12). The sensitivity of afferent fibers to mechanical stimuli is believed to be linked to the expression of different receptor subtypes (10, 13, 17, 19, 24), and differences in receptor type and density are likely to explain why mechanoreflex sensitivity can in turn be linked to muscle fiber type, training status, and severity of disease states, e.g., chronic heart failure (CHF) (9). Some afferent fibers may be purely mechanosensitive (2, 12, 16), but the response of others to mechanical stimulation is influenced by the prevailing local metabolic conditions (2, 5, 15, 23, 24, 32, 33). A further distinction can be made between populations of afferents that respond to passive tendon stretch or active force generated by muscle contraction (14). This makes it quite difficult to develop tests of muscle mechanoreflex involvement in human cardiovascular control during exercise and to establish whether muscle mechanoreflex sensitivity has been changed by training or disease. Further complexity is added when it is considered that during voluntary exercise, central command plays a role in the cardiovascular control system, as does activation of the muscle metaboreflex, if metabolites are accumulated in sufficient quantity. This makes it even more difficult to attribute the precise contribution made by mechanoreceptive afferents to any cardiovascular change during voluntary exercise.

A number of different approaches have been used to try to evaluate the contribution of the muscle mechanoreflex to human cardiovascular control in exercise. For example, electrically evoked exercise has been used to remove central command (6). When this is followed by a period of circulatory occlusion (CO) to establish the contribution of the muscle metaboreflex, the muscle mechanoreflex contribution to the exercise pressor response is then revealed by subtracting the response during CO from that seen during evoked exercise (6). Alternatively, the role of muscle mechanoreceptive afferents in human cardiovascular control has been examined using passive stretch (7, 8, 11, 12) or external compression of muscle (5, 20, 38) in resting subjects. There have also been attempts to examine metabolite sensitization of the mechanoreflex by applying these techniques during CO following isometric exercise (5, 8).

Although abnormal muscle afferent feedback has been linked to overactivation of the sympathetic nervous system and effort intolerance in disease states such as CHF, here the exact role of muscle mechanoreceptors remains fiercely disputed (6, 18, 25, 29, 35). This is largely because of the methodological problems outlined above, and indeed the search for a test of muscle mechanoreflex sensitivity in humans is ongoing.

For both practical and theoretical reasons, it has proved quite difficult to establish a reliable method for examining the influence of the muscle mechanoreflex on efferent sympathetic nerve activity in humans. The apparently small and transient effect of mechanoreceptor activation via passive stretch on human muscle sympathetic nerve activity (7), even in patients thought to possess increased muscle mechanoreflex sensitivity (25), suggests that this approach is unlikely to lead to a universally useful tool with which to examine the level of muscle mechanoreceptor afferent activation. In the present study, we have taken a different approach in the search for a noninvasive tool that reveals muscle mechanoreflex involvement and sensitivity in human cardiovascular control. With this goal in mind, we set out to examine the influence of controlled passive muscle stretch on parasympathetically-mediated changes in heart rate (HR), R-R interval (RRI), and spontaneous baroreflex sensitivity (SBRS) applied during CO at rest and following graded increases in isometric exercise intensity.

Gladwell et al. (12) demonstrated that in resting humans, activation of mechanoreceptive afferents by passive calf muscle stretch decreased indexes of vagal tone and caused HR to rise, by vagal inhibition. They termed the mechanoreceptive afferents responsible for this response, "tentonoreceptors." Using different intensities of isometric calf exercise followed by CO to manipulate metabolic conditions in the muscle interstitium, Fisher et al. (8) showed that cardiovascular changes caused by a short but standard passive stretch stimulus of the same calf were not influenced by the level of preceding exercise. They argued that this indicated unchanged sensitivity of muscle mechanoreceptive afferents during stretch, irrespective of metabolite accumulation. It is known that CO following increasingly intense calf exercise results in progressively greater blood pressure (BP) elevations (4, 8). Higher BP inevitably causes greater activation of baroreceptors, so increasing their afferent input to the nucleus tractus solitarius (NTS). This input is known to exert a powerful modulatory effect on cardiac vagal outflow under both resting and exercise conditions (36). Against this background of increased baroreceptor activation, the effects of a standardized mechanoreceptor afferent input might therefore be expected to become less effective at modulating vagal tone and altering HR (21, 30). However, if there is metabolite sensitization of the mechanoreceptors and so their activation during a standard stretch stimulus is increased, then it might be hypothesized that changes in HR and indexes of vagal tone would be maintained during stretch, despite elevated baroreceptor activation. This idea, although noted by Gladwell et al. (12) and Fisher et al. (8), has not been fully explored, especially the influence of a longer stretch period. The practical advantage of this longer data collection period is that it allows the use of the SBRS technique, a robust measure of the cardiac arm of the baroreflex and index of vagal tone (28). Furthermore, knowledge of the behavior of such measures during the present experimental conditions could be useful in the development of future tests of muscle mechanoreflex sensitivity in humans. Therefore, we have sought to extend the studies of Gladwell et al. (12) and Fisher et al. (8) to examine whether HR, SBRS, and other indexes of vagal tone can be altered by passive stretch of the human calf muscle against a background of increased metabolite accumulation and BP elevation. We hypothesize that passive calf muscle stretch will alter cardiac vagal control at rest and will still do so during CO following isometric exercise of progressively increasing intensities, irrespective of increased BP elevation.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Ten healthy subjects (7 male) aged 22 ± 1 yr (mean ± SE) were recruited from the University of Birmingham student population (weight 71 ± 4 kg, height 171 ± 3 cm). All subjects gave informed written consent and were habituated to the experimental procedures, which were approved by the local ethics committee and conformed to the Declaration of Helsinki (2000). Subjects were asked to refrain from consuming food and caffeine in the 2 h preceding the trials and from performing strenuous exercise in the 24 h preceding the trials. Each subject participated in all four experimental trials once (after completing a habituation session), with no more than one trial performed each day, and the order of all trials was randomized.

Experimental protocol.   Subjects were seated in a semi-recumbent position in a Biodex System 3 Pro isokinetic dynamometer (Biodex Medical Systems, Shirley, NY) with the right knee flexed by 30° and the foot strapped to the footplate so the lower leg was horizontal to the floor. Velcro straps were used to fix the foot and minimize heel lift during voluntary plantar flexor exercise and passive stretch. Before each trial, passive range of dorsiflexion of the ankle joint was established by manually moving the footplate as far as was comfortable. This information was programmed into the machine so that the subsequent stretching movement could be performed automatically by the Biodex. Maximal voluntary contractions (MVC) of the calf plantar flexors were assessed by recording maximal efforts and accepting three that were within 5% of each other. During all trials, subjects breathed to a metronome set at a rate that they found to be most comfortable.

A schematic diagram of the experimental protocol is shown in Fig. 1A. After subjects were settled for 10 min, the protocol began with a 5-min baseline period. 10 s before the end of this period, a cuff placed around the right thigh was inflated to 200 mmHg by a rapid cuff inflator (model E20, Hokanson, Bellevue, WA) and this remained inflated for a further 9 min. At the end of the rest period, subjects were instructed to either rest for a further 1.5 min (0% control trial), or perform ischaemic isometric plantar flexion using their right calf muscles to produce a torque that matched a predetermined exercise intensity of 30, 50, or 70% MVC, for 1.5 min. The level of torque produced during the exercise period was displayed on a computer screen in front of the subjects for visual feedback. After a further 3.5 min of local CO, the foot was passively dorsiflexed by the Biodex to the preset angle at a velocity of 30°/s, and it was held there for the next 3 min with continued occlusion. After this stretch period, the foot was returned to its starting position and local CO continued for a further 1 min. The thigh cuff was then deflated to restore circulation to the lower leg and subjects recovered in situ for a further 2 min.


Figure 1
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  		Fig. 1. A: schematic diagram of experimental protocol. EX, exercise; STR, stretch. B: original recording of a typical torque trace during the whole 3-min stretch phase. Scale; 0.1 V = 3.57 N·m.

 
Measured variables.   RRI was measured using a three-lead electrocardiogram (ECG; Cardiorater CR7, Cardiac Records, London, UK) in the lead II position, from which HR was derived. BP was measured noninvasively using a Finapres (Ohmeda 2300, Louisville, CO) on the middle finger of the right hand, which was supported at heart level. Phase of respiratory cycle was monitored using a band strapped around the subjects' chest that was attached to a strain gauge. Active and passive plantar flexor torques were recorded using the Biodex. All signals were sampled by an analog-to-digital converter (Cambridge Electronic Design 1401plus, CED, Cambridge, UK) at 100 Hz, with the exception of the ECG signal, which was sampled at 1,000 Hz. Data were recorded and displayed using Spike 2 software (CED).

SBRS at the operating point of the baroreflex function curve was assessed offline using the sequence technique, which involved detecting sequences of three or more successive beats where systolic BP (SBP) and RRI were either both increasing or both decreasing. Regression equations from these sequences of SBP (x-axis) and RRI (y-axis) provided slope values representative of SBRS and provided intercept values. These slope values also provide an index of cardiac vagal tone because they disappear almost completely after injection of atropine (28). Root mean square of successive differences (RMSSD) assesses the variation between RRIs by calculating the square root of the mean of the sum of the squares of differences between successive RRIs. This is a recommended time-domain measure of short-term HR variability, and it is a sensitive index of vagal tone (37). RMSSD was calculated over four 15-s periods during the 1 min preceding stretch and the first two 15-s periods of stretch (the time of the greatest HR changes during stretch). A third index of vagal tone, common coefficient of variance (CCV), measures the variation between RRIs when normalizing for different HRs, which removes the confounding influence of smaller RRIs (higher HRs) having naturally less variation between RRI. This was calculated using the following formula:-(standard deviation of RRI/mean RRI) x 100 (3). CCV was calculated for the 3 min of local CO before stretch and the last 2 min of stretch with continued occlusion (which excluded the first minute of stretch to ensure only stable HR data were analyzed).

Statistical analysis.   Raw data files were analyzed using custom-written script files to produce beat-to-beat values for RRI, HR, SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP). Fifteen-second averages were calculated for each subject over the whole protocol, and these were averaged across the group to produce group means during each period and each condition. The first two 15-s averages following exercise were excluded from the group means calculation, as only steady-state data was required for the CO phase. SBRS was calculated using a custom-written sequence analysis program, and only baroreflex sequences with correlation coefficients >0.95 were accepted. Mean SBRS values were calculated from all slope data for the rest (5 min), exercise (1.5 min), CO (3 min), and stretch with concurrent CO (3 min) phases of the protocol. HR variability analysis was performed using Nevrokard software (Medistar, Ljubljana, Slovenia). All values are expressed as means ± SE. One-way and repeated-measures ANOVA or paired-samples t-tests were used to identify significant differences within the protocol. Statistical significance was set at P < 0.05, and if this was reached using ANOVA, post hoc analysis using paired-samples t-tests with a Bonferroni correction was performed (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Contraction and stretch torques.   No MVCs were measured before the 0% control trial as no exercise was performed in this trial. MVCs measured before each exercise trial were not significantly different between conditions, with values of 128.8 ± 6.9, 124.9 ± 6.1, and 123.6 ± 6.8 N·m being recorded before the 30, 50, and 70% MVC trials, respectively. Exercise torques averaged 38.6 ± 2.1, 62.4 ± 3.1, and 86.5 ± 4.8 N·m for the 30, 50, and 70% trials, respectively. The range of ankle motion assessed by passive stretch was not significantly different between conditions, with an overall mean of 31 ± 1° of dorsiflexion from vertical. There was no significant difference between peak torques during stretch in the 30, 50, and 70% trials. Values of 25.2 ± 4.0, 23.8 ± 3.9 and 25.5 ± 5.4 N·m, respectively, were seen within the first 5 s of stretch. This corresponded to 20, 19, and 20% of the MVC assessed before the 30, 50, and 70% trials, respectively. By the end of the stretch period, torque had fallen significantly from initial levels in all conditions. Torque decreased to 60, 55, and 57% of the initial peak levels (14.7 ± 2.0, 12.8 ± 1.8, and 14.0 ± 2.7 N·m) by the end of stretch in the 30, 50, and 70% trials, respectively (Fig. 1B).

Cardiovascular variables.   HR, MAP, and DBP values in the rest phase were not significantly different between conditions (Table 1). However, SBP in the rest phase during the 50 and 70% trials was significantly higher than during the 0% trial (P < 0.05). BP increased from baseline during exercise and was elevated above baseline during local occlusion following exercise. The magnitude of this change was related to increasing exercise intensity. SBP, MAP and DBP changed with similar time course during the different phases of the protocol, so for simplicity and in keeping with our previous publications, we illustrate only the DBP response to the different trials.


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  		Table 1. Resting values for cardiovascular variables for the 0, 30, 50, and 70% trials

 
DBP and HR changes from rest during the whole protocol are shown in Fig. 2, A and B, respectively. DBP and HR rose progressively during exercise, reaching significantly higher levels with increasing exercise intensity (P < 0.05). During CO, DBP fell from end-exercise levels but remained significantly elevated above baseline in all exercise trials, with significantly greater elevation with increasing exercise intensity (P < 0.05). Stretch, applied to the limb with no prior exercise and when applied during CO following progressively more intense exercise, caused a progressive increase in DBP over the 3 min (P < 0.05). This increased DBP by an average of 4 ± 1, 4 ± 1, 4 ± 0, and 2 ± 1 mmHg during the 0, 30, 50, and 70% trials, respectively (Fig. 3A). There was no significant difference in the magnitude of the change between trials (P = 0.809). Once stretch was removed, there was a significant fall in DBP (P < 0.05) but it remained elevated above resting levels during the continued occlusion.


Figure 2
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  		Fig. 2. A: group mean changes from rest in diastolic blood pressure (DBP) during each phase of the 0, 30, 50, and 70% maximal voluntary contraction (MVC) trials. *Significant effect of condition P < 0.05. {dagger}Significant effect of time P < 0.05. B: group mean changes from rest in heart rate (HR) during each phase of the 0, 30, 50, and 70% trials. b.min–1, Beats/min. *Significant effect of condition, P < 0.05. {dagger}Significant effect of time, P < 0.05.

 

Figure 3
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  		Fig. 3. A: group mean (±SE) changes from rest in diastolic blood pressure (DBP) during circulatory occlusion (CO)-alone (CO), stretch with concurrent CO (Stretch), and poststretch CO-alone (Post) phases of the 0, 30, 50, and 70% MVC trials. *Significantly different from CO and Post, P < 0.05. *(Above Bracket) Significantly different from 0% trial, P < 0.05. B: group mean (±SE) changes from rest in HR during CO, Stretch, and Post phases of the 0, 30, 50, and 70% trials. *Significantly different from CO and Post, P < 0.05.

 
After exercise, HR fell from end-exercise levels in all trials and returned to resting values, with the exception of the 70% trial where HR remained significantly elevated above rest (P < 0.05). At the onset of stretch, there was an immediate increase in HR (P < 0.05), which was of a similar magnitude in each trial. Stretch increased HR by 6 ± 1, 6 ± 1, 8 ± 1, and 6 ± 2 beats/min during the 0, 30, 50, and 70% trials, respectively, within the first 15 s of stretch. This peak value was not sustained throughout the whole stretch phase, where the HR increase averaged 3 ± 1, 4 ± 1, 3 ± 2, and 1 ± 1 beats/min during the 0, 30, 50, and 70% trials, respectively (P < 0.05; Fig. 3B). Once stretch was removed, HR fell to prestretch levels (P < 0.05).

Baroreflex sensitivity.   There was no significant difference in SBRS during the rest phases of the four trials (Table 2). When exercise was performed, there was a significant decrease in SBRS (P < 0.05), with significantly greater decreases occurring during exercise of greater intensity (P < 0.05). During CO following rest or exercise, SBRS returned to resting levels. During stretch with concurrent CO, there was a significant decrease in SBRS (P < 0.05), which was of a similar magnitude in each trial. From CO-alone levels, stretch decreased SBRS by 1.2 ± 0.9, 1.1 ± 0.6, 2.5 ± 0.9, and 2.0 ± 0.6 ms/mmHg in the 0, 30, 50, and 70% trials, respectively.


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  		Table 2. Slope values from sequence analysis, representing spontaneous baroreflex sensitivity

 
There was no significant difference in the mean intercept of the regression lines, which were calculated from the sequence data, during the rest phases of all trials (Table 3). When exercise was performed, there was a significant increase in intercept (P < 0.05), with significantly greater increases occurring during exercise of greater intensity (P < 0.05). During CO following rest or exercise, intercepts returned to resting levels and remained at these levels thereafter.


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  		Table 3. Intercept values from sequence analysis

 
HR variability.   Over the phase of the experimental protocol examined with this technique (transition from CO to stretch with concurrent CO), there was no significant difference between trials in RMSSD, so the data were pooled to give mean value for each time point. CO –4, CO –3, CO –2 and CO –1 are the last four 15-s periods of CO, and S +1 and S +2 are the first two 15-s periods of stretch with concurrent CO (Fig. 4). There was no significant difference in RMSSD during the CO-alone time points. At the onset of stretch, there was an immediate and significant decrease in RMSSD (P < 0.05). From a mean CO-alone level of 42.2 ± 1.2 ms, stretch decreased RMSSD to 31.2 ± 2.3 ms, within the first 15s of stretch (coincident with the peak torque values obtained during stretch; see Fig. 1B).


Figure 4
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  		Fig. 4. Group mean (±SE) ensemble averages of root mean square of successive differences (RMSSD) for the last four 15-s periods of CO alone (CO –4, CO –3, CO –2, and CO -1) and the first two 15-s periods of stretch with concurrent CO (S +1 and S +2). *Significantly different from CO-alone time points, P < 0.05.

 
Mean CCV values during CO following rest or exercise were 3.8 ± 0.4, 3.9 ± 0.4, 4.3 ± 0.6, and 4.6 ± 0.3% in the 0, 30, 50, and 70% trials, respectively, and this decreased to 3.7 ± 0.4, 3.4 ± 0.4, 3.5 ± 0.2, and 3.2 ± 0.2% during the last 2 min of stretch with concurrent CO. The magnitude of this decrease became progressively greater with higher preceding exercise intensity (Fig. 5), with CCV being significantly lower in the 70% compared with the 0% trial (P < 0.05).


Figure 5
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  		Fig. 5. Group mean (±SE) changes from CO alone in common coefficient of variance (CCV) with application of concurrent stretch during the 0, 30, 50, and 70% MVC trials. *Significantly different from 0% trial, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
The major new finding in this study is that passive stretch of the calf muscles after rest or increasingly intense isometric exercise caused similar decreases in spontaneous cardiac baroreflex sensitivity, and other indexes of vagal tone, irrespective of the level of blood pressure sustained by circulatory occlusion.

Murata and Matsukawa (26) found that in a decerebrate cat preparation, cardiac vagal tone decreased gradually during sustained passive stretch of the hindlimb or the triceps surae. The HR rise that this caused was therefore slow in onset. However, Gladwell and Coote (11) demonstrated that passive stretch of resting human calf muscle caused an immediate increase in HR. They suggested that this was caused by activation of a population of mechanoreceptive afferents, which they termed tentonoreceptors. Subsequently, they provided evidence from pharmacological blockade (glycopyrrolate) and time-domain analysis (RMSSD) that the initial HR rise during stretch is mediated by immediate vagal inhibition (12). In the present study, we found that during the first 15 s of stretch in each trial, HR rapidly increased from CO-alone levels and RMSSD was similarly decreased from CO-alone levels. Additionally, when HR had recovered from the initial high-torque transient of the stretch (see Fig. 1B) but remained stable and still elevated above CO-alone levels, CCV was decreased during the second and third minute of each stretch. We also show, for the first time, that over the 3 min of stretch that were used to gather information on baroreflex function, there was a sustained decrease in the slope of the regression lines, which give SBRS, in all conditions. The sequence technique that we used to assess SBRS, located at the operating point of the cardiac function curve, is known to reflect baroreflex modulation of vagal tone (28), and this, together with the observations of change in HR and its variability, suggests that stretch caused a similar level of vagal inhibition in each trial. This was irrespective of the level of preceding exercise and consequent muscle metaboreflex activation, BP increase and presumably baroreceptor excitation that the CO maintained.

Because the muscle was relaxed and there was no intention by the subject to exercise during CO following exercise, the muscle mechanoreflex and central command can be ruled out as causes of the increase in BP at this time. Therefore, the progressive increase in BP following exercise of greater intensity can only be because of greater metaboreflex activation. Increased systemic BP during CO must result in greater stimulation of baroreceptors and thus presumably increase the level of their modulatory input to the NTS (36). However, studies on animals have shown that the muscle mechanoreflex opposes baroreceptor modulation of cardiac vagal neurons (22), and passive stretch of the human calf muscles has been shown to cause a decrease in vagal tone and increase in resting HR (12). We observed well-maintained decrements in indexes of vagal tone and increases in HR during passive calf stretch applied during CO. This happened despite progressive elevations in BP and so could be taken to suggest that stretch-activated input to the NTS increased in parallel with the increased baroreceptor activation (due to the raised BP) during CO.

One possible source of this increased input could be from the stretch-sensitive muscle mechanoreceptors themselves. Because the stretch stimulus was standardized across each trial, muscle mechanoreceptors would have to be sensitized for this increased input to be supplied solely by the muscle mechanoreflex. Indeed, sensitization of stretch-sensitive muscle mechanoreceptors by metabolites has been demonstrated in animal studies, especially those concerned with afferent sensitization and effort intolerance in heart failure (16, 19, 35). This mechanism would facilitate mechanoreflex-driven elevation in HR during exercise, irrespective of the metabolic conditions within the muscle.

For this appealing explanation to hold true, we would have expected to find a graded increase in vagal tone during CO after exercise of increasing intensity and HRs held below baseline. Although CCV was increased during CO following greater exercise intensities, our observations that HR was maintained at baseline levels, RMSSD was unchanged, and there was a trend toward decreased SBRS during CO before stretch suggests that vagal tone was not elevated. The implication of this is that there is another source of modulatory input to cardiac vagal neurons during the steady-state phase of CO alone. It is possible that the increased levels of metabolite in the muscle interstitium during CO-alone not only caused sympathoexcitation (34) but also caused activation of afferents that influence cardiac vagal neurons. Polymodal afferents, capable of being activated without direct mechanical stimulation, are known to exist (16). Their progressive activation during CO following each increment in exercise intensity might then explain the maintenance of low vagal tone, despite progressive elevations in BP. Therefore, when the standard stretch was applied to the calf, some mechanoreceptors were activated normally, and they in combination with the polymodal afferents opposed baroreflex-mediated input to the NTS. This caused a standard rise in HR, and decreases in indices of vagal tone at the onset (RMSSD) and later phases (SBRS and CCV) of the stretch period.

The slope of the regression line between SBP and RRI represents the gain, at the operating point, of the cardiac arm of the baroreflex function curve (27). We observed that during exercise of increasing intensity, there was a progressive decrease in the slope of this regression line and there was a progressive right shift in the SBP vs. RRI relationship. This right shift is commensurate with the now well-established resetting of the baroreflex during voluntary exercise (31). The progressive decrease in slope (SBRS) with increasing intensity of isometric exercise has not, to our knowledge, been reported before but is compatible with what is known in dynamic exercise; i.e., that the baroreflex operates at a position of lower gain in its operating range during exercise (31). However, without measuring the full baroreflex function curve using neck pressure manipulation, we cannot be more specific than this. During CO alone, we found that SBRS was not significantly altered prior to stretch, despite the progressive increases in BP we saw after more intense exercise. This suggests a progressive resetting of the baroreflex without obvious movement of the operating point. As discussed earlier, this fits with the idea that the muscle metaboreflex causes sympathoexcitation and so promotes BP increase, but at the same time, some polymodal afferent activation opposes baroreceptor-driven modulation of cardiac vagal neurons. The net result is that SBRS is unchanged in the presence of a higher BP.

With each increment in preceding exercise, the "baseline" BP was increased during CO alone. During 3 min of concurrent stretch, we found that BP gradually increased and then on cessation of stretch, fell back to the prestretch CO value. This agrees with the pattern of BP change during CO and 1 min of stretch reported by Fisher et al. (8), who also used the Biodex system to passively stretch the calf. However, Gladwell and Coote (11) and Gladwell et al. (12), applying the stretch to the calf manually, found that BP did not rise over 1 min of stretch. It is possible that these differences simply reflect how well maintained the stretch stimulus is in the two different apparatus. Furthermore, it is clear from examination of published original records that when an observer applies external force to a limb, it is much more variable than when applied by machine, and when stretch is applied to the forearm it appears to be relatively less intense, which could further limit the BP response (7). In Fig. 1B, we show that torque around the ankle joint declined by ~40% over 3 min of stretch applied by the Biodex, presumably because of tendon creep and muscle fiber readjustment (the muscle-tendon complex overall must remain at a fixed length).

Limitations.   On the basis of the known discharge characteristics of mechanoreceptive afferent fibers (2, 16), it is possible that some fibers may have adapted to the stretch stimulus during the sustained stretch period. This would tend to reduce the level of afferent feedback that was generated as the stretch period progressed. However, it is also likely that some reactivation of these mechanoreceptive afferents would occur after their initial burst of firing, due to metabolite sensitization, so restoring their modulatory input (2, 16). We attempted to take account of this possible variation in feedback by assessing vagal tone at the onset of the stretch period and over the longer term using different tools with different time resolutions. The SBRS technique relies on sequences being present, and this cannot be guaranteed at any given time point (typically sequences occur in no more than 50% of the cardiac cycles recorded), but it is nevertheless a robust index of cardiac vagal tone. We therefore used it to explore changes in vagal tone over the whole stretch period. The RMSSD measure can be used over shorter time periods, and therefore it was used to detect any change in vagal tone immediately after stretch onset when the probability of muscle mechanoreflex activation was highest.

The rapid fall in BP that was observed at the end of the exercise phase in each exercise trial, despite CO, could be taken to suggest that there was little activation or indeed variation on the level of muscle metaboreflex activation that was induced by the different exercise intensities. However, after these well-documented initial falls in BP, which may relate to withdrawal of central command and loss of muscle mechanoreflex activation, there is a clear increase in BP to a progressively higher, stable level with increasing exercise intensity. This suggests progressively greater muscle metabolite accumulation and muscle metaboreflex activation with each increment in exercise intensity, but only direct measurement of afferent traffic and metabolite levels could confirm this.

In summary, we have shown that during circulatory occlusion at rest and following ischemic isometric exercise of progressively increasing intensities, passive stretch of the human calf muscles can decrease spontaneous baroreflex sensitivity and other indexes of vagal tone, and increase HR. These changes occur irrespective of the levels of blood pressure increase caused by muscle metaboreflex activation. This implies central modulation of baroreceptor input mediated by the actions of stretch-activated mechanoreceptive and/or polymodal muscle afferent fibers. Clearly, further studies are required, but we believe that the present study provides important new information suggesting that an approach based on the measurement of modulation of cardiac parasympathetic outflow could in the future lead to a useful tool for the noninvasive measurement of muscle mechanoreflex sensitivity in humans.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
We are grateful to Prof. John Coote for insight and helpful comments on this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. C. Drew, School of Sport and Exercise Sciences, Univ. of Birmingham, Edgbaston, Birmingham B15 2TT, UK (e-mail: rxd117{at}bham.ac.uk)

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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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