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J Appl Physiol 90: 308-316, 2001;
8750-7587/01 $5.00
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Vol. 90, Issue 1, 308-316, January 2001

Reflex cardiovascular responses evoked by selective activation of skeletal muscle ergoreceptors

B. G. Leshnower1, J. T. Potts1, M. G. Garry2, and J. H. Mitchell1

1 Departments of Internal Medicine and Physiology and 2 Anesthesiology and Pain Management, Harry S. Moss Heart Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

It is well known that the exercise pressor reflex (EPR) is mediated by group III and IV skeletal muscle afferent fibers, which exhibit unique discharge responses to mechanical and chemical stimuli. Based on the difference in discharge patterns of group III and IV muscle afferents, we hypothesized that activation of mechanically sensitive (MS) fibers would evoke a different pattern of cardiovascular responses compared with activation of both MS and chemosensitive (CS) fibers. Experiments were conducted in chloralose-urethane-anesthetized cats (n = 10). Passive muscle stretch was used to activate MS afferents, and electrically evoked contraction of the triceps surae was used to activate both MS and CS muscle afferents. No significant differences were shown in reflex heart rate and mean arterial pressure (MAP) responses between passive muscle stretch and evoked muscle contraction. However, when the reflex responses were matched according to tension-time index (TTI), the peak MAP response (67 ± 4 vs. 56 ± 4 mmHg, P < 0.05) was significantly greater at higher TTI (427 ± 18 vs. 304 ± 13 kg · s, high vs. low TTI, P < 0.05), despite different modes of afferent fiber activation. When the same mode of afferent fiber activation was compared, the peak MAP response (65 ± 7 vs. 55 ± 5 mmHg, P < 0.05) was again predicted by the magnitude of TTI (422 ± 24 vs. 298 ± 19 kg · s, high vs. low TTI, P < 0.05). Total sensory input from skeletal muscle ergoreceptors, as predicted by TTI and not the modality of afferent fiber activation (muscle contraction vs. passive stretch), is suggested to be the primary determinant of the magnitude of the EPR-evoked cardiovascular response.

exercise pressor reflex; muscle contraction; muscle stretch


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ACTIVATION OF THINLY MYELINATED (group III) and unmyelinated (group IV) muscle afferent fibers by skeletal muscle contraction reflexly increases blood pressure and heart rate (HR) via coordinated changes in autonomic outflow (11). It has been shown that, based on conduction velocities, the discharge properties of group III and IV afferents during muscle contraction are categorized into two distinct populations (7, 13). On one hand, the majority of group III afferents exhibit mechanosensitivity and are activated abruptly at the onset of contraction (7, 9, 10, 13, 14). In contrast, group IV afferents tend to be insensitive to mechanical stimuli and are activated by changes in skeletal muscle metabolism (7, 9, 10, 13, 14). This suggests that group IV afferents are primarily sensitive to metabolic by-products, such as lactic acid, diprotonated phosphate, potassium, bradykinin, serotonin, and adenosine, which are released during muscle contraction. However, it has been reported that a subpopulation of group III/IV afferent fibers are polymodal (i.e., they respond to both mechanical and chemical stimuli) (7, 13).

Previous studies have investigated the relationship between the strength and duration of muscle contraction and the magnitude of the reflex cardiovascular responses (1, 5, 16, 22). Perez-Gonzalez (16) reported that the intensity of muscle activity, expressed as the tension-time index (TTI), was a determinant of the pressor response during skeletal muscle contraction. However, a separation of the relative contributions of group III and group IV afferents to the evoked cardiovascular response has not been clearly elucidated.

It is also known that the responses of group III and group IV afferents can be altered by chemical changes in the muscle interstitium. Kniffki et al. (10) and Mense and Stahnke (13) reported that muscle ischemia potentiated the firing rate of group III and IV afferents during muscle contraction. In addition, Kaufman and Rybicki (8) and Rotto et al. (20) found that intra-arterial injection of arachidonic acid sensitized group III but not group IV afferents during static muscle contraction. However, it is unclear whether sensitization of group III muscle afferents during muscle contraction would translate to a larger cardiovascular response.

Therefore, the purpose of the present study was twofold. First, we sought to determine the relative contribution of mechanically sensitive (MS) and chemosensitive (CS) muscle afferents to the reflex cardiovascular responses evoked by muscle contraction. Specifically, we determined whether the mode of afferent fiber activation (i.e., muscle contraction vs. passive stretch) or the total amount of sensory input from skeletal muscle was the primary determinant of the reflex cardiovascular responses evoked by skeletal muscle ergoreceptors. Second, we hypothesized that sensitization of group III afferents during muscle contraction would evoke a greater cardiovascular response.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Surgical procedures. The experiments were conducted on 10 mongrel cats of either sex (2.5-4.3 kg body wt). After initial induction of anesthesia with a gas mixture [3-5% halothane in oxygen (1-2 l/min)], a solution of alpha -chloralose (80 mg/kg) and urethane (200 mg/kg) was administered intravenously via the left external jugular vein. Catheters (polyethylene tubing, PE-60) were inserted into the left common carotid artery for the measurement of systemic arterial pressure. Animals were artificially ventilated by a mechanical respirator (model 661, Harvard Apparatus, South Natick, MA). Arterial blood gasses and pH were measured every 45-60 min by an automated blood-gas analyzer (model ABL-3, Radiometer) and maintained within normal ranges (arterial PO2 = 80-100 Torr, arterial PCO2 = 35-45 Torr, pH 7.3-7.4). If necessary, 100% oxygen was supplemented to maintain arterial PO2 above 80 Torr. Rectal temperature was continuously monitored throughout each experiment and was maintained between 37 and 38°C by a temperature-controlled, water-perfused heating pad and a near-infrared heat lamp. Gradual increases in baseline HR and blood pressure over the course of the experiment were used to indicate the need for additional anesthesia. When supplemental anesthesia was required, a solution of alpha -chloralose (15 mg/kg) and urethane (75 mg/kg) was administered intravenously.

A laminectomy was performed, exposing the lower lumbar and upper sacral portions of the spinal cord from approximately L5 to S2. The cat was placed into head and spinal units (David Kopf Instruments, Tujunga, CA), the dura was opened longitudinally, and the L7 and S1 spinal roots were identified. The dorsal and ventral roots of L7 and S1 were carefully dissected, and the ventral roots were sectioned and positioned over a pair of bipolar platinum stimulating electrodes. Animals in which the ventral roots from both L7 and S1 could not be obtained were excluded from the study. This resulted in the elimination of one animal from the analyses. The stimulating electrodes were covered in a pool of warmed mineral oil (37°C) and connected to a stimulator (model S88, Grass Instruments, Quincy, MA). The pelvis was stabilized in a spinal unit (David Kopf Instruments), and the lower limb was secured by attaching the patellar tendon to a steel post. The calcaneal bone was cut and the Achilles tendon was connected to a force transducer (model F10, Grass Instruments) to measure the amount of tension generated during electrically induced contraction or passive stretch of the triceps surae.

Data acquisition. Systemic arterial pressure was measured by connecting the common carotid artery catheter to a pressure transducer (model P23ID, Statham, Oxnard, CA). Mean arterial pressure (MAP) was determined by dampening of the arterial signal using a 4-s time constant. HR was derived from the systemic arterial pulse pressure by using a biotachometer (Gould Instruments, Cleveland, OH) All data were simultaneously recorded on an eight-channel physiological recorder (model 2800S, Gould Instruments). After each experiment, the traces were scanned into a computer, and the TTI, mean arterial pressure index (MAPI), and heart rate index (HRI) were obtained using the Metamorph imaging software (Universal Imaging, version 3.5).

Experimental protocol. After the sectioned ventral roots of L7 and S1 were placed on the stimulating electrodes, a period of 60 min was used to allow MAP and HR to stabilize. We developed a strategy to compare the cardiovascular responses evoked by different combinations of passive muscle stretch (primarily mechanoreceptor activation) and electrically evoked contraction (mixed mechanoreceptor and chemoreceptor activation) of the triceps surae in the anesthetized cat. These perturbations were used to selectively activate group III and IV muscle afferents. In addition, the relative contribution of each afferent population to the evoked cardiovascular responses was assessed at different levels of muscle receptor activation. This was facilitated by calculation of the TTI.

The following four experimental conditions were used to selectively activate MS and MS + CS afferents during different perturbations of the hindlimb: 1) electrically evoked static contraction (EEC), 2) passive stretch to mimic the tension developed during contraction (stretch-mimic), 3) passive stretch at constant tension (stretch-constant), and 4) EEC with the addition of stretch at constant tension (EEC + stretch). These four conditions resulted in the following two classifications: 1) low TTI (EEC, stretch-mimic) and 2) high TTI (stretch-constant, EEC + stretch). Within each classification, the specific perturbation produced a variable degree of MS and CS fiber activation. Therefore, with the use of this strategy, it was possible to determine the relative importance of the mode of afferent fiber activation (i.e., MS vs. MS + CS) and the total amount of sensory input (low vs. high TTI) on the reflex cardiovascular responses. A schematic outlining the experimental paradigm is illustrated in Fig. 1.


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  		Fig. 1.   Schematic illustration of the tension traces produced by the 4 experimental perturbations: EEC, electrically evoked static contraction; stretch-mimic, passive stretch mimicking the tension developed by contraction; stretch-const, passive stretch at constant tension; and EEC + stretch, electrically evoked static contraction with the addition of stretch at constant tension. Top: activation of muscle receptors at a variable tension and low tension-time index (low TTI). Bottom: activation of muscle receptors at constant tension and high TTI. The predicted contribution of mechano- and chemosensitive receptors is illustrated by the stippled and hatched areas in each trace. An outline of the data comparisons is also shown (analyses I-IV).

EEC was always performed first by stimulating the L7 and S1 ventral roots for 60 s at a frequency of 40 Hz, a pulse duration of 0.1 ms, and a voltage representing 3.0 times the motor threshold with the hindlimb preloaded with 0.8-1.0 kg of tension. These stimulation parameters, in conjunction with determination of the motor threshold, have been shown to elicit consistent muscular force generation during electrically induced tetanic contractions that activate group III and group IV muscle afferents (11). The peak tension development was set during the initial EEC and was closely matched during the three remaining conditions. Stretch-mimic, stretch-constant, and EEC + stretch were subsequently performed, with a minimum period of 20 min separating each 60-s stimulus to allow MAP and HR to return to baseline values. The order of stretch-mimic, stretch-constant, and EEC + stretch was randomized. The order of experimental trials did not appear to affect the reflex-evoked cardiovascular responses.

Because the protocol involved four consecutive perturbations to the triceps surae in the same leg, muscle fatigue may have negatively affected peak tension development in the latter perturbations. Fatigue, if significant, was usually evidenced during contraction by the production of lower peak tension that resulted in lower TTI. In an attempt to closely match TTI, any animal with a difference in peak tension of >15% was eliminated from the analyses. This resulted in the elimination of one animal from the analyses.

Data and statistical analyses. Peak changes in MAP and HR were determined by calculating the difference between the baseline and maximum value of the reflex response evoked during each perturbation. TTI was derived by integrating the area between the tension trace and either the zero baseline for the stretch maneuvers or a preload baseline for the contraction maneuvers. MAPI and HRI were derived by integrating the area between the MAP and HR traces and the baseline MAP and HR calculated from the 30 s preceding each perturbation. These indices were used to represent the total amount of afferent input (TTI) and the total efferent responses (MAPI, HRI) generated by each perturbation.

Analysis I and analysis II were performed using an ANOVA (2 × 2 block design) with two classification variables (TTI and ergoreceptor populations). Each classification variable contained two levels (low TTI vs. high TTI; MS vs. MS + CS, respectively). Analysis I was performed to determine the effect of the intensity of muscle ergoreceptor activation on the reflex cardiovascular responses. Data from EEC and stretch-mimic (low TTI) were compared with the data obtained from stretch-constant and EEC + stretch (high TTI). Analysis II was performed to identify whether different modes of muscle afferent fiber activation (i.e., MS vs. MS + CS) would alter the reflex cardiovascular responses. To perform this analysis, perturbations that activated MS and CS afferents were compared with perturbations that solely activated MS ergoreceptors. This resulted in the following comparison: EEC and EEC + stretch vs. stretch-mimic and stretch-constant. TTI was matched (see Fig. 1).

Analysis III was conducted to determine the effect of different levels of afferent input from MS receptors alone on reflex cardiovascular responses. To facilitate this analysis, the peak and index MAP and HR responses evoked by stretch-mimic were compared, using a paired t-test, to the responses produced by stretch-constant to examine the effect of MS ergoreceptor activation at different levels of TTI (see Fig. 1).

Analysis IV was conducted to examine the effect of duration on the reflex cardiovascular responses evoked by different modes of skeletal muscle ergoreceptor activation at similar TTI. The initial 30 s of data from the perturbations of EEC and stretch-mimic were analyzed and compared. Average tension and average Delta MAP were calculated by taking the mean of data points collected every 6 s over the initial 30 s of the stimulus. A paired t-test was used to compare average tension, TTI, peak tension, average Delta MAP, MAPI, and peak MAP between these two maneuvers.

Data are presented as means ± SE. The criterion for significance was determined as P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Figure 2 shows an original trace of the four experimental conditions from one animal. The four perturbations produced two different levels of TTI (low TTI vs. high TTI). All four experimental conditions were performed in each animal (n = 8). Each perturbation significantly increased HR, HRI, MAP, MAPI, and TTI. The mean baseline, peak, and index values for HR, MAP, and tension for each perturbation are presented in Table 1. The mean baseline, peak, and index values for HR, MAP, and tension for the low TTI vs. high TTI groupings are presented in Table 2. There were no significant differences in baseline HR and MAP between the four experimental conditions [P = not significant (NS)].


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  		Fig. 2.   Original recordings of the tension traces and cardiovascular responses evoked by the 4 experimental perturbations: A: EEC. B: stretch-mimic. C: stretch-const. D: EEC + stretch. black-down-triangle , initiation of passive stretch. MAP, mean arterial pressure; HR, heart rate; bpm, beats/min.


                              
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  		Table 1.   Baseline, peak, percent increase, and index values for reflex changes in heart rate, mean arterial pressure, and tension-time index to EEC, stretch-mimic, stretch-const, and EEC + stretch


                              
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  		Table 2.   Comparison of baseline, peak, and index values for reflex changes in HR and MAP between low TTI and high TTI

Analysis I: Effect of varying the intensity of muscle ergoreceptor activation on the reflex cardiovascular responses independent of mode of ergoreceptor activation. The effect of varying the intensity of muscle ergoreceptor activation on the reflex cardiovascular responses, independent of mode of activation, was examined by comparing data from EEC and stretch-mimic (low TTI) with data obtained from stretch-constant and EEC + stretch (high TTI) (see Table 2). The reflex increases in MAP (67 ± 4 vs. 56 ± 4 mmHg; F = 6.9, P = 0.02) and MAPI (2,875 ± 274 vs. 2,511 ± 262 mmHg · s; F = 4.4, P = 0.04) were significantly greater during the high TTI vs. the low TTI (427 ± 18 vs. 304 ± 13 kg · s; F = 129.6, P = 0.0001), respectively. However, there were no significant differences in the reflex increase in HR (22 ± 4 vs. 22 ± 3 beats/min; F = 0.03, P = 0.86) and HRI (1,007 ± 220 vs. 1,028 ± 155 beats · s; F = 0.03, P = 0.86). These data are presented in Fig. 3.


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  		Fig. 3.   Analysis I: summary of comparisons of reflex changes in HR, heart rate index (HRI), MAP, and MAP index (MAPI) at low and high TTI. The low-TTI group contains the average reflex cardiovascular responses elicited from EEC and stretch-mimic. The high-TTI group contains the average reflex cardiovascular responses elicited from stretch-const and EEC + stretch. *Significant difference between low TTI and high TTI (P < 0.05). NS, nonsignificant. Values are means ± SE; n = 8.

Analysis II: Comparison of reflex cardiovascular responses evoked by different modes of skeletal muscle ergoreceptor activation at similar TTI. The effect of varying the mode of muscle ergoreceptor activation on the reflex cardiovascular responses was examined independent of the level of TTI by comparing data from EEC and EEC + stretch with data obtained from stretch-mimic and stretch-constant. There was no significant difference in the reflex increases in MAP (F = 0.97, P = 0.34), MAPI (F = 0.21, P = 0.65), HR (F = 1.67, P = 0.21), HRI (F = 1.83, P = 0.19), or TTI (F = 1.08, P = 0.31).

Analysis III: Effect of varying TTI on the reflex cardiovascular responses evoked by mechanoreceptors alone. Stretch-mimic and stretch-constant were examined to compare the reflex cardiovascular responses evoked by perturbations with the same mode of ergoreceptor activation (MS only). The TTI evoked by stretch-constant was significantly greater than that evoked by stretch-mimic (422 ± 24 vs. 298 ± 19 kg · s, respectively; P < 0.05). The reflex increase in MAP (65 ± 7 vs. 55 ± 5 mmHg; P < 0.05) and MAPI (2,926 ± 319 vs. 2,537 ± 241 mmHg · s; P < 0.05) was also significantly greater during stretch-constant. However, there was no significant difference in the reflex-evoked changes in HR and HRI in either group (P > 0.05). These data are presented in Fig. 4.


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  		Fig. 4.   Analysis III: summary of comparisons of reflex changes in HR, HRI, MAP, and MAPI evoked by passive muscle stretch at low TTI and high TTI (stretch-mimic, stretch-const). *Significant difference between stretch-mimic and stretch-const (P < 0.05). NS, nonsignificant. Values are means ± SE; n = 8.

Analysis IV: Effect of duration on the reflex pressor response evoked by different modes of skeletal muscle ergoreceptor activation at similar TTI. The effect of duration on the reflex increase in MAP evoked by EEC and stretch-mimic was examined. Over the initial 30 s of each maneuver, the average tension, TTI, and peak tension were similar between EEC and stretch-mimic. Likewise, no significant differences were found in the average, index, or peak MAP (P = NS). These data are presented in Fig. 5.


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  		Fig. 5.   Summary of comparisons of average tension (AVG TEN), TTI, peak tension (PEAK TEN), and reflex increases in average MAP (AVG Delta MAP), MAPI, and peak MAP (PEAK MAP) for the initial 30 s of data from the perturbations of EEC and stretch-mimic. Values are means ± SE; n = 8.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The main purpose of this study was to determine whether the mode of afferent fiber activation was an important determinant of the reflex cardiovascular responses evoked by skeletal muscle ergoreceptors. It is generally agreed that muscle contraction activates both mechanoreceptors and chemoreceptors, whereas passive stretch selectively activates mechanoreceptors (7, 13). However, the relative contribution of each afferent population to the magnitude of the reflex cardiovascular responses evoked by group III and IV muscle afferents has not been identified. Using different combinations of electrically evoked muscle contraction and passive muscle stretch, we attempted to isolate and activate different populations of group III and IV afferents to examine the reflex cardiovascular responses evoked by different sensory modalities. Our results suggest that the total amount of afferent input from skeletal muscle ergoreceptors, rather than the mode of afferent fiber activation, is the primary determinant of the cardiovascular responses evoked by the exercise pressor reflex.

Previous studies reported that group III afferent fibers (primarily MS) discharge vigorously at the onset of contraction and their firing rates tend to adapt despite maintained muscle tension (3, 7). Conversely, it was reported that group IV afferent fibers (primarily CS) have a delayed discharge pattern following the onset of contraction, with latencies of 15-20 s (7, 13). This discharge pattern has been correlated with the local production of metabolites produced by contracting muscle (6, 8). It is the accumulation of the metabolic by-products released during skeletal muscle contraction that is thought to account for the latency in activating these CS afferent fibers.

Past studies reported that contraction of hindlimb skeletal muscle increases the concentration of adenosine, lactic acid, arachidonic acid, and other metabolic by-products in the venous outflow of working muscle (2, 4, 17, 26). These contraction-induced changes in the chemical composition of the interstitial space of skeletal muscle have been associated with a sensitization of muscle afferents. It has been reported that direct intra-arterial injection of arachidonic acid increases the discharge rate of group III afferents to static muscle contraction (20). Furthermore, Kaufman and Rybicki (8) reported that the discharge rates of group III and IV afferents were potentiated during ischemic muscle contraction. Therefore, we speculated that endogenous production of metabolites during muscle contraction would sensitize muscle afferent fibers and evoke a greater efferent cardiovascular response compared with passive muscle stretch alone. However, results from analysis II found that this was not the case. Instead, when TTI was matched, the reflex cardiovascular responses evoked by different sensory modalities (EEC and EEC + stretch vs. stretch-mimic and stretch-constant) were similar. On the basis of these results, it appears that sensitization of muscle afferents that occurs during muscle contraction does not translate into a greater efferent cardiovascular response compared with passive muscle stretch at equivalent levels of ergoreceptor activation. Furthermore, these findings suggest that selective activation of distinct populations of skeletal muscle afferent fibers did not affect the magnitude of the reflex cardiovascular responses. Therefore, the unique finding from the present study is that the total amount of afferent input from skeletal muscle appears to be the primary determinant of the reflex cardiovascular responses independent of the mode of afferent fiber activation.

Our findings are in contrast to a previous investigation by Stebbins et al. (22). In their study, the magnitude of the stretch-induced cardiovascular responses was roughly 50% of that evoked by static muscle contraction when the two perturbations were matched for average tension. In contrast, in the present study, we found that the pressor responses evoked by contraction and stretch were similar. In attempting to explain the difference in our results from those of Stebbins et al. (22), we first examined differences in the experimental parameters of the two studies. Three main differences were identified: 1) duration of stimulus (30 vs. 60 s), 2) the parameter used to quantify afferent input (average tension vs. TTI), and 3) level of peak tension development. Each perturbation in our study was 60 s, which was twice the duration used by Stebbins et al. (22). Second, we used TTI as the parameter to quantify the total amount of afferent input, whereas Stebbins et al. used average tension. Therefore, to address these two differences, the first 30 s of our data from EEC and stretch-mimic (analysis IV) were reanalyzed and compared with those of Stebbins et al. (22). We calculated average tension, peak tension, and TTI over the first 30 s of these two perturbations and found that the level of tension development (as reflected by each of these independent measures) was essentially the same (see Fig. 5). Therefore, muscle afferent activation was closely matched by these three indices. When the reflex pressor responses evoked over the first 30 s were examined, the average changes in MAP, peak MAP, and MAPI were found to be essentially the same (differed by <10%). Thus, from these results, there appears to be no significant difference in the reflex pressor responses over the first 30 s evoked by muscle contraction or passive stretch at equal levels of muscle afferent activation.

By analyzing the first 30 s of data and calculating average tension, we addressed two of the three major differences between our study and that of Stebbins et al. The remaining factor is the level of peak tension development. In our study, electrical stimulation of the L7 and S1 ventral roots of the hindlimb preloaded with 0.8-1.0 kg of tension resulted in an average peak tension of 7.8 ± 1 kg. This peak tension was matched in the stretch-mimic maneuver, resulting in an average peak tension of 7.7 ± 1 kg. Stebbins et al. (22) reported average rather than peak tension; however, the peak tension taken from an original tracing presented in their study was ~6 kg. The amount of preload tension and the electrical stimulation parameters used for hindlimb contraction were not reported in their study, and differences from our parameters could explain the difference in peak tension developed during EEC. This difference in peak tension consequently resulted in differences in average tension. EEC and stretch-mimic produced average tensions of 6.6 ± 0.3 and 6.4 ± 0.3 kg over 30 s in our study (analysis IV), whereas Stebbins et al. reported average tensions of 3.6 ± 0.3 and 3.5 ± 0.3 kg, respectively.

Thus the greater peak and average tension values in our study may have contributed to the different results. One possible explanation for this may be that, at higher levels of tension development, a subpopulation of high-threshold muscle afferents may have been activated in our study. The recruitment of this additional amount of afferent input would not have occurred at the lower levels of tension used by Stebbins et al.

Previous work suggested that the magnitude of the reflex cardiovascular response is determined by the intensity of muscle activity (1, 5, 16, 25). The derivation of TTI has been shown to serve as a sensitive index of the amount of sensory input from working muscle (16). When we compared the reflex cardiovascular responses during the same mode of ergoreceptor activation but at two different levels of TTI (analysis III: stretch-mimic vs. stretch-constant), there was a relationship between TTI and the magnitude of the efferent blood pressure responses. The reflex pressor response evoked by stretch-constant (TTI: 422 ± 24 kg · s) was significantly larger than the pressor response evoked by stretch-mimic (TTI: 298 ± 19 kg · s). In fact, the magnitude of the pressor response was more closely related to TTI than the mode of ergoreceptor activation, as shown by the results of analysis I (see Table 2, Fig. 3). These results stress the magnitude of the TTI, rather than the mode of afferent fiber activation, as the primary determinant of the magnitude of the blood pressure response evoked by the exercise pressor reflex. These analyses support previous work that showed a linear relationship between TTI and the magnitude of the reflex cardiovascular responses to muscle contraction (16, 25).

Limitations. We did not examine the pressor response elicited solely by chemical activation of skeletal muscle afferent fibers for several reasons. First, we were interested in investigating the reflex responses evoked by changes in muscle tension that resulted from either electrically evoked contraction or passive stretch. These two perturbations have been used to mimic the physiological changes in muscle tension during exercise (18, 22). Past studies have elucidated some of the metabolites that may be involved in the reflex pressor response evoked by muscle contraction (12, 19, 24). These studies have shown that certain populations of group III and IV muscle afferents are stimulated by potassium (12, 24), arachidonic acid (19), and lactic acid (19). However, the endogenous concentration of each metabolite produced by muscle contraction has not yet been determined. Furthermore, TTI was used as a means to quantify the total amount of sensory input related to changes in muscle tension. Because of the lack of tension development following a pure chemical activation of muscle afferent fibers, it would not have been possible to perform a similar analysis.

Previous work has defined passive muscle stretch as a paradigm to selectively activate MS afferent nerve fibers. Stebbins et al. (22) examined the metabolic activity during stretch and reported no change in venous blood gases, pH, lactate, or potassium levels. This suggests that passive muscle stretch does not activate CS muscle afferents. However, it has been shown from neural recording studies that some afferent units respond to both static contraction and passive muscle stretch (13), therefore, suggesting that the same MS afferent that responds to stretch may also be activated by the mixed mechanical and chemical stimulus of contraction. However, the possibility remains that a mechanoreceptor may respond differently during static contraction than during passive stretch. Perhaps the degree of afferent unit activation is different when a muscle fiber is shortened, as opposed to when it is lengthened. This possibility was also raised by Stebbins et al. (22).

In the present study, we assumed that activation of muscle afferents was equivalent when TTI was matched. However, if the amount of afferent activation is different when a mechanoreceptor is shortened vs. lengthened at the same magnitude and pattern of tension, then TTI alone may not be the best index of total afferent input.

It might be argued that the peak tension developed during both static contraction and passive stretch was not within a physiological range and, therefore, may have been associated with activation of nociceptive afferents. Regarding passive stretch, Stebbins et al. (22) reported that flexion of the cat hindlimb increased muscle length by ~2 mm, which was associated with an average increase in muscle tension of 2 kg. Because the magnitude of tension development by passive stretch in the present study exceeded 2 kg, we cannot completely eliminate the possibility that some nociceptive muscle afferents may have contributed to the reflex cardiovascular responses. With regard to static muscle contraction, previous studies from our group and others (1, 21, 22) reported peak tensions in a higher range (6-12 kg). Furthermore, Walmsley et al. (23) reported that muscle contraction in the conscious cat generated 8-10 kg of hindlimb tension. Therefore, although we cannot completely eliminate the possibility that nociceptive afferents may have also contributed to the reflex evoked responses during muscle contraction, we feel that these levels of tension development fall within the physiological range.

The use of the perturbation EEC + stretch in our study raises some concern about the alteration of muscle length and its effect on the length-tension relationship. Initially, the muscle was contracted and the addition of stretch to the precontracted muscle should have activated an additional population of MS afferent fibers. The concern lies in whether we were stretching the precontracted muscle to such a degree that the amount of active tension was significantly reduced. If this were the case, then the mode of afferent input from the perturbations of EEC + stretch and stretch-constant would primarily come from the same source (i.e., mechanoreceptors alone). Because we did not measure muscle lengths in this study, we did not have a direct means of answering this question. However, Morgan et al. (15) demonstrated that lengthening of the feline hindlimb up to 6 mm during contraction did not alter the level of active tension development. The amount of additional tension from stretch during EEC + stretch was ~3 kg, which, based on the results reported by Stebbins et al. (22), results in a muscle length change of ~3 mm. Therefore, we feel that it is unlikely that that the muscle was overstretched during EEC + stretch to lengths at which the total developed tension was comprised solely from the passive tension of stretch.

In conclusion, our results suggest that the mode of activation of the afferent limb of the exercise pressor reflex, whether by activation of both mechanoreceptors and chemoreceptors (muscle contraction) or by activation of mechanoreceptors alone (passive muscle stretch), is not the primary determinant of the magnitude of efferent cardiovascular responses. Rather, it is the total amount of afferent input from muscle ergoreceptors that appears to be the primary determinant of the magnitude of the exercise pressor reflex.


    ACKNOWLEDGEMENTS

We thank James Jones, Julius Lamar, Jr., and Margaret Robledo for expert technical assistance.


    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-06296 and the Lawson and Rogers Lacy Research Fund in Cardiovascular Diseases.

Address for reprint requests and other correspondence: J. H. Mitchell, Dept. of Internal Medicine, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9174. (E-mail: Jere.Mitchell{at}UTSouthwestern.edu).

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.

Received 12 January 2000; accepted in final form 8 August 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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J APPL PHYSIOL 90(1):308-316
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