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Am J Physiol Heart Circ Physiol 293: H2335-H2343, 2007. First published June 15, 2007; doi:10.1152/ajpheart.00469.2007
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Differential sympathetic outflow elicited by active muscle in rats

Satoshi Koba, Jihong Xing, Lawrence I. Sinoway, and Jianhua Li

Penn State Heart and Vascular Institute, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 17 April 2007 ; accepted in final form 11 June 2007


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
The present study was undertaken to test the hypothesis that activation of the muscle reflex elicits less sympathetic activation in skeletal muscle than in internal organs. In decerebrate rats, we examined renal and lumbar (mainly innervating hindlimb blood vessels) sympathetic nerve activities (RSNA and LSNA, respectively) during 1 min of 1) repetitive (1- to 4-s stimulation-to-relaxation) contraction of the triceps surae muscle, 2) repetitive tendon stretch, and 3) repetitive contraction with hindlimb circulatory occlusion. During these interventions, RSNA and LSNA responded synchronously as tension developed. The increase was greater in RSNA than in LSNA [+51 ± 14 vs. +24 ± 5% (P < 0.05) with contraction, +46 ± 8 vs. +17 ± 4% (P < 0.05) with stretch, +76 ± 20 vs. 39 ± 7% (P < 0.05) with contraction during occlusion] during all three interventions: repetitive contraction (n = 10, +508 ± 48 g tension from baseline), tendon stretch (n = 12, +454 ± 34 g), and contraction during occlusion (n = 9, +473 ± 33 g). Additionally, hindlimb circulatory occlusion significantly enhanced RSNA and LSNA responses to contraction. These data demonstrate that RSNA responses to muscle contraction and stretch are greater than LSNA responses. We suggest that activation of the muscle afferents induces the differential sympathetic outflow that is directed toward the kidney as opposed to the limbs. This differential outflow contributes to the distribution of cardiac output observed during exercise. We further suggest that as exercise proceeds, muscle metabolites produced in contracting muscle sensitize muscle afferents and enhance sympathetic drive to limbs and renal beds.

sympathetic nervous system; exercise; muscle metabolites; contraction; stretch

THE SYMPATHETIC NERVOUS SYSTEM is activated during exercise (31). Two major neural mechanisms have been proposed to elicit sympathetic activation, namely, central command and the exercise pressor reflex. Central command is a feedforward mechanism that originates in the higher brain and stimulates cardiovascular and somatomotor centers in the brain stem (10, 65). The exercise pressor reflex is a feedback neural mechanism that originates from metabolic and mechanical activation of afferent endings in contracting skeletal muscles (7, 19, 34). Signals from the nerve endings project to the dorsal horn of the spinal cord via group III and IV skeletal muscle afferent fibers and then to the brain stem. In previous animal studies using anesthetized or decerebrate rats, rabbits, and cats, activation of the muscle reflex by static muscle contraction has been reported to increase sympathetic nerve activity (SNA) directed to the heart (33), kidney (12, 22, 25, 32, 62, 66), adrenal gland (63), and skeletal muscle (15). Moreover, passive calcaneal tendon stretch, a mechanical stimulus that evokes an increase in muscle afferent discharge, was shown to increase cardiac SNA (33) and renal SNA (RSNA) (12, 22, 25, 32, 66). In human studies, muscle SNA increases with activation of muscle mechanoreceptors (8) as well as metaborecepors (31).

During exercise, cardiac output distribution is altered. Specifically, the increase in active muscle blood flow is associated with a decrease in renal blood flow (27). These peripheral blood flow responses are essential to maintain adequate blood pressure as well as to ensure a balance between muscle blood supply and metabolic demand. In active muscles, local vasodilator mechanisms independent of neural pathways play a role in hyperemia. Muscle contraction triggers hyperpolarization of vascular smooth muscle cells by releasing local vasodilator substances from skeletal muscle cells (9, 60) and red blood cells (48) and by stimulating endothelial cell pathways (5, 61). The vasodilation caused by the nonneural mechanisms counters the sympathetic vasoconstriction in the muscles. This effect of exercise hyperemia is termed "functional sympatholysis" (47).

Besides functional sympatholysis, the neural mechanism that produces differential sympathetic outflow may also play a role in the distribution of cardiac output during exercise. Recently, it was suggested that central command contributes to the distribution of cardiac output (24). Koba et al. (24) examined RSNA and lumbar SNA (LSNA) innervating hindlimb circulation (3, 37) as well as renal and hindlimb muscle blood flow during fictive locomotion (induced by central command with an intact exercise pressor reflex) of the rat. They reported that activation of central command evoked less sympathetic activation and, consequently, less sympathetic vasoconstriction directed to the muscle than to the kidney (24). This finding suggests that differential sympathetic outflow evoked by central command activation also contributes to cardiac output distribution. On the other hand, the neural contribution to the distribution of cardiac output caused by muscle reflex engagement is unclear. In a series of studies, Hill and co-workers showed that static contraction increases muscle SNA (15), but not skin SNA (16), in anesthetized cats. Human studies further demonstrated that muscle SNA is more sensitive to the muscle reflex than is skin SNA (64). With respect to skin and muscle SNA, these findings suggest that the muscle reflex induces differential sympathetic outflow to the skin and skeletal muscle, respectively. However, skin and muscle SNA were not simultaneously recorded in these experiments. It remains unknown whether the muscle reflex elicits differential sympathetic outflow directed to the internal organs and the limbs.

Peripheral reflex responses, including those evoked by arterial baroreflex disengagement (42, 52), thermal stimulation (41), coronary artery ischemia (58), and hypoxic stimulation of arterial chemoreceptors (53), have been demonstrated to induce differential sympathetic outflows directed to various organs. Previous studies performed in conscious animals have indicated that characteristics of RSNA responses differ from those of LSNA responses during sleep in rats (37, 67) and during volume expansion stimuli in rabbits (46).

Therefore, we have recorded the RSNA and LSNA simultaneously in decerebrate rats and examined the sympathetic responses to repetitive contraction of the triceps surae muscles and to muscle tendon stretch. We hypothesized that the muscle reflex activation would induce less sympathetic vasoconstriction in the exercising skeletal muscle than in the kidney. Similar SNA and vasoconstrictor responses to fictive locomotion have previously been observed (24).

In addition, metabolites induced by muscle ischemia increase the discharge of group III and IV muscle afferents (1, 21, 35) and renal sympathetic efferents during muscle contraction (12). However, it is unclear whether ischemia sensitizes muscle reflex-elicited sympathetic nerve responses of the muscles. Thus the effect of hindlimb circulatory occlusion on the reflex renal and lumbar sympathetic nerve responses to contraction was also examined. We hypothesized that the muscle metabolites would enhance the muscle reflex.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
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General

All procedures were approved by the Animal Care Committee of this institution. Sixteen male Sprague-Dawley rats (14–20 wk old, 412–640 g body wt) were anesthetized with a mixture of isoflurane (<4%) and oxygen. The trachea was cannulated, and the lungs were artificially ventilated with a respirator (model 683, Harvard). The animal was mechanically ventilated with a tidal volume of 2.0–2.5 ml at a rate of 70 min–1. The left jugular vein and common carotid artery were cannulated for administration of drugs and arterial pressure (AP) recording, respectively. The arterial catheter was attached to a pressure transducer (model MLT0380/D, ADInstruments). Needle electrodes, placed on the back of the animal, were used to record the ECG. The ECG signal was amplified with an alternating-current preamplifier (model P55, Grass Instruments). Heart rate (HR) was calculated beat-to-beat by detection of the time between successive R waves in the ECG. Arterial pH was measured with a pH meter (model B-212, Horiba) during the experiment and maintained within normal limits (pH 7.5) by intravenous infusion of sodium bicarbonate solution (8.4%). Body temperature was adequately maintained with a heating pad. Hindlimb circulation was arrested with a vessel occluder positioned around the caudal part of the left femoral artery and vein. RSNA and LSNA on the left side were simultaneously recorded as previously described (24, 25, 37, 67). A bundle of renal nerves or the lumbar sympathetic trunk at L3–L4 or L4–L5 was carefully dissected from other connective tissues. LSNA at L3–L5 mainly reflects the component regulating hindlimb muscle circulation (3, 24, 37). A piece of laboratory film was placed under the isolated nerves, and a bipolar electrode, which was used to record neural activity, was placed between the nerves and the film. These electrodes were embedded in a silicone gel (Kwik-Sil, WPI). Once the gel was hardened, the silicone rubber was fixed to the surrounding tissue with a glue containing {alpha}-cyanoacrylate. RSNA and LSNA signals were amplified with a differential amplifier (model P511, Grass Instruments) with a band-pass filter of 100 Hz in low-cut frequency and 3 kHz in high-cut frequency and made audible. The rat was then placed in a stereotaxic apparatus (model 900LS, David Kopf Instruments).

The calcaneus bone was cut, and the left Achilles tendon then the triceps surae muscles were isolated. The hindlimb was fixed in space with a patellar precision clamp to prevent limb movement. All visible branches of the left sciatic nerve, except those innervating the triceps surae muscles, were cut. The tibial nerve was carefully dissected and then placed on a shielded bipolar electrode to electrically evoke contraction of the left triceps surae muscles. The electrode was connected to a stimulator (model S88, Grass Instruments). The tension generated by the triceps surae muscles was recorded with a force transducer (model FT03, Grass Instruments) connected to the Achilles tendon. Baseline tension of the left triceps surae muscles was set at 50–100 g.

The right carotid artery was occluded to reduce bleeding in the brain during decerebration. The brain was then sectioned coronally at the midcollicular level. With this procedure, the pressor response to static muscle contraction was observed in rats (11). All tissues rostral to the section, as well as cortical tissues covering the cerebellum, were removed. After bleeding was controlled, the cranial vault was filled with mineral oil. A recovery period of >75 min was allowed after withdrawal of the anesthesia.

Experimental Protocols

Muscle contraction. The motor threshold (MT), which is the minimum current intensity necessary to evoke twitching of the triceps surae muscles, was determined by electrical stimulation of the tibial nerve with a 0.1-ms pulse duration. After 30 s of baseline data collection, 1 min of repetitive contraction of the left triceps surae muscles was induced. The duty cycle was 1- to 4-s stimulation-to-relaxation, so that the muscle was stimulated 12 times in 1 min. Contraction was evoked by electrical stimulation of the tibial nerve (40-Hz frequency, 0.1-ms pulse duration, <2 x MT of intensity) (43).

Contraction with hindlimb circulatory occlusion. Tightening of the femoral artery and vein occluded the left hindlimb circulation. After 30 s of baseline data were collected, the muscle was repetitively contracted for 1 min in a manner similar to that described above (see Muscle contraction).

Muscle stretch. The left Achilles tendon was repetitively stretched manually for 1 min. The duty cycle was similar to that described above (see Muscle contraction).

After data collection, the animal was paralyzed with an infusion of pancuronium bromide (0.5 mg/kg iv). The left tibial nerve was then stimulated at 2 x MT intensity for 30–60 s. The stimulation did not change SNA after muscle paralysis; therefore, the responses to contraction were not due to direct stimulation of the muscle afferents.

After all protocols, the renal nerve was cut between the electrode and the neuraxis, and the background noise of RSNA was recorded. At the end of the experiment, the animal was euthanized with an overdose of potassium chloride. Background noise of LSNA was then recorded.

Data Acquisition and Statistical Analyses

All measured variables were displayed continuously on a computer monitor and stored on a hard disk via analog-digital conversion (Powerlab/8s, AD Instruments) at a 1-kHz sampling rate. Representative and simultaneous recording of muscle tension, RSNA, LSNA, AP, and HR responses during 1 min of repetitive freely perfused contraction of the triceps surae muscles are presented in Fig. 1. Full-wave-rectified signals of SNA, as well as the background noise signals, were obtained (Fig. 1A); then the noise component was subtracted from the rectified signal, and a moving average over 50 ms was determined. The sympathetic responses to muscle stimulation were quantified from basal values obtained from mean values for 30 s of baseline, and this value was denoted as 100%. Then changes relative to baseline were evaluated ({Delta}RSNA and {Delta}LSNA in Fig. 1, A and B) (24, 25, 32, 33, 37, 46, 52, 66, 67). The values were averaged over 100-ms periods. SNA responses to 12 muscle stimulations were then superimposed on one another to remove any effects that may be due to respiration and blood pressure (Fig. 1C). The data collected from each animal after this normalization process were used to obtain the results reported in the present study.


Figure 1
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  		Fig. 1. Responses to freely perfused muscle contraction and contraction with hindlimb circulatory occlusion. A: typical record of tension developed in left triceps surae muscles, rectified renal sympathetic nerve activity (RSNArec), rectified lumbar sympathetic nerve activity (LSNArec), arterial pressure (AP), and heart rate [HR, beats/min (bpm)] before and during 1 min of 12 repeated contractions with high tension development. *, Recording artifact. Data were obtained from the same animal. B: magnified record of tension, RSNArec, and LSNArec during a 5-s cycle of freely perfused contraction (data from 7th contraction) and contraction with hindlimb circulatory occlusion (data from 7th contraction). Relative changes in RSNA and LSNA averaged over 100 ms from baseline (30-s averaged value before muscle contraction) are also shown during this interval. Recording durations are indicated by arrows in A. C: tension, RSNA, and LSNA of 12 repeated muscle contractions. Time 0 indicates onset of tension development. Changes were evaluated relative to each basal value averaged for 30 s just before the 1st contraction. The 12 points at each time were averaged. RSNA and LSNA responded synchronously as muscle tension was developed, and increase in RSNA was greater than increase in LSNA.

 
Values are means ± SE. Baseline data were obtained from the averaged values for 30 s immediately before the first muscle tension development. Baseline data were compared between groups with an unpaired t-test. One- or two-way repeated-measures ANOVA with Dunnett's (vs. baseline) or Tukey's (RSNA vs. LSNA and freely perfused vs. hindlimb circulatory occluded) post hoc test was used to determine statistical significance. The level of significance was set at P < 0.05.


   RESULTS
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DISCUSSION
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Basal Values

The data were categorized as "low tension" if the peak muscle tension was <350 g and "high tension" if it was >350 g. Baseline mean AP (MAP) and HR were 88 ± 5 mmHg and 392 ± 10 beats/min, respectively, before the low-tension trial and 90 ± 7 mmHg and 390 ± 11 beats/min, respectively, before the high-tension trial. With circulatory occlusion, baseline MAP and HR were 89 ± 3 mmHg and 378 ± 11 beats/min before the low-tension trial and 91 ± 7 mmHg and 384 ± 15 beats/min before the high-tension trial. Baseline MAP and HR before low-tension muscle stretch were 87 ± 4 mmHg and 400 ± 11 beats/min and 91 ± 3 mmHg and 392 ± 3 beats/min before the high-tension trial. There were no significant differences between the trials.

Sympathetic Nerve Responses to Freely Perfused Muscle Contraction

An example of tension generated within the triceps surae muscles, RSNA, LSNA, AP, and HR before and during 1 min of repetitive contraction of the freely perfused triceps surae muscles with high tension development is shown in Fig. 1A. Changes in RSNA and LSNA during contraction are magnified in Fig. 1B. The superimposed developed tension and SNA data for 12 stimulation-relaxation cycles are shown in Fig. 1C. During contractions, RSNA and LSNA responded synchronously as tension was developed. RSNA responses were larger than LSNA responses. We observed rapid increases in RSNA and LSNA at the onset of tension development and subsequent rapid decreases to baseline.

The cycle-averaged developed muscle tension and changes in RSNA and LSNA for 12 freely perfused stimulation-relaxation cycles are presented in Fig. 2. Results of the low- and high-tension trials are shown in Fig. 2, A and B, respectively. Freely perfused muscle contraction significantly increased RSNA during the low-tension trial (n = 11 animals) and RSNA and LSNA during the high-tension trial (n = 10 animals). The increases in RSNA were significantly greater than the increases in LSNA in the high-tension trials. Significant differences between RSNA and LSNA responses to contraction were not found in the low-tension trials (P > 0.05). RSNA and LSNA responses to contraction occurred rapidly, with the time delay from the onset of tension development of 0.50 ± 0.06 s in RSNA and 0.40 ± 0.04 s in LSNA at low tension and 0.40 ± 0.04 s in RSNA and 0.44 ± 0.07 s in LSNA at high tension. The increases in RSNA and LSNA rapidly returned toward baseline. A decrease in RSNA was observed after the end of muscle contraction. There were significant differences between RSNA and LSNA transients after the end of muscle contraction in the high-tension trials.


Figure 2
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  		Fig. 2. Changes in muscle tension, RSNA, and LSNA during a stimulation-relaxation cycle averaged over 12 freely perfused contractions and contractions with occlusion. A and B: low- and high-tension development trials, respectively. Time 0 indicates onset of tension development. Changes were evaluated relative to each basal value averaged for 30 s just before the 1st contraction. Values are means ± SE; n = 11 animals in low-tension group (freely perfused contraction and contraction with occlusion), 10 in freely perfused high-tension trial, and 9 in high-tension trial with occlusion. Statistical analysis using 2-way repeated-measures ANOVA showed a significant effect of muscle contraction on LSNA and RSNA (in all contraction trials) and a significant difference between {Delta}RSNA and {Delta}LSNA (in all contraction trials except low-tension with freely perfused contraction). *, {dagger}, {dagger}{dagger}: P < 0.05 vs. baseline in tension, RSNA, and LSNA, respectively. Thick horizontal bars indicate significant difference between {Delta}RSNA and {Delta}LSNA.

 
Sympathetic Nerve Responses to Contraction With Hindlimb Circulatory Occlusion

Nerve responses to contraction with hindlimb circulatory occlusion, detailed RSNA and LSNA data during a cycle, and overlapped SNA data over 12 cycles are shown in Fig. 1.

Muscle contraction with hindlimb circulatory occlusion significantly increased RSNA and LSNA in low-tension (n = 11 animals) and high-tension (n = 9 animals) trials (Fig. 2). During low- and high-tension trials, the increases in RSNA were significantly greater than the increases in LSNA (Fig. 2). The time to peak response was 0.47 ± 0.05 s in RSNA and 0.41 ± 0.06 s in LSNA at low tension and 0.42 ± 0.06 s in RSNA and 0.38 ± 0.06 s in LSNA at high tension. At the end of contraction, the fall in RSNA was greater than the fall in LSNA for low- and high-tension trials.

Peak sympathetic nerve responses to freely perfused contraction and contraction with hindlimb circulatory occlusion are shown in Fig. 3. The peak tension was similar: +212 ± 12 and +207 ± 12 g at low tension and +508 ± 48 and +473 ± 33 g at high tension in freely perfused contraction and contraction with occlusion, respectively (P > 0.05). During the low-tension trial, hindlimb circulatory occlusion increased the LSNA response to muscle contraction from +16 ± 3% during the freely perfused trial to +23 ± 4% during the occluded circulation trial. This represents a 44% increase in the magnitude of the response. During the high-tension trial, circulatory occlusion enhanced the RSNA and LSNA responses to muscle contraction by 44% (+64 ± 15 and +92 ± 20% increases in RSNA during freely perfused and occluded circulation trials, respectively) and 45% (+31 ± 5 and +45 ± 6% increases in LSNA during the freely perfused trial and circulatory arrest, respectively).


Figure 3
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  		Fig. 3. Peak RSNA and LSNA responses to freely perfused contraction and contraction with hindlimb circulatory occlusion. Values are means ± SE. Peak values were detected from 100-ms-averaged highest data during muscle tension development (Fig. 1C). #P < 0.05, free perfusion vs. hindlimb circulatory occlusion. Developed tension was 212 ± 12 and +207 ± 12 g at low tension and +508 ± 48 and +473 ± 33 g at high tension in freely perfused contraction and contraction with occlusion, respectively.

 
Sympathetic Nerve Responses to Muscle Stretch

Responses to 1 min of repetitive muscle stretch, RSNA and LSNA data during a stretch cycle, and overlapped SNA data for 12 cycles are shown in Fig. 4. SNA responded synchronously as tension was developed. RSNA responses were greater than LSNA responses. SNA responded rapidly at the onset of tension development. SNA returned rapidly toward baseline after stretch. These characteristics were similar to those observed in muscles subjected to freely perfused contraction and contraction with hindlimb circulatory occlusion.


Figure 4
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  		Fig. 4. Responses to muscle stretch. A: typical record of tension, RSNArec, LSNArec, AP, and HR before and during 12 repetitive tendon stretches for 1 min with high tension development. B: magnified record of tension, RSNArec, and LSNArec during a cycle (12th stretch) for 5 s. Relative changes in RSNA and LSNA in 100-ms average from baseline are also shown. Recording durations are indicated by arrows in A. C: tension, RSNA, and LSNA responses to 12 repeated tendon stretches. Changes were evaluated with each basal value averaged for 30 s just before the 1st contraction. Time 0 indicates onset of tension development. RSNA and LSNA responded synchronously as muscle tension was developed, and increase in RSNA was greater than increase in LSNA.

 
Tendon stretch intervention significantly increased RSNA during the low-tension trial (n = 12 animals) and RSNA and LSNA during the high-tension trial (n = 12 animals; Fig. 5). In the high-tension group, RSNA increases were significantly greater than LSNA increases (Fig. 5). In the low-tension group, no significant differences were observed between RSNA and LSNA responses to stretch (P > 0.05; Fig. 5). The time to peak response was 0.54 ± 0.06 s for RSNA and 0.51 ± 0.05 s for LSNA at low tension and 0.51 ± 0.04 s for RSNA and 0.40 ± 0.05 s for LSNA at high tension. There were significant differences in the decreases of RSNA and LSNA after the end of tendon stretch in the high-tension group (Fig. 5).


Figure 5
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  		Fig. 5. Changes in tension, RSNA, and LSNA during a stimulation-relaxation cycle averaged over 12 tendon stretches. Time 0 indicates onset of tension development. Changes were evaluated with each basal value averaged for 30 s just before the 1st stretch. Values are means ± SE; n = 12 in each group. Statistical analysis using 2-way repeated-measures ANOVA showed a significant effect of muscle contraction on SNA (in low- and high-tension trials) and a significant difference between {Delta}RSNA and {Delta}LSNA (in high-tension trial). *, {dagger}, {dagger}{dagger}: P < 0.05 vs. baseline in tension, RSNA, and LSNA, respectively. Thick horizontal bars indicate significant difference between {Delta}RSNA and {Delta}LSNA.

 
Effects of Repetitive Muscle Stimulation on MAP and HR

Repetitive muscle stimulation with contraction, contraction with occlusion, or stretch induced a pressor (greater than +5 mmHg) and a depressor (less than –5 mmHg) response or no change (within ±5 mmHg; Figs. 1 and 4). These results are consistent with those reported previously for anesthetized cats (20). In all rats, the blood pressure response to either muscle stimulation was limited within ±15 mmHg. The different blood pressure responses between individuals might be due to the different balance between sympathetic vasoconstriction and nonneural vasodilation elicited by active muscle (20). HR responses to either muscle stimulation were not significantly different from baseline (less than +10 beats/min).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main findings of this study are as follows: 1) the muscle reflex activated by repetitive muscle contraction or tendon stretch induced less increase in LSNA than in RSNA, and 2) hindlimb circulatory occlusion enhanced RSNA and LSNA responses to muscle contraction.

Peripheral reflexes that originate from arterial baroreceptors, chemoreceptors, and thermoreceptors have been reported to induce differential sympathetic outflow directed toward various organs (40–42, 52, 53, 58). In the present study, by observing the RSNA and LSNA simultaneously, we provide additional information that skeletal muscle receptors play a role in differential sympathetic outflow that is directed toward the kidney, rather than the limbs. Reductions in blood flow to the kidney and hindlimb muscles correlate with increases in RSNA and LSNA, respectively (24, 37, 67). Thus our results suggest that the muscle reflex-elicited sympathetic vasoconstriction signal directed to the skeletal muscles is less than the sympathetic vasoconstrictor signal directed to the kidney.

Possible mechanisms by which cardiac output is distributed during exercise include functional sympatholysis within the active muscle (5, 9, 47, 48, 60, 61) and differential sympathetic outflow (24). The results from the present study suggest that activation of muscle afferents induces less increase in LSNA than in RSNA, and this contributes to the pattern of distribution of cardiac output seen during exercise.

Similar to findings from the present report, Koba et al. (24) demonstrated that fictive locomotion in the rat evoked less increase in LSNA than in RSNA. Taken together with the present data, we suggest that, during exercise, central cardiovascular pathways activated by central command, as well as muscle afferents, make an important contribution to cardiac output distribution during exercise.

Several sites in the medulla, for example, the rostral ventrolateral medulla, rostral ventromedial medulla, and raphe, have been identified as having direct neural projections to the intermediolateral cell column in the spinal cord and as regulating sympathetic outflows differentially to various organs (40, 59). Electrophysiological (4, 17) and neuroanatomic (28, 29) studies have reported that muscle contraction stimulates neurons in those supraspinal neural circuits. Thus central neural sites are very likely to produce the muscle reflex-mediated differential sympathetic outflow.

The exercise pressor reflex comprises the muscle mechanoreflex and metaboreflex (19). Tendon stretch stimulates muscle mechanosensitive receptors without leading to dramatic changes in the metabolic profile of the muscle (57). Thus the SNA responses to tendon stretch are considered to activate muscle mechanosensitive afferents in this study. Previous studies (14, 62) reported that, during repetitive muscle contraction, sympathetic activation is synchronized with muscle tension development. This synchronization has been attributed to activation of mechanosensitive afferents in skeletal muscle. Our data also suggest that SNA responses to muscle contraction were predominantly due to muscle mechanoreflex activation. 1) SNA responses observed in the present study were synchronized as tension was developed during contraction, consistent with previous studies (14, 62). It was also reported that, among some populations of group III and IV muscle afferents, discharges are synchronized as muscle tension is developed during rhythmic contraction (20). 2) RSNA and LSNA responded rapidly at the onset of muscle tension development, with a short time delay to reach the peak SNA response. The mechanoreflex is activated rapidly when the muscle is contracted, since this reflex is activated by deformation of the receptors in the muscle (19). 3) The characteristics of the dynamics of SNA during contraction were similar to those during stretch that stimulates the muscle mechanoreceptors. These observations suggest that repetitive muscle contraction employed in the present study mainly activated muscle mechanosensitive components of the exercise pressor reflex.

Previous studies showed that muscle ischemia enhances responses of the group III and IV muscle afferents to contraction (1, 21, 35). Muscle ischemia can also increase the number of renal sympathetic single fibers that respond to static contraction (12). Moreover, active muscle ischemia has been reported to induce the exaggerated vasoconstriction at renal and hindlimb blood vessels during treadmill exercise in dogs (2, 38, 39). In the present study, we have found that hindlimb circulatory occlusion augmented LSNA and RSNA responses to contraction. Muscle metabolites trapped within the active muscle during muscle ischemia may play a role in exaggerating SNA responses to contraction by stimulating metabosensitive muscle afferents. In addition, metabolites in active muscles may also sensitize mechanosensitive muscle afferents during contraction (55). A number of substances, including diprotonated phosphate, prostaglandin, lactic acid, potassium, and ATP, have been suggested as potential muscle metaboreceptor stimulants and mechanoreceptor sensitizers (13, 23, 30, 36, 49, 50, 54, 56). It cannot be determined which substances within the active muscle were engaged in stimulating and sensitizing muscle afferents in the present study. Nevertheless, our data suggest that muscle metabolites in the active muscle enhance the reflex SNA responses by stimulating muscle metaboreceptors and by sensitizing activation of muscle mechanosensitive afferents.

After muscle contraction is initiated, the baroreflex is engaged and modulates the muscle reflex-mediated cardiovascular responses (45). Interaction between the baroreflex and the muscle reflex depends on the baroreceptor afferent input (44). Moreover, the baroreflex regulates sympathetic outflow differentially (40, 42, 52). This baroreflex engagement may have to contribute to the relative changes in RSNA and LSNA. However, differential sympathetic nerve responses were observed independent of a pressor or depressor response during muscle stimulation. This suggests that the SNA responses were unlikely to be dramatically influenced by the baroreflex. In addition, it is unlikely that changes in the ventilation cycle affect the responses. SNAs fluctuated synchronously with the artificial respiration. In the present study, we set the artificial respiratory frequency such that it was not synchronized with the muscle stimulation interventions. SNA data were normalized by averaging results of 12 muscle stimulation interventions. Thus the effect of respiratory fluctuation on SNA was minimal. Also, the characteristics of the response of muscle SNA to passive muscle stretch have been reported not to be different between spontaneous and controlled breathing conditions in humans (8). Taken together, the respiratory-related reflex is unlikely to elicit the differential sympathetic outflow.

In the present study, rapid decreases in RSNA were observed after muscle stimulation interventions. The postexcitatory depression of sympathetic outflow as somatosympathetic reflexes are engaged has been reported previously (26, 51). The neural arc includes supraspinal and spinal reflex pathways, both of which contain sympathoexcitatory and inhibitory mechanisms (6, 17, 26, 51). However, it has been suggested that supraspinal pathways play an essential role in the development of the reflex sympathetic responses, since transection of the cervical spinal cord at C1 in cats eliminates the reflex responses to static muscle contraction (18). Thus we speculate that these transient inhibitory effects are likely due to a reflex engagement of central cardiovascular inhibitory pathways.

In conclusion, the data demonstrate that RSNA responses to muscle contraction and tendon stretch are greater than LSNA responses. We suggest that activation of muscle afferents mediates differential sympathetic outflow, which contributes to the distribution of cardiac output during exercise. Moreover, ischemic metabolites produced in contracting muscle are likely to stimulate muscle receptors and sensitize the muscle reflex.


   GRANTS
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 ABSTRACT
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 GRANTS
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This study was supported by National Heart, Lung, and Blood Institute Grants R01 HL-075533 and HL-078866 (J. Li) and HL-060800 (L. I. Sinoway).


   ACKNOWLEDGMENTS
 
The authors thank Jennie Stoner for outstanding secretarial skills.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Li, Penn State Heart & Vascular Institute, H047, Pennsylvania State Univ. College of Medicine, Milton S. Hershey Medical Center, 500 Univ. Dr., Hershey, PA 17033 (e-mail: jzl10{at}psu.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.


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 ABSTRACT
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 DISCUSSION
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