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1 Department of Physiology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois 60515; and 2 Departments of Anesthesiology and Physiology, Medical College of Wisconsin and Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
O'Hagan, Kathleen P., Susan M. Casey, and Philip S. Clifford. Muscle chemoreflex increases renal
sympathetic nerve activity during exercise. J. Appl.
Physiol. 82(6): 1818-1825, 1997.
Activation of
the muscle chemoreflex increases sympathetic drive to skeletal muscle
in humans. This study investigated whether activation of the muscle
chemoreflex augments the renal sympathetic nerve activity (RSNA)
response to dynamic exercise in rabbits. The muscle chemoreflex was
evoked by hindlimb ischemia during exercise on a motorized treadmill.
Seven New Zealand White rabbits performed a nonischemic control
protocol and a hindlimb ischemia protocol in which terminal aortic
blood flow (
ta) was reduced to 51 ± 2% of
preocclusion ta by partial aortic occlusion after 1.5 min of exercise. Mean arterial pressure (MAP), heart rate, RSNA and
ta increased in response to exercise and were
similar between trials during the first 1.5 min of exercise. In the
control trial, ta, MAP, and RSNA were stable at an
elevated level through an additional 3.5 min of exercise. Hindlimb
ischemia produced a potent pressor response that plateaued after 2.5 min (
+17 ± 4 mmHg, where designates change). RSNA began to
increase after 1.5 min of ischemic exercise and was significantly
elevated relative to preocclusion RSNA at 2.5 (+25 ± 9%) and
3.5 (+47 ± 12%) min of occlusion. These results suggest that
the muscle chemoreflex can augment sympathoexcitatory drive to the
kidney during dynamic exercise.
rabbit; blood pressure; exercise pressor reflex; metaboreflex; sympathetic nervous system
INTRODUCTION CONTROL OF CENTRAL SYMPATHETIC outflow during sustained
exercise is influenced by interactions between central command (a feed-forward mechanism), reflexes arising from active skeletal muscle,
and arterial and cardiopulmonary baroreflexes (see Refs. 25, 28 for
review). The muscle chemoreflex is a blood pressure-raising reflex
originating in active skeletal muscle that is triggered by stimulation
of chemically sensitive nerve endings (primarily group IV afferents) by
chemical by-products of metabolism (8, 14). A mismatch between
metabolic demand and muscle blood flow and/or oxygen delivery
(30) generates a metabolic error signal, which results in a reflex
pressor response that partially corrects the flow deficit (23, 26).
Increases in cardiac output and vasoconstrictor tone are responsible
for the augmented pressor response associated with stimulation of the
muscle chemoreflex (3, 26, 33). The muscle chemoreflex is hypothesized
to serve as the major link between the central hemodynamic responses to
exercise and metabolic demands of the active musculature (25). It is
believed that the accentuated pressor response associated with
intermittent claudication during exercise originates from stimulation
of the muscle chemoreflex (9).
In humans, static leg or handgrip exercise with postexercise trapping
of accumulated metabolites in the exercised limb has been used to study
the muscle chemoreflex isolated from the effects of central command and
skeletal muscle mechanoreflexes (see Refs. 25, 28 for review). These
studies have clearly demonstrated that stimulation of the muscle
chemoreflex results in an increase in sympathetic activity to resting
skeletal muscle (28). An augmented sympathetic drive to active skeletal
muscle may also occur with activation of the muscle chemoreflex (5).
Increased sympathetic drive to visceral circulatory beds evoked by the
muscle chemoreflex could contribute to the augmented pressor response.
In the present study, we tested the hypothesis that activation of the
muscle chemoreflex during dynamic exercise results in an augmentation
of renal sympathetic nerve activity (RSNA). To evoke the muscle
chemoreflex during dynamic exercise, we utilized partial terminal
aortic occlusion to produce a hindlimb ischemia, which is a paradigm
used extensively in dogs (15, 16, 21, 23, 24, 29, 30, 33) and,
recently, in rats (2). The animal model chosen for this study was the
rabbit because of our ability to directly measure RSNA during dynamic exercise in this species (19, 20).
METHODS The experimental and animal care protocols were reviewed and approved
by the Institutional Review Board for the Use and Care of Animals of
Midwestern University. Seven New Zealand White female rabbits (3.30 ± 0.39 kg) were selected for willingness to run on a motor-driven
treadmill (AccuScan, Columbus, OH) that had a usable belt length of 1 m. After selection, rabbits were exercised once or twice per week over
the 5-19 wk preceding the experiment to maintain familiarity with
treadmill running. These sessions consisted of two short (3-5 min)
exercise bouts at 10-12 m/min at a 20% grade.
Surgical Preparation
Implantation of flow probe and vascular occluder. An ultrasonic transit-time volume flow probe (2-3 mm, Transonic Systems, Ithaca, NY), and a Silastic vascular occluder (3-4 mm, In Vivo Metric, Healdsburg, CA) were implanted on the terminal aorta via a lower abdominal midline incision. Immediately proximal to the aortic-iliac bifurcation, the aorta was dissected free from surrounding tissue to accommodate the probe and vascular occluder. The vascular occluder was placed on the aorta rostral to the probe. Before placement of the probe, a 1 × 2 cm piece of silicone rubber medical-grade sheeting (0.007 in. thickness, Technical Products, Decatur, GA) was placed under the aorta. The probe was then placed around the aorta, and the sliding bracket was secured. The ends of the silicone sheeting were brought together around the probe and sutured to the underlying musculature. The silicone sheeting maintained correct orientation of the probe and prevented trapping of adipose tissue in the reflecting bracket during the ingrowth phase. The connector end of the probe was wrapped in sterile parafilm and routed subcutaneously, along with the free end of the vascular occluder, to a right flank subcutaneous pocket for storage. Rats resumed treadmill running 7-14 days after the abdominal surgery. Three to six weeks after the abdominal surgery the rabbits were instrumented with a renal sympathetic nerve recording electrode.
Implantation of renal nerve recording
electrodes. In each animal, chronic recording
electrodes were implanted on the left renal nerves. Via a
retroperitoneal approach, the left kidney was exposed, and one or two
renal nerves were dissected away from the renal artery. The recording
electrodes were two 30-cm lengths of Teflon-coated multistranded
stainless steel wire (0.009 in. diameter; 316SS7/44T, Medwire, Mt.
Vernon, NY). One end of each electrode was stripped and curled into a
J-shaped hook. The renal nerves were placed in the hooks and suspended
above the renal artery. The bare end of a third length of wire was
embedded in perirenal fat to serve as a ground. The entire
nerve-electrode-ground complex was then embedded in silicone gel
(Silgel 604, Wacker Chemie). The three electrode leads were secured to
muscle at the incision site, routed subcutaneously to the dorsal aspect
of the neck, and externalized. Small gold pins were crimped onto the exposed ends of the leads. The leads were wrapped in a strip of cloth
adhesive tape for protection, wound into a small bundle, and secured to
the skin for storage. Rabbits were studied on the second day
postsurgery. There was a small but significant decrease in body weight
after the renal electrode implant surgery (
0.11 ± 0.03 kg, where denotes change; n = 7).
Experimental Procedures
Instrumentation. Arterial blood pressure was obtained from a small Teflon catheter [Angiocath 24 gauge (OD = 0.7 mm), Deseret, Sandy, UT] placed into the central ear artery by percutaneous placement or via a cut-down under local anesthetic block with 2% lidocaine hydrochloride. A short pressure line was connected to a solid-state pressure transducer that was strapped to the animal's back. Heart rate (HR) was derived from the arterial pressure pulse by using a Grass tachograph. Venous access was obtained by percutaneous placement of a 24-gauge Teflon catheter into the contralateral ear vein. The connector end of the flow probe and the free end of the vascular occluder were retrieved from the subcutaneous pocket. The probe end was connected by a 2-m extension cable to the Transonic flowmeter (model T206) for measurement of terminal aortic blood flow. A water-filled 1-ml syringe was used for manual inflation of the vascular occluder.Nasopharyngeal reflex. After instrumentation, the nasopharyngeal reflex was assessed. In rabbits, activation of the nasopharyngeal reflex with cigarette smoke produces a dramatic increase in RSNA (4). It is likely that the RSNA response to activation of the nasopharyngeal reflex represents the "maximum" RSNA that can be elicited by physiological means in a conscious rabbit, because increases in RSNA elicited by other physiological reflexes, such as hypotension (4), severe hypoxemia (18), and moderate exercise (19, 20), fall short of the level achieved during activation of the nasopharyngeal reflex.
To elicit the nasopharyngeal reflex, cigarette smoke contained in a syringe was intermittently puffed toward the nares of the rabbit for a period of 60-120 s. The five 2-s intervals with the highest RSNA were averaged. The nasopharyngeal reflex was elicited at the start and end of each day's experiment. The higher of the two smoke-elicited RSNA values was defined as maximum RSNA for that day. Use of a paired t-test revealed no statistical difference between RSNA responses elicited by the nasopharyngeal reflex within a day.
Minimum or baseline RSNA was obtained at the end of the day's experiment after suppression of postganglionic activity by intravenous infusion of trimethaphan camsylate (5 mg/kg; Arfonad, Roche Laboratories, Nutley, NJ). This voltage was subsequently subtracted from all RSNA measurements. RSNA recorded during the experiment was then expressed as a percentage of the smoke-elicited maximum activity. Use of this normalization procedure allows comparison of relative levels of RSNA between animals.
Experimental protocol. All hemodynamic and sympathetic activity measurements were made while the animal was on the treadmill. After the assessment of the nasopharyngeal reflex, the rabbit was allowed to rest for at least 30 min. While the rabbit was sitting quietly, data were continuously collected during a 2-min baseline period followed by a 3.5-min occlusion at ~50% of baseline aortic flow. After the ~50% occlusion at rest, rabbits rested a minimum of 15 min before the first exercise trial. Each rabbit completed at least two exercise trials. Forty-five minutes of rest were allowed between exercise trials. As the treadmill belt began to move and increase in speed, rabbits rode the belt for 2-4 s before taking their first hop. Thus time 0 for analyzing the hemodynamic and RSNA responses to exercise was defined as the start of the first hop, as visually identified by one of the investigators.
Two exercise protocols were executed. Data were continuously recorded during 2 min of rest and 5 min of exercise at 10 m/min and a 6.4% grade. The control exercise protocol was conducted without inflation of the vascular occluder. In the second protocol, partial occlusion of the terminal aorta was used to produce hindlimb ischemia during exercise. Aortic flow during occlusion averaged 51 ± 2% (range 42-57%) of preocclusion exercise aortic flow.
Manual inflation of the vascular occluder began 90 s into the exercise run. The partial aortic occlusion was maintained through the remaining 210 s (3.5 min) of exercise and was released at least 10 s after the cessation of the treadmill exercise. A third exercise trial was performed in three animals because of excessive RSNA artifacts in one of the previous exercise trials. For the trials chosen for analysis, in four rabbits the control exercise trial preceded the hindlimb ischemia exercise trial, whereas in three rabbits the order of the trials was reversed.
Data Analysis
RSNA potentials were amplified by a preamplifier (1,000 times) and a low-noise differential amplifier (20-100 times) with use of a bandwidth of 100-3,000 Hz. The signal was full-wave rectified and averaged by using a 100-ms moving time averager. Arterial blood pressure, HR, and averaged RSNA signals were simultaneously stored on magnetic tape using a Vetter data recorder and written to paper on a Grass polygraph. Data were analyzed off-line using custom-written software on a Hewlett-Packard 310 workstation.Rest (baseline) data are represented by a single 2-min average. As
shown in Fig. 1, data during exercise were
initially averaged in consecutive 10-s intervals. For
statistical analysis of the responses to exercise, four 30-s intervals
were chosen: immediately before occlusion (60-90 s of exercise),
at 1.5 min of occlusion (150-180 s of exercise), at 2.5 min of
occlusion (210-240 s of exercise), and at 3.5 min of occlusion
(270-300 s of exercise). The data were averaged over the selected
30-s intervals. The responses to partial occlusion at rest are
represented by the average of the last 30 s of the 3.5-min
occlusion.
) and hindlimb ischemia (
) exercise
trials. Arrows denote onset of partial aortic occlusion (after 90 s of
exercise). With the exception of time
0 (Rest; average of 2-min baseline period before
exercise), each data point represents a 10-s average. Error bars were
deleted when necessary for presentation purposes. The 4 boxes represent
four 30-s intervals used for statistical analysis of responses to
exercise. Results of statistical tests are summarized in Table 2;
b/min, beats/min.
Statistics. A paired t-test was utilized to compare body weight data and the responses to partial aortic occlusion at rest. The responses to exercise were analyzed with a two-way analysis of variance with repeated measures. If the analysis of variance group × time interaction term was significant, post hoc comparisons between means were completed with the Tukey-Kramer procedure (10). The statistical analysis was performed with NCSS 6.0 software (Kaysville, UT). Values are represented as means ± SE. Differences were considered statistically significant at P < 0.05.
RESULTS
Partial Aortic Occlusion at Rest
While the rabbits were sitting quietly on the treadmill, terminal aortic blood flow was reduced to 53 ± 4% of resting aortic flow by manual inflation of the vascular occluder. As shown in Table 1, 3.5 min of occlusion at rest resulted in a minor increase in mean arterial pressure (MAP) (4 ± 2 mmHg,
where denotes change; P = 0.07)
and a small but significant fall in HR (8 ± 2 beats/min).
RSNA was not affected.
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Partial Aortic Occlusion During Exercise
Original data tracings from a control and a hindlimb ischemia trial performed by one rabbit are presented in Fig. 2. On average, there were no differences in the resting hemodynamic or RSNA values between the two exercise trials (Table 2; Fig. 1). Additionally, the tachycardic, blood pressure, aortic flow, and renal sympathoexcitatory responses to the first 90 s of exercise were similar between the two exercise trials.
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As exercise continued through the subsequent 3.5 min in the control exercise trial, there were no further changes in terminal aortic flow, MAP, or RSNA. HR continued to rise from 330 ± 6 beats/min (at 90 s of exercise) to 348 ± 8 beats/min by the end of the exercise period (P < 0.05).
Inflation of the vascular occluder commenced after 90 s of exercise in the hindlimb ischemia exercise trial. On average, terminal aortic flow decreased steadily over the subsequent 30 s and stabilized at 51 ± 2% of exercise aortic flow after 40 s of partial occlusion (Fig. 1). At this level of occlusion, exercise aortic flow was similar to aortic flow observed at rest (Table 2).
The blood pressure response to exercise was altered by partial aortic
occlusion (interaction term P < 0.001). Within 20 s of the commencement of partial aortic occlusion,
MAP began to increase. MAP at 1.5 min of partial aortic occlusion was
elevated by 10 ± 3 mmHg relative to the preocclusion level
(P < 0.05; Table 2). MAP was
increased an additional 7 ± 2 mmHg at 2.5 min of partial aortic
occlusion (P < 0.05 from 1.5 min)
and did not increase further during the last minute of ischemic
exercise. Thus ischemic exercise resulted in a potentiated blood
pressure response compared with the same time points in the control
exercise trial (9 ± 3 mmHg at 1.5 min of occlusion, 16 ± 4 mmHg at 2.5 min of occlusion, and 21 ± 3 mmHg at 3.5 min of
occlusion; P < 0.05).
Partial aortic occlusion altered the HR response to exercise
(interaction term P = 0.02). During
the progressive rise in MAP that occurred during the first 2.5 min of
occlusion, HR remained stable at the preocclusion level. This is in
contrast to the average 16 beats/min increase in HR that was observed
in the control exercise trial (Fig. 1; Table 2). Thus, through the
first 2.5 min of occlusion, HR in the hindlimb ischemia trial was
significantly lower (13 ± 7 beats/min) than what was
observed in the nonischemic trial. During the last minute of exercise,
HR values were again similar between the ischemic and control exercise
trials (8 ± 8 beats/min).
The RSNA response to partial aortic occlusion contrasts sharply with the stable RSNA response observed during the nonischemic control trial (interaction term P < 0.001). In the control trial, RSNA remained stable at 18-19% of maximum through the final 3.5 min of exercise. In contrast, RSNA during the hindlimb ischemia trial began to increase after 100 s of partial aortic occlusion (after 190 s of exercise; Fig. 1). RSNA plateaued at an elevated level from 130-190 s of partial aortic occlusion (220-280 s of exercise) followed by a further rise during the last 10 s of exercise. RSNA at 3.5 min of ischemic exercise was significantly higher (25 ± 2% of maximum; P < 0.05) than RSNA observed at the same time point in the control exercise trial (Table 2).
The RSNA responses over the last 3.5 min of exercise for the control
and hindlimb ischemia trials are presented in Fig.
3 as the relative change in RSNA from the
preocclusion exercise level. During the control trial, RSNA during the
last 3.5 min of nonischemic exercise was stable and similar to the
level observed after 90 s of exercise. In contrast, exercise during
hindlimb ischemia augmented RSNA at 2.5 min (25 ± 9%) and 3.5 min (47 ± 12%) relative to preocclusion levels, despite the
concomitant exaggerated blood pressure response. The changes in RSNA at
2.5 and 3.5 min of hindlimb ischemic exercise were significantly
greater than the RSNA responses observed at the same time points in the nonischemic control exercise (Fig. 3).
DISCUSSION
In this study, hindlimb ischemia was employed to stimulate the muscle chemoreflex during dynamic exercise in the rabbit. During the 3.5 min of exercise with hindlimb ischemia, the rabbits developed a marked pressor response, which is consistent with an activation of chemically sensitive nerve endings in skeletal muscle. Importantly, we found that exercise during hindlimb ischemia resulted in an increase in directly measured RSNA. These findings support the hypothesis that activation of the muscle chemoreflex during dynamic exercise can result in an augmented sympathoexcitatory drive to the kidney.
The method utilized to stimulate the muscle chemoreflex in this experiment, partial aortic occlusion during dynamic exercise, has been used extensively in dogs (15, 16, 21, 23, 24, 29, 30, 33) and, recently, in rats (2). Partial aortic occlusion reduces hindlimb muscle perfusion and oxygen delivery, resulting in decreased washout as well as increased production of metabolic by-products capable of stimulating chemically sensitive nerve endings (30). Graded reductions in terminal aortic flow below a threshold value result in progressive increases in blood pressure (15, 16, 21, 29, 30, 33). The threshold value is dependent on the intensity of the exercise performed (33) and is ~70% of exercise blood flow during mild exercise in dogs (15, 16, 21, 29, 30, 33). Similar to the dog, the hemodynamic response to hindlimb ischemia in the exercising rabbit was marked by a considerable pressor response. We utilized a single-stage reduction in aortic flow (~50% of exercise blood flow), which precluded estimation of the threshold of the MAP-terminal aortic flow relationship in the rabbit.
As discussed by Wyss et al. (33), the pressor response to ischemic exercise has a passive component, due to the mechanical increase in aortic resistance. For dogs, the gain of the MAP-terminal aortic flow relationship was at least 3.5 times greater than the calculated passive effect of partial occlusion on blood pressure. Because cardiac output was not measured in the present study, we cannot quantitatively evaluate the passive contribution of partial aortic occlusion to the observed pressor response. However, the passive component should become immediately evident as aortic resistance during exercise is rapidly increased due to aortic occlusion. As shown in Fig. 1, there was only a small rise in blood pressure during the first minute following the onset of partial aortic occlusion. The subsequent progressive increase in blood pressure after the first minute of partial aortic occlusion is consistent with a time-dependent accumulation of metabolites within the exercising ischemic musculature.
There is ample evidence in anesthetized animals and in humans that stimulation of chemically sensitive nerve endings in muscle results in an augmented sympathetic drive to skeletal muscle. In humans, static leg or handgrip exercise with postexercise trapping of metabolites in the exercised limb has been used extensively as a paradigm for studying the muscle chemoreflex isolated from the effects of central command and skeletal muscle mechanoreflexes (see Refs. 25, 28 for review). These studies have clearly demonstrated that stimulation of the muscle chemoreflex results in an increase in sympathetic activity to resting skeletal muscle (28). An augmented sympathetic drive to active skeletal muscle may also occur with activation of the muscle chemoreflex. Hansen and colleagues (5) observed a rise in MSNA directed to the ipsilateral as well as contralateral leg during ischemic static toe extension. Recently, Hill and colleagues (6) demonstrated that static contraction of the triceps surae in the decerebrate cat reflexly increased the discharge of sympathetic efferents innervating the contralateral muscle group. The latency of the response suggested a chemosensitive receptor rather than mechanoreceptor origin. Stimulation of group III and IV muscle afferents via direct electrical stimulation, static contraction, or chemical stimulation in anesthetized animals results in vasoconstriction in skeletal muscle (3, 17, 32). Stimulation of the muscle chemoreflex during dynamic exercise is also likely to augment muscle sympathetic nerve activity, as forelimb vasoconstriction was observed during hindlimb ischemia in treadmill-exercised dogs (15).
Vasoconstriction in visceral circulatory beds, including the kidney, accompanies stimulation of muscle afferents in anesthetized animals (3, 13, 17). In the anesthetized cat, the renal vasoconstriction and sustained rise in RSNA associated with static muscle contraction was attributed to stimulation of both mechanoreceptors and chemosensitive receptors (12, 13, 31). Acute renal denervation abolished the fall in renal blood flow and attenuated the pressor response, demonstrating that the renal vasoconstriction was neurogenic in origin and that the renal vasoconstriction contributed to the increase in MAP. In exercising dogs, dynamic exercise with hindlimb ischemia resulted in renal vasconstriction but no significant fall in renal blood flow (16, 24). Interestingly, chronic renal denervation did not alter the relationship between renal vascular conductance and hindlimb blood flow in the dog. It is possible that in the dog RSNA did not respond to stimulation of the muscle chemoreflex. However, it is far more likely that renal autoregulation provided a redundant mechanism for control of renal blood flow under those specific conditions. In the anesthetized cat during isometric muscle contraction (13) and in the conscious baboon during dynamic leg exercise (7), the renal blood flow response in a denervated kidney was characterized by an initial rise in flow rather than the immediate decrease in blood flow observed in an innervated kidney. However, as exercise continued, renal blood flow in the denervated kidney returned to resting levels (7, 13). These data in two different species provide evidence for a role for renal autoregulation in the control of blood flow during exercise in the absence of neurogenic drive.
There is accumulating evidence from studies in conscious animals that stimulation of muscle chemosensitive receptors augments sympathetic drive to visceral circulatory beds. In conscious cats, the slow, secondary rise in RSNA associated with voluntary static contraction is consistent with stimulation of chemosensitive receptors (11). Moderate-to-heavy dynamic exercise in rabbits provokes a sustained increase in RSNA (19). In this study, imposition of hindlimb ischemia during dynamic exercise in the rabbit resulted in an augmented RSNA response, which was delayed with respect to the rise in blood pressure. Although not responsible for the initial phase of the pressor response, it is likely that renal sympathoexcitation and the associated renal vasoconstriction contribute to the augmented blood pressure associated with stimulation of the muscle chemoreflex during dynamic exercise.
It is likely that arterial baroreflexes attenuated the full expression of the muscle chemoreflex-stimulated pressor and sympathoexcitatory responses. In anesthetized animals, carotid sinus hypotension enhanced the regional vasoconstrictor responses to electrical or chemical stimulation of muscle afferents (1, 32), illustrating an inhibitory interaction between baroreflexes and muscle reflexes on reflex sympathetic outflow. In conscious exercising dogs, sinoaortic denervation was shown to enhance the gain of the systemic blood pressure-hindlimb perfusion pressure relationship (29), resulting in greater pressor responses for a given reduction in terminal aortic flow once the threshold of the relationship was exceeded. However, no estimate was made of the relative contributions of cardiac output and peripheral vasoconstriction to the augmented pressor response after sinoaortic denervation. Scherrer et al. (27) evaluated in humans the effect of the arterial baroreflex on the muscle sympathetic nerve activity (MSNA) response to static handgrip exercise by limiting the normal muscle chemoreflex-induced rise in systemic blood pressure with a nitroprusside infusion. A 50% reduction in the pressor response resulted in a fourfold increase in the MSNA response. Additionally, the latency between the onset of the pressor response and the rise in RSNA in the present study may be partially attributable to opposition from arterial baroreflexes. In humans, the latency of the MSNA response to static handgrip was shortened with nitroprusside-induced attenuation of the pressor response to handgrip exercise (27).
Cardiopulmonary baroreflexes may also limit the pressor and sympathoexcitatory responses to activation of the muscle chemoreflex. Cardiac receptors attenuate the RSNA response to nonischemic dynamic exercise in rabbits (20) and the muscle chemoreflex-induced rise in blood pressure in rats during dynamic exercise (2). In the present study, the large reduction in hindlimb blood flow caused by partial aortic occlusion during exercise would be expected to raise central blood volume. This artifactual increase in central blood volume could result in heightened cardiopulmonary afferent activity, which, in turn, would limit the muscle chemoreflex-induced rise in RSNA. It should be noted that this heightened inhibitory effect of cardiopulmonary receptors on sympathetic outflow is unlikely to occur if the muscle chemoreflex is stimulated by a mis- match between oxygen supply and demand in skeletal muscle during heavy exercise under normal conditions.
The reflex response to hindlimb ischemia in the rabbit appears to differ from the dog (21, 22, 33) as well as the rat (2) in the lack of a net tachycardic component to the pressor response. There are three mechanisms that could have contributed to the lack of a tachycardic response. One possibility is that, in the rabbit, muscle chemosensitive receptors have less influence on cardiac sympathetic activity than apparently is the case in the dog or rat. A second mechanism could stem from competing effects of the muscle chemoreflex and the arterial baroreflex on cardiac sympathoexcitation during the ischemic exercise. In the present study, a slight reduction in HR accompanied the rise in blood pressure associated with the first 2.5 min of partial aortic occlusion (Fig. 1). In contrast, HR continued to increase slowly during the nonischemic control exercise. A reasonable explanation for this depressed HR response during the ischemic exercise is that strong activation of the cardiac component of the arterial baroreflex opposed a potentially weak excitatory influence of the muscle chemoreflex on the control of HR. The modulatory effect of the arterial baroreflex on the HR response to activation of the muscle chemoreflex in humans was demonstrated by Scherrer and colleagues (27), whose results are particularly striking, since the muscle chemoreflex in humans was previously believed to have little influence on the tachycardic response to static handgrip exercise (22). A third contributing mechanism to the depressed HR response in the rabbit could be augmented stimulation of cardiopulmonary receptors due the artifactual rise in central blood volume associated with partial aortic occlusion. In the rat, blood vol- ume expansion decreased the gain of the muscle chemoreflex regulation of HR during ischemic exercise (2).
Limitation of the Model
Use of partial aortic occlusion to evaluate the influence of the muscle chemoreflex on reflex circulatory control is dependent on the assumption that hindlimb ischemia does not markedly affect the level of central command or muscle mechanoreceptor activation during the exercise. An additional factor that theoretically could augment RSNA is ischemic pain. The abrupt increase in RSNA observed during the last 10 s of the ischemic exercise could possibly be due to a combination of an augmented muscle chemoreflex, increased central command due to emerging fatigue, or some degree of ischemic pain. The contributions of augmented central command or ischemic pain to the RSNA response are difficult to objectively evaluate in animals.In summary, hindlimb ischemia produced by partial aortic occlusion resulted in potentiated blood pressure and RSNA responses to dynamic exercise in rabbits. These findings support the hypothesis that activation of the muscle chemoreflex during dynamic exercise can result in an augmented sympathoexcitatory drive to the kidney.
ACKNOWLEDGEMENTS
This project was supported by the Department of Veterans Affairs Medical Research Service and Midwestern University.
FOOTNOTES
Address for reprint requests: K. P. O'Hagan, Dept. of Physiology, Midwestern Univ., 555 31st St., Downers Grove, IL 60515 (E-mail: kohaga{at}midwestern.edu).
Received 18 November 1996; accepted in final form 24 February 1997.
REFERENCES
| 1. | Abboud, F. M., A. L. Mark, and M. D. Thames. Modulation of the somatic reflex by carotid baroreceptors and by cardiopulmonary afferents in animals and in humans. Circ. Res. 48, Suppl. I: I-131-I-137, 1981. |
| 2. |
Collins, H. L.,
and
S. E. DiCarlo.
Cardiac afferents attenuate the muscle metaboreflex in the rat.
J. Appl. Physiol.
75:
114-120,
1993
|
| 3. | Crayton, S. C., J. H. Mitchell, and F. C. Payne III. Reflex cardiovascular response during injection of capsaicin into skeletal muscle. Am. J. Physiol. 240 (Heart Circ. Physiol. 9): H315-H319, 1981 . |
| 4. |
Dorward, P. K.,
W. Riedel,
S. L. Burke,
J. Gipps,
and
P. I. Korner.
The renal sympathetic baroreflex in the rabbit: arterial and cardiac baroreceptor influences, resetting, and effect of anesthesia.
Circ. Res.
57:
618-633,
1985 .
|
| 5. |
Hansen, J.,
G. D. Thomas,
T. N. Jacobsen,
and
R. G. Victor.
Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle.
Am. J. Physiol.
266 (Heart Circ. Physiol. 35):
H2508-H2514,
1994 .
|
| 6. |
Hill, J. M.,
C. M. Adreani,
and
M. P. Kaufman.
Muscle reflex stimulates sympathetic postganglionic efferents innervating triceps surae muscles of cats.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H38-H43,
1996 .
|
| 7. | Hohimer, A. R., and O. A. Smith. Decreased renal blood flow in the baboon during mild dynamic exercise. Am. J. Physiol. 236 (Heart Circ. Physiol. 5): H141-H150, 1979 . |
| 8. |
Kaufman, M. P.,
K. J. Rybicki,
T. G. Waldrop,
and
G. A. Ordway.
Effect of ischemia on responses of group III and IV afferents to contraction.
J. Appl. Physiol.
57:
644-650,
1984.
|
| 9. |
Lorentsen, E.
Systemic arterial blood pressure during exercise in patients with atherosclerosis obliterans of the lower limbs.
Circulation
46:
257-263,
1972 .
|
| 10. | Ludbrook, J. On making multiple comparisons in clinical and experimental pharmacology and physiology. Clin. Exp. Pharmacol. Physiol. 18: 379-392, 1991 . [Medline] |
| 11. |
Matsukawa, K.,
J. H. Mitchell,
P. T. Wall,
and
L. B. Wilson.
The effect of static exercise on renal sympathetic nerve activity in conscious cats.
J. Physiol. (Lond.)
434:
453-467,
1991 .
|
| 12. |
Matsukawa, K.,
P. T. Wall,
L. B. Wilson,
and
J. H. Mitchell.
Reflex responses of renal nerve activity during isometric muscle contraction in cats.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H1380-H1388,
1990 .
|
| 13. |
Matsukawa, K.,
P. T. Wall,
L. B. Wilson,
and
J. H. Mitchell.
Neurally mediated renal vasoconstriction during isometric muscle contraction in cats.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H833-H838,
1992 .
|
| 14. |
McCloskey, D. I.,
and
J. H. Mitchell.
Reflex cardiovascular and respiratory responses originating in exercising muscle.
J. Physiol. (Lond.)
224:
173-186,
1972 .
|
| 15. |
Mittelstadt, S. W.,
L. B. Bell,
K. P. O'Hagan,
and
P. S. Clifford.
Muscle chemoreflex alters vascular conductance in nonischemic exercising skeletal muscle.
J. Appl. Physiol.
77:
2761-2766,
1994
|
| 16. |
Mittelstadt, S. W.,
L. B. Bell,
K. P. O'Hagan,
J. E. Sulentic,
and
P. S. Clifford.
Muscle chemoreflex causes renal vascular constriction.
Am. J. Physiol.
270 (Heart Circ. Physiol. 39):
H951-H956,
1996 .
|
| 17. | Nutter, D. O., and C. W. Wickliffe. Regional vasomotor responses to the somatopressor reflex from muscle. Circ. Res. 48, Suppl. I: I-98-I-103, 1981. |
| 18. |
O'Hagan, K. P.,
L. B. Bell,
and
P. S. Clifford.
Effects of pulmonary denervation on renal sympathetic and heart rate responses to hypoxia.
Am. J. Physiol.
269 (Regulatory Integrative Comp. Physiol. 38):
R923-R929,
1995.
|
| 19. |
O'Hagan, K. P.,
L. B. Bell,
S. W. Mittelstadt,
and
P. S. Clifford.
Effect of dynamic exercise on renal sympathetic nerve activity in conscious rabbits.
J. Appl. Physiol.
74:
2099-2104,
1993.
|
| 20. |
O'Hagan, K. P.,
L. B. Bell,
S. W. Mittelstadt,
and
P. S. Clifford.
Cardiac receptors modulate the renal sympathetic response to dynamic exercise in rabbits.
J. Appl. Physiol.
76:
507-515,
1994.
|
| 21. |
O'Leary, D. S.
Autonomic mechanisms of muscle metaboreflex control of heart rate.
J. Appl. Physiol.
74:
1748-1754,
1993.
|
| 22. | O'Leary, D. S. Heart rate control during exercise by baroreceptors and skeletal muscle afferents. Med. Sci. Sports Exercise 28: 210-217, 1996. [Medline] |
| 23. |
O'Leary, D. S.,
and
D. D. Sheriff.
Is the muscle metaboreflex important in control of blood flow to ischemic active skeletal muscle in dogs?
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H980-H986,
1995.
|
| 24. | O'Leary, D. S., and D. D. Sheriff. Muscle metaboreflex control of renal vascular conductance during dynamic exercise in conscious dogs (Abstract). FASEB J. 9: A899, 1995. |
| 25. | Rowell, L. B., D. S. O'Leary, and D. L. Kellogg. Integration of cardiovascular control systems in dynamic exercise. In: Exercise: Regulation and Integration of Multiple Systems, edited by L. B. Rowell, and J. T. Shepherd. New York: Oxford Univ. Press, 1996, p. 770-838. |
| 26. |
Rowell, L. B.,
M. V. Savage,
J. Chambers,
and
J. R. Blackmon.
Cardiovascular responses to graded reductions in leg perfusion in exercising humans.
Am. J. Physiol.
261 (Heart Circ. Physiol. 30):
H1545-H1553,
1991 .
|
| 27. | Scherrer, U., S. L. Pryor, L. A. Bertocci, and R. G. Victor. Arterial baroreflex buffering of sympathetic activation during exercise-induced elevations in arterial pressure. J. Clin. Invest. 86: 1855-1861, 1990 . |
| 28. | Seals, D. R., and R. G. Victor. Regulation of muscle sympathetic nerve activity during exercise in humans. Exerc. Sport Sci. Rev. 19: 313-349, 1991 . [Medline] |
| 29. |
Sheriff, D. D.,
D. S. O'Leary,
A. M. Scher,
and
L. B. Rowell.
Baroreflex attenuates pressor response to graded muscle ischemia in exercising dogs.
Am. J. Physiol.
258 (Heart Circ. Physiol. 27):
H305-H310,
1990 .
|
| 30. | Sheriff, D. D., C. R. Wyss, L. B. Rowell, and A. M. Scher. Does inadequate oxygen delivery trigger pressor response to muscle hypoperfusion during exercise? Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1199-H1207, 1987. |
| 31. |
Victor, R. G.,
D. M. Rotto,
S. L. Pryor,
and
M. P. Kaufman.
Stimulation of renal sympathetic activity by static contraction: evidence for mechanoreceptor-induced reflexes from skeletal muscle.
Circ. Res.
64:
592-599,
1989 .
|
| 32. | Webb-Peploe, M. M., D. Brender, and J. T. Shepherd. Vascular responses to stimulation of receptors in muscle by capsaicin. Am. J. Physiol. 221: 189-195, 1972. |
| 33. |
Wyss, C. R.,
J. L. Ardell,
A. M. Scher,
and
L. B. Rowell.
Cardiovascular responses to graded reductions in hindlimb perfusion in exercising dogs.
Am. J. Physiol.
245 (Heart Circ. Physiol. 14):
H481-H486,
1983 .
|
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