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Department of Physiology, Institute of Health Sciences, Hiroshima University Faculty of Medicine, Hiroshima 734-8551, Japan
Submitted 8 January 2003 ; accepted in final form 31 March 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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aortic depressor nerve; aortic baroreceptors; baroreflex sensitivity; baroreflex depressor response; central modulation of the arterial baroreflex
The effect of exercise on the arterial baroreflexes has been extensively studied in humans and animals. When baroreflex sensitivity was assessed as a ratio of the change in R-R interval or HR in response to an alteration in AP, it was reduced during dynamic or static exercise in humans (3, 14) and dogs (25). In addition, the response in R-R interval or HR to a change in carotid sinus transmural pressure was blunted during dynamic or static exercise in humans (18, 19, 47) and baboons (5), although Bevegård and Shephard (2) reported that a reflex decrease in HR in response to neck suction was similar during rest and exercise. On the other hand, the responses in AP to neck pressure and suction were less affected or preserved during exercise (2, 8, 18, 47). These results suggest that the sensitivity of the cardiac component of the carotid and aortic baroreflexes is attenuated around the operating point during exercise. However, it is uncertain whether the attenuated baroreflex sensitivity around the operating point is caused by a reduction in the average and/or maximal slope of the stimulus-response curves of the baroreflex relationships or by a shift of the curves. To solve this issue, Melcher and Donald (27) studied the stimulus-response curve of the carotid baroreflex (carotid sinus pressure vs. HR) with isolated carotid sinuses during dynamic exercise in conscious dogs. They found that the stimulus-response curve was shifted upward without changing the maximal slope of the curve. The similar results have been reported in humans when the stimulus-response curve of the carotid baroreflex was examined with a neck chamber during dynamic exercise (39, 41). The stimulus-response curve between carotid sinus transmural pressure and HR was shifted rightward (to a higher carotid sinus pressure) and upward (to a higher HR) during exercise without changing the maximal slope of the curve. Either central command descending from higher brain centers or the exercise pressor reflex arising from contracting muscles may contribute to the resetting of the stimulus-response curve of the carotid sinus baroreflex (11, 24, 38, 40, 42, 43). On the basis of these findings, the attenuation in the baroreflex sensitivity around the operating point during exercise will be explained by the rightward shift of the baroreflex stimulus-response curve rather than by a reduction in the average and/or maximal slope of the baroreflex curve. However, the stimulus-response curve was measured during a steady state of exercise, i.e., 3–20 min after the start of exercise, and it took a certain period to obtain the stimulus-response curve of the carotid baroreflex. Therefore, it remains unknown whether such modulation of the arterial baroreflexes can be applied over the whole period of exercise, especially at the beginning of exercise. In fact, the response of the R-R interval to a step increase in carotid sinus transmural pressure is transiently reduced at the beginning of isometric hand-grip exercise in humans, even in the anticipation period preceding the start of exercise (8, 19). Also, it cannot be denied that the functional characteristics of the arterial baroreflexes are dynamically altered from moment to moment during exercise.
HR and renal and skin sympathetic nerve activities increase immediately before or at the onset of voluntary static exercise in cats (7, 12, 21) and humans (45, 50). Cardiac, renal, and lumbar sympathetic nerve activities also demonstrate a rapid increase at the beginning of dynamic exercise or natural body movement in cats (13, 20, 22, 30, 48), rabbits (37), and rats (6). Central command is the most likely to cause the prompt sympathoexcitation, which in turn contributes to the cardiovascular adaptation at the beginning of static or dynamic exercise. Recently, we (22, 44) found that sinoaortic denervation blunted the centrally induced initial tachycardia at the beginning of spontaneous locomotion but exaggerated the pressor response. From these data, we proposed that the cardiac component of the arterial baroreflexes, but not the vasomotor component, is inhibited transiently at the beginning of spontaneous locomotion, which in turn contributes to the rapid cardiac acceleration (22, 44). This conclusion is supported by previous studies (8, 19) demonstrating that the baroreflex response of the R-R interval to a step increase in carotid sinus transmural pressure was blunted at the beginning of isometric handgrip exercise. Central descending output from higher brain centers seems to interact with the brain stem circuit of the arterial baroreflexes and to modulate its central property at the start of exercise. Indeed, it is known that electro- or chemical stimulation of a localized area in the hypothalamus or midbrain periaqueductal gray, which is capable of inducing the defense reaction, suppresses reflex bradycardia evoked by stimulation of the aortic depressor nerve (ADN) or carotid sinus nerve in anesthetized rats and cats (28, 32, 34).
In this study, we hypothesized that the cardiac component of the arterial baroreflex was temporarily suppressed by central command at the onset of voluntary exercise. To examine this, we used electrical stimulation of the left ADN, which evoked baroreflex bradycardia and depressor response with short latency. The sizes of the baroreflex bradycardia and depressor response were assumed to reflect the central characteristics of the cardiac and vasomotor components of the aortic baroreflex. The aim of this work was to evaluate the dynamic changes in the baroreflex bradycardia and depressor response by ADN stimulation given at various time points before and during voluntary static exercise in conscious cats. Particularly, a contribution of central command to modulation of the aortic baroreflex function was challenged using ADN stimulation given immediately before the right forelimb was extended to perform static exercise, i.e., in the absence of muscular exertion.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Exercise training. The cats were operantly conditioned to perform static exercise as previously described in detail (7, 12, 21). All cats were trained to sit quietly in a transparent plastic box (width 35 cm x height 40 cm x depth 50 cm) with a small window (width 5 cm x height 7 cm), extend the right forelimb through the window, and press a bar for 20–40 s while maintaining a sitting posture. As long as the cats pressed the bar, the sound of a buzzer was emitted as an audiofeedback. If the animal completed the static exercise, food was given as a reward. The training was conducted over a period of 1–4 mo (5 days/wk).
Implantation surgery. After the training procedure was finished, surgery was conducted to implant catheters and an electrode for stimulating the left ADN. After an overnight fast, atropine sulfate (0.1–0.2 mg/kg im) was given as a preanesthetic medication to reduce salivation and bronchial secretion. Anesthesia was introduced by the inhalation of a mixture of 4% halothane (Fluothane, Takeda Chemical Industries; Osaka, Japan), N2O (0.5 l/min), and O2 (1.0 l/min), and an endotracheal tube was inserted. Subsequently, the cats inhaled the halothane-N2O-O2 mixture through the endotracheal tube. ECG, HR, rectal temperature, and respiration were continuously monitored. To maintain an appropriate level of surgical anesthesia, the concentration of halothane was adjusted in the range of 1.0–2.5% if an increase in HR and/or respiration and/or withdrawal of the limb in response to noxious pinch of the paw and/or a surgical procedure was observed. Rectal temperature was maintained at 36.5–37.5°C with a heating pad. Polyethylene catheters were inserted into the left external jugular vein for administration of drugs and into the left carotid artery for measuring AP. The left ADN was carefully isolated with the aid of an operating microscope (OME, Olympus Optical; Tokyo, Japan). The miniature cuff electrode for stimulation of the ADN consisted of a pair of Teflon-coated silver wires (0.15 mm in diameter) and Silastic silicone tubing (SFM3–1350, SF Medical; Hudson, MA). After the electrode was implanted on the nerve, the nerve-electrode complex was covered with silicone gel. The ADN was left intact in the present study. Another silver wire electrode was placed as a ground electrode under the skin of the back. To verify whether the stimulating electrode was correctly implanted on the ADN, we recorded ADN activity through the electrode during surgery. The lead wires of the electrodes and the arterial and venous catheters were tunneled subcutaneously and brought to the exterior in the interscapular region. During the exercise experiments, the wires were connected to a stimulating instrument by a light lead cable. After the implantation surgery was finished, antibiotics (20,000 U/kg im benzylpenicillin potassium) were injected, and the cats were housed in their cages. Antibiotics (100,000 units benzylpenicillin benzathine, Bicillin Tablets, Banyu Pharmaceutical; Tokyo, Japan) were orally given for 5–7 postoperative days.
Data measurement and ADN stimulation. AP was measured through the carotid artery catheter connected to a pressure transducer (DPTIII, Baxter; Tokyo, Japan). Systolic (SAP), mean (MAP), and diastolic AP (DAP) were calculated at every pulse. HR was derived from the AP pulse by a tachometer (model 1321, GE Marquette Medical Systems; Tokyo, Japan). The actual force that the cats applied to the bar was measured with strain gauges (KFG-2N-120, Kyowa Electronic Instruments; Tokyo, Japan) affixed on the bar. The onset and offset of static exercise were defined from the force development. The stimulation of the ADN was automatically monitored with an electric signal. Timing at the start of forelimb movement was manually marked with an electric switch. AP, HR, force, and the timing signals for ADN stimulation and for the start of forelimb movement were simultaneously recorded on an eight-channel pen-writing recorder (8M14, GE Marquette Medical Systems) and were also stored in a computer via an analog-to-digital converter (MP100, BIOPACK Systems; Santa Barbara, CA) at a sampling frequency of 400 Hz.
To evoke the baroreflex bradycardia and depressor response, electrical stimulation of the ADN was conducted using a stimulator (SEN-7103, Nihon Kohden; Tokyo, Japan). A brief train of electrical pulses was delivered for 1 s (20-ms pulse interval, 1-ms pulse duration, and 1.5–5 V pulse intensity). The ADN stimulation used in the present study did not evoke any uncomfortable signs, limb withdrawal, or increases in HR and AP. In addition, we recognized no changes in respiratory movement during ADN stimulation when thoracic movement was directly observed.
Experimental protocols and data analysis. When the cats were in good condition and were able to perform static exercise voluntarily, the experiments were conducted. On days of the experiments, each cat was put into the transparent plastic box. A period of >30 min was allowed to establish that the animal was quiescent and the cardiovascular variables were stable. When sitting quietly, the cat voluntarily extended the forelimb through the window and pressed the bar for 20–40 s while maintaining a sitting posture. The changes in HR, SAP, MAP, DAP, and force applied to the bar during voluntary static exercise were measured in 18 total trials of static exercise without ADN stimulation in 3 cats; 4–7 trials were conducted per animal.
To evaluate the effect of static exercise on the central properties of the aortic baroreflex, ADN stimulation was given before, during, and after static exercise. Forty-eight total trials of static exercise were performed in three cats; six to twenty-seven trials were conducted per animal. In each trial, ADN stimulation was repeatedly delivered one to three times during resting and two to four times during exercise; the interstimulation interval was 6–26 s. ADN stimulation was started independently of the cardiac cycle in two cats, and it started in synchronization with the cardiac cycle or regardless of the cardiac cycle in one cat. To examine the possibility of whether the ongoing activity of aortic baroreceptors might interfere with ADN stimulation, the baroreflex bradycardia evoked by ADN stimulation was compared between the two different methods in the cat. As a result, the size of the baroreflex bradycardia was not significantly different between the two stimulation methods: 55 ± 8 beats/min (ADN stimulation irrespective of the cardiac cycle) versus 52 ± 7 beats/min (ADN stimulation in synchronization with the cardiac cycle) before exercise, 28 ± 5 versus 34 ± 4 beats/min at the initial period of exercise, 51 ± 8 versus 35 ± 4 beats/min during the later period of exercise, and 44 ± 7 vs. 43 ± 5 beats/min after exercise, respectively. Thus it is unlikely that the ongoing activity of aortic baroreceptors might interfere with ADN stimulation. Both data with the two different stimulation methods were pooled to obtain the average responses in the cat.
To examine the effect of repetition of ADN stimulation on the baroreflex bradycardia and depressor response, the ADN was repeatedly stimulated, with an interval of 5–17 s during resting (n = 11 trials). The baroreflex bradycardia by the first ADN stimulation (44 ± 4 beats/min) was not different from that by the second ADN stimulation (47 ± 5 beats/min). Similarly, the repetition of ADN stimulation did not affect the depressor responses (9 ± 1 mmHg for the first ADN stimulation and 10 ± 1 mmHg for the second ADN stimulation). Thus the repetition of ADN stimulation used in the present study did not cause any adaptive changes in the baroreflex bradycardia and depressor response during resting.
To examine whether the central properties of the aortic baroreflex were similarly modified at the beginning of naturally occurring body movement as in the case of voluntary static exercise, the baroreflex bradycardia in response to ADN stimulation was determined at the beginning of spontaneous postural movement (n = 4 trials) or grooming behavior (n = 4 trials) in two cats.
Baroreflex bradycardia and depressor response. ADN stimulation induced bradycardia and depressor response at rest. As the baroreflex response, we defined a bradycardia response with a short latency of <7 beats or 3 s from the onset of ADN stimulation and a depressor response with a latency of <14 beats or 6 s. We then measured the amplitudes of the baroreflex bradycardia (defined as the peak decrease in HR) and depressor response (defined as the peak fall in SAP). After the average values of the bradycardia and depressor response during the preexercise control period were determined as 100%, the relative percent changes in the amplitudes of the baroreflex bradycardia and depressor response were calculated before, during, and after static exercise. As soon as the animals started to extend the right forelimb, they pressed the bar and developed force with a short time delay of 0.5 ± 0.2 s from the onset of forelimb movement. Taking this time relationship into consideration, we examined the changes in the sizes of the baroreflex bradycardia and depressor response when ADN stimulation was given at various time points near the onset of voluntary static exercise. The exercise period was arbitrarily divided into the initial period (up to 8 s after the exercise onset) and the later period until the cessation of static exercise, because the increase in HR lasted for 8 ± 2 s at the initial period of exercise and thereafter HR returned to the control level.
Statistical analysis. In a given trial of static exercise, ADN stimulation was repetitively imposed at the four different periods (before exercise, at the initial period of exercise, during the later period of exercise, and after exercise). At each of the four periods, the sizes of the bradycardia and depressor response evoked by ADN stimulation were measured and averaged over trials in an individual animal. The mean sizes of the bradycardia and depressor response were further averaged among the three cats and statistically analyzed by a one-way ANOVA with repeated measures. If a significant main effect about the four periods was found, a Dunnett's post hoc test was performed to detect the difference in mean values from the preexercise control value. On the other hand, the size of the bradycardia due to ADN stimulation at the beginning of spontaneous body movement was compared with the control value during resting by a paired t-test. The level of statistical significance was defined as P < 0.05 in all cases. The data are expressed as means ± SE.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Responses in HR, AP, and force during voluntary static exercise.
An example of the changes in HR and AP during static exercise is shown in
Fig. 1. HR began to increase
immediately before the bar was pressed and reached the peak value at 5 s from
the onset of exercise. Thereafter, HR returned to the preexercise level in
10 s after the exercise onset, although the static exercise was not
ended. An increase in AP followed the initial tachycardia and persisted
throughout the static exercise. After exercise, a subsequent increase in HR
was observed in association with eating behavior.
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The average duration of static exercise was 31 ± 1 s. The peak force applied to the bar was 337 ± 22 g, and the average force over the whole period of exercise was 127 ± 3 g. The increase in HR at the beginning of static exercise lasted for 8 ± 2 s; the peak increase in HR was 34 ± 7 beats/min at 3 ± 1 s from the onset of exercise. The increase in SAP was delayed from the tachycardia and sustained throughout the static exercise. The peak increase in SAP was 16 ± 2 mmHg observed at 12 ± 3s from the onset of exercise; the peak increases in MAP and DAP were 14 ± 1 and 13 ± 1 mmHg, respectively.
Baroreflex bradycardia and depressor response evoked by ADN stimulation at rest. ADN stimulation caused baroreflex bradycardia and depressor response at rest, as shown in Fig. 2 and summarized in Table 1. The peak decrease in HR was 41 ± 7 beats/min, which occurred at 3.2 ± 0.5 beats (i.e., 1.2 ± 0.1 s) from the onset of ADN stimulation. The peak depressor response in SAP was 13 ± 4 mmHg at 9.2 ± 2.2 beats (i.e., 3.6 ± 0.5 s) from the stimulation onset. The peak depressor responses in MAP and DAP were 12 ± 3 and 13 ± 3 mmHg at the same moment, respectively.
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Baroreflex bradycardia and depressor response evoked by ADN stimulation at the onset and offset of voluntary static exercise. The effects of voluntary static exercise on the baroreflex bradycardia and depressor response evoked by ADN stimulation are exemplified in Fig. 2. When the ADN was stimulated at the onset of exercise, the evoked baroreflex bradycardia was markedly attenuated compared with the bradycardia before exercise. Subsequently, when the ADN was stimulated in the middle of static exercise, the baroreflex bradycardia remained blunted but became greater than that evoked at the onset of exercise. The ADN stimulation given after static exercise caused the same bradycardia as before exercise. In contrast to the baroreflex bradycardia, the depressor response evoked by ADN stimulation was not altered by voluntary static exercise.
When the time relationship between phasic forelimb movement and voluntary static exercise is taken into account, the bradycardia in response to ADN stimulation given at various points near the onset and offset of static exercise was examined as exemplified in Figs. 3 and 4. When the ADN was stimulated before force development (immediately before or at the start of limb movement) or immediately after force development (Fig. 3), the baroreflex bradycardia was suppressed to 21 ± 3 beats/min from the control value of 48 ± 5 beats/min at rest. The same ADN stimulation evoked a greater bradycardia of 39 ± 4 beats/min 8–12 s after the exercise onset. In Fig. 4, the bradycardia in response to ADN stimulation during the last 10-s period of static exercise remained blunted. When ADN was stimulated simultaneously with the offset of exercise, bradycardia was markedly suppressed to 16 ± 3 beats/min. The same ADN stimulation given 3–8 s after exercise caused a significant bradycardia of 46 ± 6 beats/min. It is of interest that ADN stimulation-evoked bradycardia was temporarily suppressed immediately before or when the animals were voluntarily extending their forelimb at the onset of static exercise and also when the forelimb was retracted at the end of static exercise.
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Effect of voluntary static exercise on the baroreflex bradycardia and depressor response. Relative changes in the sizes of the baroreflex bradycardia and depressor response from preexercise control before, during, and after static exercise are plotted in Fig. 5. If the bradycardia or depressor response exceeded the upper or lower level of mean ± 1.65 SD of the preexercise values, we defined it as a significant response and then counted the occurrence frequency of the significant responses at the initial and later period of exercise. If a statistical distribution of the data was the same as the control, only 5% of the observations would exceed the upper or lower limit, respectively. The bradycardia less than the lower limit (less than mean – 1.65 SD) appeared more frequently at the initial period of exercise (40% of 48 observations) than during the later period of exercise (18% of 76 observations). However, the bradycardia exceeding the upper limit (greater than mean + 1.65 SD) was never observed at the initial period of exercise and sparsely appeared during the later period of exercise. On the other hand, the depressor response less than the lower limit was observed at the initial period of exercise (26% of 29 observations) more than during the later period of exercise (13% of 62 observations). After exercise, the occurrence frequency of the responses exceeding the upper or lower limit was almost the same as the preexercise control.
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The prestimulation cardiovascular values and responses to aortic nerve stimulation before exercise, at the initial period of and during the later period of exercise, and after exercise are summarized in Table 1. The relative percent changes in the baroreflex bradycardia and depressor response due to ADN stimulation against their 100% control values obtained before exercise are shown in Fig. 6. In Table 1, the prestimulation cardiovascular values were not significantly different from the prestimulation values before exercise, except for HR at the initial period of exercise. HR was significantly increased at the initial period of exercise, whereas the decrease in HR due to ADN stimulation was significantly blunted (Table 1). The baroreflex bradycardia at the initial period of exercise was significantly attenuated to 62 ± 5% of the preexercise value (Fig. 6). However, bradycardia during the later period of exercise was not significantly different from the control, although it was reduced to 83 ± 9%. After exercise, bradycardia returned to the control level. In contrast to bradycardia, depressor response was not significantly influenced by static exercise, although it tended to decrease to 84 ± 7% at the initial period of exercise (Fig. 6).
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Effect of naturally occurring body movement on baroreflex bradycardia. When ADN was stimulated at the beginning of spontaneous postural movement (n = 4 trials), the baroreflex bradycardia was significantly blunted to 21 ± 3 beats/min from the control value of 36 ± 5 beats/min. Furthermore, when ADN stimulation was given at the beginning of grooming (n = 4 trials), the baroreflex bradycardia was blunted to 29 ± 6 beats/min from the control value of 36 ± 6 beats/min.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Limitations. Several potential problems involved in this study
must be discussed. First, because the baroreflex bradycardia and depressor
response were evoked by direct stimulation of ADN without mechano-transduction
process in aortic baroreceptors, they did not reflect the entire baroreflex
responses evoked by an alteration in AP. Instead, the reflex responses with
short latency in HR and AP in response to constant electrical stimulation of
ADN are considered to reflect the central characteristics of the aortic
baroreflex function. Furthermore, ADN stimulation given at various time points
before and during voluntary static exercise enabled us to study how such
central characteristics of the aortic baroreflex were dynamically modified by
exercise. Second, because the aortic nerve was left intact in the present
study, the ongoing activity of aortic baroreceptors might interfere with ADN
stimulation despite the uniform stimulating condition. As a matter of fact, AP
had not increased yet at the initial period of exercise at which an ADN
stimulation-evoked bradycardia was blunted, suggesting that aortic
baroreceptor activity is not raised at the moment of exercise. Moreover, when
ADN stimulation was synchronized with the cardiac cycle, the same attenuating
effect of exercise on the baroreflex bradycardia was seen as in the case of
unsynchronized ADN stimulation. The bradycardia evoked by ADN stimulation,
therefore, is less likely to be influenced considerably by the ongoing aortic
nerve activity. Third, we did not confirm whether the ADN stimulation
recruited A-fibers only or both A- and C-fibers. Because it has been reported
that stimulation of ADN with low voltage (<4–5 V) predominantly
activates A-fibers and stimulation of ADN with higher voltage starts to
activate C-fibers in anesthetized cats and rats
(10,
36), we consider that the
present stimulation of ADN for 1 s (1.5–5 V intensity, 1.0 ms duration,
50 Hz frequency) is likely to activate A-fibers rather than C-fibers. In
addition, because the cat aortic depressor nerve contains not only
barosensitive but also chemosensitive afferents from the aortic bodies, the
stimulation of ADN might excite chemosensitive afferents. It is known that the
aortic chemoreceptor reflex increases HR and MAP
(4). Indeed, when the intensity
of ADN stimulation was raised to 6–10 V, we observed a tachycardia and
pressor response instead of a bradycardia and depressor response. As long as
the voltage intensity of ADN stimulation was low, neither tachycardia nor
pressor response was evoked, suggesting that barosensitive afferents are more
likely to be activated by the ADN stimulation used in this study than
chemosensitive afferents. Finally, it is uncertain whether the force
development and/or muscle mass involved during static exercise in this study
were high enough to evoke a reflex inhibition by muscle afferents of the
cardiac component of the arterial baroreflex. The peak force produced during
static exercise in this study was 337 ± 22 g, which corresponds to
10–13% of their body weight. In previous studies using the same animal
model of static exercise, the holding force was 100–700 g depending on
the period of the exercise training
(7,
12) and the average peak force
was 536 ± 46 g (21). It
seems that the force development during static exercise in this study is
almost comparable with or somewhat less than that obtained in previous
studies. Although the maximal voluntary force during static exercise in a
given cat was uncertain, the maximally developed force was nearly 1.0 kg in
the present and previous studies
(7,
12,
21). If so, we expect that the
animals may produce 30% of the maximal voluntary force. On the other
hand, the responses in HR and MAP (34 ± 7 beats/min and 14 ± 1
mmHg) observed during static exercise in this study were greater than previous
data (22 ± 2 beat/min for HR and 11 ± 1 mmHg for MAP)
(21). The intensity of static
exercise in the present study may be mild or moderate but is sufficient to
produce such significant cardiovascular responses. However, whether a higher
intensity of exercise leads to the same conclusion about central modulation of
the aortic baroreflex as in the present study remains unknown.
Dynamic changes in the aortic baroreflex function during static exercise. We revealed the dynamic changes in the aortic baroreflex function by identifying the reflex responses to ADN stimulation given at various times during static exercise. ADN stimulation-induced bradycardia was suppressed immediately before or at the onset of exercise but was somewhat restored during the later period of exercise. This finding implies that the sensitivity of the aortic baroreceptor-HR reflex changes dynamically from moment to moment during voluntary static exercise and is particularly inhibited at the onset of exercise. This conclusion is in good agreement with the previous studies showing that the baroreflex response of the R-R interval to a step increase in carotid sinus transmural pressure is blunted at the beginning of isometric hand-grip exercise in humans, even in the anticipation period preceding the start of exercise (8, 19). It is therefore conceivable that the sensitivity around the operating point on the stimulus-response curves of the carotid and aortic baroreflexes is attenuated at the onset of voluntary static exercise. This blunted baroreflex sensitivity is explained by two different ways. One is that the stimulus-response curve is reset toward an appropriate direction without changing the average and/or maximal slope of the baroreflex curve. The other is that the slope of the curve itself is reduced without shifting the baroreflex curve. A resetting of the baroreflex curve cannot explain the reduction of the bradycardia induced by ADN stimulation, unless the operating point is beyond the quasilinear range of the reset baroreflex curve. Alternatively, a reduction in the slope of the baroreflex curve is more likely to explain the blunted baroreflex bradycardia, because such reduced slope is applicable irrespective of the blood pressure range and AP was not raised yet at the onset of exercise. However, to precisely answer whether the blunted baroreflex bradycardia is due to reduction in the slope of the stimulus-response curve or due to resetting of the curve, the dynamic changes in the characteristics of the baroreflex stimulus-response curve at the start of exercise should be investigated.
On the other hand, with respect to the arterial baroreflex function during a steady-state period of dynamic exercise, it has been reported that the aortic baroreflex sensitivity did not change in humans (46), and the stimulus-response curve of the carotid sinus baroreflex was shifted toward a higher level of carotid sinus pressure without changing its maximal sensitivity in humans (39, 41) and dogs (27). In this study, HR returned to the preexercise level during the later period of static exercise, whereas MAP remained elevated (Fig. 1), indicating a rightward shift of the operating point in the MAP-HR relationship. ADN stimulation-induced bradycardia observed during that period was not significantly different from the control, although it tended to be less throughout exercise. Furthermore, there were no remarkable changes in the bradycardia induced by stimulation of the carotid sinus nerve before and during a steady-state period of exercise in humans (9) and dogs (49). The preserved baroreflex-induced bradycardia and rightward shift of the operating point may correspond to resetting of the baroreflex curve to the same direction. Taking the above results into consideration, we hypothesize that the gain of the stimulus-response baroreflex curve is temporarily suppressed at the initial period of voluntary exercise, after which the baroreflex curve is shifted toward a higher level of AP during exercise with restoring the baroreflex gain.
Effect of central command and muscle afferent inputs on the aortic baroreflex. Two neural mechanisms responsible for the cardiovascular adaptation during exercise have been suggested (29). One is a feedforward control by descending output from higher brain centers termed central command, and the other is a feedback control by a reflex arising from the contracting skeletal muscle termed the exercise pressor reflex. Group III and IV muscle afferents, which are supposed to be mechanosensitive and metabosensitive, respectively, play a role in generating the exercise pressor reflex (16, 17, 23). A baroreceptor-induced bradycardia is inhibited by electrical stimulation of either group III or IV muscle afferents (26, 33, 35). Electro- or chemical stimulation of a localized area in the hypothalamus or midbrain periaqueductal gray matter suppresses the baroreceptor-induced bradycardia (28, 32, 34). Therefore, it is possible that either central command or the exercise pressor reflex may blunt the ADN stimulation-induced bradycardia during voluntary static exercise obtained in this study. The prompt attenuation of the ADN stimulation-induced bradycardia at the onset of exercise favors either central command or the muscle mechanoreflex as a candidate mechanism. We feel that central command is more likely to interact with the aortic baroreflex arc within the brain stem so as to inhibit the cardiac limb of the baroreflex, because the attenuated baroreflex bradycardia was observed immediately before the forelimb was extended, i.e., in the absence of muscular exertion (Figs. 3 and 5). This conclusion is supported by a recent finding by McIlveen et al. (24): neither tendon stretch nor static muscle contraction did not suppress the slope of the function curve of the carotid sinus baroreflex but shifted upward the baroreflex curve. Dynamic changes in the ADN stimulation-induced bradycardia near the cessation of static exercise are interesting. ADN stimulation-induced bradycardia was clearly inhibited when the forelimb was retracted at the end of static exercise and recovered quickly to the control level within a few seconds (Figs. 4 and 5). It is difficult for the muscle metaboreflex to explain such dynamic modulation of the baroreflex bradycardia. Probably, central command plays a more important role in determining the dynamic changes in the central properties of the aortic baroreflex not only at the initial period but also at the end of exercise.
Regarding a neural mechanism responsible for suppression by central command of the arterial baroreflex function, Mifflin et al. (28) reported that stimulation of the hypothalamic defense area evokes a long-lasting postsynaptic inhibitory potential in neurons in the nucleus of the solitary tract (NTS) that receive excitatory synaptic input from carotid sinus baroreceptors in anesthetized cats. Nosaka and colleagues (15, 35) found that stimulation of the defense area in the hypothalamus or midbrain periaqueductal gray matter suppresses ADN stimulation-evoked unitary responses of neurons in the nucleus ambiguus rather than barosensitive neurons in the NTS and that vagal bradycardia evoked by microinjection of glutamate into the nucleus ambiguus was markedly inhibited by the defense area stimulation. From the above electrophysiological evidence, it is suggested that central command descending from higher brain centers may impose an inhibitory action on barosensitive neurons in the medullary area such as the NTS and the vagal preganglionic motor nuclei so as to interact with the arterial baroreflex arc.
Differential effects on the cardiac and vasomotor components of the arterial baroreflexes. The bradycardia evoked by ADN stimulation was modulated by voluntary static exercise, whereas the evoked depressor response was not significantly affected by the exercise, in this study. Similarly, isometric handgrip exercise reduced the baroreflex bradycardia caused by an increase in carotid sinus transmural pressure but did not affect the depressor response in humans (18, 47). Static exercise is, therefore, considered to have differential influences on the cardiac and vasomotor components of the aortic and carotid sinus baroreflexes. We (22, 44) have previously reported that sinoaortic denervation blunts the centrally induced initial tachycardia at the beginning of spontaneous overground locomotion in decerebrate cats, whereas the initial increases in renal sympathetic nerve activity and MAP are exaggerated. Likewise, sinoaortic denervation attenuated an increase in HR during physical activity in conscious rabbits (31) and caused a reduction in HR variability but a marked increase in blood pressure variability in conscious cats (1). These data consistently indicate that the central nervous system is capable of differentially modulating the cardiac and vasomotor components of the arterial baroreflexes. Taken together, we proposed that the central inhibition of the cardiac component of the arterial baroreflexes is selectively induced at the beginning of voluntary exercise, which in turn produces rapid cardiac acceleration via an increase in cardiac sympathetic nerve activity and/or a decrease in cardiac vagal nerve activity.
Functional significance. An attenuation of the ADN stimulation-induced bradycardia was also recognized at the beginning of naturally occurring body movement such as a spontaneous postural change or grooming behavior in conscious cats. This result indicates that the gain of the aortic baroreflex is temporarily blunted at the beginning of natural body movement as well as voluntary static exercise and such modulation of the arterial baroreflex function occurs within the brain stem but not at a level of aortic baroreceptors in the periphery. It is of interest to compare the attenuating effect of static exercise on the ADN stimulation-induced bradycardia with the efferent nerve responses in cardiac and renal sympathetic outflows during exercise and natural body movement such as postural change, walking, turning, and grooming in conscious cats (21, 22, 30, 48). Cardiac sympathetic nerve activity increases promptly after the start of treadmill exercise (48) and immediately before or at the onset of natural body movement (22, 30). Renal sympathetic nerve activity increases immediately before or at the onset of voluntary static exercise or grooming behavior (21). The rapid time course of the increases in cardiac and renal sympathetic outflows implies that they are probably caused by central command descending from higher brain centers. However, if the central characteristics of the cardiac and vasomotor components of the arterial baroreflexes are differentially modified at the onset of exercise, an underlying neural mechanism may be different between the two sympathetic outflows even though central command excites them. When baseline MAP is highly elevated, the centrally induced increase in renal sympathetic nerve activity is not evoked, suggesting that the arterial baroreceptors-renal sympathetic nerve activity reflex is operating even at the initial period of exercise and the centrally induced increase in renal sympathetic nerve activity is not able to overcome the baroreceptor-induced inhibition (21). These data match well with the present finding that the central property of the vasomotor component of the aortic baroreflex is preserved during voluntary static exercise including the initial period. On the contrary, if the central inhibition of the cardiac component of the aortic baroreflex contributes to the rapid activation of cardiac sympathetic nerve activity, the initial increase in cardiac sympathetic outflow may be capable of resisting such excessive baroreceptor input, which remains to be studied.
In conclusion, the central inhibition of the cardiac component of the aortic baroreflex is induced by central command during voluntary static exercise in conscious cats, in particular near the onset of static exercise, while the central property of the vasomotor component of the baroreflex is preserved.
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, start of forelimb movement; vertical
dotted line, onset of force development. When ADN was stimulated immediately
before or at the start of forelimb movement preceding force development, the
baroreflex bradycardia was nearly abolished. When ADN was stimulated at or
immediately after the onset of force development, a slight bradycardia was
evoked. Thereafter, when the ADN stimulation was given 
, Before exercise; 
, immediately before or during exercise;
+, after exercise. Solid horizontal lines show the mean level of the
preexercise values (100%). Dotted horizontal lines show means ± 1.65 SD
of the preexercise values. The baroreflex bradycardia less than the lower
limit (less than mean – 1.65 SD) was the most frequently observed at the
initial period of static exercise.