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Gadolinium does not blunt the cardiovascular responses at the onset of voluntary static exercise in cats: a predominant role of central command

Department of Physiology, Graduate School of Health Sciences, Hiroshima University, Hiroshima, Japan

Submitted 6 January 2006 ; accepted in final form 8 September 2006

	ABSTRACT

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The cardiovascular adaptation at the onset of voluntary static exercise is controlled by the autonomic nervous system. Two neural mechanisms are responsible for the cardiovascular adaptation: one is central command descending from higher brain centers, and the other is a muscle mechanosensitive reflex from activation of mechanoreceptors in the contracting muscles. To examine which mechanism played a major role in producing the initial cardiovascular adaptation during static exercise, we studied the effect of intravenous administration of gadolinium (55 µmol/kg), a blocker of stretch-activated ion channels, on the increases in heart rate (HR) and mean arterial blood pressure (MAP) at the onset of voluntary static exercise (pressing a bar with a forelimb) in conscious cats. HR increased by 31 ± 5 beats/min and MAP increased by 15 ± 1 mmHg at the onset of voluntary static exercise. Gadolinium affected neither the baseline values nor the initial increases of HR and MAP at the onset of exercise, although the peak force applied to the bar tended to decrease to 65% of the control value before gadolinium. Furthermore, we examined the effect of gadolinium on the reflex responses in HR and MAP (18 ± 7 beats/min and 30 ± 6 mmHg, respectively) during passive mechanical stretch of a forelimb or hindlimb in anesthetized cats. Gadolinium significantly blunted the passive stretch-induced increases in HR and MAP, suggesting that gadolinium blocks the stretch-activated ion channels and thereby attenuates the reflex cardiovascular responses to passive mechanical stretch of a limb. We conclude that the initial cardiovascular adaptation at the onset of voluntary static exercise is predominantly induced by feedforward control of central command descending from higher brain centers but not by a muscle mechanoreflex.

muscle mechanosensitive receptors; stretch-activated ion channels; mechanical stretch of skeletal muscle; exercise pressor reflex; conscious cats

A variety of ion channels sensitive to mechanical stimuli has been identified to serve many physiological functions, such as mechanosensation in specialized sensory cells and local control of blood flow and cellular volume in nonsensory cells (4, 6, 12, 15, 16, 40, 42). Mechanical perturbation influences mechanosensitive ion channels in their conductive state, leading to a change in membrane potential and triggering Ca²⁺ entry with a subsequent cascade of intracellular reactions (11, 35, 38). Since gadolinium, a trivalent lanthanide, is known to block cation-selective mechanosensitive channels, gadolinium has emerged as a commonly used tool to identify phenomena dependent on cation-selective stretch-activated ion channels (1, 3, 16, 45). Recently, Hayes and Kaufman (18) investigated the effect of gadolinium on the exercise pressor reflex in both decerebrate and chloralose-anesthetized cats to determine the role played by mechanosensitive thin fiber afferents in evoking the exercise pressor reflex. They found that gadolinium attenuated the reflex pressor response to static contraction of the triceps surae muscles and to stretch of calcaneal tendon but had no effect on the pressor response to arterial injection of capsaicin. Furthermore, they found that gadolinium attenuated the responses of group III afferents, many of which are mechanosensitive, to both static contraction and to tendon stretch, whereas gadolinium had no effect on the responses of group IV afferents, many of which are metabosensitive, to either static contraction or the capsaicin injection. Their findings (18) suggested that mechanical stimuli arising in contracting skeletal muscles contribute to the elicitation of the exercise pressor reflex and that gadolinium might exert its effect on group III skeletal muscle mechanoreceptors by blocking stretch-activated ion channels in in vivo animal experiments.

Accordingly, we used gadolinium in this study to determine whether either central command or a muscle mechanoreflex arising from contracting skeletal muscles contributes to the rapid cardiovascular adaptation at the onset of voluntary static exercise in conscious cats. We hypothesized that if gadolinium might blunt the initial cardiovascular adaptation, the muscle mechanoreflex would have a predominant role in evoking the cardiovascular responses at the onset of voluntary static exercise. Otherwise, central command would be responsible for autonomic control of the initial cardiovascular adaptation. To confirm the effect of gadolinium on skeletal muscle receptors, the cardiovascular responses to passive mechanical stretch of a fore- or hindlimb were compared before and after administration of gadolinium in anesthetized cats.

	METHODS

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The present study was conducted by using ten cats (weighing 3.3 ± 0.3 kg) in accordance with the "Guiding Principles for the Care and Use of Animals in the Fields of Physiological Sciences," approved by the Physiological Society of Japan. The experimental protocols were approved by the Committee of Research Facilities for Laboratory Animal Science, Natural Science Center for Basic Research and Development, Hiroshima University.

Static Exercise Training

The cats were operantly conditioned to perform static exercise as previously described in detail (5, 9, 22, 24, 26). They were trained to sit quietly in a transparent plastic box (width 35 x height 40 x depth 50 cm) with a small window (width 5 x height 7 cm), extend a forelimb through the window, and press a bar for 10–40 s while maintaining a sitting posture. As long as the cats pressed the bar, a sound of a buzzer was emitted as an audiofeedback. If the animal completed static exercise, food was given as a reward. The training was conducted over a period of 2–4 mo (5 days/wk).

Implantation Surgery

After the training procedure was completed, surgery was conducted to implant catheters. After an overnight fast, atropine sulfate (0.1–0.2 mg/kg im) was given as a preanesthetic drug to reduce salivation and bronchial secretion. Anesthesia was introduced by 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 usually preset in a range of 1.0–1.5% but was increased to 2.0–2.5% if an increase in HR and/or respiration and/or withdrawal of a 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 to administer drugs and into the left carotid artery to measure AP. The arterial and venous catheters were tunneled subcutaneously and brought to the exterior in the interscapular region. After implantation surgery was completed, antibiotics (benzylpenicillin potassium, 20,000 U/kg im) were injected, and the cats were housed in their cages. Antibiotics (benzylpenicillin benzathine, Bicillin tablets, 100,000 U, Banyu Pharmaceutical, Tokyo, Japan) were orally given for 5–7 postoperative days.

Data Measurement

AP was measured through the carotid artery catheter connected to a pressure transducer (DPTIII, Baxter, Tokyo, Japan). Systolic AP (SAP), mean AP (MAP), and diastolic AP (DAP) were calculated every pulse. HR was derived from 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. Timing at the start of forelimb movement was manually marked with an electric switch. AP, HR, force, and the timing signal 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, BIOPAC Systems, Santa Barbara, CA) at a sampling frequency of 400–500 Hz.

Experimental Protocols

Voluntary static exercise in conscious cats. When the cats were in good condition and were able to perform static exercise voluntarily, the experiments were conducted. On a day of the experiments, each cat was put into the transparent plastic box. A period of more than 30 min was allowed to establish that the animal was quiescent and the cardiovascular variables became stable. When sitting quietly, the cat voluntarily extended the forelimb through the window and pressed the bar while maintaining the sitting posture. HR, AP, and force applied to the bar during voluntary static exercise were measured. A typical example of the data during voluntary static exercise is shown in Fig. 1. The increase in HR at the onset of exercise lasted for about 10 s, and the HR then returned to the control level. After a total of 40 static exercise trials in four cats were repeatedly performed and the cardiovascular responses to exercise were identified, gadolinium was intravenously injected. Then a total of 46 static exercise trials [n = 14 (at 1–10 min), n = 15 (at 11–20 min), and n = 17 (at 21–30 min after injection of gadolinium)] were repeatedly evoked until 30 min following administration of gadolinium, and the cardiovascular responses to voluntary static exercise were identified in the presence of gadolinium. The duration of voluntary static exercise performed before and after gadolinium was 18 ± 0.4 s. As a time control, static exercise (n = 75 trials) was repeatedly evoked for more than 30 min in the absence of gadolinium in five cats, of which two were used in the voluntary exercise protocol with gadolinium.

View larger version (7K): [in this window] [in a new window]   Fig. 1. Responses in heart rate (HR), arterial blood pressure (AP), and force during voluntary static exercise before (A) and 20 min after intravenous administration of gadolinium (B) in a conscious cat. HR began to increase immediately before pressing a bar and reached the peak value at 1.5 s after the onset of exercise. Thereafter, HR returned to the preexercise level during the later period of exercise, although static exercise was not ended. AP increased at the beginning of exercise, and the rise in AP persisted throughout the static exercise. Gadolinium did not apparently affect the initial increases in HR and AP at the onset of static exercise.

The anesthetized cats were placed in the lateral posture with normal joint angles, avoiding any fixation of the body trunk and limbs. Passive stretch of a hindlimb was performed by holding the knee and ankle joints and manually extending the hip and knee joints and dorsiflexing the ankle joint for 1 min. When femoral blood flow was recorded, the contralateral hindlimb was passively stretched. During the hindlimb stretch, the hip and knee joints were extended by 20 ± 5° and 40 ± 9°, respectively, and the ankle joint was dorsiflexed by 32 ± 20°. It is estimated from the changes in joint angles that the hindlimb triceps surae muscle was stretched by 16–18 mm according to previous studies (10, 33). Similarly, passive stretch of a forelimb was performed by holding the shoulder and elbow joints and manually extending the scapular and shoulder joints and flexing the elbow joint for 1 min. During the forelimb stretch, the scapular and shoulder joints were extended by 22 ± 6° and 28 ± 6°, respectively, and the elbow joint was flexed by 62 ± 23°. Care was taken not to move the body trunk. In this study we did not isolate any tendon and did not measure muscle tension during passive stretch to allow the animals to recover from anesthesia. After the cardiovascular and femoral blood flow responses to passive stretch of a limb were determined, gadolinium was intravenously injected. Until 40 min following administration of gadolinium, the changes in the cardiovascular responses to passive limb stretch were identified.

Gadolinium

Gadolinium chloride hexahydrate (Aldrich Chemical, Milwaukee, WI) was dissolved in HEPES buffer with a concentration of 20 mM (pH 7.3–7.4) according to previous studies (13, 18). The gadolinium solution was intravenously administered with a volume of 2.7 ± 0.3 ml/kg (55 ± 6 µmol/kg).

Statistical Analysis

The cardiovascular responses to voluntary static exercise or passive stretch of a limb were divided into five groups: 1) before, 2) 1–10 min, 3) 11–20 min, 4) 21–30 min, and 5) 31–40 min after administration of gadolinium. The data were compared among the groups by a one-way repeated-measures ANOVA. If a significant main effect was found, a Dunnett post hoc test was performed to detect a difference from the control. The cardiovascular responses either to static exercise or passive stretch of a limb at 21–30 min after administration of gadolinium were compared with the control responses before gadolinium 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.

	RESULTS

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Effect of Gadolinium on the Cardiovascular Responses at the Onset of Voluntary Static Exercise

The effects of gadolinium on the baseline values in HR and AP in conscious cats are summarized in Table 1. Baseline HR, SAP, MAP, and DAP did not change significantly following intravenous injection of gadolinium, except an increase in HR at the 31- to 40-min period. The effect of gadolinium on the initial increases in HR and AP at the onset of voluntary static exercise is exemplified in Fig. 1. In the absence of gadolinium, HR began to increase immediately before a bar was pressed and reached the peak value of 153 beats/min from the control value of 117 beats/min at 1.5 s from the onset of exercise (Fig. 1A). Thereafter, HR returned to the preexercise level, although static exercise was not ended. SAP increased from 89 mmHg to 104 mmHg at the onset of static exercise, and the rise in SAP persisted throughout static exercise. Gadolinium did not affect the increases in HR and AP at the onset of exercise (Fig. 1B).

View larger version (9K): [in this window] [in a new window]   Fig. 2. The average increases in HR and mean arterial blood pressure (MAP) and the peak force taken during voluntary static exercise before and over a period of 30 min after intravenous administration of gadolinium. Gadolinium did not significantly affect the initial increases in HR and MAP at the onset of static exercise. However, the peak force tended to decrease following administration of gadolinium. As time control, the changes in HR and MAP, and the peak force during voluntary static exercise were examined over a period of more than 30 min in the absence of gadolinium. Essentially, the increases in HR and MAP were the same throughout the period examined, and the peak force was not deteriorated.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Comparison in the increases in HR and MAP and the peak force taken during voluntary static exercise before and 21–30 min after intravenous administration of gadolinium. Although gadolinium did not affect the initial increases in HR and MAP at the onset of static exercise, the peak force was significantly decreased following administration of gadolinium. As time control, the changes in HR and MAP and the peak force during voluntary static exercise, which were taken at an interval of 21–30 min in the absence of gadolinium, were not significantly different. *P < 0.05, significant difference before and after gadolinium. NS, not statistically significant.

View larger version (18K): [in this window] [in a new window]   Fig. 4. The time courses of the average changes in HR and MAP during voluntary static exercise are compared among the 4 periods before and after gadolinium. The grouped data were obtained over exercise trials at each period. Gadolinium did not significantly affect the time courses of the increases in HR and MAP during static exercise.

Effect of Gadolinium on the Cardiovascular Responses During Mechanical Stretch of a Limb

The effects of gadolinium on the baseline values in HR and AP in anesthetized cats are summarized in Table 1. Baseline HR, SAP, MAP, and DAP did not change significantly following intravenous injection of gadolinium in the anesthetized condition, as well as the conscious condition, except an increase in AP at the 31- to 40-min period. Figure 5 exemplifies the effects of gadolinium on the reflex increases in HR and AP in response to passive mechanical stretch of a fore- or hindlimb. HR increased from 217 to 227 beats/min during passive stretch of a forelimb; SAP increased from 129 to 159 mmHg during the passive stretch. The reflex increases in HR and AP were also produced during passive mechanical stretch of a hindlimb. Gadolinium obviously blunted the reflex responses in HR and AP during passive stretch of either forelimb or hindlimb (Fig. 5).

View larger version (16K): [in this window] [in a new window]   Fig. 5. Responses in HR and AP during passive mechanical stretch of a forelimb (A) or hindlimb (B) before and 21–26 min after intravenous administration of gadolinium in an anesthetized cat. The increases in HR and AP during passive stretch of either limb were blunted by gadolinium.

View larger version (10K): [in this window] [in a new window]   Fig. 6. The average increases in HR and MAP during passive stretch of a forelimb or hindlimb before and over a period of 40 min after intravenous administration of gadolinium. Gadolinium significantly blunted the increases in HR and MAP in response to passive stretch of either limb. *P < 0.05, significant difference before and after gadolinium.

View larger version (11K): [in this window] [in a new window]   Fig. 7. Comparison in the increases in HR and MAP during passive stretch of a forelimb or hindlimb before and 21–30 min after intravenous administration of gadolinium. Gadolinium significantly blunted the increases in HR and MAP in response to passive stretch of either limb. *P < 0.05, significant difference before and after gadolinium.

Femoral blood flow decreased to 6.6 ± 1.1 ml/min during passive stretch of the contralateral hindlimb from the control value of 7.5 ± 1.8 ml/min in two anesthetized cats; calculated femoral vascular resistance increased by 28% (from 15 ± 5 to 19 ± 6 mmHg·ml^–1·min). The increase in femoral vascular resistance, which was thought to be induced by the muscle mechanoreflex due to the passive stretch, was virtually abolished by administration of gadolinium; femoral vascular resistance did not change during hindlimb passive stretch (from 20 ± 6 to 20 ± 6 mmHg·ml^–1·min at 21–30 min after gadolinium and from 17 ± 6 to 17 ± 5 mmHg·ml^–1·min at 31–60 min after gadolinium).

	DISCUSSION

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We have studied the effect of gadolinium, a blocker of stretch-activated ion channels, on the increases in HR and MAP at the beginning of voluntary static exercise in conscious cats to understand whether either central command or muscle mechanoreflex played a major role in the initial cardiovascular adaptation during static exercise. Although gadolinium blocked stretch-activated ion channels and thereby attenuated the muscle mechanoreflex responses to passive stretch of a fore- or hindlimb in anesthetized cats, gadolinium did not blunt the initial increases in HR and MAP at the beginning of voluntary static exercise. We inferred from the present findings that the initial cardiovascular adaptation during voluntary static exercise was induced predominantly by central command descending from higher brain centers but not by the muscle mechanoreflex, at least in the presence of gadolinium.

Limitations

Several potential limitations are involved in this study. The finding that gadolinium did not affect the initial cardiovascular responses during voluntary static exercise in conscious cats needed careful consideration. First of all, the size of central command might be altered in the course of the experiments. Since the peak tension during static exercise reduced 35% following gadolinium, a greater activation of central command may have occurred during exercise in the presence of gadolinium and may elicit greater responses in HR and MAP. If so, the present findings do not always imply the major role of central command in the initial cardiovascular adaptation during static exercise in the normal condition. However, augmented central command may not be sufficient to produce full force development if any. Furthermore, if there is an occlusive nonlinear summation of the cardiovascular responses between central command and muscle mechanoreflex, it is difficult to clarify a role of one mechanism by a simple destructive intervention to interrupt the other mechanism. These possibilities remain to be solved. Second, since the number of the conscious cats used in the voluntary exercise protocol was small, the obtained results were lacking in statistical power. However, the same tendency that gadolinium had no effects on the responses in HR and MAP during voluntary exercise was observed in all cats. In addition, when analyzing the changes in MAP and HR over 14–40 exercise trials at each period, we confirmed no significant effect of gadolinium on the magnitude and time course of the cardiovascular responses (Fig. 4). Taken together, it is unlikely that the insignificant effect of gadolinium on the increases in HR and MAP during voluntary static exercise was derived from the small sample size. Third, the maximal voluntary force that the cats could produce during static exercise was uncertain. The peak force during static exercise in conscious cats corresponded to 17% of their body weight. Since the maximally developed force was nearly 1.0 kg in the present and previous studies (5, 9, 24, 26), the cats seemed to produce 60% of the maximal voluntary force at the most, and the intensity of static exercise appeared mild or moderate. Thus the exercise intensity might be insufficient to initiate the muscle mechanoreflex, the contribution of which remains to be studied with a higher intensity of static exercise. Fourth, it is possible that plasma concentration of free gadolinium ions might not be enough to affect mechanosensitive receptors in skeletal muscle, because gadolinium may be bound with negatively charged ions in plasma and become inactive (3). Moreover, Hayes and Kaufman (18) noticed that the effect of intraarterially injected gadolinium on the cardiovascular responses during static contraction and mechanical tendon stretch peaked 60 min after the injection. In this study, the effect of gadolinium on the cardiovascular responses during static exercise was examined for 30 min after administration of gadolinium in most cats, because it was difficult for the cats to perform voluntary static exercise repeatedly over a longer period. For these reasons the effect of gadolinium on muscle mechanosensitive receptors might not be developed fully within the observation period. However, such a possibility seems unlikely because the same dose of gadolinium significantly attenuated the increases in HR and MAP in response to passive stretch of a fore- or hindlimb in the anesthetized condition. Furthermore, if gadolinium may inhibit primary (group Ia) and secondary (group II) afferent activity from muscle spindles, stretch reflex will be attenuated by gadolinium, leading to decreased force development during static exercise. Activity of group Ia and II spindle afferents of a finger extensor muscle is known to show increased firing during voluntary isometric contraction in humans (7, 37). In this study the peak tension during voluntary static exercise was gradually attenuated following gadolinium. Gadolinium administered systemically in the present study seemed effective on muscle mechanosensitive afferents.

No Significant Effects of Gadolinium on the Baseline Hemodynamics

Since arterial baroreceptors in the cardiovascular system are mechanosensitive and spontaneously active, gadolinium may influence mechanoelectrical transduction in arterial baroreceptors. Indeed, gadolinium inhibited mechanoelectrical transduction in rabbit and cat carotid sinus baroreceptors in the vascularly isolated in vivo preparation (13, 46) and in rat aortic baroreceptor neurons isolated from the nodose ganglia (41), although gadolinium did not block mechanoelectrical transduction of rat aortic baroreceptors in the isolated aortic arch preparation (2). If gadolinium decreases the ongoing activity of arterial baroreceptors, systemic administration of gadolinium may affect baseline hemodynamics; for example, decreased activity in arterial baroreceptors will cause an increase in sympathetic nerve activity and, in turn, raise HR and MAP. However, in this study gadolinium (55 µmol/kg iv) did not alter the baseline values of HR and MAP in both conscious and anesthetized cats, except for the last period of 31–40 min taken after the treatment. Similarly, it has been reported that a smaller dose of gadolinium (20–40 µmol/kg iv) had no significant effects on baseline hemodynamics in anesthetized cats and dogs; however, a larger dose of gadolinium >75 µmol/kg produced hypotension and myocardial contractility impairment (1, 14, 36). Intravenous injection of gadolinium <55 µmol/kg, therefore, may not affect the ongoing activity of arterial baroreceptors, although previous studies (13, 46) reported that gadolinium (0.1–1 mM ia) inhibited activity of carotid sinus baroreceptors. This discrepancy may be partly explained by a difference in the drug injection method (intraarterial vs. intravenous) and, accordingly, by a difference in concentration of gadolinium in the carotid sinus and aortic regions.

Central Command, But Not the Muscle Mechanoreflex, Is Responsible for the Initial Cardiovascular Regulation at the Onset of Static Exercise

As mentioned before, the size of central command may be augmented following gadolinium. Furthermore, if there is an occlusive summation of the cardiovascular responses between central command and muscle mechanoreflex, it is difficult to estimate a functional role of the muscle mechanoreflex from the sole effect of gadolinium on the cardiovascular responses during exercise. Although these limitations must be taken into account, the present finding that gadolinium did not at all alter the time course and magnitude of the cardiovascular responses at the onset of voluntary static exercise in conscious cats suggests a role of central command in producing the initial cardiovascular adaptation at least in the presence of gadolinium. The central command hypothesis is supported by previous findings from Matsukawa and colleagues (24, 25, 43) demonstrating that cardiac and renal sympathetic efferent nerve activities start to increase immediately before or at the onset of static and dynamic exercise, which in turn contributes to tachycardia and pressor response in several seconds. The rapid sympathetic nerve responses are hardly explained by the muscle mechanoreflex. Momen et al. (31, 32) recently reported that a 15-s bout of evoked static muscle contraction by percutaneous electrical stimulation increased renal vascular resistance in humans, suggesting that muscle mechanoreflex engagement was responsible for the increase in renal vascular resistance. Taken together, the muscle mechanoreflex may not work on the whole vascular system but may affect the renal vascular bed particularly. This is in agreement with an increase in renal sympathetic nerve activity at the onset of static contraction or during passive mechanical stretch of skeletal muscle in anesthetized cats, which caused renal vasoconstriction (27, 28).

An influence of conditioning and/or learning on the autonomic nerve and cardiovascular responses during voluntary static exercise might be involved, because the cats were operantly trained for a long period to perform static exercise. To consider this issue, we compared the responses in renal sympathetic nerve activity, HR, and MAP during static exercise to their responses at the beginning of natural body movement, such as spontaneous postural changes, walking, and grooming (23, 24). The magnitude and time course of the increases in renal sympathetic nerve activity, HR, and MAP during static exercise were comparable with those during natural body movement. Furthermore, a buzzer sound emitted as audiofeedback in exercise training did not evoke any significant changes in renal sympathetic nerve activity, HR, and MAP (24). An influence of conditioning and/or learning in association with exercise training is unlikely to affect the autonomic nerve and cardiovascular responses during static exercise. We feel that central command, generated for feedforward regulation of the cardiovascular system in association with voluntary exercise in daily life, also occurs immediately before or at the onset of voluntary static exercise.

Central command has an important role not only in determining sympathetic outflows at the beginning of voluntary static exercise but also in interacting with the arterial baroreflex circuit in the brainstem. Matsukawa and colleagues (22, 26, 34) have recently provided clear evidence that central command acts upon the arterial baroreflex circuit within the brainstem and modulates its central property at the start of static exercise. The baroreflex bradycardia elicited by aortic nerve stimulation was blunted immediately before static exercise in conscious cats, even in the absence of muscular exertion, and at the onset of spontaneous muscle contraction in decerebrate cats; in contrast, the depressor response to aortic nerve stimulation was not affected by static exercise (22, 34). It is likely that central command inhibits selectively the cardiac component of the arterial baroreflex at the onset of exercise, which, in turn, induces an abrupt increase in HR. Central command, therefore, has a predominant role in interacting with the cardiac limb of the arterial baroreflex circuit in the brainstem.

Stimulation of Mechanosensitive Afferents Causes Increases in HR and MAP

The present finding that gadolinium attenuated the reflex increases in HR and MAP in response to passive stretch of either forelimb or hindlimb in the anesthetized condition is in good agreement with the previous study by Hayes and Kaufman (18) demonstrating that gadolinium attenuated the cardiovascular responses during tendon stretch of the hindlimb triceps surae muscle in anesthetized or decerebrate cats. They also found that gadolinium attenuated the responses of group III afferents from the triceps surae muscle to tendon stretch, suggesting that gadolinium might exert its effect on group III skeletal muscle mechanoreceptors by blocking stretch-activated ion channels (18). Taken together, passive mechanical stretch of a forelimb as well as a hindlimb stimulates muscle mechanosensitive receptors, which is able to cause significant increases in HR and MAP in the anesthetized or decerebrate condition.

It is surprising that gadolinium did not attenuate the cardiovascular responses during voluntary static exercise in conscious cats, because the muscle mechanoreflex caused the cardiovascular and autonomic nerve responses in the anesthetized or decerebrate condition. Indeed, passive stretch of the hindlimb triceps surae muscle increased HR by 6–11 beats/min and MAP by 14–46 mmHg in anesthetized (27–29, 39) or decerebrate cats (33); passive stretch of the forelimb triceps brachii muscle increased HR by 16 beats/min and MAP by 38 mmHg in anesthetized cats (17). Moreover, passive stretch increased cardiac sympathetic efferent nerve activity by 40–50% (29, 33) and renal sympathetic efferent nerve activity by 20% (27, 28) in anesthetized or decerebrate cats and decreased cardiac vagal efferent nerve activity by 30% (33). Since the cardiovascular variables and autonomic nerve activities responded depending on the extent of passive muscle stretch, some muscle mechanoreflex-induced responses would be expected during voluntary static exercise, even though the exercise intensity appeared mild or moderate. Gadolinium, however, did not blunt the cardiovascular responses at the onset of voluntary static exercise in this study. Thus we hypothesize that the muscle mechanoreflex, which can produce the cardiovascular responses in the anesthetized or decerebrate condition, appears to be inhibited in the conscious condition.

In conclusion, gadolinium did not blunt the cardiovascular responses at the beginning of voluntary static exercise in conscious cats, whereas it blunted the reflex cardiovascular responses during passive muscle stretch in the anesthetized condition of the same cats. Therefore, the cardiovascular adaptation at the onset of voluntary exercise in conscious cats is induced by feedforward control due to central command but not by feedback control due to the muscle mechanosensitive reflex. Furthermore, gadolinium can be used as a tool for identifying the reflex component originated from muscle mechanosensitive afferents stimulated during exercise.

	GRANTS

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This study was supported by a Grant-in-Aid for Scientific Research B from the Japan Society for the Promotion of Science and by a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

	ACKNOWLEDGMENTS

 
We thank Tomoko Ishida for excellent technical assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: K. Matsukawa, Dept. of Physiology, Graduate School of Health Sciences, Hiroshima Univ., Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan (e-mail: matsuk{at}hiroshima-u.ac.jp)

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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