宮本 忠吉

New Findings What is the central question of this study? Recently, the heterogeneity of the cerebral arterial circulation has been argued. Orthostatic tolerance may be associated with an orthostatic stress-induced change in blood flow in vertebral arteries rather than in internal carotid arteries, because vertebral arteries supply blood to the medulla oblongata, which is the location of important cardiac, vasomotor and respiratory control centres. What is the main finding and its importance? The effect of graded orthostatic stress on vertebral artery blood flow is different from that on internal carotid artery blood flow. This response allows for the possibility that orthostatic tolerance may be associated with haemodynamic changes in posterior rather than anterior cerebral blood flow. Recently, the heterogeneity of the cerebral arterial circulation has been argued, but the characteristics of vertebral artery (VA) and internal carotid artery (ICA) blood flow during graded orthostatic stress remain unknown. We hypothesized that the change in blood flow in VA is not similar to that in ICA blood flow during graded orthostatic stress. We measured blood flows in both ICA and VA during graded lower body negative pressure (LBNP; -20, -35and -50mmHg) by using two colour-coded ultrasound systems. The effect of graded orthostatic stress on the VA blood flow was different from that on the ICA blood flow (LBNPxartery, P=0.006). The change in ICA blood flow was associated with the level of LBNP (r = 0.287, P=0.029), and a reduction in ICA blood flow from pre-LBNP was observed during -50mmHg LBNP (from 411 +/- 35 to 311 +/- 40mlmin(-1), P=0.044) without symptoms of presyncope. In contrast, VA blood flow was unchanged during graded LBNP compared with the baseline (P=0.597) relative to the reduction in ICA blood flow and thus there was no relationship between VA blood flow and the level of LBNP (r=0.167, P=0.219). These findings suggest that the change in ICA blood flow is due to the level of LBNP during graded orthostatic stress, but the change in VA blood flow is different from that in ICA blood flow across the different levels of LBNP. These findings provide the possibility that posterior cerebral blood flow decreases only during severe orthostatic stress and is therefore more likely to be linked with orthostatic tolerance.

BACKGROUND: Spatially resolved near-infrared spectroscopy-determined frontal lobe tissue oxygenation (Sco2) is reduced with administration of phenylephrine, while cerebral blood flow may remain unaffected. We hypothesized that extracranial vasoconstriction explains the effect of phenylephrine on Sco2. METHODS: We measured Sco2 and internal and external carotid as well as vertebral artery blood flow in 7 volunteers (25 [SD 4] years) by duplex ultrasonography during IV infusion of phenylephrine, together with middle cerebral artery mean blood velocity, forehead skin blood flow, and mean arterial blood pressure. RESULTS: During phenylephrine infusion, mean arterial blood pressure increased, while Sco 2 decreased by -19% ± 3% (mean ± SE P = 0.0005). External carotid artery (-27.5% ± 3.0%) and skin blood flow (-25.4% ± 7.8%) decreased in response to phenylephrine administration, and there was a relationship between Sco2 and forehead skin blood flow (Pearson r = 0.55, P = 0.042, 95% confidence interval [CI], = 0.025-0.84 Spearman r = 0.81, P &lt 0.001, 95% CI, 0.49-0.94) and external carotid artery conductance (Pearson r = 0.62, P = 0.019, 95% CI, 0.13 to 0.86 Spearman r = 0.64, P = 0.012, 95% CI, 0.17-0.88). CONCLUSIONS: These findings suggest that a phenylephrine-induced decrease in Sco2, as determined by INVOS-4100 near-infrared spectroscopy, reflects vasoconstriction in the extracranial vasculature rather than a decrease in cerebral oxygenation. Copyright © 2014 International Anesthesia Research Society.

The purpose of the present study was to assess the effect of heat stress-induced changes in systemic circulation on intra- and extracranial blood flows and its distribution. Twelve healthy subjects with a mean age of 22 +/- 2 (s.d.) years dressed in a tube-lined suit and rested in a supine position. Cardiac output (Q), internal carotid artery (ICA), external carotid artery (ICA), and vertebral artery (VA) blood flows were measured by ultrasonography before and during whole body heating. Esophageal temperature increased from 37.0 +/- 0.2 degrees C to 38.4 +/- 0.2 degrees C during whole body heating. Despite an increase in Q (59 +/- 31%, P<0.001), ICA and VA decreased to 83 +/- 15% (P=0.001) and 87 +/- 8% (P=0.002), respectively, whereas ECA blood flow gradually increased from 188 +/- 72 to 422 +/- 189 mL/minute (135%, P<0.001). These findings indicate that heat stress modified the effect of Q on blood flows at each artery; the increased Q due to heat stress was redistributed to extracranial vascular beds.

The respiratory chemoreflex is known to be modified during orthostatic stress although the underlying mechanisms remain to be established. To determine the potential role of cerebral hypoperfusion, we examined the relationship between changes in MCA Vmean (middle cerebral artery mean blood velocity) and V̇E (pulmonary minute ventilation) from supine control to LBNP (lower body negative pressure -45mmHg) at different CO2 levels (0, 3.5 and 5% CO2). The regression line of the linear relationship between V̇ E and PETCO2 (end-tidal CO2) shifted leftwards during orthostatic stress without any change in sensitivity (1.36±0.27 l/min per mmHg at supine to 1.06±0.21 l/min per mmHg during LBNP P=0.087). In contrast, the relationship between MCA Vmean and PETCO2 was not shifted by LBNP-induced changes in PETCO2. However, changes in V̇E from rest to LBNP were more related to changes in MCA Vmean than changes in PETCO2. These findings demonstrate for the first time that postural reductions in CBF (cerebral blood flow) modified the central respiratory chemoreflex by moving its operating point. An orthostatically induced decrease in CBF probably attenuated the "washout" of CO2 from the brain causing hyperpnoea following activation of the central chemoreflex. © The Authors Journal compilation 2013 Biochemical Society.

New Findings: • What is the central question of this study? Does hypoxia enhance blood flow to all parts of the brain uniformly? • What is the main finding and its importance? During hypoxia, internal carotid artery flow is maintained despite a reduction in (end-tidal) carbon dioxide tension, while vertebral artery blood flow increases. Only with maintained end-tidal carbon dioxide tension is there an increase in both vertebral and internal carotid blood flow during hypoxia. Hypoxia changes the regional distribution of cerebral blood flow and stimulates the ventilatory chemoreflex, thereby reducing CO2 tension. We examined the effects of both hypoxia and isocapnic hypoxia on acute changes in internal carotid (ICA) and vertebral artery (VA) blood flow. Ten healthy male subjects underwent the following two randomly assigned respiratory interventions after a resting baseline period with room air: (i) hypoxia and (ii) isocapnic hypoxia with a controlled gas mixture (12% O2 inspiratory mmHg). In the isocapnic hypoxia intervention, subjects were instructed to maintain the rate and depth of breathing to maintain the level of end-tidal partial pressure of CO2 () during the resting baseline period. The ICA and VA blood flow (velocity × cross-sectional area) were measured using Doppler ultrasonography. The was decreased (-6.3 ± 0.9%, P &lt 0.001) during hypoxia by hyperventilation (minute ventilation +12.9 ± 2.2%, P &lt 0.001), while was unchanged during isocapnic hypoxia. The ICA blood flow was unchanged (P= 0.429), while VA blood flow increased (+10.3 ± 3.1%, P= 0.010) during hypoxia. In contrast, isocapnic hypoxia increased both ICA (+14.5 ± 1.4%, P &lt 0.001) and VA blood flows (+10.9 ± 2.4%, P &lt 0.001). Thus, hypoxic vasodilatation outweighed hypocapnic vasoconstriction in the VA, but not in the ICA. These findings suggest that acute hypoxia elicits an increase in posterior cerebral blood flow, possibly to maintain essential homeostatic functions of the brainstem. © 2012 The Physiological Society.

A vertical and cross slope, waves (unevenness) of a sidewalk are significant barrier to the mobility of wheelchair users. In Japan, the Law for Promoting Barrier-free Transport and Facilities for the Elderly and the Disabled specifies that a cross slope in sidewalk is recommended to be 1% gradient or less and it is allowed to be no greater than 2% when it is unavoidable. However, it is necessary to clarify the evidence for the guidelines how changes in a cross slope gradient affect the accessibility and the physical load of wheelchair users. And the objective assessment of barrier-free road construction to resolve wave-road should be investigated. The objective of this study was to experimentally clarify the relationship between the cross slope of an actual sidewalk environment and the physical load of wheelchair users by the oxygen uptake and the wheelchair propelling force. Our experimental results showed that the physical load of a wheelchair user in the 2% cross slope was not so strong statistically compared with the level surface. On the other hand, the required force of a downhill side handrim was significantly greater than that of an uphill side handrim. This unbalance of propelling force caused by the cross slope would increase the physical load of wheelchair users especially with hemiplegia. The reduced oxygen cost index indicated that the barrier-free road construction was effective for improving the accessibility of wheelchair. Based on these findings, we propose the evidence of a wheelchair user's physical load while propelling a cross slope and a wave-road. © 2013 The authors and IOS Press. All rights reserved.

The purpose of this study was to investigate the effects of 12 weeks of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women. Twenty healthy middle-aged women were recruited for this study. Several measurements were performed pre and post exercise training, including: body weight and composition, peak oxygen consumption (peak VO2), energy intake after the single bout of exercise, and the release of gut hormones with fasting and after the single bout of exercise. Exercise training resulted in significant increases in acylated ghrelin fasting levels (from 126.6 +/- 5.6 to 135.9 +/- 5.4 pmol/l, P < 0.01), with no significant changes in GLP-1 (from 0.54 +/- 0.04 to 0.55 +/- 0.03 pmol/ml) and PYY (from 1.20 +/- 0.07 to 1.23 +/- 0.06 pmol/ml) fasting levels. GLP-1 levels post exercise training after the single bout of exercise were significantly higher than those pre exercise training (areas under the curve (AUC); from 238.4 +/- 65.2 to 286.5 +/- 51.2 pmol/ml x 120 min, P < 0.001). There was a tendency for higher AUC for the time courses of PYY post exercise training than for those pre exercise training (AUC; from 519.5 +/- 135.5 to 551.4 +/- 128.7 pmol/ml x 120 min, P = 0.06). Changes in (delta) GLP-1 AUC were significantly correlated with decreases in body weight (r = -0.743, P < 0.001), body mass index (r = -0.732, P < 0.001), percent body fat (r = -0.731, P < 0.001), and energy intake after a single bout exercise (r = -0.649, P < 0.01) and increases in peak VO2 (r = 0.558, P < 0.05). These results suggest that the ability of exercise training to create a negative energy balance relies not only directly on its impact on energy expenditure, but also indirectly on its potential to modulate energy intake.

We have reported that minute ventilation [Vover dot(E)] and end- tidal CO(2) tension [P(ETCO2)] are determined by the interaction between central controller and peripheral plant properties. During exercise, the controller curve shifts upward with unchanged central chemoreflex threshold to compensate for the plant curve shift accompanying increased metabolism. This effectively stabilizes PETCO(2) within the normal range at the expense of exercise hyperpnea. In the present study, we investigated how endurancetrained athletes reduce this exercise hyperpnea. Nine exercise- trained and seven untrained healthy males were studied. To characterize the controller, we induced hypercapnia by changing the inspiratory CO(2) fraction with a background of hyperoxia and measured the linear PETCO(2) Vover dot(E) relation [Vover dot(E) = S (P(ETCO2) - B)]. To characterize the plant, we instructed the subjects to alter Vover dot(E) voluntarily and measured the hyperbolic Vover dot(E) - P(ETCO2) relation (P(ETCO2) A/Vover dot(E) + C). We characterized these relations both at rest and during light exercise. Regular exercise training did not affect the characteristics of either controller or plant at rest. Exercise stimulus increased the controller gain (S) both in untrained and trained subjects. On the other hand, the P(ETCO2) - intercept (B) during exercise was greater in trained than in untrained subjects, indicating that exercise- induced upward shift of the controller property was less in trained than in untrained subjects. The results suggest that the additive exercise drive to breathe was less in trained subjects, without necessarily a change in central chemoreflex threshold. The hyperbolic plant property shifted rightward and upward during exercise as predicted by increased metabolism, with little difference between two groups. The Vover dot(E) during exercise in trained subjects was 21% lower than that in untrained subjects (P < 0.01). These results indicate that an adaptation of the controller, but not that of plant, contributes to the attenuation of exercise hyperpnea at an iso- metabolic rate in trained subjects. However, whether training induces changes in neural drive originating from the central nervous system, afferents from the working limbs, or afferents from the heart, which is additive to the chemoreflex drive to breathe, cannot be determined from these results.

Objective The vertical slope in sidewalk is a big barrier for the wheelchair users. In Japan, the Law for Promoting Barrier-free Transport and Facilities for the Elderly and the Disabled and it's guideline indicate that the vertical slope in sidewalk is expected to be 5% gradient or less and it can be allowed 8% or less when it is unavoidable. Grounds of this guideline depended from existing studies and related documents reported that most of wheelchair users were able to climb up 5% gradient slope and 24/25 subjects were able to climb up 8% slope. However, the research on the relationship between the feature of slope with gradient, distance, ascending speed and the physical load of wheelchair users was still remained. The purpose of this study is to evaluate the physical load of the wheelchair users by the oxygen uptake values and the wheelchair driving force while they are propelling a wheelchair upward on a slope, and to realize barrier-free environment. Methods The dynamic wheelchair driving force was measured by using a torque meter equipped on a wheelchair to analyze the required force when ascending on a slope. The oxygen uptake values and heart rate were measured with the portable metabolic analysis system and the heart rate monitor system. Unimpaired adult subjects were asked to propel the wheelchair on the slope that was used for the emergency escape route of the handicapped person's sports facilities. The profile of the slope was 8% gradient, 120m distance, and 7.6m height. The strokes and speed to propel the wheelchair was set to be free of each subject. Results and Conclusion The Oxygen Cost Index of the wheelchair users while propelling manual wheelchair upward on the slope indicated approximately 0.017 (liter/one meter) and it was about three times higher than that of by flat floor in the room (0.006 l/meter). The averaged heart rate value at the summit of the slope showed an increase of 150bpm, and was equivalent to the Borg Scale 15 (hard). It was corresponding to the feeling of physical load (it was a very hard, limit) with all subjects. The averaged wheelchair driving power while ascending the slope presented approximately 58W, and it was needed by about four times as large as flat floor (15W). We conclude that 8% gradient and 120m distance of the slope cause extremely high physical load for the wheelchair users even in the case of unimpaired persons. So, we should pay attention to the slope gradient of guideline, and should improve the slope of sidewalk to reduce the physical load of wheelchair users. The Oxygen Cost Index and the power of wheelchair driving force are useful index for the assessment of barrier-free road environment, route selection with lower stress, and the universal design of slope.

We estimated the transfer function of autonomic heart rate (HR) control by using random binary sympathetic or vagal nerve stimulation in anaesthetized rats. The transfer function from sympathetic stimulation to HR response approximated a second-order, low-pass filter with a lag time (gain, 4.29 +/- 1.55 beats min-1 Hz-1; natural frequency, 0.07 +/- 0.03 Hz; damping coefficient, 1.96 +/- 0.64; and lag time, 0.73 +/- 0.12 s). The transfer function from vagal stimulation to HR response approximated a first-order, low-pass filter with a lag time (gain, 8.84 +/- 4.51 beats min-1 Hz-1; corner frequency, 0.12 +/- 0.06 Hz; and lag time, 0.12 +/- 0.08 s). These results suggest that the dynamic characteristics of HR control by the autonomic nervous system in rats are similar to those of larger mammals.

Ogoh S, Nakahara H, Ainslie PN, Miyamoto T. The effect of oxygen on dynamic cerebral autoregulation: critical role of hypocapnia. J Appl Physiol 108: 538-543, 2010. First published January 7, 2010; doi:10.1152/japplphysiol.01235.2009.-Hypoxia is known to impair cerebral autoregulation (CA). Previous studies indicate that CA is profoundly affected by cerebrovascular tone, which is largely determined by the partial pressure of arterial O(2) and CO(2). However, hypoxic-induced hyperventilation via respiratory chemoreflex activation causes hypocapnia, which may influence CA independent of partial pressure of arterial O(2). To identify the effect of O(2) on dynamic cerebral blood flow regulation, we examined the influence of normoxia, isocapnia hyperoxia, hypoxia, and hypoxia with consequent hypocapnia on dynamic CA. We measured heart rate, blood pressure, ventilatory parameters, and middle cerebral artery blood velocity (transcranial Doppler). Dynamic CA was assessed (n = 9) during each of four randomly assigned respiratory interventions: 1) normoxia (21% O(2)); 2) isocapnic hyperoxia (40% O(2)); 3) isocapnic hypoxia (14% O(2)); and 4) hypocapnic hypoxia (14% O(2)). During each condition, the rate of cerebral regulation (RoR), an established index of dynamic CA, was estimated during bilateral thigh cuff-induced transient hypotension. The RoR was unaltered during isocapnic hyperoxia. Isocapnic hypoxia attenuated the RoR (0.202 +/- 0.003/s; 27%; P = 0.043), indicating impairment in dynamic CA. In contrast, hypocapnic hypoxia increased RoR (0.444 +/- 0.069/s) from normoxia (0.311 +/- 0.054/s; + 55%; P = 0.041). These findings indicated that hypoxia disrupts dynamic CA, but hypocapnia augments the dynamic CA response. Because hypocapnia is a consequence of hypoxic-induced chemoreflex activation, it may provide a teleological means to effectively maintain dynamic CA in the face of prevailing arterial hypoxemia.

To investigate the effect of resistance training at lower than the recommended frequency (2–3 times a week) on muscular strength, we recruited 103 college students (67 males 61±8 kg, 36 females 51±4 kg, mean±SD) who had never regularly engaged in resistance training. They performed resistance training in a PE class once a week for seven to ten weeks. We measured one repetition maximum (1 RM) for the bench press and arm curl, and the girth of the thigh and upper arm before and after the training. The training included stretching, three sets of ten repetitions on a bench press, half squat lift, arm curl and three types of training chosen by each subject. The weight load was 10 RM, which was progressively increased; when the subject succeeded in lifting a load ten times at the first set, the load was increased in the following week. After the training period 1RM was increased by more than 10% compared with that before training, for either the bench press or the arm curl, in all subjects. The 1 RM for the bench press significantly increased from 46±9 kg to 54±9 kg in males, and from 22±4 kg to 28±5 kg in females, and that for the arm curl also increased significantly. No significant change was found in the girth of the thigh and upper arm. On the other hand, 49 male students who undertook softball in a PE class did not show any significant change in 1 RM after the eight-week control period, compared to that before the period. These results demonstrate that resistance training at a frequency lower than the recommended one increases muscular strength in college students, possibly through adaptations in the nervous system.

Background: Autonomic neural intervention is a promising tool for modulating the Circulatory system thereby treating some cardiovascular diseases. Methods and Results: In 8 pentobarbital-anesthetized cats, it was examined whether the arterial pressure (AP) could be controlled by acupuncture-like hind-limb electrical stimulation (HES). With a 0.5-ms Pulse width, HES monotonically reduced AP as the stimulus current increased from I to 5 mA, suggesting that the stimulus current could be a primary control variable. In contrast, the depressor effect of HES showed a nadir approximately 10 Hz in the frequency range between 1 and 100Hz. Dynamic characteristics of the AP response to HES approximated a second-order low-pass filter with dead time (gain: -10.2 +/- 1.6mmHg/mA, natural frequency: 0.040 +/- 0.004Hz, damping ratio 1.80 +/- 0.24, dead time: 1.38 +/- 0.13s, mean +/- SE). Based on these dynamic characteristics, a servo-controlled HES system was developed. When a target AP value was set at 20 mmHg below the baseline AP, the time required for the AP response to reach 90% of the target level was 38 +/- 10s. The steady-state error between the measured and target AP values was 1.3 +/- 0.1 mmHg. Conclusions: Autonomic neural intervention by acupuncture-like HES might provide an additional modality to quantitatively control the circulatory system. (Circ J 2009; 73: 851-859)

Ogoh S, Ainslie PN, Miyamoto T. Onset responses of ventilation and cerebral blood flow to hypercapnia in humans: rest and exercise. J Appl Physiol 106: 880-886, 2009. First published January 8, 2009; doi:10.1152/japplphysiol. 91292.2008.-The respiratory and cerebrovascular reactivity to changes in arterial PCO(2) (Pa(CO2)) is an important mechanism that maintains CO(2) or pH homeostasis in the brain. It remains unclear, however, how cerebrovascular CO(2) reactivity might influence the respiratory chemoreflex. The purpose of the present study was therefore to examine the interaction between onset responses of the respiratory chemoreflex and middle cerebral artery (MCA) mean blood velocity (V(mean)) to hypercapnia (5.0% CO(2)-40% O(2)-balance N(2)) at rest and during dynamic exercise (similar to 1.01/min O(2) consumption). Each onset response was evaluated using a single-exponential regression model consisting of the response time latency [CO(2)-response delay (t(0))] and time constant (tau). At rest, t(0) and tau data indicated that the MCA V(mean) onset response was faster than the ventilatory ((V) over dot E) response (P < 0.001). In contrast, during exercise, t(0) of (V) over dot E and MCA V(mean) onset responses were decreased. In addition, despite the enhanced Pa(CO2) response to CO(2) administration (P = 0.014), tau of MCA V(mean) tended to increase during exercise (P = 0.054), whereas tau of (V) over dot(E) decreased (P = 0.015). These findings indicate that 1) at rest, faster washout of CO(2) via cerebral vasodilation results in a reduced activation of the central chemoreflex and subsequent reduced (V) over dot E onset response, and 2) during exercise, despite higher rates of increasing Pa(CO2), the lack of change in the onset response of cerebral blood flow and reduced washout of CO(2) may act to augment the (V) over dot E onset response.

Although muscarinic K(+) (K(ACh)) channels contribute to a rapid heart rate (HR) response to vagal stimulation, whether background sympathetic tone affects the HR control via the K(ACh) channels remains to be elucidated. In seven anesthetized rabbits with sinoaortic denervation and vagotomy, we estimated the dynamic transfer function of the HR response by using random binary vagal stimulation (0-10 Hz). Tertiapin, a selective K(ACh) channel blocker, decreased the dynamic gain (to 2.3 +/- 0.9 beats. min(-1).Hz(-1), from 4.6 +/- 1.1, P < 0.01, mean +/- SD) and the corner frequency (to 0.05 +/- 0.01 Hz, from 0.26 +/- 0.04, P < 0.01). Under 5 Hz tonic cardiac sympathetic stimulation (CSS), tertiapin decreased the dynamic gain (to 3.6 +/- 1.0 beats.min(-1).Hz(-1), from 7.3 +/- 1.1, P < 0.01) and the corner frequency (to 0.06 +/- 0.02 Hz, from 0.23 +/- 0.06, P < 0.01). Two-way analysis of variance indicated significant interaction between the tertiapin and CSS effects on the dynamic gain. In contrast, no significant interactions were observed between the tertiapin and CSS effects on the corner frequency and the lag time, In conclusion, although a cyclic AMP-dependent mechanism has been well established, an accentuated antagonism also occurred in the direct effect of ACh via the KACh channels. The rapidity of the HR response obtained by the KACh channel pathway was robust during the accentuated antagonism.

Miyamoto T, Kawada T, Yanagiya Y, Akiyama T, Kamiya A, Mizuno M, Takaki H, Sunagawa K, Sugimachi M. Contrasting effects of presynaptic alpha(2)-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control. Am J Physiol Heart Circ Physiol 295: H1855-H1866, 2008. First published August 29, 2008; doi:10.1152/ajpheart.522.2008. - Presynaptic alpha(2)-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits (n = 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg . kg(-1) . h(-1) iv). We also examined the effect of the alpha(2)-adrenergic receptor agonist clonidine (0.3 and 1.5 mg . kg(-1) . h(-1) iv) in different rabbits (n = 5). Yohimbine increased the maximum step response (from 7.2 +/- 0.8 to 12.2 +/- 1.7 beats/min, means +/- SE, P < 0.05) without significantly affecting the initial slope (0.93 +/- 0.23 vs. 0.94 +/- 0.22 beats . min(-1) . s(-1)). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 +/- 0.8 to 6.8 +/- 1.0 and 2.8 +/- 0.5 beats/min, P < 0.05) and also reduced the initial slope (from 0.56 +/- 0.07 to 0.51 +/- 0.04 and 0.22 +/- 0.06 beats . min(-1) . s(-1), P < 0.05). Our findings indicate that presynaptic alpha(2)-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response.

Cerebrovascular reactivity to changes in the partial pressure of arterial carbon dioxide (P(a,CO2)) via limiting changes in brain [H(+)] modulates ventilatory control. It remains unclear, however, how exercise-induced alterations in respiratory chemoreflex might influence cerebral blood flow (CBF), in particular the cerebrovascular reactivity to CO(2). The respiratory chemoreflex system controlling ventilation consists of two subsystems: the central controller (controlling element), and peripheral plant (controlled element). In order to examine the effect of exercise-induced alterations in ventilatory chemoreflex on cerebrovascular CO(2) reactivity, these two subsystems of the respiratory chemoreflex system and cerebral CO(2) reactivity were evaluated (n = 7) by the administration of CO(2) as well as by voluntary hypo- and hyperventilation at rest and during steady-state exercise. During exercise, in the central controller, the regression line for the P(a,CO2)-minute ventilation ((V) over dot(E)) relation shifted to higher (V) over dot(E) and P(a,CO2) with no change in gain (P = 0.84). The functional curve of the peripheral plant also reset rightward and upward during exercise. However, from rest to exercise, gain of the peripheral plant decreased, especially during the hypercapnic condition (-4.1 +/- 0.8 to -2.0 +/- 0.2 mmHg l(-1) min(-1), P = 0.01). Therefore, under hypercapnia, total respiratory loop gain was markedly reduced during exercise (-8.0 +/- 2.3 to -3.5 +/- 1.0 U, P = 0.02). In contrast, cerebrovascular CO(2) reactivity at each condition, especially to hypercapnia, was increased during exercise (2.4 +/- 0.2 to 2.8 +/- 0.2% mmHg(-1), P = 0.03). These findings indicate that, despite an attenuated chemoreflex system controlling ventilation, elevations in cerebrovascular reactivity might help maintain CO(2) homeostasis in the brain during exercise.

Background: We have demonstrated that modification of autonomic balance by electrical vagal stimulation delays progression of cardiac dysfunction and cardiac remodeling, and prolongs survival in rats with severe heart failure. We have also shown that we were able to modify autonomic balance by electrical acupuncture at the acupoint of Zusanli, potentially applicable for the treatment of heart failure. We examined the effect of the acupuncture on the dynamic characteristics of the baroreflex system to exclude the possible deleterious effect on orthostatic tolerance. Method: In anesthetized 8 and 6 rabbits, we examined static and dynamic characteristics of baroreflex, respectively, with and without electrical acupuncture (1 Hz, 5 mA, and 5msec). Dynamic characteristics were examined by imposing pseudorandom binary changes in isolated carotid sinus pressure. Results: With the stimulation condition to decrease arterial blood pressure and sympathetic nerve activity (resulted form decreased response range of neural arc), either of the dynamic characteristics of neural arc or those of peripheral arc did not change by electrical acupuncture at Zusanli. Conclusion: We conclude that application of electrical acupuncture at Zusanli can suppress sympathetic nerve activity but does not affect the dynamic characteristics of the arterial baroreflex system, indicating no deleterious effect on orthostatic tolerance.

Vagal control of heart rate (HR) is mediated by direct and indirect actions of ACh. Direct action of ACh activates the muscarinic K(+) ( KACh) channels, whereas indirect action inhibits adenylyl cyclase. The role of the KACh channels in the overall picture of vagal HR control remains to be elucidated. We examined the role of the KACh channels in the transfer characteristics of the HR response to vagal stimulation. In nine anesthetized sinoaortic-denerved and vagotomized rabbits, the vagal nerve was stimulated with a binary white-noise signal (0-10 Hz) for examination of the dynamic characteristic and in a step-wise manner ( 5, 10, 15, and 20 Hz/min) for examination of the static characteristic. The dynamic transfer function from vagal stimulation to HR approximated a firstorder, low-pass filter with a lag time. Tertiapin, a selective KACh channel blocker ( 30 nmol/kg iv), significantly decreased the dynamic gain from 5.0 +/- 1.2 to 2.0 +/- 0.6 ( mean +/- SD) beats . min(-1) . Hz(-1) ( P < 0.01) and the corner frequency from 0.25 +/- 0.03 to 0.06 +/- 0.01 Hz ( P < 0.01) without changing the lag time ( 0.37 +/- 0.04 vs. 0.39 +/- 0.05 s). Moreover, tertiapin significantly attenuated the vagal stimulation-induced HR decrease by 46 +/- 21, 58 +/- 18, 65 +/- 15, and 68 +/- 11% at stimulus frequencies of 5, 10, 15, and 20 Hz, respectively. We conclude that KACh channels contribute to a rapid HR change and to a larger decrease in the steady-state HR in response to more potent tonic vagal stimulation.

Aim. The aim of this study was to investigate the effect of exhaustive exercise on the time course of arterial blood pressure (BP) and heart rate (HR) during upright resting (inactive) and loadless pedaling (active) recovery from a bicycle exercise to exhaustion. Methods. The subjects were 11 healthy normotensive males. Systolic, diastolic and mean BP, and HR were recorded every 20 s for the initial 6 min of the recovery period. Results. The time course of all BP measures during inactive and active recovery was characterized by a marked and sudden drop during the initial 20-s period, followed by a quick rise. This was followed by a gradual decline till the end of the recovery period. The time course of HR recovery, on the other hand, exhibited a smooth decline without the initial drop. With active recovery, the initial drop of diastolic and mean BP was ss than the inactive recovery. After the 20 s period, the diastolic BP and HR were kept slightly higher with the active recovery than the inactive recovery. Conclusions. A sudden drop of the BP occurred at the initial recovery period of postcycle exercise to exhaustion though HR did not show such a change. The initial BP drop could be attenuated by the actively pedaling the cycle without load.

Despite accumulating data of muscle sympathetic nerve activity (SNA) measured by human microneurography, whether neural discharges of muscle SNA correlates and coheres with those of other SNAs controlling visceral organs remains unclear. Further, how the baroreflex control of SNA affects the relations between these SNAs remains unknown. In urethane and alpha-chloralose anesthetized, vagotomized, and aortic-denervated rabbits, we recorded muscle SNA from the tibial nerve using microneurography and simultaneously recorded renal and cardiac SNAs. After isolating the carotid sinuses, we produced a baroreflex closed-loop condition by matching the isolated intracarotid sinus pressure (CSP) with systemic arterial pressure (CLOSE). We also fixed CSP at operating pressure (FIX) or altered CSP widely (WIDE: operating pressure 40 mmHg). Under these conditions, we calculated time-domain and frequency-domain measures of the correlation between muscle SNA and renal or cardiac SNAs. At CLOSE, muscle SNA resampled at 1 Hz correlated with both renal (r(2) = 0.71 +/- 0.04, delay = 0.10 +/- 0.004 s) and cardiac SNAs (r(2) = 0.58 +/- 0.03, delay = 0.13 +/- 0.004 s) at optimal delays. Moreover,muscle SNA at CLOSE strongly cohered with renal and cardiac SNAs(coherence > 0.8) at the autospectral peak frequencies, and weakly (0.4-0.5) at the remaining frequencies. Increasing the magnitude of CSP change from FIX to CLOSE and further to WIDE resulted in corresponding increases in correlation and coherence functions at nonpeak frequencies, and the coherence functions at peak frequencies remained high (> 0.8). In conclusion, muscle SNA correlates and coheres approximately with renal and cardiac SNAs under closed-loop baroreflex conditions. The arterial baroreflex is capable of potently homogenizing neural discharges of these SNAs by modulating SNA at the nonpeak frequencies of SNA autospectra.

The sympathetic regulation of heart rate (HR) may be attained by neural and humoral factors. With respect to the humoral factor, plasma noradrenaline (NA) and adrenaline (Adr) can reportedly increase to levels approximately 10 times higher than resting level during severe exercise. Whether such high plasma NA or Adr interfered with the sympathetic neural regulation of HR remained unknown. We estimated the transfer function from cardiac sympathetic nerve stimulation (SNS) to HR in anesthetized and vagotomized rabbits. An intravenous administration of NA (n = 6) at 1 and 10 mu g.kg(-1).h(-1) increased plasma NA concentration (pg/ml) from a baseline level of 438 +/- 117 (mean +/- SE) to 974 +/- 106 and 6,830 +/- 917 (P < 0.01), respectively. The dynamic gain (bpm/Hz) of the transfer function did not change significantly (from 7.6 +/- 1.2 to 7.5 +/- 1.1 and 8.1 +/- 1.1), whereas mean HR (in bpm) during SNS slightly increased from 280 +/- 24 to 289 +/- 22 (P < 0.01) and 288 22 (P < 0.01). The intravenous administration of Adr (n = 6) at 1 and 10 mu g.kg(-1).h(-1) increased plasma Adr concentration (pg/ml) from a baseline level of 257 +/- 86 to 659 +/- 172 and 2,760 +/- 590 (P < 0.01), respectively. Neither the dynamic gain (from 8.0 +/- 0.6 to 8.4 +/- 0.8 and 8.2 +/- 1.0) nor the mean HR during SNS (from 274 +/- 13 to 275 +/- 13 and 274 +/- 13) changed significantly. In contrast, the intravenous administration of isoproterenol (n = 6) at 10 mu g.kg(-1).h(-1) significantly increased mean HR during SNS (from 278 +/- 11 to 293 +/- 9, P < 0.01) and blunted the transfer gain value at 0.0078 Hz (from 5.9 +/- 1.0 to 1.0 +/- 0.4, P < 0.01). In conclusion, high plasma NA or Adr hardly affected the dynamic sympathetic neural regulation of HR.

Using a water immersion (WI) method, the combined effect of central blood volume (CBV) loading and work intensity on the time course of heart rate (HR) at the onset of upright dynamic exercise was investigated. Seven males cranked a cycle ergometer for 12 min using their un-immersed arms at low-, moderate- and high-work intensities, followed by a 12-min rest. For WI, the pre-exercise resting cardiac output increased by 36%, while HR decreased by 22% [from 76.8 (10.4) to 59.6 (9.8) beats/min]. WI also increased the high-frequency (HF, 0.15-0.40 Hz) component of the HR variability, suggesting an increased vagal activity. During the initial 2 min of the exercise period at low-work intensity, HR increased by 34.9 and 25.8% in the WI and control conditions, respectively. These were 117 and 73% at high-work intensity, indicating more accelerated HR with WI than the control. The plasma norepinephrine concentration increased less during high- work intensity exercise during WI, as compared to exercise during control conditions. In conclusion, the HR increase at the onset of high- work intensity exercise is accelerated by CBV loading but not at low intensity, possibly reflecting vago-sympathetic interaction and reduced baroreflex sensitivity.

Background. To understand the pathophysiologic basis of exercise hyperpnea in chronic heart failure (CHF), we have developed an experimental method quantitatively characterizing ventilatory regulation system in rats. An equilibrium diagram illustrates the characteristics of two subsytems, i.e., the central controller (arterial CO2 tension [Pa-CO2] to minute ventilation [V-E] relationship) and peripheral plant (V-E to Pa-CO2 relationship). In this study, we compared these between normal and CHIF rats at rest. Method: In anesthetized 6 postinfarction CHF rats and 6 normal rats, we induced hypercapnia by changing inspiratory CO2 fraction and measured the steady-state Pa-CO2 to V-E relation. We altered V-E by varying the level of artificial ventilation and measured the V-E to Pa-CO2 relation. Results: Central controller gain S was significantly lager in CHF rats, confirming clinical observation. The VE at rest (operating point) in CHF was 24 % larger; central hypersensitivity, however, contributed little (6 %) to this increase. Conclusion: Central hypersensitivity alone would not explain hyperpnea at rest in CHF rats. Considering the right and upward shift of V-E to Pa-CO2 relation, central hypersensitivity contributes more to hyperpnea during exercise. The potential difference between normal and CHF rats in exercise-induced changes in controller and plant should be examined to fully understand the mechanism of exercise hyperpnea and to develop a method to attenuate this.

Dynamic and static baroreflex control of muscle sympathetic nerve activity (SNA) parallels that of renal and cardiac SNA during physiological change in pressure. Am J Physiol Heart Circ Physiol 289: H2641-H2648, 2005. First published July 29, 2005; doi:10.1152/ajpheart. 00642.2005. -Despite accumulated knowledge on human baroreflex control of muscle sympathetic nerve activity (SNA), whether baroreflex control of muscle SNA parallels that of other SNAs, in particular renal and cardiac SNAs, remains unclear. Using urethane and alpha-chloralose-anesthetized, vagotomized and aortic-denervated rabbits (n = 10), we recorded muscle SNA from tibial nerve by microneurography, simultaneously with renal and cardiac SNAs by wire electrode. To produce a baroreflex open-loop condition, we isolated the carotid sinuses from systemic circulation and altered the intracarotid sinus pressure (CSP) according to a binary white noise sequence of operating pressure +/- 20 mmHg (for investigating dynamic characteristics of baroreflex) or in stepwise 20-mmHg increments from 40 to 160 mmHg (for investigating static characteristics of baroreflex). Dynamic high-pass characteristics of baroreflex control of muscle SNA, assessed by the increasing slope of transfer gain, showed that more rapid change of arterial pressure resulted in greater response of muscle SNA to pressure change and that these characteristics were similar to cardiac SNA but greater than renal SNA. However, numerical simulation based on the transfer function shows that the differences in dynamic baroreflex control at various organs result in detectable differences among SNAs only when CSP changes at unphysiologically high rates (i.e., 5 mmHg/s). On the other hand, static reverse-sigmoid characteristics of baroreflex control of muscle SNA agreed well with those of renal or cardiac SNAs. In conclusion, dynamic-linear and static-nonlinear baroreflex control of muscle SNA is similar to that of renal and cardiac SNAs under physiological pressure change.

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, similar to 0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP ( finger photoplethysmography) variability during a 15-min 60 degrees HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability ( index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.

Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomzed and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP-SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA-AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP-AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.

Background - Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown. Method and Results - In experiment 1, muscle ( microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits ( n = 6) while arterial pressure was changed by intravenous bolus injections of nitroprusside ( 3 mu g/kg) followed by phenylephrine ( 3 mu g/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits ( n = 10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal ( r = 0.96 +/- 0.01, mean +/- SE) and cardiac ( r = 0.96 +/- 0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal ( r = 0.97 +/- 0.01) and cardiac ( r = 0.97 +/- 0.01) SNAs in experiment 2 ( baroreflex open-loop condition). Conclusions - Muscle SNA averaged over 1 minute parallels renal and cardiac SNAs in response to a forced baroreceptor pressure change.