宮本 忠吉

Although Gaussian white noise (GWN) inputs offer a theoretical framework for identifying higher-order nonlinearity, an actual application to the data of the neural arc of the carotid sinus baroreflex did not succeed in fully predicting the well-known sigmoidal nonlinearity. In the present study, we assumed that the neural arc can be approximated by a cascade of a linear dynamic (LD) component and a nonlinear static (NS) component. We analyzed the data obtained using GWN inputs with a mean of 120 mmHg and standard deviations (SDs) of 10, 20, and 30 mmHg for 15 min each in anesthetized rats (n = 7). We first estimated the linear transfer function from carotid sinus pressure to sympathetic nerve activity (SNA) and then plotted the measured SNA against the linearly predicted SNA. The predicted and measured data pairs exhibited an inverse sigmoidal distribution when grouped into 10 bins based on the size of the linearly predicted SNA. The sigmoidal nonlinearity estimated via the LD-NS model showed a midpoint pressure (104.1 ± 4.4 mmHg for SD of 30 mmHg) lower than that estimated by a conventional stepwise input (135.8 ± 3.9 mmHg, P < 0.001). This suggests that the NS component is more likely to reflect the nonlinearity observed during pulsatile inputs that are physiological to baroreceptors. Furthermore, the LD-NS model yielded higher R2 values compared with the linear model and the previously suggested second-order Uryson model in the testing dataset.NEW & NOTEWORTHY We examined the input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs. A linear dynamic-static nonlinear model yielded higher R2 values compared with a linear model and captured the well-known sigmoidal nonlinearity of the neural arc, indicating that the nonlinear dynamics contributed to determining sympathetic nerve activity. Ignoring such nonlinear dynamics might reduce our ability to explain underlying physiology and significantly limit the interpretation of experimental data.

Background: Alterations in central blood volume (CBV) play a pivotal role in the functionality of the respiratory and circulatory systems. This study elucidates the adaptive changes in respiration, cerebral circulation, and cardiovascular function in response to orthostatic stress in male volleyball players compared to healthy non-athletes. The athletes’ unique physiological adaptability may help them cope with the frequent CBV changes related to their sports activities. Methods: Fourteen male university students participated in this study; seven were volleyball players and seven were non-athletes. Participants underwent a maximal ramp exercise test and a lower body negative pressure (LBNP) test conducted to examine the cardiorespiratory response under LBNP and no-LBNP conditions. Respiratory, metabolic, hemodynamic, and cardiac measurements were collected and analyzed. Results: Volleyball players (Ath group) were significantly taller and exhibited higher maximal oxygen uptake (VO2max) and maximum work rate compared to non-athletes (Non-Ath group). Under the LBNP condition, end-tidal CO2 partial pressure (PETCO2) decreased by 4.1% in the Non-Ath group, but was maintained stable in the Ath group. The CBV reduction rate due to LBNP was notably less in the Ath group (−12.5%) compared to the Non-Ath group (−24.5%). In all participants, a significant correlation was observed between the CBV and PETCO2 reduction rates. However, cerebral blood flow and cardiovascular responses to LBNP load did not differ between the two groups. Conclusion: Male volleyball players demonstrate distinctive adaptability in response to orthostatic stress, specifically in maintaining stable PETCO2 and attenuating CBV reduction rate under LBNP load. These findings suggest that the sport-specific training in volleyball may induce some protective mechanisms against abrupt changes in CBV, although cerebral blood flow and cardiovascular responses appear unaffected. Further research is warranted to understand the underlying mechanisms of these adaptations.

Purpose: High-intensity interval training (HIIT) may induce training-specific physiological adaptations such as improved respiratory and cardiovascular adjustments before and after the onset of high-intensity exercise, leading to improved exercise performance during high-intensity exercise. The present study investigated the effects of HIIT on time-dependent cardiorespiratory adjustment during maximal exercise and before and after initiation of high-intensity exercise, as well as on maximal exercise performance. Methods: 21 healthy male college students were randomly assigned to HIIT group (n = 11) or control group (n = 10). HIIT group performed training on a cycle ergometer once a week for 8 weeks. The training consisted of three bouts of exercise at 95% maximal work rate (WRmax) until exhaustion. Before and after the HIIT program, dynamic cardiorespiratory function was investigated by ramp and step exercise tests, and HIIT-induced cardiac morphological changes were assessed using echocardiography. Results: HIIT significantly improved not only maximal oxygen uptake and minute ventilation, but also maximal heart rate (HR), systolic blood pressure (SBP), and time to exhaustion in both exercise tests (p < 0.05). Time-dependent increases in minute ventilation (VE) and HR before and at the start of exercise were significantly enhanced after HIIT. During high-intensity exercise, there was a strong correlation between percent change (from before to after HIIT program) in time to exhaustion and percent change in HRmax (r = 0.932, p < 0.001). Furthermore, HIIT-induced cardiac morphological changes such as ventricular wall hypertrophy was observed (p < 0.001). Conclusion: We have demonstrated that HIIT at 95% WRmax induces training-specific adaptations such as improved cardiorespiratory adjustments, not only during maximal exercise but also before and after the onset of high-intensity exercise, improvement of exercise performance mainly associated with circulatory systems.

Moxibustion is a traditional East Asian medicine treatment that involves burning moxa directly or indirectly on or near the skin at a specific site of the body, called an acupoint. However, whether moxibustion induces cardiovascular responses by modulating autonomic nervous activity remains unknown. The purpose of this study was to elucidate the effects of indirect moxibustion on cardiovascular responses and autonomic nervous activity. Fifteen healthy volunteers participated in the study. Each subject received regional heat stimulation by indirect moxibustion at the lower leg acupoint. Heart rate, RR intervals, blood pressure and skin temperature were measured continuously for 3 min at rest and 5 min during indirect moxibustion. Local skin temperature increased reaching a peak (45.3 ± 3.3 °C) at 2 min after moxibustion was started, and was accompanied by a significant decrease in heart rate (63.0 ± 7.8 to 60.8 ± 7.8 bpm, p < 0.05) together with a significant increase in root mean square difference of successive RR intervals. Regional heat stimulation by indirect moxibustion induced bradycardic response, which was modulated by autonomic nervous system.

Since the arterial baroreflex system is classified as an immediate control system, the focus has been on analyzing its dynamic characteristics in the frequency range between 0.01 and 1 Hz. Although the dynamic characteristics in the frequency range below 0.01 Hz are not expected to be large, actual experimental data are scant. The aim was to identify the dynamic characteristics of the carotid sinus baroreflex in the frequency range down to 0.001 Hz. The carotid sinus baroreceptor regions were isolated from the systemic circulation, and carotid sinus pressure (CSP) was changed every 10 s according to Gaussian white noise with a mean of 120 mmHg and standard deviation of 20 mmHg for 90 min in anesthetized Wistar-Kyoto rats (n = 8). The dynamic gain of the linear transfer function relating CSP to arterial pressure (AP) at 0.001 Hz tended to be greater than that at 0.01 Hz (1.060 ± 0.197 vs. 0.625 ± 0.067, p = 0.080), suggesting that baroreflex control was largely maintained at 0.001 Hz. Regarding nonlinear analysis, a second-order Uryson model predicted AP with a higher R2 value (0.645 ± 0.053) than a linear model (R2  = 0.543 ± 0.057, p = 0.025) or a second-order Volterra model (R2  = 0.589 ± 0.055, p = 0.045) in testing data. These pieces of information may be used to create baroreflex models that can add a component of autonomic control to a cardiovascular digital twin for predicting acute hemodynamic responses to treatments and tailoring individual treatment strategies.

Muscarinic potassium channels (IK,ACh ) are thought to contribute to the high frequency (HF) dynamic heart rate (HR) response to vagal nerve stimulation (VNS) because they act faster than the pathway mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. However, the interactions between the two pathways have not yet been fully elucidated. We previously demonstrated that HCN channel blockade by ivabradine (IVA) increased the HF gain ratio of the transfer function from VNS to HR. To test the hypothesis that IVA increases the HF gain ratio via an interaction with IK,ACh , we examined the dynamic HR response to VNS under conditions of control (CNT), IK,ACh blockade by tertiapin-Q (TQ, 50 nM/kg), and TQ plus IVA (2 mg/kg) (TQ + IVA) in anesthetized rats (n = 8). In each condition, the right vagal nerve was stimulated for 10 min with binary white noise signals between 0-10, 0-20, and 0-40 Hz. On multiple regression analysis, the HF gain ratio positively correlated with the VNS rate with a coefficient of 1.691 ± 0.151 (×0.01) (p < 0.001). TQ had a negative effect on the HF gain ratio with a coefficient of -1.170 ± 0.214 (×0.01) (p < 0.001). IVA did not significantly increase the HF gain ratio in the presence of TQ. The HF gain ratio remained low under the TQ + IVA condition compared to controls. These results affirm that the IVA-induced increase in the HF gain ratio is dependent on the untethering of the hyperpolarizing effect of IK,ACh .

Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under β-blockade. In anesthetized rats (n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0-10), between 0 and 20 Hz (V0-20), and between 0 and 40 Hz (V0-40). The transfer function from VNS to HR was estimated. Under β-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz, P < 0.01) and V0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via the IK,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.NEW & NOTEWORTHY Since ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under β-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.

New Findings: What is the central question of this study? The lack of useful small-animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anaesthetized-rat model for studying exercise hyperpnoea, using a respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. Abstract: Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiological basis of various disease models, the lack of an integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anaesthetized-rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anaesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO2 pressure ((Formula presented.)) and minute ventilation ((Formula presented.)), and the plant by the hyperbolic relationship between (Formula presented.) and (Formula presented.). During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen uptake. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points ((Formula presented.) and (Formula presented.)) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anaesthetized-rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models.

Aims: To assess the acute effects of intravenous ivabradine, a selective bradycardic agent, on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) and heart rate (HR) responses. Methods and results: In anesthetized and vagotomized Wistar–Kyoto rats (n = 6), carotid sinus baroreceptor regions were isolated. Changes in splanchnic sympathetic nerve activity (SNA), AP, and HR in response to a step-wise pressure input were examined before and after intravenous ivabradine (2 mg/kg). Ivabradine did not affect the response range of SNA (91.8 ± 6.5 vs. 93.5 ± 9.8%) or AP (89.6 ± 10.6 vs. 91.0 ± 9.7 mm Hg). Ivabradine significantly reduced the minimum HR from 369.4 ± 8.4 to 223.3 ± 13.2 (P &lt 0.001) but did not attenuate the HR response range (69.1 ± 7.0 vs. 82.5 ± 9.6 beats/min). Conclusions: Ivabradine does not acutely affect baroreflex-mediated sympathetic AP regulation and also spares the magnitude of the sympathetic HR response, despite significant bradycardia. The preserved sympathetic HR response, which could not be afforded by beta-blockers, may contribute to some beneficial clinical effects of ivabradine.

The effects of water exercise on gut hormone concentrations and appetite currently remain unclear. The aim of the present study was to investigate the effects of treadmill walking in water on gut hormone concentrations and appetite. Thirteen men (mean ± s.d. age: 21.6 ± 2.2 years, body mass index: 22.7 ± 2.8 kg/m2, peak oxygen uptake (VO2peak): 49.8 ± 7.8 mL/kg per min) participated in the walking in water and on land challenge. During the study period, ratings of subjective feelings of hunger, fullness, satiety and motivation to eat were reported on a 100-mm visual analog scale. A test meal was presented after walking, and energy intake (EI) was calculated. Blood samples were obtained during both trials to measure glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and acylated ghrelin (AG) concentrations. Hunger scores (How hungry do you feel?) were significantly lower during the water trial than during the land trial (P &lt 0.05). No significant differences were observed in EI between water and land trials. GLP-1 concentrations were significantly higher in the water trial than in the land trial (P &lt 0.05). No significant differences were observed in PYY concentrations between water and land trials. AG concentrations were significantly lower in the water trial than in the land trial (P &lt 0.01). In conclusion, changes in gut hormone concentrations during walking in water contribute to the exercise-induced suppression of appetite and provide novel information on the influence of walking in water on the acute regulation of appetite.

Although hypoxia has the potential to impair the cognitive function, the effects of acute hypoxia on the high-order brain function (executive and/or inhibitory processing) and somatosensory ascending processing remain unknown. We tested the hypothesis that acute hypoxia impairs both motor executive and inhibitory processing and somatosensory ascending processing. Fifteen healthy subjects performed two sessions (sessions 1 and 2), consisting of electroencephalographic event-related potentials with somatosensory Go/No-go paradigms and somatosensory-evoked potentials (SEPs) under two conditions (hypoxia and normoxia) on different days. On 1 day, participants breathed room air in the first and second sessions of the experiment; on the other day, participants breathed room air in the first session, and 12% O-2 in the second session. Acute hypoxia reduced the peak amplitudes of Go-P300 and No-go-P300, and delayed the peak latency of Go-P300. However, no significant differences were observed in the peak amplitude or latency of N140, behavioral data, or the amplitudes and latencies of individual SEP components between the two conditions. These results suggest that acute hypoxia impaired neural activity in motor executive and inhibitory processing, and delayed higher cognitive processing for motor execution, whereas neural activity in somatosensory processing was not affected by acute hypoxia. NEW & NOTEWORTHY Hypoxia has the potential to impair the cognitive function, but the effects of acute hypoxia on the cognitive function remain debatable. We investigated the effects of acute hypoxia on human cognitive processing using electroencephalographic event-related potentials and somatosensory-evoked potentials. Acute normobaric hypoxia impaired neural activity in motor executive and inhibitory processing, but no significant differences were observed in neural activity in somatosensory processing.

Although the pulsatility of an input pressure is an important factor that determines the arterial baroreflex responses, whether the difference in the input waveforms can meaningfully affect the baroreflex function remains unknown. This study aimed to compare baroreflex responses between two distinct pressure waveforms: a forward saw wave (FSW) and a backward saw wave (BSW). In seven anesthetized rats, carotid sinus pressure was exposed to the FSW or the BSW with a mean of 120 mmHg, pulse pressure of 40 mmHg, and pulse frequency of 1 Hz. Changes in efferent sympathetic nerve activity (SNA) and arterial pressure (AP) during six consecutive saw wave trials (FSW1, BSW1, FSW2, BSW2, FSW3, and BSW3) were examined. The steady-state SNA value during FSW1 was 91.1 +/- 1.9%, which was unchanged during FSW2 and FSW3 but significantly increased during BSW1 (106.6 +/- 3.4%, P &lt; 0.01), BSW2 (110.6 +/- 2.5%, P &lt; 0.01), and BSW3 (111.6 +/- 2.3%, P &lt; 0.01). The steady-state AP value during FSW1 was 98.2 +/- 8.1 mmHg, which was unchanged during FSW2 and FSW3 but significantly increased during BSW1 (106.7 +/- 7.4 mmHg, P &lt; 0.01), BSW2 (105.6 +/- 7.8 mmHg, P &lt; 0.01), and BSW3 (103.8 +/- 7.2 mmHg, P &lt; 0.05). In conclusion, the FSW was more effective than the BSW in reducing mean SNA and AP. The finding could be applied to designing an artificial pulsatile pressure such as that generated by left ventricular assist devices. NEW & NOTEWORTHY This study examined whether the waveforms of an input pressure alone can affect the baroreflex function by using a forward saw wave and a backward saw wave with the same mean pressure, pulse pressure, and pulse frequency. The forward saw wave was more effective than the backward saw wave in reducing sympathetic nerve activity and arterial pressure. The finding could be applied to designing an artificial pulsatile pressure such as that generated by left ventricular assist devices.

Central chemoreflex activation induces sympatho-excitation. However, how central chemoreflex interacts with baroreflex function remains unknown. This study aimed to examine the impact of central chemoreflex on the dynamic as well as static baroreflex functions under open-loop conditions. In 15 anesthetized, vagotomized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled intra-sinus pressure (CSP). We then recorded sympathetic nerve activity (SNA) at the celiac ganglia, and activated central chemoreflex by a gas mixture containing various concentrations of CO2. Under the baroreflex open-loop condition (CSP = 100 mmHg), central chemoreflex activation linearly increased SNA and arterial pressure (AP). To examine the static baroreflex function, we increased CSP stepwise from 60 to 170 mmHg and measured steady-state SNA responses to CSP (mechanoneural arc), and AP responses to SNA (neuromechanical arc). Central chemoreflex activation by inhaling 3% CO2 significantly increased SNA irrespective of CSP, indicating resetting of the mechanoneural arc, but did not change the neuromechanical arc. As a result, central chemoreflex activation did not change baroreflex maximum total loop gain significantly (-1.29 ± 0.27 vs. -1.68 ± 0.74, N.S.). To examine the dynamic baroreflex function, we randomly perturbed CSP and estimated transfer functions from 0.01 to 1.0 Hz. The transfer function of the mechanoneural arc approximated a high-pass filter, while those of the neuromechanical arc and total (CSP-AP relationship) arcs approximated a low-pass filter. In conclusion, central chemoreflex activation did not alter the transfer function of the mechanoneural, neuromechanical, or total arcs. Central chemoreflex modifies hemodynamics via sympathoexcitation without compromising dynamic or static baroreflex AP buffering function.

【目的】簡便かつ低侵襲な呼吸化学受容器反射機能同定手法を開発する。【方法】健常者6名に対し、吸入二酸化炭素濃度をランダムに変化させた際の分時換気量(中枢制御部)とランダムな換気負荷を行なった際の呼気終末二酸化炭素濃度(末梢プラント)を測定した。時系列データを一次遅れ+むだ時間システムに近似させパラメタ抽出を行ない、さらに同定精度を検証した。【結果】中枢制御部はゲイン0.89±0.41L/min/mmHg、時定数45.1±15.0秒、むだ時間3.0±9.3秒、末梢プラントはゲイン-0.57±0.07mmHg・min/L、時定数18.4±8.0秒、むだ時間-0.9±1.2秒であった。また、精度検証では同定手法の妥当性が示唆された(中枢:R2=0.73、末梢:R2=0.78)。【結論】本手法により簡便かつ低侵襲に呼吸化学受容器反射機能が抽出可能となった。(著者抄録)

<jats:p> The purpose of the present study was to examine whether the response of cerebral blood flow to an acute change in perfusion pressure is modified by an acute increase in central blood volume. Nine young, healthy subjects voluntarily participated in this study. To measure dynamic cerebral autoregulation during normocapnic and hypercapnic (5%) conditions, the change in middle cerebral artery mean blood flow velocity was analyzed during acute hypotension caused by two methods: 1) thigh-cuff occlusion release (without change in central blood volume); and 2) during the recovery phase immediately following release of lower body negative pressure (LBNP; −50 mmHg) that initiated an acute increase in central blood volume. In the thigh-cuff occlusion release protocol, as expected, hypercapnia decreased the rate of regulation, as an index of dynamic cerebral autoregulation (0.236 ± 0.018 and 0.167 ± 0.025 s<jats:sup>−1</jats:sup>, P = 0.024). Compared with the cuff-occlusion release, the acute increase in central blood volume (relative to the LBNP condition) with LBNP release attenuated dynamic cerebral autoregulation ( P = 0.009). Therefore, the hypercapnia-induced attenuation of dynamic cerebral autoregulation was not observed in the LBNP release protocol ( P = 0.574). These findings suggest that an acute change in systemic blood distribution modifies dynamic cerebral autoregulation during acute hypotension. </jats:p>