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.

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.

<jats:title>Abstract</jats:title><jats:p>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, <jats:italic>p</jats:italic> < 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.</jats:p>

<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 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, <jats:italic>p</jats:italic> = 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 <jats:italic>R</jats:italic><jats:sup>2</jats:sup> value (0.645 ± 0.053) than a linear model (<jats:italic>R</jats:italic><jats:sup>2</jats:sup> = 0.543 ± 0.057, <jats:italic>p</jats:italic> = 0.025) or a second‐order Volterra model (<jats:italic>R</jats:italic><jats:sup>2</jats:sup> = 0.589 ± 0.055, <jats:italic>p</jats:italic> = 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.</jats:p>

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 .

<jats:p>The arterial baroreflex system plays a key role in maintaining the homeostasis of arterial pressure (AP). Changes in AP affect autonomic nervous activities through the baroreflex neural arc, whereas changes in the autonomic nervous activities, in turn, alter AP through the baroreflex peripheral arc. This closed-loop negative feedback operation makes it difficult to identify open-loop dynamic characteristics of the neural and peripheral arcs. Regarding sympathetic AP controls, we examined the applicability of a nonparametric frequency-domain closed-loop identification method to the carotid sinus baroreflex system in anesthetized rabbits. This article compares the results of an open-loop analysis applied to open-loop data, an open-loop analysis erroneously applied to closed-loop data, and a closed-loop analysis applied to closed-loop data. To facilitate the understanding of the analytical method, sample data files and sample analytical codes were provided. In the closed-loop identification, properties of the unknown central noise that modulated the sympathetic nerve activity and the unknown peripheral noise that fluctuated AP affected the accuracy of the estimation results. A priori knowledge about the open-loop dynamic characteristics of the arterial baroreflex system may be used to advance the assessment of baroreflex function under closed-loop conditions in the future.</jats:p>

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.

<jats:sec><jats:title>New Findings</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item> <jats:p><jats:bold>What is the central question of this study?</jats:bold></jats:p> <jats:p>What are the dynamic characteristics of cerebrovascular carbon dioxide reactivity and the central respiratory chemoreflex?</jats:p> </jats:list-item> <jats:list-item> <jats:p><jats:bold>What is the main finding and its importance?</jats:bold></jats:p> <jats:p>The transfer function gain from the end‐tidal partial pressure of carbon dioxide to cerebral blood flow or ventilation decreased in the high frequency range at rest and during exercise. These findings indicate that the dynamic characteristics of both systems were not constant in all frequency ranges, and this trend was not modified by exercise.</jats:p> </jats:list-item> </jats:list></jats:p></jats:sec><jats:sec><jats:title>Abstract</jats:title><jats:p>The purpose of this study was to examine the dynamic characteristics of cerebrovascular reactivity and ventilatory response to change in arterial CO<jats:sub>2</jats:sub> in all frequency ranges at rest using frequency domain analysis, and also to examine whether this is modified by dynamic exercise as with the traditionally determined cerebrovascular CO<jats:sub>2</jats:sub> reactivity. In nine healthy young subjects, at rest and during exercise (cycling exercise at constant predetermined work rate corresponding to a <jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0001.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0001" /> level of 0.90 l min<jats:sup>−1</jats:sup>), the dynamic characteristics of cerebrovascular CO<jats:sub>2</jats:sub> reactivity and the central respiratory chemoreflex were assessed by transfer function analysis using a binary white‐noise sequence (0–7% inspired CO<jats:sub>2</jats:sub> fraction) from the end‐tidal partial pressure of CO<jats:sub>2</jats:sub> (<jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0002.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0002" />) to the mean middle cerebral artery mean blood velocity (MCA <jats:italic>V</jats:italic><jats:sub>m</jats:sub>) or minute ventilation (<jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0003.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0003" />), respectively. In the high frequency range, both transfer function gains decreased but, interestingly, the cut‐off frequency in the transfer function gain from <jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0004.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0004" /> to MCA <jats:italic>V</jats:italic><jats:sub>m</jats:sub> response was higher than that from <jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0005.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0005" /> to <jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/eph12826-math-0006.png" xlink:title="urn:x-wiley:09580670:media:eph12826:eph12826-math-0006" /> response at rest (0.024 <jats:italic>vs</jats:italic>. 0.015 Hz) and during exercise (0.030 <jats:italic>vs</jats:italic>. 0.011 Hz), indicating that cerebrovascular CO<jats:sub>2</jats:sub> reactivity or central respiratory chemoreflex was not constant in all frequency ranges, and this trend was not modified by exercise. These findings suggest that dynamic characteristics of the cerebrovascular CO<jats:sub>2</jats:sub> reactivity or central chemoreflex need to be assessed to identify the whole system because the traditional method cannot identify the property of time response of these systems.</jats:p></jats:sec>

Previously, we demonstrated that pre-exercise feed-forward cardiorespiratory control mechanism by the higher brain center plays a significant role in enhancing physiological efficiency to exercise. If such mechanism of central predictive and prospective control plays an important role in optimization of respiratory and circulatory control during exercise, the quantitative and temporal dynamics of cardiorespiratory response before exercise may depend on subsequent exercise intensity. To confirm this hypothesis, we investigated the predictive control of respiratory and circulatory systems before onset of exercise at low-, moderate-and high-work intensities. Eight healthy males underwent a 10 min seated rest period which followed by an ergometer bicycle exercise for 2 min. The gas-exchange parameters were recorded by breath-by-breath method. During pre-exercise resting period, minute ventilation and heart rate and were augmented immediately 1 minute before the higher intensity exercise(P<0.05). This intensity-dependent preparatory cardiorespiratory responses can be caused by central neural control mechanisms involving learning and memory.

AIMS: Moxonidine is a centrally acting antihypertensive agent with a selectivity to I1-imidazoline receptors higher than that to α2-adrenergic receptors. The present study aimed to quantify a peripheral effect of moxonidine on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) regulation separately from its central effect. MAIN METHODS: In eight anesthetized Wistar rats, changes in efferent sympathetic nerve activity (SNA) and AP in response to a carotid sinus pressure input were compared before and during an intravenous administration of moxonidine (100μgkg-1 bolus followed by a continuous infusion at 200μg·kg-1·h-1). KEY FINDINGS: Moxonidine significantly narrowed the range of the AP response (55.3±5.8 to 39.1±6.1mmHg, P<0.05) without changing the minimum AP (77.2±6.4 to 80.7±5.1mmHg, not significant). In the neural arc, moxonidine reduced the minimum SNA (56.6±5.9 to 29.7±6.2%, P<0.05) without affecting the range of the SNA response (45.3±5.5 to 40.2±5.0%, not significant). In the peripheral arc, moxonidine increased the intercept (3.0±8.5 to 51.1±7.2mmHg, P<0.01) and reduced the slope (1.28±0.06 to 0.92±0.15mmHg/%, P<0.05). SIGNIFICANCE: Moxonidine increased AP at any given SNA, suggesting that the peripheral vasoconstrictive effect is stronger than generally recognized. The peripheral vasoconstrictive effect of moxonidine may partly offset the vasodilatory effect attained by centrally-mediated sympathoinhibition.

PURPOSE: Acupuncture stimulation is known to act on the autonomic nervous system and elicits depressor and bradycardic effects. However, previous studies on humans did not conduct quantitative analyses on optimal acupuncture conditions such as the stimulation frequency and duration to achieve maximum depressor and bradycardic effects. The aim of the present study was to investigate the effects of varying stimulation frequencies of electroacupuncture on time-dependent changes in blood pressure and heart rate in humans. METHODS: Twelve healthy volunteers participated in the study. An acupuncture needle was inserted at the Ximen acupoint (PC4 according to WHO nomenclature), located at the anterior aspect of the forearm. An electrical stimulation was delivered through the acupuncture needle at an intensity of 1 V, pulse width of 5 ms, and stimulation frequencies of 0.5, 1, 5, and 10 Hz in a random order. The duration of electroacupuncture was 6 min, during which blood pressure and heart rate responses were monitored. RESULTS: Group-averaged data indicated that 1-Hz electroacupuncture decreased blood pressure and heart rate. Blood pressure was significantly decreased from the prestimulation baseline value of 86.6 ± 2.9 to 81.4 ± 2.3 mmHg during 4-6 min of 1-Hz electroacupuncture (mean ± SE, P < 0.01). Heart rate was also significantly decreased (from 66.2 ± 2.0 to 62.7 ± 1.7 beats/min, P < 0.01). CONCLUSIONS: These results provide fundamental evidence that bradycardiac and depressor responses are effectively produced by electrical acupuncture in humans.

<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>