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Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)—termed cerebral autoregulation (CA)—bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to ‘ identify novel therapeutic targets for treatment and management in acute ischemic stroke’. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

Accumulating evidence suggests asymmetrical responses of cerebral blood flow during large transient changes in mean arterial pressure. Specifically, the augmentation in cerebral blood flow is attenuated when mean arterial pressure acutely increases, compared with declines in cerebral blood flow when mean arterial pressure acutely decreases. However, common analytical tools to quantify dynamic cerebral autoregulation assume autoregulatory responses to be symmetric, which does not seem to be the case. Herein, we provide the rationale supporting the notion we need to consider the directional sensitivity of large and transient mean arterial pressure changes when characterizing dynamic cerebral autoregulation.

Accentuated blood pressure (BP) fluctuation and low cerebral blood flow (CBF) response to CO2 increase the risk of transient ischemic attack (TIA) recurrence and stroke in TIA patients. Improving cardio- and cerebrovascular function may reduce stroke risk. We found dietary nitrate lowered dynamic blood pressure variability (BPV) in rats and improved cerebrovascular CO2 reactivity in healthy individuals. In 30 TIA patients, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day-1) on cerebrovascular function using a randomized, single-blinded, placebo-controlled study design. We hypothesized that 7-day dietary nitrate supplementation would decrease variabilities in BP and CBF and improve CBF-CO2 slope and cerebral autoregulation (CA). We assessed beat-to-beat middle cerebral artery blood velocity (MCAv; index of CBF) and BP at rest and during CO2 breathing. Transfer function analysis was performed on beat-to-beat MCAv and BP to determine CA parameters (gain, phase, and coherence). Irrespective of treatment, high- and low-frequency BP-MCAv gain and MCAv-CO2 slope increased 7 days following TIA onset, while low-frequency BPV decreased (P 0.05). Concurrent with standard treatment, dietary nitrate supplementation reduces BP and CBF fluctuation and improves cerebral autoregulation in TIA patients, without affecting cerebrovascular CO2 reactivity.NEW & NOTEWORTHY We found dietary nitrate supplementation reduced blood pressure and brain blood flow fluctuations and improved the relationship between blood pressure and brain blood flow in transient ischemic attack patients. Meanwhile, dietary nitrate had no effects on the brain blood vessels' response to CO2. We attribute the improved brain blood flow stability to the improved myogenic control of blood pressure with dietary nitrate. Our findings indicate that dietary nitrate could be an effective strategy for stabilizing blood pressure and brain blood flow following transient ischemic attack.

We present a novel technique to overcome the use of vasoactive agents when studying cerebrovascular dynamics in the conscious rat. Our method of vena cava occlusion to reduce BP was associated with decreased iCBF and no change in iCVR. In contrast, comparable BP falls with intravenous SNP increased iCBF and reduced iCVR. Thus, the dynamic cerebral pressure-flow relationship shows a narrower, less level autoregulatory plateau than conventionally thought. We confirm our method allows repeatable assessment of cerebrovascular dynamics in conscious rats.

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg−1·day −1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% ( P < 0.001) and lowered gain ( d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment ( d = 0.7, P = 0.043), while coherence was unaffected ( P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men ( d = 1.0, P = 0.014 vs. placebo), but had no effect in women ( P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function. NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels’ response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.

Blood pressure (BP) regulation is widely recognized as being integral to the control of end-organ perfusion, but it remains unclear whether end-organ perfusion also plays a role in driving changes in BP. A randomized and placebo-controlled study design was followed to examine feedback relationships between very-low-frequency fluctuations in BP and cerebral blood flow (CBF) in humans under placebo treatment and α1-adrenergic blockade. To determine the causal relations among hemodynamic variables, BP, middle cerebral artery blood velocity (MCAv), and end-tidal CO 2 time-series were decimated, low-pass filtered (1-adrenergic blockade results in the dominant causal direction from BP to MCAv. These results suggest that, between subjects, cerebral pressure-flow interactions at time scales < 0.07 Hz are frequently bidirectional, and that in the presence of an intact autonomic nervous system BP may be regulated by reflex pathways sensitive to changes in CBF.

SummaryPurpose Blood pressure (BP) is commonly assessed by brachial oscillometry in clinical practice, whereas in physiological studies, finger plethysmography is often employed. This study assessed the limits of agreement between BP metrics obtained from each device. Methods In 96 participants, we simultaneously recorded BP by brachial oscillometry (BP+; Uscom, Sydney, NSW, Australia) and finger plethysmography (Finometer MIDI, MLE1054-V; Finapres Medical Systems B.V., Amsterdam, the Netherlands). Agreement between the two devices was assessed by correlation and Bland–Altman analysis. We assessed average BP differences between the two devices using the criteria of the Association for the Advancement of Medical Instruments (AAMI), which require systolic and diastolic BP differences to be within ≤5 ± 8 (mean ± SD). Results Bland–Altman analysis showed wide limits of agreement (±~17 mmHg or greater) between finger-derived brachial and oscillometric BP. Both systolic and mean BP exhibited positive proportional biases (both P

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg

The dynamic regulation of cerebral blood flow (CBF) is thought to involve myogenic and chemoreflex mechanisms, but the extent to which the sympathetic nervous system also plays a role remains debated. Here we sought to identify the role of human sympathetic neurovascular control by examining cerebral pressure-flow relations using linear transfer function analysis and multivariate wavelet decomposition analysis that explicitly accounts for the confounding effects of dynamic end-tidal Pco2 (PetCO2) fluctuations. In 18 healthy participants randomly assigned to the α1-adrenergic blockade group ( n = 9; oral Prazosin, 0.05 mg/kg) or the placebo group ( n = 9), we recorded blood pressure, middle cerebral blood flow velocity, and breath-to-breath PetCO2. Analyses showed that the placebo administration did not alter wavelet phase synchronization index (PSI) values, whereas sympathetic blockade increased PSI for frequency components ≤0.03 Hz. Additionally, three-way interaction effects were found for PSI change scores, indicating that the treatment response varied as a function of frequency and whether PSI values were PetCO2 corrected. In contrast, sympathetic blockade did not affect any linear transfer function parameters. These data show that very-low-frequency CBF dynamics have a composite origin involving, not only nonlinear and nonstationary interactions between BP and PetCO2, but also frequency-dependent interplay with the sympathetic nervous system.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) likely plays an important role in the prevention of stroke, which is three- to fourfold more common after spinal cord injury (SCI). Although the directional relationship between BP and cerebral blood flow (CBF) has traditionally been thought to travel solely from BP to CBF, a Cushing-like mechanism functioning in the inverse direction, in which changes in CBF influence BP, has recently been revealed using Granger causality analysis. Although both CBF buffering of BP and the Cushing- like mechanism are influenced by the sympathetic nervous system, we do not understand the impact of disruption of descending sympathetic pathways within the spinal cord, caused by cervical SCI on these regulatory systems. We hypothesized that people with cervical SCI would have greater BP to CBF transmission, as well as a reduced Cushing- like mechanism. The directional relationships between mean arterial BP (MAP ; Finometer((R)) PRO) and middle cerebral artery blood velocity (MCAv ; transcranial Doppler) were assessed at rest in 14 cervical SCI subjects and 16 uninjured individuals using Granger causality analysis, while also accounting for end-tidal CO2 tension. Those with SCI exhibited 66% increased forward MAPMCAv information transmission as compared with the uninjured group (p=0.0003), indicating reduced cerebrovascular buffering of BP, and did not have a predominant backward Cushing-like MCAvMAP phenotype. These results indicate that both forward and backward communication between BP and CBF are influenced by SCI, which may be associated with impaired cerebrovascular BP buffering after SCI as well as widespread BP instability.

It is known that high blood pressure variability (BPV) in acute ischemic stroke is associated with adverse outcomes, yet there are no therapeutic treatments to reduce BPV. Studies have found increasing nitric oxide (NO) bioavailability improves neurological function following stroke, but whether dietary nitrate supplementation could reduce BPV remains unknown. We investigated the effects of dietary nitrate supplementation on heart rate (HR), blood pressure (BP), and beat-to-beat BPV using wireless telemetry in a rat model of distal middle cerebral artery occlusion. Blood pressure variability was characterized by spectral power analysis in the low frequency (LF; 0.2–0.6 Hz) range prestroke and during the 7 days poststroke in a control group ( n = 8) and a treatment group ( n = 8, 183 mg/l sodium nitrate in drinking water). Dietary nitrate supplementation moderately reduced systolic BPV in the LF range by ~11% compared with the control group ( P = 0.03), while resting BP and HR were not different between the two groups ( P = 0.28 and 0.33, respectively). Despite systolic BPV being reduced with dietary nitrate, we found no difference in infarct volumes between the treatment and the control groups (1.59 vs. 1.62 mm3, P = 0.86). These findings indicate that dietary nitrate supplementation is effective in reducing systolic BPV following stroke without affecting absolute BP. In light of mounting evidence linking increased BPV with poor stroke patient outcome, our data support the role of dietary nitrate as an adjunct treatment following ischemic stroke. NEW & NOTEWORTHY Using a rat model of stroke, we found that dietary nitrate supplementation reduced low frequency blood pressure fluctuations following stroke without affecting absolute blood pressure values. Since blood pressure fluctuations are associated with poor clinical outcome in stroke patients, our findings indicate that dietary nitrate could be an effective strategy for reducing blood pressure fluctuations, which could help reduce stroke severity and improve patient recovery.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) is crucial to prevent stroke, the incidence of which is three- to fourfold elevated after spinal cord injury (SCI). Disruption of descending sympathetic pathways within the spinal cord due to cervical SCI may result in impaired cerebrovascular buffering. Only linear analyses of cerebrovascular buffering of BP, such as transfer function, have been used in SCI research. This approach does not account for inherent nonlinearity and nonstationarity components of cerebrovascular regulation, often depends on perturbations of BP to increase the statistical power, and does not account for the influence of arterial CO2 tension. Here, we used a nonlinear and nonstationary analysis approach termed wavelet decomposition analysis (WDA), which recently identified novel sympathetic influences on cerebrovascular buffering of BP occurring in the ultra-low-frequency range (ULF; 0.02–0.03Hz). WDA does not require BP perturbations and can account for influences of CO2 tension. Supine resting beat-by-beat BP (Finometer), middle cerebral artery blood velocity (transcranial Doppler), and end-tidal CO2 tension were recorded in cervical SCI ( n = 14) and uninjured ( n = 16) individuals. WDA revealed that cerebral blood flow more closely follows changes in BP in the ULF range ( P = 0.0021, Cohen’s d = 0.89), which may be interpreted as an impairment in cerebrovascular buffering of BP. This persisted after accounting for CO2. Transfer function metrics were not different in the ULF range, but phase was reduced at 0.07–0.2 Hz ( P = 0.03, Cohen’s d = 0.31). Sympathetically mediated cerebrovascular buffering of BP is impaired after SCI, and WDA is a powerful strategy for evaluating cerebrovascular buffering in clinical populations.

Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked.Twenty young adults (16 male, age: 26.7 ± 6.6 years, BMI: 24.9 ± 3.0 kg/mThere were main effects for both cardiac cycle and frequency for phase and gain metrics (p0.001). The systolic phase (mean ± SD) was elevated at 0.05 (1.07 ± 0.51 radians) and 0.10 Hz (0.70 ± 0.46 radians) compared to the diastolic phase (0.05 Hz: 0.59 ± 0.14 radians; 0.10 Hz: 0.33 ± 0.11 radians). Conversely, the systolic normalized gain was reduced (0.05 Hz: 0.49 ± 0.12%/%; 0.10 Hz: 0.66 ± 0.20%/%) compared to the diastolic normalized gain (0.05 Hz: 1.46 ± 0.43%/%; 0.10 Hz: 1.97 ± 0.48%/%).These findings indicate there are differential systolic and diastolic aspects of the cerebral pressure-flow relationship. The oscillations associated with systole are extensively buffered within the cerebrovasculature, whereas diastolic oscillations are relatively unaltered. This indicates that the brain is adapted to protect itself against large increases in systolic blood pressure, likely as a mechanism to prevent cerebral haemorrhages.

Evidence derived from spontaneous measures of cardiovagal baroreflex sensitivity (BRS) suggests that slow breathing at 6 breaths/min augments BRS. However, increases in BRS associated with slow breathing may simply reflect the frequency-dependent nature of the baroreflex rather than the modulation of baroreflex function by changes in breathing rate per se. To test this hypothesis we employed a crossover study design ( n = 14) wherein breathing rate and systolic arterial blood pressure (SAP) oscillation induced via the application of oscillating lower body negative pressure (OLBNP) were independently varied at fixed frequencies. Breathing rate was controlled at 6 or 10 breaths/min with the aid of a metronome, and SAP oscillations were driven at 0.06 Hz and 0.1 Hz using OLBNP. The magnitudes of SAP and R-R interval (cardiac period) oscillations were quantified using power spectral analysis, and the transfer function gain between SAP and R-R interval was used to estimate BRS. Linear mixed-effects models were used to examine the main effects and interactions between breathing rate and OLBNP frequency. There was no statistical interaction between breathing and OLBNP frequency ( P = 0.59), indicating that the effect of breathing rate on BRS did not differ according to OLBNP frequency (and vice versa). Additionally, there was no main effect for breathing rate ( P = 0.28). However, we observed a significant main effect for OLBNP frequency ( P = 0.01) consistent with the frequency-dependent nature of baroreflex. These findings suggest that increases in spectral indices of BRS reflect the frequency dependence of the baroreflex and are not due to slow breathing per se.

We examined the between-day reproducibility of active (squat-stand maneuvers)- and passive [oscillatory lower-body negative pressure (OLBNP) maneuvers]-driven oscillations in blood pressure. These relationships were examined in both younger ( n = 10; 25 ± 3 yr) and older ( n = 9; 66 ± 4 yr) adults. Each testing protocol incorporated rest (5 min), followed by driven maneuvers at 0.05 (5 min) and 0.10 (5 min) Hz to increase blood-pressure variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal partial pressure of CO2 were monitored. The pressure-flow relationship was quantified in the very low (0.02-0.07 Hz) and low (0.07–0.20 Hz) frequencies (LF; spontaneous data) and at 0.05 and 0.10 Hz (driven maneuvers point estimates). Although there were no between-age differences, very few spontaneous and OLBNP transfer function metrics met the criteria for acceptable reproducibility, as reflected in a between-day, within-subject coefficient of variation (CoV) of

Objective: Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked.

Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R2 values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04–0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.

Cerebral autoregulation (CA) is integral to the delicate process of maintaining stable cerebral perfusion and brain tissue oxygenation against changes in arterial blood pressure. The last four decades has seen dramatic advances in understanding CA physiology, and the role that CA might play in the causation and progression of disease processes that affect the cerebral circulation such as stroke. However, the translation of these basic scientific advances into clinical practice has been limited by the maintenance of old constructs and because there are persistent gaps in our understanding of how this vital vascular mechanism should be quantified. In this review, we re-evaluate relevant studies that challenge established paradigms about how the cerebral perfusion pressure and blood flow are related. In the context of blood pressure being a major haemodynamic challenge to the cerebral circulation, we conclude that: (1) the physiological properties of CA remain inconclusive, (2) many extant methods for CA characterisation are based on simplistic assumptions that can give rise to misleading interpretations, and (3) robust evaluation of CA requires thorough consideration not only of active vasomotor function, but also the unique properties of the intracranial environment.

Aim The ability to maintain arterial blood pressure when faced with a postural challenge has implications for the occurrence of syncope and falls. It has been suggested that posture-induced declines in the mechanical component of the baroreflex response drive reductions in cardiovagal baroreflex sensitivity associated with postural stress. However, these conclusions are largely based upon spontaneous methods of baroreflex assessment, the accuracy of which has been questioned. Therefore, the aim was to engage a partially open-loop approach to explore the influence of posture on the mechanical and neural components of the baroreflex. Methods In nine healthy participants, we measured continuous blood pressure, heart rate, RR interval and carotid artery diameter during supine and standing postures. The modified Oxford method was used to quantify baroreflex sensitivity. Results In response to falling pressures, baroreflex sensitivity was similar between postures (P = 0.798). In response to rising pressures, there was an attenuated (P = 0.042) baroreflex sensitivity (mean ± SE) in the standing position (−0.70 ± 0.11 beats min−1 mmHg−1) compared with supine (−0.83 ± 0.06 beats min−1 mmHg−1). This was explained by a diminished (P = 0.016) neural component whilst standing (−30.17 ± 4.16 beats min−1 mm−1) compared with supine (−38.23 ± 3.31 beats min−1 mm−1). These effects were consistent when baroreflex sensitivity was determined using RR interval. Conclusion Cardiovagal baroreflex sensitivity in response to rising pressures is reduced in young individuals during postural stress. Our data suggest that the mechanical component is unaffected by standing, and the reduction in baroreflex sensitivity is driven by the neural component.

This study sought to determine whether models of cerebrovascular function based on Laguerre- Volterra kernels that account for nonlinear cerebral blood flow (CBF) dynamics can detect the effects of functional cerebral sympathetic blockade. We retrospectively analysed continuous beat-to-beat blood pressure, middle cerebral blood velocity, and partial-pressure of end-tidal CO2 (PETCO2) recordings from eighteen healthy individuals who were treated with either an oral dose of the alpha1-adrenergic receptor blocker Prazosin or a placebo treatment. The global principal dynamic modes (PDMs) were analysed using Laguerre-Volterra kernels to examine the nonlinear system dynamics. Our principal findings were: 1) very low frequency (

Key points • Cerebral autoregulation maintains cerebral perfusion relatively constant in the face of slow changes in arterial pressure, but is less effective against more rapid changes (i.e. functions as a ‘high-pass’ filter). • While thought to be maintained mainly through myogenic adjustments to changes in transmural pressure, recent work has highlighted a possibility of active autonomic involvement in cerebral autoregulation. • In this study we examined the cerebrovascular effects of cholinergic blockade on nine healthy volunteers during the application of oscillatory lower body pressure at six frequencies from 0.03 to 0.08 Hz. • Cholinergic blockade impaired autoregulation at frequencies above 0.04 Hz, suggesting a role for active cholinergic vasodilatation in the maintenance of cerebral perfusion. Abstract Despite growing evidence of autonomic nervous system involvement in the regulation of cerebral blood flow, the specific contribution of cholinergic vasodilatation to cerebral autoregulation remains unknown. We examined cerebral and forearm blood flow responses to augmented arterial pressure oscillations with and without cholinergic blockade. Oscillatory lower body negative pressure was applied at six frequencies from 0.03 to 0.08 Hz in nine healthy subjects with and without cholinergic blockade via glycopyrrolate. Cholinergic blockade increased cross-spectral coherence between arterial pressure and cerebral flow at all frequencies except 0.03 Hz and increased the transfer function gain at frequencies above 0.05 Hz. In contrast, gain between pressure and forearm flow increased only at frequencies below 0.06 Hz. These data demonstrate that the cholinergic system plays an active and unique role in cerebral autoregulation. The frequency region and magnitude of effect is very similar to what has been seen with sympathetic blockade, indicating a possible balance between the two reflexes to most effectively respond to rising and falling pressure. These findings might have implications for the role of dysfunction in autonomic control of the vasculature in cerebrovascular disease states.

Although the cerebrovasculature is known to be exquisitely sensitive to CO2, there is no consensus on whether the sympathetic nervous system plays a role in regulating cerebrovascular responses to changes in arterial CO2. To address this question, we investigated human cerebrovascular CO2 reactivity in healthy participants randomly assigned to the α1-adrenoreceptor blockade group (9 participants; oral prazosin, 0.05 mg/kg) or the placebo control (9 participants) group. We recorded mean arterial blood pressure (MAP), heart rate (HR), mean middle cerebral artery flow velocity (MCAV mean), and partial pressure of end-tidal CO2 (PetCO2) during 5% CO2 inhalation and voluntary hyperventilation. CO2 reactivity was quantified as the slope of the linear relationship between breath-to-breath PetCO2 and the average MCAvmean within successive breathes after accounting for MAP as a covariate. Prazosin did not alter resting HR, PetCO2, MAP, or MCAV mean. The reduction in hypocapnic CO2 reactivity following prazosin (−0.48 ± 0.093 cm·s−1·mmHg−1) was greater compared with placebo (−0.19 ± 0.087 cm·s−1·mmHg−1; P < 0.05 for interaction). In contrast, the change in hypercapnic CO2 reactivity following prazosin (−0.23 cm·s−1·mmHg−1) was similar to placebo (−0.31 cm·s−1·mmHg−1; P = 0.50 for interaction). These data indicate that the sympathetic nervous system contributes to CO2 reactivity via α1-adrenoreceptors; blocking this pathway with prazosin reduces CO2 reactivity to hypocapnia but not hypercapnia.

Diminished baroreflex sensitivity in the morning negatively influences morning coronary blood flow and blood pressure control in hypertensive patients. Our aim was to determine the contribution of the mechanical and neural components of the cardiac baroreflex to diurnal variation in blood pressure control. In 12 healthy participants, we used the modified Oxford method to quantify baroreflex sensitivity for rising (G up ) and falling (G down ) pressures in the morning (7:00 am ) and afternoon (4:00 pm ). Beat-to-beat blood pressure, R-R intervals, and carotid artery diameter measurements were recorded. Integrated sensitivity was determined by plotting R-R intervals against systolic blood pressure. The mechanical component was carotid artery diameter plotted against systolic blood pressure, and the neural component was R-R intervals plotted against carotid artery diameter. Linear mixed models were used to compare the integrated, mechanical, and neural sensitivities between morning and afternoon. We found significant diurnal variation in integrated sensitivity, with an attenuated response in the morning (G up =13.0±0.6; G down =6.3±0.4 ms/mm Hg) when compared with the afternoon (G up =15.1±0.6; G down =12.6±0.4 ms/mm Hg). For rising pressures, the diminished integrated sensitivity in the morning was caused by a reduction in mechanical sensitivity, whereas for falling pressures it was caused by a reduction in neural sensitivity. Our findings explicate the mechanisms underlying diurnal variation in baroreflex function. Pharmacological and lifestyle interventions targeted specifically at the diminished component of the cardiac baroreflex in the morning may lead to better management of hypertension.

Non-technical summary Brain function is critically dependent on the regulation of cerebral blood flow (CBF) by cerebral blood vessels. We show that a mechanical blood vessel property called compliance plays an important role in determining the way cerebral blood vessels respond to changes in blood pressure. These results enhance our knowledge of how cerebral blood vessels regulate CBF, which is critical to understanding the causes and effects of cerebrovascular diseases such as stroke and dementia. Abstract The fundamental determinants of human dynamic cerebral autoregulation are poorly understood, particularly the role of vascular compliance and the myogenic response. We sought to 1) determine whether capacitive blood flow associated with vascular compliance and driven by the rate of change in mean arterial blood pressure (dMAP/dt )i s an important determinant of middle cerebral artery velocity (MCAv) dynamics and 2) characterise the impact of myogenic blockade on these cerebral pressure-flow velocity relations in humans. We measured MCAv and mean arterial pressure (MAP) during oscillatory lower body negative pressure (n =8) at 0.10 and 0.05 Hz before and after cerebral Ca 2+ channel blockade (nimodipine). Pressure-flow velocity relationships were characterised using transfer function analysis and a regression-based Windkessel analysis that incorporates MAP and dMAP/dt as predictors of MCAv dynamics. Results show that incorporation of dMAP/dt accounted for more MCAv variance (R 2 0.80-0.99) thanifonlyMAPwasconsidered(R 2 0.05-0.90).ThecapacitivegainrelatingdMAP/dt andMCAv was strongly correlated to transfer function gain (0.05 Hz, r =0.93, P

The Windkessel properties of the vasculature are known to play a significant role in buffering arterial pulsations, but their potential importance in dampening low-frequency fluctuations in cerebral blood flow has not been clearly examined. In this study, we quantitatively assessed the contribution of arterial Windkessel (peripheral compliance and resistance) in the dynamic cerebral blood flow response to relatively large and acute changes in blood pressure. Middle cerebral artery flow velocity (MCAV; transcranial Doppler) and arterial blood pressure were recorded from 14 healthy subjects. Low-pass-filtered pressure-flow responses (V responses during both hypertension and hypotension ( R2 = 0.89 ± 0.03 and 0.85 ± 0.05, respectively), with a significant improvement in adjusted coefficients of determination ( P < 0.005) compared with the single-resistance model ( R2 = 0.62 ± 0.06 and 0.61 ± 0.08, respectively). No differences were found between the two interventions in the Windkessel capacitive and resistive gains, suggesting similar vascular properties during pressure rise and fall episodes. The results highlight that low-frequency cerebral hemodynamic responses to transient hypertension and hypotension may include a significant contribution from the mechanical properties of vasculature and, thus, cannot solely be attributed to the active control of vascular tone by cerebral autoregulation. The arterial Windkessel should be regarded as an important element of dynamic cerebral blood flow modulation during large and acute blood pressure perturbation.

Epidemiological data indicate that the risk of neurally mediated syncope is substantially higher in the morning. Syncope is precipitated by cerebral hypoperfusion, yet no chronobiological experiment has been undertaken to examine whether the major circulatory factors, which influence perfusion, show diurnal variation during a controlled orthostatic challenge. Therefore, we examined the diurnal variation in orthostatic tolerance and circulatory function measured at baseline and at presyncope. In a repeated-measures experiment, conducted at 0600 and 1600, 17 normotensive volunteers, aged 26 ± 4 yr (mean ± SD), rested supine at baseline and then underwent a 60° head-up tilt with 5-min incremental stages of lower body negative pressure until standardized symptoms of presyncope were apparent. Pretest hydration status was similar at both times of day. Continuous beat-to-beat measurements of cerebral blood flow velocity, blood pressure, heart rate, stroke volume, cardiac output, and end-tidal Pco2 were obtained. At baseline, mean cerebral blood flow velocity was 9 ± 2 cm/s (15%) lower in the morning than the afternoon ( P < 0.0001). The mean time to presyncope was shorter in the morning than in the afternoon (27.2 ± 10.5 min vs. 33.1 ± 7.9 min; 95% CI: 0.4 to 11.4 min, P = 0.01). All measurements made at presyncope did not show diurnal variation ( P > 0.05), but the changes over time (from baseline to presyncope time) in arterial blood pressure, estimated peripheral vascular resistance, and α-index baroreflex sensitivity were greater during the morning tests ( P < 0.05). These data indicate that tolerance to an incremental orthostatic challenge is markedly reduced in the morning due to diurnal variations in the time-based decline in blood pressure and the initial cerebral blood flow velocity “reserve” rather than the circulatory status at eventual presyncope. Such information may be used to help identify individuals who are particularly prone to orthostatic intolerance in the morning.

The respiratory component of heart rate variability (respiratory sinus arrhythmia, RSA) has been associated with improved pulmonary gas exchange efficiency in humans via the apparent clustering and scattering of heart beats in time with the inspiratory and expiratory phases of alveolar ventilation, respectively. However, since human RSA causes only marginal redistribution of heart beats to inspiration, we tested the hypothesis that any association between RSA amplitude and pulmonary gas exchange efficiency may be indirect. In 11 patients with fixed-rate cardiac pacemakers and 10 healthy control subjects, we recorded R-R intervals, respiratory flow, end-tidal gas tension and the ventilatory equivalents for carbon dioxide and oxygen during 'fast' (0.25 Hz) and 'slow' paced breathing (0.10 Hz). Mean heart rate, mean arterial blood pressure, mean arterial pressure fluctuations, tidal volume, end-tidal CO(2), and were similar between pacemaker and control groups in both the fast and slow breathing conditions. Although pacemaker patients had no RSA and slow breathing was associated with a 2.5-fold RSA amplitude increase in control subjects (39 +/- 21 versus 97 +/- 45 ms, P < 0.001), comparable (main effect for breathing frequency, F(1,19) = 76.54, P < 0.001) and reductions (main effect for breathing frequency, F(1,19) = 23.90, P < 0.001) were observed for both cohorts during slow breathing. In addition, the degree of (r = 0.36, P = 0.32) and reductions (r = 0.29, P = 0.43) from fast to slow breathing were not correlated to the degree of associated RSA amplitude enhancements in control subjects. These findings suggest that the association between RSA amplitude and pulmonary gas exchange efficiency during variable-frequency paced breathing observed in prior human work is not contingent on RSA being present. Therefore, whether RSA serves an intrinsic physiological function in optimizing pulmonary gas exchange efficiency in humans requires further experimental validation.

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of “normal” CA has not been clearly identified. While controlling for the influence of arterial P co 2 , we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal P co 2 , and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: ≈40 to ≈125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv mean was altered by 0.82±0.35% per millimeter of mercury change in mean blood pressure ( R 2 =0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=−0.18%/mm Hg; R 2 =0.60) and MCAv mean (slope=−0.26%/cm · s −1 ; R 2 =0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv mean .

Background: Patients presenting with a transient ischemic attack (TIA) are at high risk of stroke despite current treatments. Elevated blood pressure variability (BPV) and vascular dysfunction are known to increase the risk of stroke in TIA patients. Therefore, improving these hemodynamic parameters could help reduce stroke incidences in these patients. Aim: The proposed study will investigate the efficacy of dietary nitrate supplementation on cardiovascular and cerebrovascular hemodynamics in patients recently diagnosed with TIA. Methods: This study is a randomized, placebo-controlled, parallel group clinical trial, with patient recruitment based on strict inclusion/exclusion criteria. Newly diagnosed patients who present within 48 h of symptom onset will be assessed to ascertain their post-TIA, pre-treatment baseline cardiovascular and cerebrovascular parameters. These will include: beat-to-beat BPV, cerebrovascular CO2 reactivity and cerebral autoregulation (indices of cerebrovascular health), brachial artery diameter, central and peripheral blood pressures, vascular risk factors (i.e. resting blood pressure), and plasma nitrate/nitrite concentration. Following pre-treatment assessment, participants will be randomized to take either 7-day dietary nitrate supplementation (sodium nitrate in capsules, 10 mg/kg/day) or 7-day placebo. An identical follow-up assessment will be implemented post-intervention. Conclusion: This study will lay the foundation for clinical trials to assess the therapeutic potential of dietary nitrate supplementation as a secondary strategy for stroke prevention in high-risk patients.

The cerebral pressure-flow relationship can be quantified as a high-pass filter, where slow oscillations are buffered (2 were monitored. Very low frequency (0.02–0.07 Hz) and low frequency (0.07–0.20 Hz) range spontaneous data were quantified. Driven OLBNP point estimates were sampled at 0.05 and 0.10 Hz. The OLBNP maneuvers augmented coherence to >0.97 at 0.05 Hz and >0.98 at 0.10 Hz in both age groups. The OLBNP protocol conclusively revealed the cerebrovascular system functions as a high-pass filter during exercise throughout aging. It was also discovered that the older adults had elevations (+71%) in normalized gain (+0.46 ± 0.36%/%: 0.05 Hz) and reductions (−34%) in phase (−0.24 ± 0.22 radian: 0.10 Hz). There were also age-related phase differences between resting and exercise conditions. It is speculated that these age-related changes in the TFA metrics are mediated by alterations in vasoactive factors, sympathetic tone, or the mechanical buffering of the compliance vessels.

Maintenance of adequate cerebral perfusion during normal physiological challenges requires integration between cerebral blood flow (CBF) and systemic blood pressure control mechanisms. Previous studies have shown that cardiac baroreflex sensitivity (BRS) is inversely related to some measures of cerebral autoregulation. However, interactions between the sympathetic arterial baroreflex and cerebral perfusion control mechanisms have not been explored. To determine the nature and magnitude of these interactions we measured R-R interval, blood pressure, cerebral blood flow velocity and muscle sympathetic nerve activity (MSNA) in 11 healthy young males. Sympathetic BRS was estimated using modified Oxford method as the relationship between beat-to-beat diastolic blood pressure and MSNA. Integrated control of cerebral blood flow was quantified using transfer function analysis metrics derived during rest and Tieck’s autoregulatory index following bilateral thigh cuff deflation. Sympathetic BRS during modified Oxford trials was significantly related to autoregulatory index (r = 0.64, p = 0.03). Sympathetic BRS during spontaneous baseline was significantly related to transfer function gain (r = -0.74, p = 0.01). A more negative value for sympathetic BRS indicates more effective arterial baroreflex regulation, and a lower transfer function gain reflects greater cerebral autoregulation. Therefore, these findings indicate that males with attenuated CBF regulation have greater sympathetic BRS (and vice versa), consistent with compensatory interactions between blood pressure and cerebral perfusion control mechanisms.

We tested the hypothesis that transmission of arterial pressure to brain tissue oxygenation is low under conditions of arterial pressure instability. Two experimental models of hemodynamic instability were used in healthy human volunteers; (1) oscillatory lower body negative pressure (OLBNP) (N = 8; 5 male, 3 female), and; (2) maximal LBNP to presyncope (N = 21; 13 male, 8 female). Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO(2)) were measured non-invasively. For the OLBNP protocol, between 0 and −60mmHg negative pressure was applied for 20 cycles at 0.05 Hz, then 20 cycles at 0.1 Hz. For the maximal LBNP protocol, progressive 5 min stages of chamber decompression were applied until the onset of presyncope. Spectral power of MAP, mean MCAv, and scO(2) were calculated within the VLF (0.04–0.07 Hz), and LF (0.07–0.2Hz) ranges, and cross-spectral coherence was calculated for MAP-mean MCAv, MAP-ScO(2), and mean MCAv-ScO(2) at baseline, during each OLBNP protocol, and at the level prior to pre-syncope during maximal LBNP (sub-max). The key findings are (1) both 0.11-IZ OLBNP and sub-max LBNP elicited increases in LF power for MAP, mean MCAv, and scO(2) (p ≤ 0.08); (2) 0.05 Hz OLBNP increased VLF power in MAP and scO(2) only (p ≤ 0.06); (3) coherence between MAP-mean MCAv was consistently higher (≥0.71) compared with MAP-ScO(2), and mean MCAv-ScO(2) (≤0.43) during both OLBNP protocols, and sub-max LBNP (p ≤ 0.04). These data indicate high linearity between pressure and cerebral blood flow variations, but reduced linearity between cerebral tissue oxygenation and both arterial pressure and cerebral blood flow. Measuring arterial pressure variability may not always provide adequate information about the downstream effects on cerebral tissue oxygenation, the key end-point of interest for neuronal viability.

Baroreflex assessment has diagnostic and prognostic utility in the clinical and research environments, and there is a need for a reliable, simple, noninvasive method of assessment. The repeated sit-to-stand method induces oscillatory changes in blood pressure (BP) at a desired frequency and is suitable for assessing dynamic baroreflex sensitivity (BRS). However, little is known about the reliability of this method and its ability to discern fundamental properties of the baroreflex. In this study we sought to: 1) evaluate the reliability of the sit-to-stand method for assessing BRS and compare its performance against two established methods (Oxford method and Valsalva maneuver), and 2) examine whether the frequency of the sit-to-stand method influences hysteresis. Sixteen healthy participants underwent three trials of each method. For the sit-to-stand method, which was performed at 0.1 and 0.05 Hz, BRS was quantified as an integrated response (BRSINT) and in response to falling and rising BP (BRSDOWN and BRSUP, respectively). Test retest reliability was assessed using the intraclass correlation coefficient (ICC). Irrespective of frequency, the ICC for BRSINT during the sit-to-stand method was ≥0.88. The ICC for a rising BP evoked by phenylephrine (PEGAIN) in the Oxford method was 0.78 and ≤0.5 for the remaining measures. During the sit-to-stand method, hysteresis was apparent in all participants at 0.1 Hz but was absent at 0.05 Hz. These findings indicate the sit-to-stand method is a statistically reliable BRS assessment tool and suitable for the examination of baroreflex hysteresis. Using this approach we showed that baroreflex hysteresis is a frequency-dependent phenomenon.

Variability in arterial pressure and cerebral blood flow has traditionally been interpreted as a marker of cardiovascular decompensation, and has been associated with negative clinical outcomes across varying time scales, from impending orthostatic syncope to an increased risk of stroke. Emerging evidence, however, suggests that increased hemodynamic variability may, in fact, be protective in the face of acute challenges to perfusion, including significant central hypovolemia and hypotension (including hemorrhage), and during cardiac bypass surgery. We present the dichotomous views on the role of hemodynamic variability on clinical outcome, including the physiological mechanisms underlying these patterns, and the potential impact of increased and decreased variability on cerebral perfusion and oxygenation. We suggest that reconciliation of these two apparently discrepant views may lie in the time scale of hemodynamic variability; short time scale variability appears to be cerebroprotective, while mid to longer term fluctuations are associated with primary and secondary end-organ dysfunction.

We examined the hypothesis that changes in the cerebrovascular resistance index (CVRi), independent of blood pressure (BP), will influence the dynamic relationship between BP and cerebral blood flow in humans. We altered CVRi with (via controlled hyperventilation) and without [via indomethacin (INDO, 1.2 mg/kg)] changes in PaCO2. Sixteen subjects (12 men, 27 ± 7 yr) were tested on two occasions (INDO and hypocapnia) separated by >48 h. Each test incorporated seated rest (5 min), followed by squat-stand maneuvers to increase BP variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis (TFA). Beat-to-beat BP, middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv), and end-tidal Pco2 were monitored. Dynamic pressure-flow relations were quantified using TFA between BP and MCAv/PCAv in the very low and low frequencies through the driven squat-stand maneuvers at 0.05 and 0.10 Hz. MCAv and PCAv reductions by INDO and hypocapnia were well matched, and CVRi was comparably elevated ( P < 0.001). During the squat-stand maneuvers (0.05 and 0.10 Hz), the point estimates of absolute gain were universally reduced, and phase was increased under both conditions. In addition to an absence of regional differences, our findings indicate that alterations in CVRi independent of PaCO2 can alter cerebral pressure-flow dynamics. These findings are consistent with the concept of CVRi being a key factor that should be considered in the correct interpretation of cerebral pressure-flow dynamics as indexed using TFA metrics.

The arterial baroreflex is critical to both short- and long-term regulation of blood pressure. However, human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function. Over the past decade, emerging techniques based on carotid ultrasound imaging have allowed new means of understanding and measuring the baroreflex. In this review, we describe the assessment of the mechanical and neural components of the baroreflex through the use of carotid ultrasound imaging. The mechanical component refers to the change in carotid artery diameter in response to changes in arterial pressure, and the neural component refers to the change in R-R interval (cardiac baroreflex) or muscle sympathetic nerve activity (sympathetic baroreflex) in response to this barosensory vessel stretch. The key analytical concepts and techniques are discussed, with a focus on the assessment of baroreflex sensitivity via the modified Oxford method. We illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans, covering topics such as ageing and diurnal variation, and physiological challenges including exercise, postural changes and mental stress.

Cardiac baroreflex gain is usually quantified as the reflex alteration in heart rate during changes in blood pressure without considering the effect of the rate of change in blood pressure on the estimated gain. This study sought to (i) characterize baroreflex gain as a function of blood pressure oscillation frequencies using a repeat sit-to-stand method and (ii) compare baroreflex gain values obtained using the sit-to-stand method against the modified Oxford method. Fifteen healthy individuals underwent the repeated sit-to-stand method in which blood pressure oscillations were driven at 0.03, 0.05, 0.07, and 0.1 Hz. Sixteen healthy participants underwent the sit-to-stand and modified Oxford methods to examine their agreement. Sit-to-stand baroreflex gain was highest at 0.05 Hz (8.8 ± 3.2 ms·mm Hg(-1)) and lowest at 0.1 Hz (5.8 ± 3.0 ms·mm Hg(-1)). Baroreflex gains at 0.03 Hz (7.7 ± 3.0 ms·mm Hg(-1)) and 0.07 Hz (7.5 ± 3.3 ms·mm Hg(-1)) were not different from the baroreflex gain at 0.05 Hz. There was moderate correlation between phenylephrine gain and sit-to-stand gain (r values ranged from 0.52 to 0.75; all frequencies, p < 0.05), but no correlation between sodium nitroprusside gain and sit-to-stand gain (r values ranged from -0.07 to 0.22; all p < 0.05). Bland-Altman analysis of phenylephrine gain and sit-to-stand gain showed poor agreement and a positive proportional bias. These results show that baroreflex gains derived from these 2 methods cannot be used interchangeably. Furthermore, cardiac baroreflex gain is frequency dependent between 0.03 Hz and 0.1 Hz, which challenges the conventional practice of summarizing baroreflex gain as a single number.

Resting vascular sympathetic outflow is significantly increased during and beyond exposure to acute hypoxia without a parallel increase in either resistance or pressure. This uncoupling may indicate a reduction in the ability of sympathetic outflow to effect vascular responses (sympathetic transduction). However, the effect of hypoxia on sympathetic transduction has not been explored. We hypothesized that transduction would either remain unchanged or be reduced by isocapnic hypoxia. In 11 young healthy individuals, we measured beat-by-beat pressure, multiunit sympathetic nerve activity, and popliteal blood flow velocity at rest and during isometric handgrip exercise to fatigue, before and during isocapnic hypoxia (∼80% SpO2), and derived sympathetic transduction for each subject via a transfer function that reflects Poiseuille's law of flow. During hypoxia, heart rate and sympathetic nerve activity increased, whereas pressure and flow remained unchanged. Both normoxic and hypoxic exercise elicited significant increases in heart rate, pressure, and sympathetic activity, although sympathetic responses to hypoxic exercise were blunted. Hypoxia slightly increased the gain relation between pressure and flow (0.062 ± 0.006 vs. 0.074 ± 0.004 cm·s−1·mmHg−1; P = 0.04), but markedly increased sympathetic transduction (−0.024 ± 0.005 vs. −0.042 ± 0.007 cm·s−1·spike−1; P < 0.01). The pressor response to isometric handgrip was similar during normoxic and hypoxic exercise due to the balance of interactions among the tachycardia, sympathoexcitation, and transduction. This indicates that the ability of sympathetic activity to affect vasoconstriction is enhanced during brief exposure to isocapnic hypoxia, and this appears to offset the potent vasodilatory stimulus of hypoxia.

The relationships between blood pressure variability (BPV) and cerebral blood flow variability (CFV) across individuals in the presence of intact and blunted cerebrovascular control are poorly understood. This study sought to characterize the interindividual associations between spontaneous BPV and CFV under conditions of normal and blunted [calcium channel blockade (CCB)] cerebrovascular control in healthy humans. We analyzed blood pressure and flow velocity data from 12 subjects treated with CCB (60 mg oral nimodipine) and 11 subjects treated with a placebo pill. Spontaneously occurring fluctuations in mean arterial blood pressure (MAP) and middle cerebral artery flow velocity (MCAvmean; transcranial Doppler) were characterized using power spectral and transfer function analysis in the very-low- (0.02–0.07 Hz), low- (0.07–0.20 Hz), and high-frequency (0.20–0.40 Hz) ranges. Across our study sample, MAP and MCAvmean power were positively correlated in all three frequency ranges, both before ( R2 = 0.34–0.67, all P < 0.01) and after CCB ( R2 = 0.53–0.61, all P < 0.02). Compared with placebo, CCB reduced very-low-frequency MAP ( P < 0.05) and MCAvmean power ( P < 0.01) and the low-frequency cross-spectral phase angle ( P < 0.05). The magnitude of change in MAP and MCAvmean power with CCB (i.e., change scores) was positively related in the very-low-frequency range. Collectively, these findings indicate that CFV may be an explanatory factor in the association between elevated BPV and adverse cerebrovascular outcomes and support the possibility of using CCB to improve hemodynamic stability under resting conditions.

The post-exercise period is associated with hypotension, and an increased risk of syncope attributed to decreases in venous return and/or vascular resistance. Increased local and systemic vasodilators, sympatholysis, and attenuated baroreflex sensitivity following exercise are also manifest. Although resting cerebral blood flow is maintained, cerebrovascular regulation to acute decreases in blood pressure has not been characterized following exercise. We therefore aimed to assess cerebrovascular regulation during transient bouts of hypotension, before and after 40 min of aerobic exercise at 60 % of estimated maximum oxygen consumption. Beat to beat blood pressure (Finometer), heart rate (ECG), and blood velocity in the middle cerebral artery (MCAv; transcranial Doppler ultrasound) were assessed in ten healthy young humans. The MCAv-mean arterial pressure relationship during a pharmacologically (i.v. sodium nitroprusside) induced transient hypotension was assessed before and at 10, 30, and 60 min following exercise. Despite a significant reduction in mean arterial pressure at 10 min post-exercise (-10 ± 6.9 mmHg; P0.05) and end-tidal PCO2 (10 min post: -2.9 ± 2.6 mmHg; 30 min post: -3.9 ± 3.5 mmHg; 60 min post: -2.7 ± 2.0 mmHg; all P0.05), neither resting MCAv nor the cerebrovascular response to hypotension differed between pre- and post-exercise periods (P0.05). These data indicate that cerebrovascular regulation remains intact following a moderate bout of aerobic exercise.