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We sought to determine whether gravity-induced changes in intracranial pressure influence cerebral blood flow regulation. Accordingly, nine young healthy men were studied while supine (0°) and during mild changes in hydrostatic pressure induced by head-up tilt at +20° and +10° (HUT+20 and HUT+10) and head-down tilt at -20° and -10° (HDT-20, HDT-10). Blood flows were measured in the internal and external carotid and vertebral arteries (ICA, ECA, and VA). Intraocular pressure (IOP) was measured as an indicator of hydrostatic changes in intracranial pressure. A posture change from HUT+20 to HDT-20 increased IOP by +5.1 ± 1.9 mmHg (

Muscle sympathetic nerve activity (MSNA) decreases during leg cycling at low intensity because of muscle pump-induced increases in venous return and loading of the cardiopulmonary baroreceptors. However, MSNA increases during leg cycling when exercise is above moderate intensity or for a long duration, suggesting that the sympathoinhibitory effect of the cardiopulmonary baroreflex can be overridden by a powerful sympathoexcitatory drive, such as the skeletal muscle metaboreflex. Therefore, we tested the hypothesis that high-intensity muscle metaboreflex activation attenuates muscle pump-induced inhibition of MSNA during leg cycling. MSNA (left radial nerve) was recorded during graded isolation of the muscle metaboreflex in the forearm with postexercise ischemia (PEI) after low (PEI-L)- and high (PEI-H)-intensity isometric handgrip exercise (20% and 40% maximum voluntary contraction, respectively). Leg cycling (15–20 W) was performed alone and during each PEI trial (PEI-L+Cycling, PEI-H+Cycling). Cycling alone induced a significant decrease in MSNA burst frequency (BF) and total activity (TA). MSNA BF and TA also decreased when cycling was performed during PEI-L. However, the magnitude of decrease in MSNA during PEI-L+Cycling [∆BF: –19 ± 2% ( P < 0.001), ∆TA: –25 ± 4% ( P < 0.001); mean ± SE] was less than that during cycling alone [∆BF: –39 ± 5% ( P = 0.003), ∆TA: –45 ± 5% ( P = 0.002)]. More importantly, MSNA did not decrease during cycling with PEI-H [∆BF: –1 ± 2% ( P = 0.845), ∆TA: +2 ± 3% ( P = 0.959)]. These results suggest that muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation in an intensity-dependent manner. NEW & NOTEWORTHY There are no available data concerning the interaction between the sympathoinhibitory effect of muscle pump-induced cardiopulmonary baroreflex loading during leg cycling and the sympathoexcitatory influence of the muscle metaboreflex. In this study, muscle metaboreflex activation attenuated the inhibition of muscle sympathetic nerve activity (MSNA) during leg cycling. This may explain, in part, the response of MSNA to graded-intensity dynamic exercise in which low-intensity leg cycling inhibits MSNA whereas high-intensity exercise elicits graded sympathoexcitation.

This review summarizes the interaction between the regulatory system of respiration and cerebral vasculature. Some clinical reports provide evidence for the association between these two physiological regulatory systems. Physiologically, arterial carbon dioxide concentration is mainly regulated by two feedback control systems: respiration and cerebral blood flow. In other words, both of these systems are sensitive to the same mediator, i.e., carbon dioxide, at a set point. In addition, respiratory dysfunction alters various physiological factors that affect the cerebral vasculature. Therefore, it is physiologically plausible that these systems are closely linked. The regulation of arterial carbon dioxide concentration affected by respiration and cerebral blood flow may be a key factor for a rise in the risk of brain disease in the patients with respiratory dysfunction. For example, the management of respiratory disease (e.g., patients with chronic obstructive pulmonary disease) and the use of prophylactic therapy are essential to reduce the risk of stroke.

The role of the sympathetic nervous system in cerebral blood flow (CBF) regulation remains unclear. Previous studies have primarily measured middle cerebral artery blood velocity to assess CBF. Recently, there has been a transition toward measuring internal carotid artery (ICA) and vertebral artery (VA) blood flow using duplex Doppler ultrasound. Given that the VA supplies autonomic control centers in the brainstem, we hypothesized that graded sympathetic activation via lower body negative pressure (LBNP) would reduce ICA but not VA blood flow. ICA and VA blood flow were measured during two protocols: protocol 1, low-to-moderate LBNP (−10, −20, −30, and −40 Torr) and protocol 2, moderate-to-high LBNP (−30, −50, and −70 Torr). ICA and VA blood flow, diameter, and blood velocity were unaffected up to −40 LBNP. However, −50 and −70 LBNP evoked reductions in ICA and VA blood flow [e.g., −70 LBNP: percent change (%∆)VA-baseline = −27.6 ± 3.0] that were mediated by decreases in both diameter and velocity (e.g., −70 LBNP: %∆VA-baseline diameter = −7.5 ± 1.9 and %∆VA-baseline velocity = −13.6 ± 1.7), which were comparable between vessels. Since hyperventilation during −70 LBNP reduced end-tidal pressure of carbon dioxide ([Formula: see text]), this decrease in [Formula: see text] was matched via voluntary hyperventilation. Reductions in ICA and VA blood flow during hyperventilation alone were significantly smaller than during −70 LBNP and were primarily mediated by decreases in velocity (%∆VA-baseline velocity = −8.6 ± 2.4 and %∆VA-baseline diameter = −0.05 ± 0.56). These data demonstrate that both ICA and VA were unaffected by low-to-moderate sympathetic activation, whereas robust reflex-mediated sympathoexcitation caused similar magnitudes of vasoconstriction in both arteries. Thus, contrary to our hypothesis, the ICA was not preferentially vasoconstricted by sympathetic activation. NEW & NOTEWORTHY Our study demonstrates that moderate-to-high reflex-mediated sympathetic activation with lower body negative pressure (LBNP) decreases internal carotid artery and vertebral artery blood flow via reductions in both vessel diameter and blood velocity. This vasoconstriction was primarily sympathetically mediated as voluntary hyperventilation alone, to isolate the effect of decreases in end-tidal pressure of carbon dioxide that occurred during LBNP, resulted in a significantly smaller vasoconstriction. In contrast to our hypothesis, these data indicate a lack of heterogeneity between the anterior and posterior cerebral circulations in response to sympathoexcitation.

Posttraumatic stress disorder (PTSD) is associated with structural and functional alterations in a number of interacting brain regions, but the physiological mechanism for the high risk of cerebrovascular disease or impairment in brain function remains unknown. Women are more likely to develop PTSD after a trauma than men. We hypothesized that cerebral blood flow (CBF) regulation is impaired in women with PTSD, and it is associated with impairment in cognitive function. To test our hypothesis, we examined dynamic cerebral autoregulation (CA) and cognitive function by using a transfer function analysis between arterial pressure and middle cerebral artery blood velocity and the Stroop Color and Word test (SCWT), respectively. We did not observe any different responses in these hemodynamic variables between women with PTSD ( n = 15) and healthy counterparts (all women; n = 8). Cognitive function was impaired in women with PTSD; specifically, reaction time for the neutral task of SCWT was longer in women with PTSD compared with healthy counterparts ( P = 0.011), but this cognitive dysfunction was not affected by orthostatic stress. On the other hand, transfer function phase, gain, and coherence were not different between groups in either the supine or head-up tilt (60°) position, or even during the cognitive challenge, indicating that dynamic CA was well maintained in women with PTSD. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that PTSD-related cognitive dysfunction may not be due to compromised CBF regulation. NEW & NOTEWORTHY Cognitive function was impaired; however, dynamic cerebral autoregulation (CA) as an index of cerebral blood flow regulation was not impaired during supine and 60° head-up tilt in women with PTSD compared with healthy females. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that the mechanism of PTSD-related cognitive dysfunction may not be due to CBF regulation.

Previous studies have shown that muscle sympathetic nerve activity (MSNA) is reduced during low- and mild-intensity dynamic leg exercise. It has been suggested that such inhibition is mediated by loading of the cardiopulmonary baroreceptors and that this effect is overridden by muscle metaboreflex activation with higher-intensity exercise. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Therefore, we tested the hypothesis that cardiopulmonary baroreflex-mediated inhibition of MSNA is attenuated during high-intensity muscle metaboreflex activation. In nine young men, MSNA (right peroneal nerve), mean arterial pressure (MAP), and thoracic impedance were recorded. Graded isolation of muscle metaboreflex activation was achieved via postexercise ischemia (PEI) following low (PEI-L)-, moderate (PEI-M)-, and high (PEI-H)-intensity isometric handgrip performed at 20, 30, and 40% maximum voluntary contraction, respectively. Lower-body positive pressure (LBPP, +10 Torr) was applied at rest and during PEI, to load the cardiopulmonary baroreceptors. Handgrip exercise elicited intensity-dependent increases in MSNA and MAP that were maintained during PEI, indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency (BF: −36.7 ± 4.7%, mean ± SE, P < 0.05), whereas MAP was unchanged. When LBPP was applied during PEI, MSNA BF decreased significantly at PEI-L (−40.0 ± 9.2%, P < 0.05) and PEI-M (−27.0 ± 6.3%, P < 0.05), but not at PEI-H (+1.9 ± 7.1%, P > 0.05). These results suggest that low- and moderate-intensity muscle metaboreflex activation does not modulate the inhibition of MSNA by cardiopulmonary baroreceptor loading, whereas high-intensity metaboreflex activation can override cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow. NEW & NOTEWORTHY The interaction between the sympathoinhibitory influence of cardiopulmonary baroreflex and sympathoexcitatory effect of skeletal muscle metaboreflex is not completely understood. In the current study, light- to moderate-intensity muscle metaboreflex activation did not modulate the suppression of muscle sympathetic nerve activity by cardiopulmonary baroreceptor loading, whereas high-intensity muscle metaboreflex activation attenuated the cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity. These results provide important information concerning the neural reflex mechanisms regulating sympathetic vasomotor outflow during exercise.

Changes in cerebral blood flow (CBF) subsequent to alterations in the partial pressures of oxygen and carbon dioxide can modify dynamic cerebral autoregulation (CA). While cognitive activity increases CBF, the extent to which it impacts CA remains to be established. In the present study we determined whether dynamic CA would decrease during a cognitive task and whether hypoxia would further compound impairment. Fourteen young healthy subjects performed a simple Go/No-go task during normoxia and hypoxia (inspired O2 fraction = 12%), and the corresponding relationship between mean arterial pressure (MAP) and mean middle cerebral artery blood velocity (MCA Vmean) was examined. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated with transfer function analysis. While MCA Vmean increased during the cognitive activity ( P < 0.001), hypoxia did not cause any additional changes ( P = 0.804 vs. normoxia). Cognitive performance was also unaffected by hypoxia (reaction time, P = 0.712; error, P = 0.653). A decrease in the very low- and low-frequency phase shift (VLF and LF; P = 0.021 and P = 0.01) and an increase in LF gain were observed ( P = 0.037) during cognitive activity, implying impaired dynamic CA. While hypoxia also increased VLF gain ( P < 0.001), it failed to cause any additional modifications in dynamic CA. Collectively, our findings suggest that dynamic CA is impaired during cognitive activity independent of altered systemic O2 availability, although we acknowledge the interpretive complications associated with additional competing, albeit undefined, inputs that could potentially distort the MAP-MCA Vmean relationship. NEW & NOTEWORTHY During normoxia, cognitive activity while increasing cerebral perfusion was shown to attenuate dynamic cerebral autoregulation (CA) yet failed to alter reaction time, thereby questioning its functional significance. No further changes were observed during hypoxia, suggesting that impaired dynamic CA occurs independently of altered systemic O2 availability. However, impaired dynamic CA may reflect a technical artifact, given the confounding influence of additional inputs that could potentially distort the mean arterial pressure-mean middle cerebral artery blood velocity relationship.

Copyright © 2015 the American Physiological Society. The effect of an acute increase in central blood volume on the response of cerebral blood flow to acute hypotension. J Appl Physiol 119: 527-533, 2015. First published July 9, 2015; doi:10.1152/japplphysiol.00277.2015.-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) thighcuff 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 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.

The purpose of this study was to assess blood flow responses to changes in carbon dioxide (CO2) in the internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) during normothermic and hyperthermic conditions. Eleven healthy subjects aged 22 ± 2 (SD) yr were exposed to passive whole body heating followed by spontaneous hypocapnic and hypercapnic challenges in normothermic and hyperthermic conditions. Right ICA, ECA, and VA blood flows, as well as left middle cerebral artery (MCA) mean blood velocity ( Vmean), were measured. Esophageal temperature was elevated by 1.53 ± 0.09°C before hypocapnic and hypercapnic challenges during heat stress. Whole body heating increased ECA blood flow and cardiac output by 130 ± 78 and 47 ± 26%, respectively ( P < 0.001), while blood flow (or velocity) in the ICA, MCA, and VA was reduced by 17 ± 14, 24 ± 18, and 12 ± 7%, respectively ( P < 0.001). Regardless of the thermal conditions, ICA and VA blood flows and MCA Vmean were decreased by hypocapnic challenges and increased by hypercapnic challenges. Similar responses in ECA blood flow were observed in hyperthermia but not in normothermia. Heat stress did not alter CO2 reactivity in the MCA and VA. However, CO2 reactivity in the ICA was decreased (3.04 ± 1.17 vs. 2.23 ± 1.03%/mmHg; P = 0.039) but that in the ECA was enhanced (0.45 ± 0.47 vs. 0.95 ± 0.61%/mmHg; P = 0.032). These results indicate that hyperthermia is capable of altering dynamic cerebral blood flow regulation.

Exercise training elicits morphological adaptations in the left ventricle (LV) and large-conduit arteries that are specific to the type of training performed (i.e., endurance vs. resistance exercise). We investigated whether the mode of chronic exercise training, and the associated cardiovascular adaptations, influence the blood pressure responses to orthostatic stimulation in 30 young healthy men (10 sedentary, 10 endurance trained, and 10 resistance trained). The endurance-trained group had a significantly larger LV end-diastolic volume normalized by body surface area (vs. sedentary and resistance-trained groups), whereas the resistance-trained group had a significantly higher LV wall thickness and aortic pulse wave velocity (PWV) compared with the endurance-trained group. In response to 60° head-up tilt (HUT), mean arterial pressure (MAP) rose in the resistance-trained group (+6.5 ± 1.6 mmHg, P < 0.05) but did not change significantly in sedentary and the endurance-trained groups. Systolic blood pressure (SBP) decreased in endurance-trained group (−8.3 ± 2.4 mmHg, P < 0.05) but did not significantly change in sedentary and resistance-trained groups. A forward stepwise multiple regression analysis revealed that LV wall thickness and aortic PWV were significantly and independently associated with the MAP response to HUT, explaining ∼41% of its variability ( R2 =0.414, P < 0.001). Likewise, aortic PWV and the corresponding HUT-mediated change in stroke volume were significantly and independently associated with the SBP response to HUT, explaining ∼52% of its variability ( R2 = 0.519, P < 0.0001). Furthermore, the change in stroke volume significantly correlated with LV wall thickness ( r = 0.39, P < 0.01). These results indicate that chronic resistance and endurance exercise training differentially affect the BP response to HUT, and that this appears to be associated with training-induced morphological adaptations of the LV and large-conduit arteries.

The purpose of the present study was to examine the effect of static exercise on dynamic cerebral autoregulation (CA). In nine healthy subjects at rest before, during, and after static handgrip exercise at 30% maximum voluntary contraction, the response to an acute drop in mean arterial blood pressure and middle cerebral artery mean blood velocity was examined. Acute hypotension was induced nonpharmacologically via rapid release of bilateral thigh occlusion cuffs. Subjects were instructed to avoid executing a Valsalva maneuver during handgrip. To quantify dynamic CA, the rate of regulation (RoR) was calculated from the change in cerebral vascular conductance index during the transient fall in blood pressure. There was no significant difference in RoR between rest (mean ± SE; 0.278 ± 0.052/s), exercise (0.333 ± 0.053/s), and recovery (0.305 ± 0.059/s) conditions ( P = 0.747). In addition, there was no significant difference in the rate of absolute cerebral vasodilatory response to acute hypotension between three conditions ( P = 0.737). This finding indicates that static exercise and related elevations in blood pressure do not alter dynamic CA.

Hypoxia is known to impair cerebral autoregulation (CA). Previous studies indicate that CA is profoundly affected by cerebrovascular tone, which is largely determined by the partial pressure of arterial O2 and CO2. However, hypoxic-induced hyperventilation via respiratory chemoreflex activation causes hypocapnia, which may influence CA independent of partial pressure of arterial O2. To identify the effect of O2 on dynamic cerebral blood flow regulation, we examined the influence of normoxia, isocapnia hyperoxia, hypoxia, and hypoxia with consequent hypocapnia on dynamic CA. We measured heart rate, blood pressure, ventilatory parameters, and middle cerebral artery blood velocity (transcranial Doppler). Dynamic CA was assessed ( n = 9) during each of four randomly assigned respiratory interventions: 1) normoxia (21% O2); 2) isocapnic hyperoxia (40% O2); 3) isocapnic hypoxia (14% O2); and 4) hypocapnic hypoxia (14% O2). During each condition, the rate of cerebral regulation (RoR), an established index of dynamic CA, was estimated during bilateral thigh cuff-induced transient hypotension. The RoR was unaltered during isocapnic hyperoxia. Isocapnic hypoxia attenuated the RoR (0.202 ± 0.003/s; 27%; P = 0.043), indicating impairment in dynamic CA. In contrast, hypocapnic hypoxia increased RoR (0.444 ± 0.069/s) from normoxia (0.311 ± 0.054/s; +55%; P = 0.041). These findings indicated that hypoxia disrupts dynamic CA, but hypocapnia augments the dynamic CA response. Because hypocapnia is a consequence of hypoxic-induced chemoreflex activation, it may provide a teleological means to effectively maintain dynamic CA in the face of prevailing arterial hypoxemia.

We hypothesized that 1) acute severe hypoxia, but not hyperoxia, at sea level would impair dynamic cerebral autoregulation (CA); 2) impairment in CA at high altitude (HA) would be partly restored with hyperoxia; and 3) hyperoxia at HA and would have more influence on blood pressure (BP) and less influence on middle cerebral artery blood flow velocity (MCAv). In healthy volunteers, BP and MCAv were measured continuously during normoxia and in acute hypoxia (inspired O2 fraction = 0.12 and 0.10, respectively; n = 10) or hyperoxia (inspired O2 fraction, 1.0; n = 12). Dynamic CA was assessed using transfer-function gain, phase, and coherence between mean BP and MCAv. Arterial blood gases were also obtained. In matched volunteers, the same variables were measured during air breathing and hyperoxia at low altitude (LA; 1,400 m) and after 1–2 days after arrival at HA (∼5,400 m, n = 10). In acute hypoxia and hyperoxia, BP was unchanged whereas it was decreased during hyperoxia at HA (−11 ± 4%; P < 0.05 vs. LA). MCAv was unchanged during acute hypoxia and at HA; however, acute hyperoxia caused MCAv to fall to a greater extent than at HA (−12 ± 3 vs. −5 ± 4%, respectively; P < 0.05). Whereas CA was unchanged in hyperoxia, gain in the low-frequency range was reduced during acute hypoxia, indicating improvement in CA. In contrast, HA was associated with elevations in transfer-function gain in the very low- and low-frequency range, indicating CA impairment; hyperoxia lowered these elevations by ∼50% ( P < 0.05). Findings indicate that hyperoxia at HA can partially improve CA and lower BP, with little effect on MCAv.

We examined potential mechanisms (autonomic function, hypotension, and cerebral hypoperfusion) responsible for orthostatic intolerance following prolonged exercise. Autonomic function and cerebral hemodynamics were monitored in seven athletes pre-, post- (

We sought to test the hypothesis that the carotid baroreflex (CBR) alters mean leg blood flow (LBF) and leg vascular conductance (LVC) at rest and during exercise. In seven men and one woman, 25 ± 2 (SE) yr of age, CBR control of LBF and LVC was determined at rest and during steady-state one-legged knee extension exercise at ∼65% peak O2 uptake. The application of 5-s pulses of +40 Torr neck pressure and −60 Torr neck suction significantly altered mean arterial pressure (MAP) and LVC both at rest and during exercise. CBR-mediated changes in MAP were similar between rest and exercise ( P > 0.05). However, CBR-mediated decreases in LVC (%change) to neck pressure were attenuated in the exercising leg (16.4 ± 1.6%) compared with rest (33 ± 2.1%) and the nonexercising leg (23.7 ± 1.9%) ( P < 0.01). These data suggest CBR control of blood pressure is partially mediated by changes in leg vascular tone both at rest and during exercise. Furthermore, despite alterations in CBR-induced changes in LVC during exercise, CBR control of blood pressure was well maintained.