Search

This article provides an overview of the history behind the physiological concepts defining the role of the arterial baroreflexes and their regulation of arterial blood pressure during dynamic exercise. Initially, the case is made as to 'why the arterial baroreflexes must be involved with blood pressure regulation during exercise.' Subsequently, the historical animal and human experiments performed from the late 19th century to the present day describing how the two major neural mechanisms 'central command' and 'exercise pressor reflex' and their involvement in 'resetting' are reviewed. These historical experiments have resulted in the development of a hypothetical model identifying the major factors involved in baroreflex resetting, and these factors are described. The four manuscripts presented in these proceedings address a new set of questions. These new questions address the importance of the baroreflex control of muscle sympathetic nerve activity and vasomotor tone in the regulation of blood flow, not only in the systemic vasculature but also in the cerebral and cutaneous vasculatures. [ABSTRACT FROM AUTHOR]

Purpose: Postcardiopulmonary bypass atrial fibrillation remains a constant complication associated with coronary revascularization, the incidence of which occurs from 20% to 35%. Previous studies have addressed this problem in the postoperative setting utilizing pharmacological agents, but the results have been variable. The purpose of this study was to evaluate a novel intraoperative strategy to reduce the incidence of postcardiopulmonary bypass atrial fibrillation. We theorized that leukocyte depletion by filtration with the addition of aprotinin would reduce the systemic inflammatory effects of bypass and reduce the incidence of atrial fibrillation. Methods: One hundred and twenty-two patients participated in this randomized study. Only isolated primary coronary revascularization procedures on cardiopulmonary bypass were included. The control group (n=55) received standard moderate hypothermic blood cardioplegia cardiopulmonary bypass. The treatment group (n=65) received similar cardiopulmonary bypass with the addition of strategic leukocyte depletion with Pall Biomedical Products (East Hills, NY) leukodepletion filters and full-dose aprotinin. Results: The intraoperative addition of leukocyte depletion by filtration with aprotinin reduced the incidence of postcardiopulmonary bypass atrial fibrillation by 72%. The incidence of atrial fibrillation in the control group was 27% (15 of 55). In contrast, the occurrence of atrial fibrillation in the treated group was only 7.6% (5 of 65) (p<0.025). Conclusions: This novel intraoperative treatment strategy of both mechanical (leukocyte filtration) and pharmacological (aprotinin) intervention appears to markedly reduce the incidence of postcardiopulmonary bypass atrial fibrillation. To our knowledge, this is the first study to combine these two treatment strategies. A previous study has noted a decline in atrial fibrillation with aprotinin in the animal model, but not to the extent observed in our study. The beneficial effects of the reduction of atrial fibrillation include reduced risk of emboli formation and the incidence of ischemia in the heart, lung and brain. In addition, a decrease in length of hospital stay, recovery time and overall cost occurred. [ABSTRACT FROM AUTHOR]

The arterial baroreflex (ABR) resets during exercise in an intensity-dependent manner to operate around a higher blood pressure with maintained sensitivity. This review provides a historical perspective of ABR resetting and the involvement of other neural reflexes in mediating exercise resetting. Furthermore, we discuss potential underlying signaling mechanisms that may contribute to exercise ABR resetting in physiological and pathophysiological conditions.

Vascular resistance and conductance are reciprocal indices of vascular tone that are often assumed to be interchangeable. However, in most animals in vivo , blood flow (i.e. cardiac output) typically varies much more than arterial blood pressure. When blood flow changes at a constant pressure, the relationship between conductance and blood flow is linear, whereas the relationship between resistance and blood flow is non-linear. Thus, for a given change in blood flow, the change in resistance depends on the starting point, whereas the attendant change in conductance is proportional to the change in blood flow regardless of the starting conditions. By comparing the effects of physical activity at different temperatures or between species - concepts at the heart of comparative cardiovascular physiology - we demonstrate that the difference between choosing resistance or conductance can be marked. We also explain here how the ratio of conductance in the pulmonary and systemic circulations provides a more intuitive description of cardiac shunt patterns in the reptilian cardiovascular system than the more commonly used ratio of resistance. Finally, we posit that, although the decision to use conductance or resistance should be made on a case-by-case basis, in most circumstances, conductance is a more faithful portrayal of cardiovascular regulation in vertebrates., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

This study examined to what extent the human cerebral and femoral circulation contribute to free radical formation during basal and exercise-induced responses to hypoxia. Healthy participants (5♂, 5♀) were randomly assigned single-blinded to normoxic (21% O 2 ) and hypoxic (10% O 2 ) trials with measurements taken at rest and 30 min after cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled from the brachial artery (a), internal jugular and femoral veins (v) for non-enzymatic antioxidants (HPLC), ascorbate radical (A •- , electron paramagnetic resonance spectroscopy), lipid hydroperoxides (LOOH) and low density lipoprotein (LDL) oxidation (spectrophotometry). Cerebral and femoral venous blood flow was evaluated by transcranial Doppler ultrasound (CBF) and constant infusion thermodilution (FBF). With 3 participants lost to follow up (final n = 4♂, 3♀), hypoxia increased CBF and FBF (P = 0.041 vs. normoxia) with further elevations in FBF during exercise (P = 0.002 vs. rest). Cerebral and femoral ascorbate and α-tocopherol consumption (v < a) was accompanied by A •- /LOOH formation (v > a) and increased LDL oxidation during hypoxia (P < 0.043-0.049 vs. normoxia) implying free radical-mediated lipid peroxidation subsequent to inadequate antioxidant defense. This was pronounced during exercise across the femoral circulation in proportion to the increase in local O 2 uptake (r = -0.397 to -0.459, P = 0.037-0.045) but unrelated to any reduction in PO 2 . These findings highlight considerable regional heterogeneity in the oxidative stress response to hypoxia that may be more attributable to local differences in O 2 flux than to O 2 tension., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of the present study was to assess carotid baroreflex (CBR) function during acute changes in otolithic activity in humans. To address this question, we designed a set of experiments to identify the modulatory effects of microgravity on CBR function at a tilt angle of -2°, which was identified to minimize changes in central blood volume during parabolic flight. During parabolic flight at 0 and 1 g, CBR function curves were modeled from the heart rate (HR) and mean arterial pressure (MAP) responses to rapid pulse trains of neck pressure and neck suction ranging from +40 to -80 Torr; CBR control of HR (carotid-HR) and MAP (carotid-MAP) function curves, respectively. The maximal gain of both carotid-HR and carotid-MAP baroreflex function curves were augmented during microgravity compared with 1 g (carotid-HR, -0.53 to -0.80 beats·min -1 ·mmHg -1 , P < 0.05; carotid-MAP, -0.24 to -0.30 mmHg/mmHg, P < 0.05). These findings suggest that parabolic flight-induced acute change of otolithic activity may modify CBR function and identifies that the vestibular system contributes to blood pressure regulation under fluctuations in gravitational forces. NEW & NOTEWORTHY The effect of acute changes in vestibular activity on arterial baroreflex function remains unclear. In the present study, we assessed carotid baroreflex function without changes in central blood volume during parabolic flight, which causes acute changes in otolithic activity. The sensitivity of both carotid heart rate and carotid mean arterial pressure baroreflex function was augmented in microgravity compared with 1 g, suggesting that the vestibular system contributes to blood pressure regulation in humans on Earth.

Key Points: The arterial baroreflex's operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise., Abstract: We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back-supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): perindopril (high lipid solubility), captopril (low lipid solubility). Repeated measurements of whole venous blood (n = 8), MSNA (n = 7) and arterial blood pressures (n = 14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady state dynamic exercise. Arterial baroreflex function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance spectroscopy were elevated during exercise and were not altered by ACEi at rest (P ≥ 0.4) or during exercise (P ≥ 0.3). Baseline MSNA and mean arterial pressure were unchanged at rest (P ≥ 0.1; P ≥ 0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P < 0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise-induced increases in MSNA., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Purpose: This preliminary study tested the hypothesis that the carotid baroreflex (CBR) mediated sympathoexcitation regulates cerebral blood flow (CBF) at rest and during dynamic exercise., Methods: In seven healthy subjects (26 ± 1 years), oscillatory neck pressure (NP) stimuli of + 40 mmHg were applied to the carotid baroreceptors at a pre-determined frequency of 0.1 Hz at rest, low (10 ± 1W), and heavy (30 ± 3W) exercise workloads (WLs) without (control) and with α - 1 adrenoreceptor blockade (prazosin). Spectral power analysis of the mean arterial blood pressure (MAP), mean middle cerebral artery blood velocity (MCAV), and cerebral tissue oxygenation index (ScO 2 ) in the low-frequency range (0.07-0.20 Hz) was estimated to examine NP stimuli responses., Results: From rest to heavy exercise, WLs resulted in a greater than three-fold increase in MCAV power (42 ± 23.8-145.2 ± 78, p < 0.01) and an almost three-fold increase in ScO 2 power (0.51 ± 0.3-1.53 ± 0.8, p = 0.01), even though there were no changes in MAP power (from 24.5 ± 21 to 22.9 ± 11.9) with NP stimuli. With prazosin, the overall MAP (p = 0.0017), MCAV (p = 0.019), and ScO 2 (p = 0.049) power was blunted regardless of the exercise conditions. Prazosin blockade resulted in increases in the Tf gain index between MAP and MCAV compared to the control (p = 0.03)., Conclusion: CBR-mediated changes in sympathetic activity contribute to dynamic regulation of the cerebral vasculature and CBF at rest and during dynamic exercise in humans.

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in 1 ) SNA discharge and 2 ) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 ± 1.8, IHT: 24 ± 1.5, post-IHT 20.0 ± 1.3 bursts/min, all P < 0.01) and MAP (baseline: 89.2 ± 3.3, IHT: 92.62 ± 3.1, post-IHT: 93.83 ± 3.1 mmHg, all P < 0.02). Losartan attenuated the immediate and sustained increases in MSNA (baseline: 17.3 ± 2.5, IHT: 18.6 ± 2.2, post-IHT 20.0 ± 1.3 bursts/min, all P < 0.001) and MAP (baseline: 81.9 ± 2.6, IHT: 81.1 ± 2.8, post-IHT: 81.3 ± 3.0 mmHg, all P > 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT. NEW & NOTEWORTHY This study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients., (Copyright © 2017 the American Physiological Society.)

Purpose: This study was designed to test the hypothesis that aerobic exercise training of the elderly will increase aerobic fitness without compromising orthostatic tolerance (OT)., Methods: Eight healthy sedentary volunteers (67.0 ± 1.7 yr old, four women) participated in 1 yr of endurance exercise training (stationary bicycle and/or treadmill) program at the individuals' 65%-75% of HRpeak. Peak O2 uptake (V˙O2peak) and HRpeak were determined by a maximal exercise stress test using a bicycle ergometer. Carotid baroreceptor reflex (CBR) control of HR and mean arterial pressure (MAP) were assessed by a neck pressure-neck suction protocol. Each subject's maximal gain (Gmax), or sensitivity, of the CBR function curves were derived from fitting their reflex HR and MAP responses to the corresponding neck pressure-neck suction stimuli using a logistic function curve. The subjects' OT was assessed using lower-body negative pressure (LBNP) graded to -50 mm Hg; the sum of the product of LBNP intensity and time (mm Hg·min) was calculated as the cumulative stress index., Results: Training increased V˙O2peak (before vs after: 22.8 ± 0.92 vs 27.9 ± 1.33 mL·min·kg, P < 0.01) and HRpeak (154 ± 4 vs 159 ± 3 bpm, P < 0.02) and decreased resting HR (65 ± 5 vs 59 ± 5 bpm, P < 0.02) and MAP (99 ± 2 vs 87 ± 2 mm Hg, P < 0.05). CBR stimulus-response curves identified a leftward shift with an increase in CBR-HR Gmax (from -0.13 ± 0.02 to -0.27 ± 0.04 bpm·mm Hg, P = 0.01). Cumulative stress index was increased from 767 ± 68 mm Hg·min pretraining to 946 ± 44 mm Hg·min posttraining (P < 0.05)., Conclusion: Aerobic exercise training improved the aerobic fitness and OT in elderly subjects. An improved OT is likely associated with an enhanced CBR function that has been reset to better maintain cerebral perfusion and cerebral tissue oxygenation during LBNP.

Background: The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O 2 tension and blood flow., Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O 2 ) and hypoxic (10% O 2 ) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle., Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05)., Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation., (© 2016 American Heart Association, Inc.)

New Findings: What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea., (© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.)

The technique of microneurography and the assessment of muscle sympathetic nerve activity (MSNA) are used in laboratories throughout the world. The variables used to describe MSNA, and the criteria by which these variables are quantified from the integrated neurogram, vary among studies and laboratories and, therefore, can become confusing to those starting to learn the technique. Therefore, the purpose of this educational review is to discuss guidelines and standards for the assessment of sympathetic nervous activity through the collection and analysis of MSNA. This review will reiterate common practices in the collection of MSNA, but will also introduce considerations for the evaluation and physiological inference using MSNA., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Systemic blood distribution is an important factor involved in regulating cerebral blood flow (CBF). However, the effect of an acute change in central blood volume (CBV) on CBF regulation remains unclear. To address our question, we sought to examine the CBF and systemic hemodynamic responses to microgravity during parabolic flight. Twelve healthy subjects were seated upright and exposed to microgravity during parabolic flight. During the brief periods of microgravity, mean arterial pressure was decreased (-26 ± 1%, P < 0.001), despite an increase in cardiac output (+21 ± 6%, P < 0.001). During microgravity, central arterial pulse pressure and estimated carotid sinus pressure increased rapidly. In addition, this increase in central arterial pulse pressure was associated with an arterial baroreflex-mediated decrease in heart rate (r = -0.888, P < 0.0001) and an increase in total vascular conductance (r = 0.711, P < 0.001). The middle cerebral artery mean blood velocity (MCA Vmean) remained unchanged throughout parabolic flight (P = 0.30). During microgravity the contribution of cardiac output to MCA Vmean was gradually reduced (P < 0.05), and its contribution was negatively correlated with an increase in total vascular conductance (r = -0.683, P < 0.0001). These findings suggest that the acute loading of the arterial and cardiopulmonary baroreceptors by increases in CBV during microgravity results in acute and marked systemic vasodilation. Furthermore, we conclude that this marked systemic vasodilation decreases the contribution of cardiac output to CBF. These findings suggest that the arterial and cardiopulmonary baroreflex-mediated peripheral vasodilation along with dynamic cerebral autoregulation counteracts a cerebral overperfusion, which otherwise would occur during acute increases in CBV., (Copyright © 2015 the American Physiological Society.)

The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered., (Copyright © 2015 the American Physiological Society.)

Unlabelled: The accepted model of autonomic control of heart rate (HR) during dynamic exercise indicates that the initial increase is entirely attributable to the withdrawal of parasympathetic nervous system (PSNS) activity and that subsequent increases in HR are entirely attributable to increases in cardiac sympathetic activity. In the present review, we sought to re-evaluate the model of autonomic neural control of HR in humans during progressive increases in dynamic exercise workload. We analysed data from both new and previously published studies involving baroreflex stimulation and pharmacological blockade of the autonomic nervous system. Results indicate that the PSNS remains functionally active throughout exercise and that increases in HR from rest to maximal exercise result from an increasing workload-related transition from a 4 : 1 vagal-sympathetic balance to a 4 : 1 sympatho-vagal balance. Furthermore, the beat-to-beat autonomic reflex control of HR was found to be dependent on the ability of the PSNS to modulate the HR as it was progressively restrained by increasing workload-related sympathetic nerve activity., In Conclusion: (i) increases in exercise workload-related HR are not caused by a total withdrawal of the PSNS followed by an increase in sympathetic tone; (ii) reciprocal antagonism is key to the transition from vagal to sympathetic dominance, and (iii) resetting of the arterial baroreflex causes immediate exercise-onset reflexive increases in HR, which are parasympathetically mediated, followed by slower increases in sympathetic tone as workloads are increased., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

Pneumatic antishock garments (PASG) have been proposed to exert their blood pressure-raising effect mechanically, i.e. by increasing venous return and vascular resistance of the lower body. We tested whether, alternatively, PASG inflation activates the sympathetic nervous system. Five men and four women wore PASG while mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), heart rate and stroke volume were measured. One leg bladder (LEG) and the abdominal bladder (ABD) of the trousers were inflated individually and in combination (ABD+LEG), at 60 or 90 mmHg for 3 min. By the end of 3 min of inflation, conditions that included the ABD region caused significant increases in MAP in a dose-dependent fashion (7 ± 2, 8 ± 3, 14 ± 4 and 13 ± 5 mmHg for ABD60, ABD+LEG60, ABD90 and ABD+LEG90, respectively, P < 0.05). Likewise, inflation that included ABD caused significant increases in total MSNA compared with control values [306 ± 70, 426 ± 98 and 247 ± 79 units for ABD60, ABD90 and ABD+LEG90, respectively, P < 0.05 (units = burst frequency × burst amplitude]. There were no changes in MAP or MSNA in the LEG-alone conditions. The ABD inflation also caused a significant decrease in stroke volume (-11 ± 3 and -10 ± 3 ml per beat in ABD90 and ABD+LEG90, respectively, P < 0.05) with no change in cardiac output. Neither cardiopulmonary receptor deactivation nor mechanical effects can account for a slowly developing rise in both sympathetic activity and blood pressure during ABD inflation. Rather, these data provide direct evidence that PASG inflation activates the sympathetic nervous system secondarily to abdominal, but not leg, compression.

The aortic pulse pressure (PP), which consists mainly of the incident wave and the reflected wave, has emerged as an important property of systemic blood vessels underlying the pathophysiology of cardiovascular disease. To determine the role of sympathetic nerve activity on the aortic PP response during dynamic exercise, we evaluated aortic hemodynamics during the right-leg knee-extension (40 and 60 % of maximal voluntary contraction) in six young adults with and without the systemic α1-adrenergic receptor blockade using prazosin (1 mg/20 kg body weight). The use of prazosin attenuated the exercise-induced increase in aortic PP (P < 0.05) but not in radial arterial PP. The amplitude of the reflected waves (via augmentation index) significantly decreased with the exercise and decreased more with the use of prazosin. These results suggest that during dynamic exercise the α1-adrenergic-mediated vasoconstrictor tone of the peripheral resistance vessels is manifestly involved in the magnitude of the reflected wave and the modulation of the aortic PP responses.

We tested the hypothesis that pharmacological blockade of α(1)-adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 ± 0.2 to 3.2 ± 0.3 pmol (ml plasma)(-1)). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low-frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 ± 3 to 24 ± 4 to 31 ± 4 mmHg). An average of 74 ± 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 ± 0.3 to 4.4 ± 0.5 pmol (ml plasma)(-1)). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that α(1)-adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation and CCP, we conclude that increases in sympathetic activity have a role in establishing cerebral vascular tone in humans.

After considerable debate and key experimental evidence, the importance of the arterial baroreflex in contributing to and maintaining the appropriate neural cardiovascular adjustments to exercise is now well accepted. Indeed, the arterial baroreflex resets during exercise in an intensity-dependent manner to continue to regulate blood pressure as effectively as at rest. Studies have indicated that the exercise resetting of the arterial baroreflex is mediated by both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex). Another perhaps less appreciated neural mechanism involved in evoking and maintaining neural cardiovascular responses to exercise is the cardiopulmonary baroreflex. The limited information available regarding the cardiopulmonary baroreflex during exercise provides evidence for a role in mediating sympathetic nerve activity and blood pressure responses. In addition, recent investigations have demonstrated an interaction between cardiopulmonary baroreceptors and the arterial baroreflex during dynamic exercise, which contributes to the magnitude of exercise-induced increases in blood pressure as well as the resetting of the arterial baroreflex. Furthermore, neural inputs from the cardiopulmonary baroreceptors appear to play an important role in establishing the operating point of the arterial baroreflex. This symposium review highlights recent studies in these important areas indicating that the interactions of four neural mechanisms (central command, the exercise pressor reflex, the arterial baroreflex and cardiopulmonary baroreflex) are integral in mediating the neural cardiovascular adjustments to exercise.

Cerebral vasculature is richly innervated by the α-1 adrenergic receptors similar to that of the peripheral vasculature. However, the functional role of the α-1adrenergic receptors in cerebral blood flow (CBF) regulation is yet to be established. The traditional thinking being that during normotension and normocapnia sympathetic neural activity does not play a significant role in CBF regulation. Reports in the past have stated that catecholamines do not penetrate the blood brain barrier (BBB) and therefore only influence cerebral vessels from outside the BBB and hence, have a limited role in CBF regulation. However, with the advent of dynamic measurement techniques, beat-to-beat CBF assessment can be done during dynamic changes in arterial blood pressure. Several studies in the recent years have reported a functional role of the α-1adrenergic receptors in CBF regulation. This review focuses on the recent developments on the role of the sympathetic nervous system, specifically that of the α-1 adrenergic receptors in CBF regulation.

Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O(2), glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA V(mean); transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n = 9) and the MCA V(mean) during ergometer cycling (n = 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from approximately 60 to approximately 110 beats min(-1) (P < 0.01) and cardiac output by approximately 40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA V(mean) (approximately 16%; P < 0.01) and CBF (approximately 12%; P < 0.01) during static handgrip, as well as the increase in MCA V(mean) during cycling (approximately 15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

The aim of the present study was to calculate critical closing pressure (CCP) of the cerebral vasculature at rest and during exercise to estimate cerebral vascular tone. Five men and two women were seated upright for 15 min and then performed 15 min of right-legged knee extension exercise at 40, 60 and 75% of their maximal workload (WL(max)). Middle cerebral artery blood velocity (MCA V) and blood pressure in the radial artery were recorded. The CCP was calculated by linear extrapolation from 1 min recordings of pairs of systolic and diastolic pressure and MCA V waveforms from both the right and the left MCA. In both arteries, the CCP increased (right MCA, +6.6 +/- 8.5 mmHg, P = 0.023; left MCA, +7.3 +/- 9.1 mmHg, P = 0.016) during 75% WL(max) without changes in resistance-area product, while femoral vascular resistance of the non-exercising leg decreased (from 0.32 +/- 0.07 to 0.18 +/- 0.05 mmHg min ml(1); P < 0.001). There was no significant difference in CCP between the right and left MCA (P = 0.31). These findings suggest an increase in cerebral vascular tone in both the right and the left MCA from rest to exercise despite a decrease in vascular resistance of the systemic vasculature. In addition, the increases in CCP were related to the increases in plasma noradrenaline concentrations (right, P = 0.001; left, P = 0.025) and decreases in the partial pressure of arterial carbon dioxide (right, P = 0.008; left, P = 0.086), but not to changes in mean arterial pressure (right, P = 0.282; left, P = 0.564) or adrenaline concentrations (right, P = 0.138; left, P = 0.108). We consider that an exercise-induced increase in cerebral vascular tone serves to protect the blood-brain barrier from the exercise-induced hypertension.

The stability of a physiological control system, such as the arterial baroreflex, depends critically upon both the magnitude (i.e. gain or sensitivity) and timing (i.e. latency) of the effector response. Although studies have examined resting arterial baroreflex sensitivity in older subjects, little attention has been given to the influence of ageing on the latency of peak baroreflex responses. First, we compared the temporal pattern of heart rate (HR) and mean arterial blood pressure (BP) responses to selective carotid baroreceptor (CBR) unloading and loading in 14 young (22 +/- 1 years) and older (61 +/- 1 years) subjects, using 5 s pulses of neck pressure (NP, +35 Torr) and neck suction (NS, -80 Torr). Second, CBR latency was assessed following pharmacological blockade of cardiac parasympathetic nerve activity in eight young subjects, to better understand how known age-related reductions in parasympathetic nerve activity influence CBR response latency. In response to NP, the time to the peak increase in HR and mean BP were similar in young and older groups. In contrast, in response to NS the time to peak decrease in HR (2.1 +/- 0.2 vs. 3.8 +/- 0.2 s) and mean BP (6.7 +/- 0.4 vs. 8.3 +/- 0.2 s) were delayed in older individuals (young vs. older, P < 0.05). The time to peak HR and mean BP were delayed in young subjects following cardiac parasympathetic blockade (glycopyrrolate). Collectively, these data suggest that ageing is associated with delayed peak cardiovascular responses to acute carotid baroreceptor loading that may be, in part, due to age-related reductions in cardiac parasympathetic tone.

A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n = 6), central sympathetic inhibition (clonidine, n = 4) and neuronal noradrenaline uptake blockade (desipramine, n = 13) and in a group of patients (n = 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 +/- 1.8, and 186.4 +/- 25 ng min(-1), respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min(-1) +/- 34.4 ng min(-1). As expected, trimethaphan infusion lowered brain noradrenaline spillover (P = 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P = 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P = 0.004), without changing brain metabolite overflow (P = 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P = 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P = 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P = 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow from the brain under these different circumstances indicates that the two measures arise from different sources, i.e. noradrenaline spillover originates from the cerebral vasculature outside the blood-brain barrier, and the noradrenaline metabolites originate primarily from brain noradrenergic neurons. We suggest that measurements of transcranial plasma noradrenaline spillover have utility as a method for assessing the sympathetic nerve activity of the cerebral vasculature.

Previous studies have demonstrated an increase in the arterial baroreflex (ABR) control of muscle sympathetic nerve activity (MSNA) during isolated activation of the muscle metaboreflex with postexercise muscle ischemia (PEMI). However, the increased ABR-MSNA control does not appear to manifest in an enhancement in the ABR control of arterial blood pressure (BP), suggesting alterations in the transduction of MSNA into a peripheral vascular response and a subsequent ABR-mediated change in BP. Thus we examined the operating gains of the neural and peripheral arcs of the ABR and their interactive relationship at rest and during muscle metaboreflex activation. In nine healthy subjects, graded isolation of the muscle metaboreflex was achieved by PEMI following isometric handgrip performed at 15% and 30% maximal voluntary contraction (MVC). To obtain the sensitivities of the ABR neural and peripheral arcs, the transfer function gain from BP to MSNA and MSNA to femoral vascular conductance, respectively, was analyzed. No changes from rest were observed in the ABR neural or peripheral arcs during PEMI after 15% MVC handgrip. However, PEMI following 30% MVC handgrip increased the low frequency (LF) transfer function gain between BP and MSNA (ABR neural arc; +58 +/- 28%, P = 0.036), whereas the LF gain between MSNA and femoral vascular conductance (ABR peripheral arc) was decreased from rest (-36 +/- 8%, P = 0.017). These findings suggest that during high-intensity muscle metaboreflex activation an increased ABR gain of the neural arc appears to offset an attenuation of the peripheral arc gain to help maintain the overall ABR control of systemic BP.

The purpose of this investigation was to determine whether cardiovascular adaptations characteristic of long-term endurance exercise compensate more effectively during cardioselective beta(1)-adrenergic receptor blockade-induced reductions in sympathoadrenergic-stimulated contractility. Endurance-trained (ET) athletes (n = 8) and average-trained (AT; n = 8) subjects performed submaximal cycling exercise at moderate [45% maximum oxygen uptake (Vo(2max))] and heavy (70% Vo(2max)) workloads, with and without metoprolol. Cardiac output (Qc), heart rate (HR), and systolic blood pressure were recorded at rest and during exercise. Cardiac work was calculated from the triple product of HR, stroke volume, and systolic blood pressure, and myocardial efficiency is represented as cardiac work for a given total body oxygen consumption. Metoprolol reduced Qc at 45% Vo(2max) (P = 0.004) and 70% Vo(2max) (P = 0.022) in ET subjects, but did not alter Qc in the AT subjects. In ET subjects at 45% Vo(2max), metoprolol-induced reductions in Qc were a result of decreases in HR (P < 0.05) and the absence of a compensatory increase in stroke volume (P > 0.05). The cardiac work and calculated cardiac efficiency were reduced with metoprolol in ET subjects at both exercise intensities and in the AT subjects during the high-intensity workload (P < 0.01). The cardiac work and the calculated cardiac efficiency were not affected by metoprolol in the AT subjects during the 45% Vo(2max) exercise. Therefore, in AT subjects, beta-blockade reduced the amount of pressure generation necessary to produce the same amount of work during moderate-intensity exercise. In patients with heart disease receiving metoprolol, a decrease in the generation of cardiac pressure necessary to perform a given amount of work during mild-to-moderate exercise would prove to be beneficial.

Although cerebral autoregulation (CA) appears well maintained during mild to moderate intensity dynamic exercise in young subjects, it is presently unclear how aging influences the regulation of cerebral blood flow during physical activity. Therefore, to address this question, middle cerebral artery blood velocity (MCAV), mean arterial pressure (MAP), and the partial pressure of arterial carbon dioxide (Pa(CO(2))) were assessed at rest and during steady-state cycling at 30% and 50% heart rate reserve (HRR) in 9 young (24 +/- 3 yr; mean +/- SD) and 10 older middle-aged (57 +/- 7 yr) subjects. Transfer function analysis between changes in MAP and mean MCAV (MCAV(mean)) in the low-frequency (LF) range were used to assess dynamic CA. No age-group differences were found in Pa(CO(2)) at rest or during cycling. Exercise-induced increases in MAP were greater in older subjects, while changes in MCAV(mean) were similar between groups. The cerebral vascular conductance index (MCAV(mean)/MAP) was not different at rest (young 0.66 +/- 0.04 cm x s(-1) x mmHg(-1) vs. older 0.67 +/- 0.03 cm x s(-1) x mmHg(-1); mean +/- SE) or during 30% HRR cycling between groups but was reduced in older subjects during 50% HRR cycling (young 0.67 +/- 0.03 cm x s(-1) x mmHg(-1) vs. older 0.56 +/- 0.02 cm x s(-1) x mmHg(-1); P < 0.05). LF transfer function gain and phase between MAP and MCAV(mean) was not different between groups at rest (LF gain: young 0.95 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.88 +/- 0.06 cm x s(-1) x mmHg(-1); P > 0.05) or during exercise (LF gain: young 0.80 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.72 +/- 0.07 cm x s(-1) x mmHg(-1) at 50% HRR; P > 0.05). We conclude that despite greater increases in MAP, the regulation of MCAV(mean) is well maintained during dynamic exercise in healthy older middle-aged subjects.

The relative contribution of alpha adrenergic receptor subtypes in the transduction of sympathetic nerve activity (SNA) during carotid baroreflex (CBR) engagement is not well understood. Therefore, we compared the hemodynamic consequence of CBR-mediated sympatho-excitation via neck pressure (NP) before and after alpha-2 adrenergic blockade with intra-arterial yohimbine. Leg blood flow was measured using 2D and Doppler ultrasound, and arterial blood pressure was determined directly. NP caused the expected vasoconstriction, and this response was significantly reduced (by 50-60%) when NP was repeated after yohimbine. These data indicate that alpha-2 adrenergic receptors contribute significantly to CBR-induced vasoconstriction in the human leg under resting conditions.