- The arterial baroreflex (ABR) resets during exercise in an intensity-dependent manner to operate around the higher exercising blood pressure with maintained sensitivity. This review discusses the neural mechanisms involved in mediating ABR resetting.
- The ABR integrates centrally with other neural reflexes in the nucleus tractus solitarius to coordinate the autonomic adjustments to exercise, which contributes vitally to blood pressure regulation during exercise. The underlying signaling pathways involved are described and the potential contribution of central reactive oxygen species as a key signaling molecule for ABR resetting during exercise is discussed.
- An increase in reactive oxygen species in the central nervous system can act directly on neurons, or indirectly by scavenging nitric oxide in cardiovascular control centers, to increase sympathetic outflow. The conceptual framework for elevations in central reactive oxygen species mediating physiological (i.e., health) and pathophysiological (i.e., disease) resetting of the ABR during exercise is put forth.
In 1628, William Harvey published his work describing the circulation of the blood in De Motu Cordis (1); however, it was not until 1863 that Marey described in his book, The Physiology of the Circulation (2), the inverse relationship between heart rate (HR) and blood pressure (BP) and identified that BP was the controlled variable. Subsequent anatomical identifications of neural connections by Hering in 1927 (3) and Koch and Meis in 1929 (4) laid the groundwork for Heymans and Neil in 1958 (5) to describe the underlying neural mechanisms and pathways involved in the reflex control of the cardiovascular system at rest. Over the next 40 yr, since the Heymans and Neil publication, animal and human investigations were focused on identifying the integrative physiological responses involved in arterial baroreflex (ABR) regulation of BP at rest and during dynamic and static exercise in health and disease (6,7). During this time, our understanding of the central integration mediating the sympathetic and parasympathetic nervous system’s regulation of the cardiovascular system during exercise has advanced significantly, as detailed by Fisher et al. (8). The purpose of our present review is to provide a historical background of research focused on examining ABR control and resetting during exercise, as well as to provide insight into the neural mechanisms involved and the potential underlying molecular signaling pathway(s) that may mediate physiological (i.e., health) and pathophysiological (i.e., disease) resetting of the ABR.
Evaluating the Human ABR During Exercise
In 2000, Raven et al. (9) provided a detailed history of using the variable pressure neck collar device to stimulate carotid baroreceptors that was initially developed by Ernsting and Parry in 1957 (10) with the intent to identify HR, arterial BP, and vascular resistance/conductance reflex responses to changes in neck pressure (NP). Notably, with further developments of computerized beat-to-beat stimulation and data acquisition by Dr. Dwain Eckberg’s team (11–13) and additional major refinements by Dr. James Pawelczyk (14,15) of both mechanical and computer programming to control (i) application of NP (hypotensive stimuli), (ii) application of neck suction (NS; hypertensive stimuli), and (iii) beat-to-beat data acquisition, we were able to characterize differences in HR and arterial BP reflex function curves at rest and during an orthostatic challenge (i.e., lower body negative pressure) (14). Subsequently, the neck collar device has become one of the most used noninvasive techniques to characterize human carotid baroreflex function from rest to steady-state dynamic exercise. In 1993, Potts et al. (16) modified the beat-to-beat NP/NS stimuli protocol and used 5-s pulses of NP and NS, with an end-expiratory breath-hold, during steady-state mild (25% V˙O2peak) and moderate (50% V˙O2peak) intensity dynamic exercise. By fitting the peak responses of HR and mean arterial pressure (MAP) from the 5-s pulses of +40, +20, 0, −20, −40, −60, and −80 NPs to a logistic function curve (17), Potts et al. (16) was able to characterize and statistically compare differences in carotid baroreflex function curve parameters including the operating point (OP), centering point, threshold, saturation, and maximal gain (Gmax) between rest and mild to moderate-intensity steady-state dynamic exercise workloads. These findings suggested that the ABR’s OP and the functional range of the reflex was being “reset” to a higher operating BP without a change in sensitivity. These investigations extended the work of Melcher and Donald (18) showing resetting of the carotid baroreflex stimulus–response curve in chronically instrumented exercising dogs. In addition, it was these successful experiments and the publication of Jeff Potts’ dissertation work (16) that set the groundwork for Raven’s group to test Rowell and O’Leary’s proposed hypothetical model regarding ABR resetting during exercise in humans (19).
Further investigation using 5-s pulses of NP and NS without an end-expiratory breath-hold during more strenuous steady-state dynamic exercise at 75% and near maximum V˙O2peak confirmed that the OP-BP and reflex function curves were resetting in direct relation to the increases in exercise intensity, see Figure 1 (21). It is important to note that the upward and rightward resetting of the OP pressures of the carotid-MAP (i.e., vasomotor) reflex function curve occurred in direct relation with the increases in exercise intensity with its location maintained at the centering point of the reflex function curve (i.e., point of Gmax). Whereas, in contrast, the carotid-HR reflex OP relocated upwards away from the centering point toward the threshold, to a position of reduced gain on the reflex function curve as the intensity of the exercise increased (21) (Fig. 1A). This relocation of the carotid-HR reflex OP to a point of reduced gain was confirmed in several studies (22,23) and has been shown to require a functional cardiac parasympathetic limb of the autonomic nervous system (24). The data of these studies explain why using the well-established “Oxford Technique” (25) or the three-beat sequence method (26) of estimating the OP gain of the HR reflex during exercise identifies the gain to be diminishing (i.e., “switching off”) with increasing exercise intensities. Furthermore, we recalculated the autonomic blockade data provided by Ogoh et al. (27,28) and identified that at rest the carotid-HR reflex provides approximately 20% control of BP via cardiac output, whereas during light-intensity (HR, ~90 bpm) steady-state exercise and subsequent increases in exercise intensity to near maximum, the carotid-HR reflex’s input to the control of arterial BP was nearly zero. These findings clearly identify that ABR control of the vasculature is essential for the control of BP during dynamic exercise (28–31). The following sections will provide a historical review of additional autonomic nervous system reflex arcs involved in the neural control of BP during exercise, which are now known to also play a role in ABR resetting during exercise.
Autonomic Neural Control of the Circulation
In 1895, Johansson (32), performed a series of experiments in rabbits using spontaneous movement, passive movement, and electrical stimulation with and without severing the spinal cord and indicated that two primary neural mechanisms resulted in the increase in HR and BP during exercise. One neural mechanism was reported to arise from the brain, which is currently described as central command (CC), and acts as a feed-forward mechanism. The other neural mechanism arises from the skeletal muscles and has been identified as the exercise pressor reflex (EPR), which acts as a feedback mechanism. Herein, we provide a brief summary of the current understanding and the historical identification of the established physiological mechanisms of CC and EPR in the neural control of the circulation during exercise. For detailed descriptions, readers are referred to the following excellent reviews (8,33–36).
In 1913, Krogh and Lindhard (37) suggested from their investigations into the cardiovascular and respiratory changes at the onset of exercise that impulses from the motor cortex were responsible for driving these responses and adopted the term “cortical irradiation” as an identifier. Over time and as the detailed investigation of neural activity emanating from the motor cortex and traveling via autonomic neural pathways to the heart and vasculature to regulate cardiac output and BP occurred, the term “central command” was introduced (38). Two primary areas of interest for the study of CC in animal protocols were the hypothalamic and mesencephalic locomotor regions (39,40). Throughout this time, several methodologies in human studies to assess the contribution of CC to neural control of the circulation during exercise had been applied, including tendon vibration, hypnosis, and local anesthesia/neuromuscular blockade. Finally, and most recently, human deep-brain stimulation experiments have provided additional information regarding the potential cortical networks involved in the generation of CC including the periaqueductal grey area (41,42).
Tendon Vibration: CC
From 1970 to 1971, Jere H. Mitchell, M.D. was a Visiting Senior Scientist at the University Laboratory of Physiology at Oxford University in the United Kingdom. During this time, he worked with a Pre-Doctoral Fellow, Guy Goodwin, and a recently appointed Reader and Rhodes Scholar, Ian McCloskey, in developing a novel approach of manipulating CC. The study used (i) biceps tendon vibration to agonize or “assist” biceps flexion (i.e., decrease CC) and (ii) biceps tendon vibration to antagonize or “resist” triceps extension (i.e., increase CC). During biceps flexion, when CC was decreased with tendon vibration, the HR and BP responses to exercise were decreased, and when CC was increased during triceps extension, the HR and BP responses also were increased (38). Subsequently in 2002, Ogoh et al. (43) evaluated carotid baroreflex resetting using patellar tendon vibration during isometric knee extension and flexion and identified that when knee extension was assisted (i.e., CC decreased) the ABR-OP pressure was reduced and the reflex function curve was reset downwards and leftwards. Conversely, when knee flexion was resisted (i.e., CC increased) the ABR-OP pressure was increased and the reflex function curve was reset further upwards and rightwards (43).
In 1971, Drs. Barbara L. Drinkwater, Peter B. Raven, William P. Morgan, and Steven M. Horvath (Director of the Institute of Environmental Stress at the University of California at Santa Barbara) were discussing a question raised by Dr. Morgan. The question posed was “whether the brain’s perception of effort, somehow, influenced the autonomic control of the human’s physiological responses to exercise?” As we were unable to arrive at a consensus, we agreed to investigate the question using hypnotic suggestions of light, moderate, and heavy workloads. Dr. Morgan had been trained as a clinical psychologist and was an accomplished hypnotist. At the time, none of the investigators were familiar with the ongoing work of Mitchell and colleagues at Oxford University using the tendon vibration technique to investigate CC. Morgan proposed to use hypnosis to vary the subject’s effort perception while exercising at a constant workload and, thereby, selectively manipulating CC’s regulation of the circulation and ventilation during exercise.
Morgan et al. (44) developed an experimental design that required the subjects rating of perceived exertion (RPE) to be evaluated during a bicycle ergometer workload of 600 KPM (moderate) while awake and also during the same workload while under hypnotic suggestion of light, moderate, and heavy workloads. Significant increases were observed between RPEs, HRs, and ventilation variables during the suggestion of a heavy workload (to increase CC) compared with the awake and suggested moderate workloads of 600 KPM. Moreover, with the hypnotic suggestion of a light workload, lower RPE values were reported. However, the physiological responses were unchanged from the moderate workload indicating that the metabolic demand was overriding the hypnotic suggestion. From these experiments, it was concluded that the hypnotic suggestions and manipulation of CC resulted in the differences in RPEs during the suggested light and heavy workload trials. Journal reviewers of these data for publication in physiological and applied physiological journals were skeptical of the results obtained using hypnosis; hence, Morgan et al. (44) settled for publication in a clinical psychology journal.
In 1973, Dr. Jere Mitchell was a member of a study section on-site review team that visited the Institute of Environmental Stress at the University of California at Santa Barbara to provide a review of their National Institutes of Health training grant application focused on “Exercise Physiology.” During this review, Dr. Morgan presented the published data of the hypnosis study. Twenty years later, Mitchell invited Drs. Morgan and Raven, along with Dr. Jon Williamson a Post-Doctoral fellow colleague of Dr. Mitchell’s at UT Southwestern Medical Center to repeat the initial investigation with a focus on brain imaging using single-photon emission computed tomography (SPECT). The RPE and HR data mirrored the initial investigation’s results and the collection of BP data further confirmed the results of the hypnotic suggestions (45). The important new findings of the study were that the SPECT imaging of the brain identified that the suggested increases in RPE (effort sense) during the constant load exercise activated the anterior cingulate cortex, insular cortex, and the thalamic regions of the brain along with the attendant cardiovascular responses, when the suggested effort sense was greater than the steady-state moderate workload (45). However, when the suggested effort sense was reduced without an actual change in workload, the cardiovascular responses were not reduced below that required to maintain the metabolic need (45). A year later in a follow-up investigation using SPECT, a group of high hypnotizable subjects were compared with low hypnotizable subjects undergoing actual handgrip and imagined handgrip exercise. The RPE and hemodynamic responses along with increased activity in the anterior cingulate and insular cortices of the high hypnotizable subjects were significantly greater than the low hypnotizable subjects during imagined exercise. These findings suggested that there exists in high hypnotizable subjects, but not in low hypnotizable subjects, a cardiovascular regulation independent of the parallel activation of motor unit activity (46) that was more influenced by effort sense (47).
Central Pathways for CC: Animal and Human Investigations
Based upon numerous decerebrate cat and rat model investigations reviewed in the 1996 Handbook of Physiology by Waldrop et al. (39), it is generally accepted that CC is a feed-forward signal emanating from the higher brain centers that is intrinsically involved in the parallel activation of the cardiovascular and respiratory systems at the onset of and during exercise (39,48). Key areas initially identified included the hypothalamic and mesencephalic locomotor regions (39). Subsequently, Matsukawa’s investigations (48) have suggested that the caudal diencephalon and rostral mesencephalon regions of the brain are activated with the onset of CC. Specifically, these investigators also identified the involvement of the ventral tegmental area of the midbrain region in synchronizing cortical motor activity with sympathetic nerve activity. Thus, although CC traditionally has been linked to parasympathetic withdrawal to increase HR, particularly at the onset of exercise, these more recent findings suggest that CC also may increase cardiac sympathetic outflow at exercise onset. This concept of an earlier contribution of cardiac sympathetic nerve activity to HR control during exercise recently has been reviewed in detail (49). In Michelini et al.’s (50) recent review of invasive animal preparations of rats and cats and the translational investigations performed in dogs and humans, the authors provide an inclusive interpretation of the central somatomotor and autonomic neural outflows controlling muscle activity and neural reflex control of the circulation. Based upon their animal investigations, Michelini et al. proposed a central neural circuitry connecting arterial baroreceptor afferents to the nucleus tractus solitarius (NTS) and the paraventricular nucleus (PVN) in the hypothalamus as being involved in ABR resetting. However, Dampney et al.’s review of the literature regarding the role of the PVN’s presympathetic neurons regulating central sympathetic outflow in normal healthy animals during short-term sympathetic challenges suggested minimal influence. In contrast, during long-term sympathetic challenges, the regulatory role of the presympathetic neurons of the PVN become much more significant (51).
A majority of investigations examining the central neural circuitry that regulates autonomic neural control of the circulation during exercise have used animal preparations. However, in recent years, Dr. David Paterson and colleagues at the Oxford University and the Department of Neurosurgery at the John Radcliffe Hospital in the United Kingdom have used translational experiments while patients undergo deep-brain stimulation for the treatment of chronic pain or movement disorders. The results of these studies identify two areas of note: (i) the periaqueductal grey and (ii) the subthalamic nucleus (41,42). The periaqueductal grey is a key part of the neural circuitry controlling the autonomic changes of the circulation and the subthalamic nucleus is involved in the control of movement and cardiovascular responses.
Anesthesia or Neuromuscular Blockade: CC
Another technique of accentuating CC in humans using moderately invasive techniques was to weaken the exercising muscle group using a (i) regional (local) anesthetic, such as lidocaine (52), or (ii) neuromuscular junctional block of acetylcholine release with a curare derivative and have the subject generate the same exercising muscle force to match that required during the control exercise (53). These protocols resulted in the subjects needing to recruit more active muscle fibers to perform the same exercise force of the control exercise and thus, increasing CC. In a series of studies performed in collaboration with Niels Secher, M.D., D.M. Sc. at the Rigshospitalet in Copenhagen using lidocaine or curare blockade, our group evaluated CC’s influence on the exercise-induced resetting of the ABR function curves during static and dynamic leg and handgrip exercise. These experiments identified a clear and important role of CC in the upward and rightward exercise resetting of the OP pressure and the ABR function curve (20,52,53).
Exercise Pressor Reflex
In 1937, Alam and Smirk (54) identified in humans that there was a BP-raising reflex arising from skeletal muscle. This finding supported Johansson’s (32) earlier conclusion observed in animals. In 1943, Schmidt and Comroe (55) demonstrated that the contracting muscle was a primary source of the increase in ventilation with exercise. This muscle reflex mechanism was further substantiated by Kao et al. (56,57) using a cross-circulation technique between pentobarbital-anaesthetized dogs, in which the hind limb of one dog was exercised by electrical stimulation that subsequently resulted in an increased ventilation and HR of the recipient cross-circulated dog. In late 1971, Coote et al. (58) further identified the reflex nature of neural afferent fibers coming from the active skeletal muscle by stimulating the ventral roots resulting in increases in BP and HR, whereas sectioning of the dorsal roots abolished this response, demonstrating that the afferent feedback to the brain mediated the pressor response to muscle contraction. The investigators suggested it was Group III and IV afferents that were involved in the reflex neural circuits and further suggested that the stimulus was primarily metabolic rather than mechanical in nature. Subsequent studies by McCloskey and Mitchell in early 1972 (59,60), using differential anodal blockade of the thinly myelinated type III fibers and anesthetic (lidocaine) blockade of the unmyelinated type IV fibers of the afferent nerves arising from the stimulated skeletal muscle, identified the type III fibers to be responding to mechanical stimulation and the type IV fibers to be responding to chemical (metabolic) stimuli. Both the type III and type IV neural fibers were responsible for transmitting the neural signals to the brain and eliciting the reflex increase in BP (60,61). In 1983, Kaufman et al. (62) confirmed that the thinly myelinated Group III afferents responded mainly to mechanical stimuli and the unmyelinated Group IV afferents responded to changes in the metabolic milieu of the skeletal muscle. In the time between 1972 and 1983, the reflex increase in BP was named the EPR (61) and the intramuscular ends of the Group III and Group IV neural afferent fibers were identified as mechanoreceptors and metaboreceptors, respectively.
In 2012, at a 40-yr anniversary symposium of Jere Mitchell’s 1972 Journal of Physiology publications on CC and EPR, Marc Kaufman (63) provided a review of his group’s investigations into the EPR using animal models. In summary, Kaufman identified that at the start of exercise, and with increasing exercise intensities, the EPR provides an error signal to the cardiovascular control centers in the central nervous system until the blood/oxygen supply is sufficient to support the required metabolic demand of the exercise. However, even when the equilibrium between supply and demand for oxygen is achieved, the EPR remains actively involved in maintaining the required perfusion pressure during steady-state exercise.
In humans, Papelier et al. (64) reported that activation of the metaboreflex using postexercise ischemia during recovery from dynamic exercise “reset” the carotid-vasomotor OP pressure and reflex function curve above the resting and exercise reflex function curves with a reduced responsiveness to hypertension (NS) and augmented responsiveness to hypotension (NP). In contrast, minimal affect was found on the carotid-cardiac reflex function curves. In addition, when, presumably, jointly activating the mechano- and metabo-reflexes of the EPR during dynamic exercise using lower body positive pressure (LBPP), Eiken et al. (65) reported an increased sensitivity of the carotid-cardiac baroreflex, whereas in contrast Shi et al. (66) reported a decrease in the sensitivity of the carotid-cardiac reflex as a result of the LBPP-induced increases in central blood volume. As Eiken et al. (65) had calculated baroreflex sensitivity using changes in R-R interval per mm Hg BP and Shi et al. (66) calculated the baroreflex sensitivity using changes in HR per mm Hg BP, we suggest that the differences in calculated sensitivities or gain of the R-R interval and beats/min measures of HR was an interpretation artifact related to the mathematical hyperbolic relationship between R-R interval in milliseconds and the HR in beats/min (67,68).
Another means of activating the mechano- and metabo-reflexes while performing leg exercise was to inflate medical anti-shock (MAS) trousers to increase EPR input to the brainstem. Using this technique, Gallagher et al. (23) reported that the carotid-vasomotor reflex function curve was “reset” further upwards on the response arm and rightward to higher arterial pressures in comparison to control exercise (no MAS trousers) without a change in sensitivity of the reflex. Whereas the carotid-cardiac reflex function curve was only relocated further rightward to higher arterial pressures with MAS trousers. Secher and Amman (69) reviewed the translational human investigations that used (i) epidural anesthetic partial blockade of afferent somatosensory neural signals from the exercising arm (52) or leg (22) to reduce EPR input to ABR resetting, (ii) neuromuscular blockade using curare derivatives to weaken the exercising muscles and accentuate CC, and (iii) using fentanyl (opiate) blockade of afferent neural input from the lower limbs (i.e., Group III and IV afferents) to selectively block skeletal muscle afferents. Their findings along with other investigations in humans (70–72) and in animals (73) confirm that the EPR alone or in combination with CC is capable of “resetting” the carotid-vasomotor’s OP pressure and reflex function curve upward and rightward to a higher BP during exercise. Conversely, reduction of the EPR’s activation during exercise by using epidural anesthesia “resets” the carotid-vasomotor’s OP-BP and reflex function curve downward and leftward to a lower BP (22).
Integrative Physiological Mechanisms for ABR Resetting
Previous work completed in our laboratory (16,20,21) and others (69,74–77) established that activation of CC and the EPR were essential for the progressive physiological resetting of the “OP” pressures of the ABR during exercise (20), see Figure 1. Indeed, similar to rest, the ABR serves as the primary negative feedback reflex regulator of arterial BP during dynamic exercise.
Given the abundance of evidence that the CC and EPR can independently “reset” the ABR during static and dynamic exercise, Gallagher et al. (78) sought to identify the interaction between CC and the EPR in mediating ABR resetting during exercise. Carotid-MAP (i.e., vasomotor) reflex function curves were constructed at rest and under four exercise conditions: (i) during control static exercise and the same static exercise condition with (ii) inflated MAS trousers to further activate mechano- and metabo-receptors, (iii) neuromuscular blockade to induce muscle weakness requiring increases in CC, and (iv) a combination of MAS trousers and neuromuscular blockade. The results clearly identified that the combination of activated EPR and activated CC increased the OP-BP more than the activated EPR and the activated CC alone. These findings identify the interactive roles of the EPR and CC in resetting of the OP pressure of the ABR during exercise demonstrating that signals from one input facilitate signals from the other, which results in an enhanced ABR resetting during exercise.
In a novel investigation, Strange et al. (76) used electrical stimulation of the leg muscles (i) to cycle an ergometer (no CC + EPR), (ii) to cycle an ergometer with epidural anesthesia (no CC and no EPR), and compared responses with (iii) control free pedaling (CC + EPR; no electrical stimulation and no epidural anesthesia). In the no CC + EPR group, BP was increased during the electrical stimulation-induced leg cycling. There was no BP response during the electrically stimulated cycling with epidural anesthesia (no CC and no EPR) condition. Likewise, no BP response was found when paraplegic patients’ legs were cycled for them using electrical stimulation (79). Notably, the BP of tetraplegic (or quadriplegic) patients decreases when their legs are electronically stimulated to cycle (79). These studies indicate that both CC and EPR alone and in combination are fundamental in mediating the BP response to exercise.
Another primary neural reflex that contributes to the cardiovascular adjustments to exercise and ABR resetting is the cardiopulmonary baroreflex (CPBR). We will highlight some of the key studies in this area here, but readers are referred to the following reviews for more detailed information and descriptions (20,80,81). Accumulating data suggest that the CPBR plays a role in modulating the muscle sympathetic nerve activity (MSNA) response during exercise (82–84). For example, during light- to mild-intensity dynamic leg cycling, MSNA decreases or does not change from that at rest (82,85–87). This has been attributed to an enhanced muscle pump-induced increase in central blood volume, indicating that loading of the CPBR inhibits sympathetic vasomotor outflow during dynamic exercise. It has been suggested that such inhibition is overridden by activation of the skeletal muscle metaboreflex with higher intensity exercise (8). Our laboratory recently provided, for the first time, clear evidence demonstrating that high-intensity muscle metaboreflex activation can indeed override CPBR-mediated inhibition of MSNA (84). The CPBR also can interact with the ABR and modulate its function during exercise (20). Several studies have indicated that the CPBR modulates the resetting and the OP pressure of the ABR with exercise in relation to central blood volume changes monitored by low-pressure mechanically sensitive stretch receptors located in the heart, great veins, and blood vessels of the lungs (88–90). In short, increases in central blood volume, produced by muscle pump-induced enhancement of venous return during leg exercise, influence the exercise-induced MSNA and BP response and the locus of the OP of the carotid baroreflex function curve. It is clear that the roles of CC, the EPR, and the CPBR are integral in their involvement in the BP response to exercise and the resetting of the ABR. However, the underlying signaling mechanism(s) that mediate the resetting of the ABR during exercise remain to be completely identified.
Central Neural Pathways for ABR Resetting
In this section, we will briefly review the central pathway(s) by which the ABR integrates with other neural reflexes in order to set the stage for discussing potential molecular mechanisms involved in exercise-induced resetting of the ABR (Fig. 2). For further detail of the afferent and efferent reflex pathways of the ABR, complete description of the anatomical arrangement of these pathways, and the neurotransmitters by which these synapses communicate, readers are referred to previously published reviews (6,8,81,91).
Carotid baroreceptor afferents travel via the sensory ganglia of cranial nerve IX (i.e., glossopharyngeal nerve) and the aortic baroreceptors travel via cranial nerve X (i.e., vagus nerve) (6,81,91,92). These afferent fibers synapse in the NTS of the medulla, where ABR afferent input is integrated with inputs from higher brain centers (i.e., CC) and afferent inputs from other peripheral reflex arcs (i.e., EPR, carotid chemoreflex, respiratory metaboreflex, and CPBR) (8). The NTS provides direct excitatory synaptic input into the caudal ventrolateral medulla (CVLM), which provides inhibitory signals to the rostral ventrolateral medulla (RVLM), the medullary site primarily responsible for the regulation of sympathetic outflow. In addition, the NTS provides excitatory input into the nucleus ambiguous (NA), the medullary area responsible for regulation of parasympathetic outflow. For example, in the case of an elevation in BP, the tonically active baroreceptor afferent firing rate increases, which subsequently increases the NTS’s excitatory input into the NA and CVLM, the latter of which reduces RVLM neuronal activity (93,94). The result is an increase in parasympathetic (vagal) tone and a reduction in sympathetic outflow leading to a reduction in HR, cardiac output, and total peripheral resistance to reduce BP back to its set point value.
The EPR, CC, and the CPBR also integrate within the NTS and these shared neural pathways provide a potential site for interactions that contribute to ABR resetting during exercise (35,36,39,77,95). Indeed, Potts provided the framework describing the interaction between the EPR and ABR that contributes to exercise resetting, see Figure 3. In this scheme, afferent input from the EPR selectively inhibits baro-sensitive neurons within the NTS through a GABAergic mechanism, which reduces the excitability of these neurons such that a greater stimulus is required to activate the ABR (95). Thus, during exercise, this allows the ABR to operate at a higher BP without any change in its reflex sensitivity. At the same time, afferent signals from the EPR also excite neurons within the RVLM increasing sympathetic outflow to the heart and blood vessels (20,63). Collectively, these neural interactions contribute to the “resetting” of the ABR during exercise along with mediating the needed cardiovascular adjustments (i.e., increases in HR, cardiac output, and BP) to assist in meeting the metabolic demands of the active skeletal muscle. The CC and CPBR likely use similar neural pathways to also contribute to ABR exercise resetting (96); however, additional studies are needed to better understand these neural pathways and interactions that allow for ABR resetting with exercise. Likewise, the neuromodulators involved in modulating GABA and neuronal output from the NTS to allow for ABR resetting during exercise require future study. Key neuromodulators include nitric oxide (NO), substance P, reactive oxygen species (ROS), and angiotensin II (Ang II) (95,97,98).
Central Signaling Mechanisms
The regulation and integration of inputs into the NTS, the first central site receiving input from ABR afferents, and other central autonomic nuclei are complex and remain to be fully resolved. However, several lines of research have implicated NO as a key signaling molecule in the central regulation of sympathetic outflow (99–103). Briefly, NO is produced by nitric oxide synthase (NOS) during oxidation of L-arginine to L-citrulline. The most widely used technique to examine NO-mediated signaling in the brainstem is to microinject exogenous NOS inhibitors or L-arginine (NO substrate) into the site of interest. Indeed, several groups have used microinjection(s) of NOS inhibitors (e.g., NG-monomethyl L-arginine: L-NMMA) into the NTS (99) as well as the RVLM (100), demonstrating increases in sympathetic outflow and BP. Furthermore, Tagawa et al. (101) identified a dose-dependent increase in NTS neuronal activity in rat brainstem slices with the application of L-arginine that were attenuated with the addition of L-NMMA. These investigators further extended their findings by applying hemoglobin, which endogenously binds NO, to block the L-arginine-induced increase in NTS neuronal activity. Together, these data suggest that NO produced in medullary neurons can excite adjacent neurons, indicating an important role for NO as a signaling molecule in the regulation of central sympathetic outflow and BP.
Importantly, work by Salgado et al. (104) provided experimental evidence to support the notion that NO may be involved in ABR resetting. The authors used controlled hemorrhage and rapid blood reinfusion with direct aortic depressor nerve (ADN) recordings to derive baroreflex function curves. Intravenous L-NAME reduced the resetting of the ABR by nearly 75% when compared with a similar BP-raising stimulus (i.e., aortic coarctation). Baroreceptor resetting was calculated as the change in systolic arterial pressure (SAP) required to elicit 50% maximal ADN activity ([INCREMENT]SAP50) divided by the change in prevailing systolic arterial pressure ([INCREMENT]SAP). Thus, for the same change in SAP, L-NAME had a greater effect in reducing ADN firing and thus, the degree of baroreflex resetting. Notably, when the selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) was intravenously infused during aortic coarctation, the degree of baroreceptor resetting also was attenuated by approximately 75% compared with the aortic coarctation alone further highlighting the effect of NO inhibition on baroreflex resetting. Although these data provide support that NO plays an important role in mediating ABR resetting, the systemic infusion of L-NAME or TRIM does not rule out potential central NO effects (i.e., directly in NTS or RVLM). There is also data identifying NOS-containing neurons of a sensory and baroreceptive nature in the carotid bodies. Indeed, Höhler et al. (105) reported that 23% of neurons at the periphery of the carotid bodies stained positive for NOS. In addition, NO seems to play a role as an autocrine regulator of baroreceptor neurons (106). Overall, although there is evidence to support NO involvement in ABR regulation and resetting, to what extent peripheral NO concentrations at the baroreceptor afferents and central NO concentrations play regulatory role(s) remains to be determined. In addition to NO, ROS also may play an important role in mediating ABR resetting directly or indirectly by influencing NO bioavailability (107–109). A particular emphasis has been placed on superoxide anion, which is primarily produced via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Indeed, a number of studies have demonstrated the importance of NADPH-derived superoxide in mediating increases in central nervous system ROS concentrations (110,111). However, other sources of superoxide, such as xanthine oxidase and mitochondrial respiration, may also be involved. Superoxide is either reduced into oxygen/hydrogen peroxide by the enzyme(s) superoxide dismutase or it reacts with NO to form peroxynitrite, which is then converted into nitrite and subsequently nitrate, until it is excreted in the urine. In the latter case, superoxide plays a direct antagonist role in NO bioavailability and excessive central superoxide would result in reduced NO concentrations. Recently, Kawada et al. (112) demonstrated that intravenous administration of a superoxide dismutase mimetic (tempol) resulted in the OP of the ABR resetting to a lower BP. Moreover, there is evidence that superoxide signaling in the nodose ganglia may reduce ABR afferent neuronal excitability (113). These studies support a role for superoxide’s involvement in ABR resetting. Indeed, it is important to note that physiological production of ROS is important for cell signaling (114) and that some amount of ROS may be requisite for appropriate regulation of the cardiovascular system (114,115).
Perspectives for Progress
Examining the Potential Role of ROS in the Resetting of the ABR during Exercise
Both animal and human investigations have established that as the intensity of dynamic exercise increases the OP-BP of the ABR increases (i.e., resets to a higher BP, see Fig. 1) in direct relation to the intensity of the exercise (20). This physiologic hypertension is a result of the central integration of the neural inputs of CC, EPR, and CPBR within the NTS, as described previously (35,36,39,95). Herein, we make a case that ROS may play a key role in mediating the magnitude of ABR resetting during exercise. Indeed, during dynamic exercise, peripheral free radical production increases in direct relation to exercise intensity (115–117). The increased peripheral ROS production may reduce ABR afferent neuronal excitability via enhancing hyperpolarization-activated currents (113) that would facilitate increases in sympathetic outflow and resetting of the ABR. Furthermore, there is evidence that peripheral ROS also may affect EPR afferent neuronal excitability (118). Administration of tempol reduced the activity of voltage-gated sodium channels on dorsal root ganglion neurons indicating that ROS can excite skeletal muscle afferents. Thus, increased ROS production during exercise may increase ABR resetting via modulation of ABR and EPR afferent input into the NTS. Importantly, recent findings also demonstrate elevations in central ROS production during exercise. Bailey et al. (119) used a multiple catheter approach (jugular vein, femoral vein, brachial artery) during cycling exercise to determine the relative changes in peripheral and central free radical production and demonstrated for the first time in humans that central ROS increases during exercise. Notably, the increase in central ROS was graded to the magnitude of exercise intensity. An increase in central ROS can act directly on neurons, or indirectly by scavenging central NO in medullary cardiovascular control centers, thereby increasing sympathetic outflow and also contributing to ABR resetting (107–109). In support of a role for central ROS in regulating neural cardiovascular control during exercise, Koba et al. (120) recently reported an exaggerated CC response in heart failure rats (mesencephalic locomotor region stimulation), which was reduced after microinjection of tempol into the RVLM. Collectively, these data suggest that central ROS is increased during exercise in an intensity-dependent manner and provide support for the premise that ROS may modulate ABR resetting by altering central neuronal excitability. However, the source(s) of increased ROS during exercise, particularly central ROS, remain to be identified. Likewise, studies examining the effects of exercise mode, intensity, and duration on ROS production are needed. This is important because we propose that the primary site for ROS contributions to ABR resetting would be within the NTS, the initial central site receiving ABR afferent input. Nevertheless, future studies need to consider both peripheral and central ROS production and their potential influences on ABR resetting during exercise.
One potential pathway of interest is peripheral blood mononuclear cells (PBMCs), which are primarily composed of T-cells, B-cells, and monocytes that contribute importantly to systemic superoxide production (121,122). Indeed, selectively depleting circulating monocytes (i.e., PBMCs) in mice significantly reduced systemic superoxide after Ang II treatment, an effect that was reversed upon restoration of these cells indicating that PBMCs are a major source of systemic oxidative stress (123). As such, PBMCs have become of recent interest because they are one of the few cell types that has access to the central nervous system and can extrude ROS extracellularly (122). Thus, we speculate that PBMCs may be a primary means by which central ROS concentrations are elevated. The major enzyme producing superoxide in PBMCs is NADPH oxidase. The primary activator of NADPH oxidase is Ang II; however, there is also evidence for a role of norepinephrine, the primary neurotransmitter of the sympathetic nervous system (124,125). Importantly, studies suggest that PBMCs play a causal role in Ang II–induced hypertension via NADPH-derived superoxide production. In this regard, animals lacking T-cells (Rag-1−/− mice) do not develop hypertension after Ang II infusion (126). Overall, there is a growing body of evidence that hypertension at rest is an autoimmune disease that involves central and peripheral mechanisms that increase BP via activation of T-lymphocytes and associated elevations in ROS (127–129). Although there is emerging and strong data supporting a role for PBMCs in mediating hypertension, the extent to which PBMCs may contribute to ROS production and BP responses during exercise remains to be fully elucidated (130,131). However, because these cells have access to the central nervous system, we propose that PBMCs may be a primary contributor to central ROS production during exercise. Recent work by Capó et al. (132) demonstrating that PBMCs showed an increase in stimulated ROS production after an acute bout of exercise lend support to this proposition. Interestingly, work by Marvar et al. (128) suggests a possible feed-forward mechanism that may lead to progressive T-cell activation during exercise. In this regard, these investigators reported that even modest elevations in BP lead to T-cell activation. Considering the graded elevations in BP with exercise intensity, this may be a mechanism by which T-cells contribute to graded elevations in ROS during exercise. Nonetheless, a caveat is that the work by Marvar et al. was focused on the increased BP in response to chronic Ang II infusion; it does not address the effect of acute, transient increases in BP on T-cell activation as occurs during exercise. Future studies are warranted.
As noted previously, a potent stimulus for PBMC-derived superoxide production is Ang II. Importantly, Ang II increases in an intensity-dependent manner during exercise, particularly during higher intensities (133,134). To begin to explore the potential role of Ang II in mediating ABR resetting during exercise, Moralez et al. (135) recently compared a centrally acting angiotensin converting enzyme inhibitor (ACEi; perindopril), to a peripherally acting ACEi (captopril) and placebo. The premise of this innovative study design was based on the single dosages of perindopril and captopril used having previously been shown to reduce plasma Ang II concentrations to a similar extent (136,137). Thus, perindopril and captopril would seem to have similar peripheral effects so any differences observed would be attributable to a central effect of perindopril. Further supporting this approach, an oral dose of perindopril reduced brain ACE activity in mice by more than 50% compared with other noncentrally active ACEi (138). As such, this study design provides an approach to differentiate central versus peripheral actions of Ang II in humans. It was reported that the MSNA response during cycling exercise was significantly reduced after perindopril compared with captopril or placebo conditions, which was accompanied by a blunting of the exercise-induced resetting of the baroreflex OP-BP. These data suggest that perindopril may have reduced the Ang II-induced production of ROS in the medulla, decreasing ROS-induced activation of sympathetic neurons, thereby reducing central sympathetic outflow as well as ABR resetting. However, additional studies are warranted to investigate further the mechanisms by which a central but not peripherally acting ACEi reduced sympathetic nerve activity and attenuated ABR resetting.
Interestingly, in Moralez et al.’s study (135), neither perindopril nor captopril changed superoxide concentrations in peripheral venous blood, measured using electron spin resonance spectroscopy. Thus, despite a marked reduction in MSNA and ABR resetting in the perindopril condition, no changes in peripheral venous superoxide concentrations were found. The caveat here is that central superoxide was not measured, and, thus, it is plausible that reductions in central ROS were present and contributed to the decreases in the observed MSNA and ABR resetting. Indeed, we interpret these findings to indicate that perindopril reduced central superoxide during exercise. Herein, we are proposing that perindopril reduced central superoxide by decreasing PBMC-derived superoxide production, which contributed to a blunted ABR exercise resetting.
In short, a certain amount of superoxide and ROS production likely is needed to allow for BP increases and ABR resetting with exercise. In this scheme, the central production of ROS and their direct neuronal effects and scavenging of central NO contributes to exercise intensity-related increases in central sympathetic neural outflow, which leads to increasing the vasoconstriction of nonexercising vascular beds (splanchnic, etc.), and this increases the OP pressure of the ABR. We propose PBMCs as key players in this process. This can be viewed as a physiologic hypertension and resetting of the OP-BP (Fig. 4). In the next section, we propose that a malignant production of superoxide via heightened T-cell activation produces an augmented MSNA and BP response to exercise that leads to exercise-induced hypertension (EIHt) and a pathophysiological resetting of the ABR’s OP-BP.
Epidemiological evaluations of exercise stress testing data have identified a condition named EIHt as being a prognostic indicator for the future development of essential hypertension and cardiovascular events (139). EIHt is defined as a systolic BP value exceeding the 90th percentile, or 210 mm Hg for men and 190 mm Hg for women (139,140). Importantly, the exaggerated exercise-induced BP has been associated with a greater total peripheral resistance (141), suggesting that mechanisms regulating vascular tone likely contribute to EIHt. Although it has been suggested that EIHt may be driven by greater arterial stiffness (142), this cannot explain all cases because EIHt also occurs in young otherwise healthy individuals with presumably normal arterial stiffness (141). Thus, other mechanism(s) likely are involved. We put forth the hypothesis that excessive ROS production contributes to the pathophysiological hypertension and resetting of the ABR with EIHt. Indeed, evidence suggests that Ang II may play a role in the exaggerated BP response to exercise in EIHt, as circulating Ang II increases to a greater extent in these subjects compared with subjects with normal BP responses to exercise, despite similar resting BPs (134). This sets the stage for a mechanism by which Ang II drives excessive PBMC-derived superoxide production leading to an elevated central ROS and an augmented BP response and resetting of the ABR. This can be viewed as a pathophysiologic hypertension and ABR resetting (Fig. 4). Because PBMCs also can be stimulated by norepinephrine (124), it is plausible that exercise-induced sympathoexcitation contributes, along with Ang II, in mediating a greater production of ROS and further drives a pathophysiologic hypertension and ABR resetting, particularly in disease states with augmented MSNA responses to exercise (143–145). Future studies are needed to further investigate the underlying mechanisms driving EIHt.
The importance of understanding mechanisms specifically related to BP responses to exercise was highlighted by the recent work of Chant et al. (146). These investigators examined the BP response to progressive increases in exercise intensity to V˙O2peak and during isolated muscle metaboreflex activation using post-handgrip ischemia in four groups: (i) normotensive at rest, (ii) treated-uncontrolled hypertension at rest, (iii) treated-controlled hypertension at rest, and (iv) untreated hypertension at rest. These groups were matched for age, body mass index, sex, and aerobic capacity. During the progressive increases in the intensity of the dynamic exercise to maximum, the patients with hypertension had similar increases in BP, but these increases in BP were significantly greater than the normotensive controls. More importantly, the three hypertensive groups all had significantly augmented BP responses during isometric hand-grip testing used to isolate muscle metaboreflex activation compared with the normotensive group. These findings are the first to demonstrate that pharmaceutical control of hypertension at rest was ineffective in reducing the BP response during moderate- to high-intensity exercise. The failure of the drugs that combat hypertension at rest but not during exercise requires the attending physician to consider evaluating their prescribed anti-hypertensive medications effectiveness during exercise stress testing. Although the importance of treating resting hypertension cannot be overstated, these data highlight the need to also focus on BP responses to exercise and specific mechanisms driving this pathophysiological exercise-induced hypertension. Indeed, heightened BP reactivity to exercise increases the risk of acute cardiovascular and cerebrovascular events, both during and after exercise (147–149). Thus, a concerted effort is needed to identify mechanisms driving augmented BP responses to exercise in both healthy and disease populations. The work of Chant et al. (146) suggests a role for an enhanced muscle metaboreflex sensitivity; however, other mechanisms may also be involved and continued research is needed.
In summary, herein we set forth the concept that the normal physiological hypertension of dynamic exercise requires exercise intensity-related ABR resetting that is driven, in part, by CC, EPR, and the CPBR with ROS being a primary central modulatory factor underlying this physiological hypertension and resetting of the ABR. In contrast, in EIHt and disease states with heightened BP responses to exercise, we propose an excessive ROS production in the central nervous system contributes to a pathophysiological hypertension of exercise and resetting of the ABR. Furthermore, a novel hypothesis is put forth wherein PBMCs activated by exercise-induced increases in Ang II and sympathetic activation (norepinephrine) contribute to a malignant ROS production that drives an exaggerated BP and ABR resetting. Although these concepts and proposed hypotheses are solidly based on a number of past and recent studies, they are speculative and there is a need for rigorous mechanistic testing to further drive this area of research in an attempt to identify therapeutic targets to offset the deleterious consequences of a heightened BP reactivity to exercise.
The authors wish to acknowledge and thank Dr. Jere H. Mitchell, Dr. Scott A. Smith, and Dr. Noah P. Jouett for their thoughtful review of this manuscript.
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