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Integration of Central and Peripheral Regulation of the Circulation during Exercise: Acute and Chronic Adaptations

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ABSTRACT

Physical movement lasting any more than a few seconds (e.g., exercise), requires coordination of motor control with concomitant changes in the cardiovascular and respiratory support necessary to respond to the rapid increases in metabolic demand. Without such coordination, delivery of oxygen and removal of waste products become rate limiting and will restrict the duration, speed, and quality of movement. Fortunately, under healthy conditions, the central and peripheral nervous systems contribute importantly to this remarkable level of coordination via complex mechanisms that remain to be fully elucidated. The purposes of this review are to present the current state of knowledge regarding: (i) mechanisms by which the body maintains appropriate perfusion pressure to all organs during acute bouts of exercise, and (ii) alterations occurring in these mechanisms via central nervous system adaptations when exercise is performed or not performed on a regular basis (e.g., physically active versus sedentary lifestyle, respectively). Results from studies performed in humans and laboratory animals provide the reader a well‐rounded knowledge base. They are intended to instill an appreciation of what is known, and not known, about how the brain regulates the cardiovascular system during acute bouts of exercise, and the adaptations that occur when individuals exercise regularly versus when chronically sedentary. Discussion of the latter is intended to provide novel mechanisms for the increased incidence of cardiovascular disease in sedentary individuals versus a reduced incidence in individuals who are regularly active. © 2018 American Physiological Society. Compr Physiol 8:103‐151, 2018.

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Figure 1. Figure 1. Direct recordings of arterial pressure, heart rate, and lumbar sympathetic nerve activity (LSNA) at rest and during increasing levels of dynamic exercise in rats. Notice the progressive increase in sympathetic activity related to work rate. RMS = root mean squared Reprinted with permission from DiCarlo et al., 1996 ().
Figure 2. Figure 2. A schematic representation of the mechanisms mediating the neural cardiovascular adjustments to exercise. Neural signals originating from the brain (central command) and afferent feedback from the aortic and carotid arteries (arterial baroreflex), the heart and lungs (cardiopulmonary baroreflex), and skeletal muscle (exercise pressor reflex) contribute to the intensity‐dependent modulation of sympathetic and parasympathetic nerve activity during exercise. These signals converge centrally within cardiovascular control areas in the medulla oblongata. The ensuing alterations in autonomic outflow mediate changes in heart rate (HR) and contractility as well as the diameter of resistance and capacitance vessels within various tissue beds to modulate cardiac output [HR × stroke volume (SV)] and total vascular conductance (TVC), respectively. These changes then lead to alterations in mean arterial pressure (MAP) appropriate for the intensity and modality of the exercise. Ach, acetylcholine; NA, noradrenaline. Reprinted, with permission, from Fadel and Raven, 2012 ().
Figure 3. Figure 3. Histograms showing the group mean data (n = 7) of changes in heart rate (HR) (A), systolic blood pressure (SBP) (B) and diastolic blood pressure (DBP) (C) at 0, 30, and 60 s (b15, b45, b75) prior to passive stretch of triceps surae, and in each of the first three respiratory cycles (s1, s2, s3) and at 30 and 60 s during passive stretch performed in young healthy subjects. Mean (± SEM) changes from baseline are shown. These findings indicate that in response to stretch, muscle mechanoreceptors increase heart rate without effect on blood pressure. Thus, mechanically sensitive muscle afferents may contribute to the cardiac acceleration in response to muscle contraction. *P < 0.01. Reprinted, with permission, from Gladwell and Coote, 2002 ().
Figure 4. Figure 4. Original data from one rat showing a dramatic effect of injecting 10 μg of mechano‐gated channel inhibitor GsMTx4 into the arterial supply of the hindlimb (i.a.) on blood pressure (BP) and heart rate (HR) responses and renal sympathetic nerve activity (RSNA) during the first ∼10 s of tendon stretch. These findings show that inhibition of mechano‐gated Piezo channels reduced the BP, HR, and RSNA responses to tendon stretch indicating a role for these channels in evoking the cardiovascular responses to muscle mechanoreceptor activation. Reprinted, with permission, from Copp SW et al. 2016 ().
Figure 5. Figure 5. A schematic illustration of the intensity‐dependent resetting of the carotid baroreflex during dynamic exercise. The centering point (CP) is the point at which there is an equal depressor and pressor response to a given change in blood pressure (BP), the operating point (OP) is the prestimulus blood pressure. Both the carotid baroreflex‐heart rate (HR; panel A) and mean arterial pressure (MAP; panel B) stimulus‐response curves progressively reset during exercise in an intensity‐dependent manner without significant changes in maximal gain (sensitivity). A consistent observation for the baroreflex control of HR is the relocation of the OP away from the CP and closer to the threshold of the stimulus‐response curve along with a reduction in the response range as exercise intensity increases (panel A). The relocation of the operating point for HR control positions the baroreflex in a more optimal position to counter hypertensive stimuli with increasing exercise intensity. In contrast, for the carotid baroreflex‐MAP stimulus‐response curve the OP does not relocate away from the centering point and the response range remains the same as at rest with an upward and rightward shift in parallel with an increase in the intensity of exercise (panel B). Reprinted, with permission, from Fadel and Raven, 2012 ().
Figure 6. Figure 6. Evidence for the contribution of central command to the cardiovascular response to exercise. A and B represent single‐photon‐emission computed tomography (CT) data transferred to images of simultaneously acquired and co‐registered magnetic resonance imaging data. Importantly, computed tomography data represent group averages for the difference between the responses to actual and imaged handgrip exercise. (A) Left: Group CT data for individuals with lower hypnotizability who also reported less perceived effort and demonstrated decreases in brain activation during imagined handgrip exercise relative to actual handgrip exercise. (A) Right: Heart rate data in the lower hypnotizability group showing no change in heart rate to imagined exercise. (B) Left: Group CT data in the higher hypnotizability group who demonstrated similar increases in brain activation during both actual and imaged handgrip exercise and also reported an increase in perceived effort during both actual and imaged handgrip exercise. (B) Right: Group heart rate data in the higher hypnotizability group who demonstrated significant increases in heart rate during imagined exercise (*P < 0.05). The top and bottom of each brain scan represent the anterior and posterior portions of the brain, respectively. White lines indicate brain regions including the insular cortices, thalamic regions (bilaterally), and anterior cingulate cortex. Changes in regional cerebral blood flow distribution were indicated by an arbitrary color range that indicated decreases for the lower hypnotizability group from 5% to 25% (purple to light blue); whereas increases in regional cerebral blood flow distribution ranged from 5% to 25% (green to red) in the higher hypnotizability group. Modified, with permission, from Williamson et al. 2002 ().
Figure 7. Figure 7. Conceptual framework for the central interaction between arterial baroreceptor and skeletal muscle receptor afferents in the nucleus tractus solitarii (NTS) at rest and during acute bouts of exercise (Ex). (A) Depicts primary baroreceptor afferents forming an excitatory synapse with second order NTS neurons that in turn converge onto an output neuron projecting to nucleus ambiguus (NA) and the caudal ventrolateral medulla (cVLM). The net effect of this NTS circuit is to establish the operating point for heart rate (HR) and central sympathetic nerve activity (SNA) depicted on the baroreflex function curve to the right. (B) In the absence of baroreflex resetting, the model (see right panel) predicts that heightened levels of baroreceptor input during exercise increase NTS output activity. This increases neural activity transmitted to the NA, exciting cardiac vagal motoneurons, and to the cVLM, exciting GABA neurons that inhibit sympathetic premotor neurons in the rostral VLM (rVLM). Activation of these central circuits results in decreased heart rate and sympathoinhibition, respectively (see baroreflex curve on right). Note that the level of neural activity in these pathways is indicated by the relative line thickness. (C) Alternatively, activation of an inhibitory circuit by neural feedback from skeletal muscle [indicated by (I, somatic input)] would normalize the level of NTS output activity and so limit the degree of baroreceptor inhibition of the heart and peripheral vasculature. Activating this inhibitory circuit would reset the arterial baroreflex function curve laterally as indicated by (i) in the right panel. Note that this mechanism is “anatomically” restricted to the caudal NTS. In addition, somatic input would activate sympathoexcitatory neurons in the rVLM, increasing HR and SNA as indicated by (ii) in the right panel. This framework depicts potential central interactions that allow for the resetting of the arterial baroreflex function curve during exercise to allow for maintained baroreflex control in the face of exercise‐induced elevations in HR, SNA, and blood pressure. GABA, γ‐aminobutyric acid; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system. Reprinted, with permission from Potts, 2006 ().
Figure 8. Figure 8. Schematic diagram depicting a sympathetic nerve fiber and nerve ending in the skeletal muscle vasculature. Norepinephrine (NE) is the primary neurotransmitter and activates α1‐ and α2 adrenergic receptors postsynaptically and α2 adrenergic receptors presynaptically. Adenosine triphosphate (ATP) and neuropeptide Y (NPY) are co‐transmitters. ATP activates G‐protein coupled purinergic receptors (P2X) on smooth muscle cells and ligand gated ion channel purinergic receptors (P2Y) on endothelial cells. NPY activates Y1 receptors on smooth muscle cells. β2 adrenergic and muscarinic (M) receptors do not appear to be activated by post‐ganglionic nerves at rest or during exercise; however β2 adrenergic receptors on smooth muscle cells are activated by circulating epinephrine under various conditions. Muscarinic receptors can be activated by acetylcholine during the defense reaction or under experimental conditions with electrical stimulation of certain brain regions.
Figure 9. Figure 9. Mean arterial pressure, hindlimb blood flow, and hindlimb conductance at onset of exercise with control (saline) and experimental intervention (ganglionic blockade). Data were averaged over 1‐s intervals (except for time 0, which represents a 10‐s average of values obtained while dogs were resting on treadmill). There were no statistically significant differences in conductance responses between the two treatments at 5, 10, and 15 s of exercise. However, conductance values were significantly elevated with ganglionic blockade at 20, 25, and 30 s of exercise (P < 0.01). Reprinted with permission from Buckwalter and Clifford, 1999 ().
Figure 10. Figure 10. Original record showing a dog proceeding from rest to exercise at 6 mph. At 2 min into exercise, an intra‐arterial bolus of selective alpha1‐antagonist prazosin (0.1 mg) was given. Note the immediate increase in blood flow and conductance in experimental limb, with no changes in systemic blood pressure or blood flow and conductance in control limb. Reprinted with permission from Buckwalter et al., 1997 ().
Figure 11. Figure 11. A schematic illustration depicting the divergent responses in contracting and inactive skeletal muscle vasculature to increases in muscle sympathetic nerve activity during exercise. The increases in sympathetic outflow are evoked, in large part, via mechanically and metabolically sensitive muscle afferents (the Exercise Pressor Reflex) with further modulation provided via the arterial baroreflex. These intensity‐dependent increases in sympathetic nerve activity cause sympathetically mediated vasoconstriction in inactive muscle, whereas in active muscle there is an attenuation of this sympathetic vasoconstrictor activity. The latter, termed functional sympatholysis, may be attributed to increases in metabolites, muscle temperature, and possibly nitric oxide. This attenuation of sympathetic vasoconstriction in the contracting muscle allows for enhanced muscle blood flow to the metabolically active skeletal muscle. At the same time, the sympathetically mediated vasoconstriction in inactive muscle (and the viscera—not pictured) enhance the redistribution of cardiac output to the contracting skeletal muscles. Collectively, this illustrates the important contributions of the sympathetic nervous system to the matching of muscle blood flow to metabolic demand in exercising muscles.
Figure 12. Figure 12. Graphical illustration of the neural control of skin blood flow in humans. Human cutaneous vasculature is controlled by a sympathetic adrenergic vasoconstrictor limb and a separate sympathetic cholinergic vasodilator limb. Under cool conditions, the vasoconstrictor limb is engaged resulting in reductions in cutaneous vascular conductance and skin blood flow. When internal temperature is elevated, the active vasodilator system is engaged, mediating 85% to 95% of the increase in skin blood flow through increases in cutaneous vascular conductance. The arrow depicts the magnitude of the increases in the respective nerve activities during cooling (increases in sympathetic adrenergic nerve activity) and heating (increases in sympathetic cholinergic nerve activity). Substances within the indicated nerves are the neurotransmitters that have either been shown to, or are proposed to, contribute to the respective responses. NE, norepinephrine; NPY, neuropeptide Y; Ach, acetylcholine; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase‐activating peptide; nNO, neuronally derived nitric oxide. Illustration used by permission from Manabu Shibasaki, PhD, Nara Women's University.
Figure 13. Figure 13. Differences in cutaneous vasodilation, expressed as a percentage of preheat stress (i.e., Control) cutaneous vascular conductance, in a subject who was passively heat stressed (Rest—solid circles) and exercise heat stressed (exercise—open circles). Notice the rightward shift of the curve during exercise such that cutaneous vascular conductance is lower at any esophageal temperature during exercise. These finding show that the increase in skin blood flow during exercise‐induced heat stress is delayed relative to passive‐induced heat stress. Figure modified from Kellogg, Johnson, and Kosiba, 1991 () with permission.
Figure 14. Figure 14. This figure depicts the linear relationship between increases in cardiac output (Q) and forearm blood flow (FBF, panel A) as well as middle cerebral artery blood velocity (MCAVmean, panel B) at rest (solid circles) and during cycling exercise (EX, open circles). These data suggest that increases in cardiac output contribute to increases in forearm blood flow and brain blood flow during rest and exercise. Reprinted with permission from Ogoh et al., 2005 ().
Figure 15. Figure 15. Reductions in splanchnic blood flow (Y‐axis expressed in mL/min) during dynamic exercise in patients with mitral valve stenosis (MS), in normal sedentary young men (Sed), and endurance trained athletes (Ath). Data in the left panel are the same as in the right panel, except the right panel is normalized to % maximum oxygen update (%Max VO2). These data demonstrate that as a workload becomes more difficult (i.e., requires more oxygen) there are linear reductions in splanchnic blood flow. Reprinted with permission from Rowell, 1973 ().
Figure 16. Figure 16. Conceptual diagram of the spectrum of physical activity and proposed influence of positive and negative brain effects on cardiovascular health (positive = green; negative = red). In this context, long term decreases in sympathetic nervous system and increases in parasympathetic nervous system activity produced by an active lifestyle are beneficial as they promote lower resting blood pressures, protection from arrhythmias, and decreased cardiac demand. In contrast, long‐term increases in sympathetic nervous system and decreases in parasympathetic nervous system activity are viewed as detrimental as they are associated with hypertension, arrhythmias, and heart failure. The rapid rise in cardiovascular benefit produced by being physically active reflects epidemiological evidence from Blair and colleagues whose data indicate that the largest relative health benefit is derived in individuals moving from the lowest quintile (i.e., 1 of 5) of fitness category to only the second lowest quintile of cardiorespiratory fitness. The diagram also allows for shifts in the curve to the right or left due to genetics, preexisting conditions, or other factors that predispose or influence individuals to more positive (green block arrow) or negative (red block arrow) cardiovascular health.
Figure 17. Figure 17. Schematic diagram illustrating the role of important neural pathways involved in integration and generation of sympathetic vasoconstrictor outflow. Under healthy conditions, which include regular physical activity, all pathways actively regulate sympathetic outflow to the vasculature, particularly during bouts of exercise. At rest, the rostral ventrolateral medulla (RVLM) serves as the primary site of sympathetic outflow and its activity is limited by inhibitory inputs (dotted lines) from the caudal ventrolateral medulla (CVLM). The CVLM provides inhibition due to inputs driven in part by the nucleus tractus solitarius (NTS). Even at rest, the NTS is tonically active due to input from arterial baroreceptors but can also be influenced by inputs from contracting muscle during exercise. “Central command” neurons in higher centers of the brain initiate movement and influence pathways that alter sympathetic outflow via projections to PVN and NTS. Under sedentary conditions (red arrows and dotted circles), there is a lack of activation of pathways produced by regular bouts of exercise and likely produces alterations in neuronal function, that is, neuroplasticity, which result in increased sympathetic outflow to the vasculature. Modified from Mueller, 2010 () with permission.
Figure 18. Figure 18. Schematic diagram illustrating the role of important neural pathways involved in the integration and generation of sympathetic and parasympathetic outflow to the heart. As with control of tonic sympathetic vasoconstrictor activity, physically active conditions result in all pathways actively regulating sympathetic outflow to the heart, particularly during periodic bouts of exercise. At rest, the nucleus ambiguus (NA), and in some species, the dorsal motor nucleus of the vagus (DMV), serve as the primary site(s) of parasympathetic outflow to the heart. Activity of the NA and DMV are driven by excitatory inputs (solid lines, plus signs) from nucleus tractus solitarius (NTS). Even at rest, the NTS is tonically active due to input from arterial baroreceptors and maintains ongoing parasympathetic nerve activity (PNA, i.e., vagal tone) to suppress baseline heart rate (HR) well below its intrinsic rate. Brain regions controlling sympathetic nerve activity (SNA) to the heart appear more complex (some not shown) but are least active at rest and typically only become active after PNA withdrawal during exercise. Under sedentary conditions (red arrows and dotted circles), there is a lack of activation of pathways produced by regular bouts of exercise and likely produces alterations in neuronal function, that is, neuroplasticity, which result in decreased PNA and increased SNA to the heart, raising resting HR. Changes in contractility may depend on whether increased SNA produces compensatory increases or over time induces decreases as a result of heart failure. Modified from Mueller, 2010 () with permission.


Figure 1. Direct recordings of arterial pressure, heart rate, and lumbar sympathetic nerve activity (LSNA) at rest and during increasing levels of dynamic exercise in rats. Notice the progressive increase in sympathetic activity related to work rate. RMS = root mean squared Reprinted with permission from DiCarlo et al., 1996 ().


Figure 2. A schematic representation of the mechanisms mediating the neural cardiovascular adjustments to exercise. Neural signals originating from the brain (central command) and afferent feedback from the aortic and carotid arteries (arterial baroreflex), the heart and lungs (cardiopulmonary baroreflex), and skeletal muscle (exercise pressor reflex) contribute to the intensity‐dependent modulation of sympathetic and parasympathetic nerve activity during exercise. These signals converge centrally within cardiovascular control areas in the medulla oblongata. The ensuing alterations in autonomic outflow mediate changes in heart rate (HR) and contractility as well as the diameter of resistance and capacitance vessels within various tissue beds to modulate cardiac output [HR × stroke volume (SV)] and total vascular conductance (TVC), respectively. These changes then lead to alterations in mean arterial pressure (MAP) appropriate for the intensity and modality of the exercise. Ach, acetylcholine; NA, noradrenaline. Reprinted, with permission, from Fadel and Raven, 2012 ().


Figure 3. Histograms showing the group mean data (n = 7) of changes in heart rate (HR) (A), systolic blood pressure (SBP) (B) and diastolic blood pressure (DBP) (C) at 0, 30, and 60 s (b15, b45, b75) prior to passive stretch of triceps surae, and in each of the first three respiratory cycles (s1, s2, s3) and at 30 and 60 s during passive stretch performed in young healthy subjects. Mean (± SEM) changes from baseline are shown. These findings indicate that in response to stretch, muscle mechanoreceptors increase heart rate without effect on blood pressure. Thus, mechanically sensitive muscle afferents may contribute to the cardiac acceleration in response to muscle contraction. *P < 0.01. Reprinted, with permission, from Gladwell and Coote, 2002 ().


Figure 4. Original data from one rat showing a dramatic effect of injecting 10 μg of mechano‐gated channel inhibitor GsMTx4 into the arterial supply of the hindlimb (i.a.) on blood pressure (BP) and heart rate (HR) responses and renal sympathetic nerve activity (RSNA) during the first ∼10 s of tendon stretch. These findings show that inhibition of mechano‐gated Piezo channels reduced the BP, HR, and RSNA responses to tendon stretch indicating a role for these channels in evoking the cardiovascular responses to muscle mechanoreceptor activation. Reprinted, with permission, from Copp SW et al. 2016 ().


Figure 5. A schematic illustration of the intensity‐dependent resetting of the carotid baroreflex during dynamic exercise. The centering point (CP) is the point at which there is an equal depressor and pressor response to a given change in blood pressure (BP), the operating point (OP) is the prestimulus blood pressure. Both the carotid baroreflex‐heart rate (HR; panel A) and mean arterial pressure (MAP; panel B) stimulus‐response curves progressively reset during exercise in an intensity‐dependent manner without significant changes in maximal gain (sensitivity). A consistent observation for the baroreflex control of HR is the relocation of the OP away from the CP and closer to the threshold of the stimulus‐response curve along with a reduction in the response range as exercise intensity increases (panel A). The relocation of the operating point for HR control positions the baroreflex in a more optimal position to counter hypertensive stimuli with increasing exercise intensity. In contrast, for the carotid baroreflex‐MAP stimulus‐response curve the OP does not relocate away from the centering point and the response range remains the same as at rest with an upward and rightward shift in parallel with an increase in the intensity of exercise (panel B). Reprinted, with permission, from Fadel and Raven, 2012 ().


Figure 6. Evidence for the contribution of central command to the cardiovascular response to exercise. A and B represent single‐photon‐emission computed tomography (CT) data transferred to images of simultaneously acquired and co‐registered magnetic resonance imaging data. Importantly, computed tomography data represent group averages for the difference between the responses to actual and imaged handgrip exercise. (A) Left: Group CT data for individuals with lower hypnotizability who also reported less perceived effort and demonstrated decreases in brain activation during imagined handgrip exercise relative to actual handgrip exercise. (A) Right: Heart rate data in the lower hypnotizability group showing no change in heart rate to imagined exercise. (B) Left: Group CT data in the higher hypnotizability group who demonstrated similar increases in brain activation during both actual and imaged handgrip exercise and also reported an increase in perceived effort during both actual and imaged handgrip exercise. (B) Right: Group heart rate data in the higher hypnotizability group who demonstrated significant increases in heart rate during imagined exercise (*P < 0.05). The top and bottom of each brain scan represent the anterior and posterior portions of the brain, respectively. White lines indicate brain regions including the insular cortices, thalamic regions (bilaterally), and anterior cingulate cortex. Changes in regional cerebral blood flow distribution were indicated by an arbitrary color range that indicated decreases for the lower hypnotizability group from 5% to 25% (purple to light blue); whereas increases in regional cerebral blood flow distribution ranged from 5% to 25% (green to red) in the higher hypnotizability group. Modified, with permission, from Williamson et al. 2002 ().


Figure 7. Conceptual framework for the central interaction between arterial baroreceptor and skeletal muscle receptor afferents in the nucleus tractus solitarii (NTS) at rest and during acute bouts of exercise (Ex). (A) Depicts primary baroreceptor afferents forming an excitatory synapse with second order NTS neurons that in turn converge onto an output neuron projecting to nucleus ambiguus (NA) and the caudal ventrolateral medulla (cVLM). The net effect of this NTS circuit is to establish the operating point for heart rate (HR) and central sympathetic nerve activity (SNA) depicted on the baroreflex function curve to the right. (B) In the absence of baroreflex resetting, the model (see right panel) predicts that heightened levels of baroreceptor input during exercise increase NTS output activity. This increases neural activity transmitted to the NA, exciting cardiac vagal motoneurons, and to the cVLM, exciting GABA neurons that inhibit sympathetic premotor neurons in the rostral VLM (rVLM). Activation of these central circuits results in decreased heart rate and sympathoinhibition, respectively (see baroreflex curve on right). Note that the level of neural activity in these pathways is indicated by the relative line thickness. (C) Alternatively, activation of an inhibitory circuit by neural feedback from skeletal muscle [indicated by (I, somatic input)] would normalize the level of NTS output activity and so limit the degree of baroreceptor inhibition of the heart and peripheral vasculature. Activating this inhibitory circuit would reset the arterial baroreflex function curve laterally as indicated by (i) in the right panel. Note that this mechanism is “anatomically” restricted to the caudal NTS. In addition, somatic input would activate sympathoexcitatory neurons in the rVLM, increasing HR and SNA as indicated by (ii) in the right panel. This framework depicts potential central interactions that allow for the resetting of the arterial baroreflex function curve during exercise to allow for maintained baroreflex control in the face of exercise‐induced elevations in HR, SNA, and blood pressure. GABA, γ‐aminobutyric acid; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system. Reprinted, with permission from Potts, 2006 ().


Figure 8. Schematic diagram depicting a sympathetic nerve fiber and nerve ending in the skeletal muscle vasculature. Norepinephrine (NE) is the primary neurotransmitter and activates α1‐ and α2 adrenergic receptors postsynaptically and α2 adrenergic receptors presynaptically. Adenosine triphosphate (ATP) and neuropeptide Y (NPY) are co‐transmitters. ATP activates G‐protein coupled purinergic receptors (P2X) on smooth muscle cells and ligand gated ion channel purinergic receptors (P2Y) on endothelial cells. NPY activates Y1 receptors on smooth muscle cells. β2 adrenergic and muscarinic (M) receptors do not appear to be activated by post‐ganglionic nerves at rest or during exercise; however β2 adrenergic receptors on smooth muscle cells are activated by circulating epinephrine under various conditions. Muscarinic receptors can be activated by acetylcholine during the defense reaction or under experimental conditions with electrical stimulation of certain brain regions.


Figure 9. Mean arterial pressure, hindlimb blood flow, and hindlimb conductance at onset of exercise with control (saline) and experimental intervention (ganglionic blockade). Data were averaged over 1‐s intervals (except for time 0, which represents a 10‐s average of values obtained while dogs were resting on treadmill). There were no statistically significant differences in conductance responses between the two treatments at 5, 10, and 15 s of exercise. However, conductance values were significantly elevated with ganglionic blockade at 20, 25, and 30 s of exercise (P < 0.01). Reprinted with permission from Buckwalter and Clifford, 1999 ().


Figure 10. Original record showing a dog proceeding from rest to exercise at 6 mph. At 2 min into exercise, an intra‐arterial bolus of selective alpha1‐antagonist prazosin (0.1 mg) was given. Note the immediate increase in blood flow and conductance in experimental limb, with no changes in systemic blood pressure or blood flow and conductance in control limb. Reprinted with permission from Buckwalter et al., 1997 ().


Figure 11. A schematic illustration depicting the divergent responses in contracting and inactive skeletal muscle vasculature to increases in muscle sympathetic nerve activity during exercise. The increases in sympathetic outflow are evoked, in large part, via mechanically and metabolically sensitive muscle afferents (the Exercise Pressor Reflex) with further modulation provided via the arterial baroreflex. These intensity‐dependent increases in sympathetic nerve activity cause sympathetically mediated vasoconstriction in inactive muscle, whereas in active muscle there is an attenuation of this sympathetic vasoconstrictor activity. The latter, termed functional sympatholysis, may be attributed to increases in metabolites, muscle temperature, and possibly nitric oxide. This attenuation of sympathetic vasoconstriction in the contracting muscle allows for enhanced muscle blood flow to the metabolically active skeletal muscle. At the same time, the sympathetically mediated vasoconstriction in inactive muscle (and the viscera—not pictured) enhance the redistribution of cardiac output to the contracting skeletal muscles. Collectively, this illustrates the important contributions of the sympathetic nervous system to the matching of muscle blood flow to metabolic demand in exercising muscles.


Figure 12. Graphical illustration of the neural control of skin blood flow in humans. Human cutaneous vasculature is controlled by a sympathetic adrenergic vasoconstrictor limb and a separate sympathetic cholinergic vasodilator limb. Under cool conditions, the vasoconstrictor limb is engaged resulting in reductions in cutaneous vascular conductance and skin blood flow. When internal temperature is elevated, the active vasodilator system is engaged, mediating 85% to 95% of the increase in skin blood flow through increases in cutaneous vascular conductance. The arrow depicts the magnitude of the increases in the respective nerve activities during cooling (increases in sympathetic adrenergic nerve activity) and heating (increases in sympathetic cholinergic nerve activity). Substances within the indicated nerves are the neurotransmitters that have either been shown to, or are proposed to, contribute to the respective responses. NE, norepinephrine; NPY, neuropeptide Y; Ach, acetylcholine; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase‐activating peptide; nNO, neuronally derived nitric oxide. Illustration used by permission from Manabu Shibasaki, PhD, Nara Women's University.


Figure 13. Differences in cutaneous vasodilation, expressed as a percentage of preheat stress (i.e., Control) cutaneous vascular conductance, in a subject who was passively heat stressed (Rest—solid circles) and exercise heat stressed (exercise—open circles). Notice the rightward shift of the curve during exercise such that cutaneous vascular conductance is lower at any esophageal temperature during exercise. These finding show that the increase in skin blood flow during exercise‐induced heat stress is delayed relative to passive‐induced heat stress. Figure modified from Kellogg, Johnson, and Kosiba, 1991 () with permission.


Figure 14. This figure depicts the linear relationship between increases in cardiac output (Q) and forearm blood flow (FBF, panel A) as well as middle cerebral artery blood velocity (MCAVmean, panel B) at rest (solid circles) and during cycling exercise (EX, open circles). These data suggest that increases in cardiac output contribute to increases in forearm blood flow and brain blood flow during rest and exercise. Reprinted with permission from Ogoh et al., 2005 ().


Figure 15. Reductions in splanchnic blood flow (Y‐axis expressed in mL/min) during dynamic exercise in patients with mitral valve stenosis (MS), in normal sedentary young men (Sed), and endurance trained athletes (Ath). Data in the left panel are the same as in the right panel, except the right panel is normalized to % maximum oxygen update (%Max VO2). These data demonstrate that as a workload becomes more difficult (i.e., requires more oxygen) there are linear reductions in splanchnic blood flow. Reprinted with permission from Rowell, 1973 ().


Figure 16. Conceptual diagram of the spectrum of physical activity and proposed influence of positive and negative brain effects on cardiovascular health (positive = green; negative = red). In this context, long term decreases in sympathetic nervous system and increases in parasympathetic nervous system activity produced by an active lifestyle are beneficial as they promote lower resting blood pressures, protection from arrhythmias, and decreased cardiac demand. In contrast, long‐term increases in sympathetic nervous system and decreases in parasympathetic nervous system activity are viewed as detrimental as they are associated with hypertension, arrhythmias, and heart failure. The rapid rise in cardiovascular benefit produced by being physically active reflects epidemiological evidence from Blair and colleagues whose data indicate that the largest relative health benefit is derived in individuals moving from the lowest quintile (i.e., 1 of 5) of fitness category to only the second lowest quintile of cardiorespiratory fitness. The diagram also allows for shifts in the curve to the right or left due to genetics, preexisting conditions, or other factors that predispose or influence individuals to more positive (green block arrow) or negative (red block arrow) cardiovascular health.


Figure 17. Schematic diagram illustrating the role of important neural pathways involved in integration and generation of sympathetic vasoconstrictor outflow. Under healthy conditions, which include regular physical activity, all pathways actively regulate sympathetic outflow to the vasculature, particularly during bouts of exercise. At rest, the rostral ventrolateral medulla (RVLM) serves as the primary site of sympathetic outflow and its activity is limited by inhibitory inputs (dotted lines) from the caudal ventrolateral medulla (CVLM). The CVLM provides inhibition due to inputs driven in part by the nucleus tractus solitarius (NTS). Even at rest, the NTS is tonically active due to input from arterial baroreceptors but can also be influenced by inputs from contracting muscle during exercise. “Central command” neurons in higher centers of the brain initiate movement and influence pathways that alter sympathetic outflow via projections to PVN and NTS. Under sedentary conditions (red arrows and dotted circles), there is a lack of activation of pathways produced by regular bouts of exercise and likely produces alterations in neuronal function, that is, neuroplasticity, which result in increased sympathetic outflow to the vasculature. Modified from Mueller, 2010 () with permission.


Figure 18. Schematic diagram illustrating the role of important neural pathways involved in the integration and generation of sympathetic and parasympathetic outflow to the heart. As with control of tonic sympathetic vasoconstrictor activity, physically active conditions result in all pathways actively regulating sympathetic outflow to the heart, particularly during periodic bouts of exercise. At rest, the nucleus ambiguus (NA), and in some species, the dorsal motor nucleus of the vagus (DMV), serve as the primary site(s) of parasympathetic outflow to the heart. Activity of the NA and DMV are driven by excitatory inputs (solid lines, plus signs) from nucleus tractus solitarius (NTS). Even at rest, the NTS is tonically active due to input from arterial baroreceptors and maintains ongoing parasympathetic nerve activity (PNA, i.e., vagal tone) to suppress baseline heart rate (HR) well below its intrinsic rate. Brain regions controlling sympathetic nerve activity (SNA) to the heart appear more complex (some not shown) but are least active at rest and typically only become active after PNA withdrawal during exercise. Under sedentary conditions (red arrows and dotted circles), there is a lack of activation of pathways produced by regular bouts of exercise and likely produces alterations in neuronal function, that is, neuroplasticity, which result in decreased PNA and increased SNA to the heart, raising resting HR. Changes in contractility may depend on whether increased SNA produces compensatory increases or over time induces decreases as a result of heart failure. Modified from Mueller, 2010 () with permission.
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Teaching Material

P. J. Mueller, P. S. Clifford, C. G. Crandall, S. A. Smith, P. J. Fadel. Integration of Central and Peripheral Regulation of the Circulation during Exercise: Acute and Chronic Adaptations. Compr Physiol. 8: 2018, 103-151.

Didactic Synopsis

Major Teaching Points:

This article presents specific topics related to control of the cardiovascular system during exercise intended for graduate or advanced undergraduate students:

  • During exercise, increased oxygen demand of contracting muscle is matched by increases in blood flow coordinated by central and peripheral nervous systems.
  • Central command activates neural pathways that initiate movement and the cardiovascular and respiratory pathways to support increased oxygen requirements of exercise.
  • After exercise starts, the brain uses peripheral sensory mechanisms to maintain appropriate oxygen delivery: (i) exercise pressor reflex (detects changes in muscle activity and subsequent byproducts); (ii) arterial baroreflex (detects changes in blood pressure); and (iii) cardiopulmonary reflex (detects changes in central blood volume).
  • Repeated bouts of exercise over time are associated with altered neural pathways (neuroplasticity), influencing the cardiovascular system both at rest and during exercise.
  • Inactivity- and exercise-related neuroplasticity may predispose sedentary individuals to higher incidences of cardiovascular disease and physically active individuals to improved cardiovascular health.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. This figure illustrates two points:

(1) There is an increase in sympathetic nerve activity during exercise compared to rest.

(2) There is a progressive increase in sympathetic nerve activity with increasing exercise intensity.

Figure 2. This schematic presents the key neural mechanisms responsible for mediating the exercise intensity-dependent modulation of the autonomic nervous system (i.e., sympathetic and parasympathetic nerve activity) that occurs during exercise. These autonomic adjustments lead to cardiac and vascular changes that modulate blood pressure and facilitate the increases in blood flow needed to support exercising muscle.

Figure 3. The findings presented from this study demonstrate that passive stretch of the triceps surae muscle in healthy humans evokes increases in heart rate without effecting blood pressure. These date suggest that mechanically sensitive muscle afferents of the exercise pressor reflex may contribute to the increase in heart rate in response to muscle contraction.

Figure 4. These findings show that inhibition of mechano-gated Piezo channels reduced the blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to tendon stretch in decerebrate rats indicating a role for these channels in evoking the cardiovascular responses to activation of the mechanically sensitive muscle afferents of the exercise pressor reflex.

Figure 5. This schematic shows the intensity-dependent resetting of the carotid baroreflex during dynamic exercise from rest to heavy exercise, which allows the baroreflex to maintain control of blood pressure throughout a given bout of exercise.

Figure 6. This figure demonstrates evidence of Central Command in which the brain is capable of initiating movement and changes in blood flow to support the increases in metabolism associated with movement (i.e., muscle contraction). In this example from Williamson and colleagues (698), individuals who were not as easily hypnotized did not have an increase in brain activation (A, left) or increase in heart rate (A, right) during imagined exercise compared to real exercise. In contrast, individuals that could be more easily hypnotized, reported greater perceived effort, similar brain activation (B, left), and increases in heart rate (B, right) during imagined exercise compared to real exercise. Thus, the brain can increase heart rate when it perceives it is performing exercise even when muscular work is not actually being performed. These experiments in particular suggest that the insular and anterior cingulate cortexes play key roles in the brain's control of the cardiovascular system during exercise.

Figure 7. This conceptual framework depicts potential interactions within the central nervous system that allow for the resetting of the arterial baroreflex function curve during exercise to permit a maintained baroreflex control in the face of exercise-induced elevations in blood pressure (BP), heart rate (HR), and sympathetic nerve activity (SNA).

Figure 8. This schematic diagram shows:

(1) There are postsynaptic alpha1 and alpha2 adrenergic, beta2 adrenergic, P2X, and NPY Y1 receptors on the smooth muscle of arterioles in skeletal muscle.

(2) There are postsynaptic muscarinic and P2Y receptors on the endothelial lining of arterioles in skeletal muscle.

(3) Sympathetic signaling to the vasculature can be interrupted by blocking binding of the neurotransmitter to its postsynaptic receptor.

Figure 9. Vascular conductance is a measure of global vessel diameter that accounts for changes in arterial pressure. This figure shows that the initial vasodilation in skeletal muscle during dynamic exercise is independent of the autonomic nervous system.

Figure 10. This figure compares the effect of administering a selective blocker of alpha1 adrenergic receptors, prazosin, to one hindlimb of an exercising dog with the other hindlimb, which received no treatment. The immediate increase in blood flow and vascular conductance in the experimental limb demonstrates that there is tonic activation of alpha1 adrenergic receptors during exercise.

Figure 11. This schematic illustration shows the divergent responses that occur in contracting and inactive skeletal muscle vasculature to increases in muscle sympathetic nerve activity during exercise. The increases in sympathetic outflow are evoked, in large part, via mechanically and metabolically sensitive muscle afferents (the Exercise Pressor Reflex) with further modulation provided by the arterial baroreflex. These intensity-dependent increases in sympathetic nerve activity cause sympathetically mediated vasoconstriction in inactive muscle, whereas in active muscle there is an attenuation of this sympathetic vasoconstrictor activity. This attenuation of sympathetic vasoconstriction in the contracting muscle has been termed functional sympatholysis, which allows for enhanced muscle blood flow to the metabolically active skeletal muscle. At the same time, the sympathetically mediated vasoconstriction in inactive muscle (and the viscera—not pictured) enhances the redistribution of cardiac output to the contracting skeletal muscles.

Figure 12. An illustration of how the brain controls two separate systems that modulate skin blood flow, along with the chemical transmitters known to contribute to those responses. During cooling, skin blood flow decreases due to activation of the vasoconstrictor system. During heating, skin blood flow increases due to activation of the vasodilator system. The chemical transmitters are as follows: NE, norepinephrine; NPY, neuropeptide Y; Ach, acetylcholine; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase-activating peptide; nNO, neuronally derived nitric oxide. Illustration used by permission from Manabu Shibasaki, PhD, Nara Women's University.

Figure 13. An illustration of the relationship between internal temperature (esophageal temperature) and the elevation in skin blood flow (expressed as cutaneous vascular conductance), during passive heat stress (rest—closed circles) and exercise-induced heat stress (open circles). These finding show that the increase in skin blood flow during exercise-induced heat stress is delayed relative to passive-induced heat stress. Figure modified from Kellogg, Johnson, and Kosiba, 1991 (280) with permission.

Figure 14. An illustration of the relationship between increases in cardiac output (Q) and corresponding changes in forearm blood flow (FBF—panel A) and brain blood flow (MCAVmean—panel B) in resting and exercising subjects. These data suggest that increases in cardiac output contribute to increases in forearm blood flow and brain blood flow during rest and exercise. Reprinted with permission from Ogoh et al., 2005 (465).

Figure 15. An illustration of the relationship between splanchnic blood flow on the Y-axis and oxygen utilization, expressed in absolute units (VO2) and relative to maximum oxygen utilization (% Max VO2) in diseased patients (MS), in nonfit subjects (Sed), and in trained athletes (Ath) on splanchnic blood flow. These data demonstrate that as a workload becomes more difficult (i.e., requires more oxygen), there are linear reductions in splanchnic blood flow. Reprinted with permission from Rowell, 1973 (533).

Figure 16. Conceptual diagram of the spectrum of physical activity and proposed influence of positive and negative brain effects on cardiovascular health.

Figure 17. Schematic diagram illustrating the role of important neural pathways involved in integration and generation of sympathetic vasoconstrictor outflow.

Figure 18. Schematic diagram illustrating the role of important neural pathways involved in the integration and generation of sympathetic and parasympathetic outflow to the heart.

 


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Patrick J. Mueller, Philip S. Clifford, Craig G. Crandall, Scott A. Smith, Paul J. Fadel . Integration of Central and Peripheral Regulation of the Circulation during Exercise: Acute and Chronic Adaptations. Compr Physiol 2017, 8: 103-151. doi: 10.1002/cphy.c160040