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Blood Pressure: Baroreceptors
Blood Pressure: Baroreceptors 259
Blood Pressure: Baroreceptors A F Sved, University of Pittsburgh, Pittsburgh, PA, USA ã 2009 Elsevier Ltd. All rights reserved.
Introduction For normal functioning of the cardiovascular system it is essential that arterial blood pressure (ABP) be highly regulated within the normal range. Usually, ABP is tightly regulated, and fluctuations in ABP on a minuteto-minute or hour-to-hour time frame are minimal. As with most homeostatic systems, the key parameter, in this case ABP, is controlled, at least in large part, by a powerful negative feedback reflex. The arterial baroreceptor reflex, the major negative feedback reflex controlling ABP, is composed of afferent nerves sensitive to changes in ABP that convey information to the central nervous system (CNS), outputs of the CNS that can impact ABP, and the central neural pathways connecting these inputs and outputs. This article describes the afferent limb of this reflex, the efferent components, and then the central neural systems connecting the inputs and outputs and providing a complex neural circuitry for the integration of these reflexes with the physiological status of the organism.
Arterial Baroreceptors The afferent component of the baroreceptor reflex is composed of pressure-sensitive receptors associated with two major blood vessels, the aortic arch and the carotid sinus, and their projections into the CNS. The blood pressures in these two major arteries are arguably the most critical to the organism, because they represent, respectively, whole-body perfusion pressure and perfusion pressure of the brain. The afferents from the aortic arch form the aortic depressor nerve, which joins with the vagus nerve in the neck. The cell bodies of these afferents, as well as other vagal afferent fibers, are present in the nodose ganglion. The baroreceptor afferents from the carotid sinus, along with chemosensitive afferents from this region, form the carotid sinus nerve, which joins with the glossopharyngeal nerve. The cell bodies of these afferents, as well as other glossopharyngeal afferents, are present in the petrosal ganglion. These baroreceptor afferents all project into the CNS and terminate in the dorsal medial medulla in a distinct region of the nucleus tractus solitarius (NTS). A few studies have suggested the presence of arterial baroreceptors in the coronary circulation, but if they exist they do not have the profound influence on
cardiovascular regulation that can be readily shown for the aortic and carotid baroreceptors. Arterial baroreceptors are stretch receptors that are activated (and therefore fire more action potentials) when ABP increases and distends the blood vessel wall (Figure 1). As with stretch receptors in other tissues, the response of these afferents adapts to prolonged stretch; in the case of baroreceptors, this adaptation, or resetting, begins to occur within minutes of a sustained change in blood pressure (Figure 1(b)). Thus, baroreceptor afferent firing codes acute changes in pressure rather than a specific pressure. It is important to keep in mind that ABP is a pulsatile parameter, and baroreceptor afferent activity follows this pressure wave and provides the brain with a dynamic and pulsating signal. In addition to being directly sensitive to changes in pressure, various local and circulating factors (e.g., endothelin, prostacyclins) also influence the firing rates of baroreceptor afferent nerves (Figure 1(c)). Thus, while changes in ABP clearly influence the baroreceptor signal provided to the brain, this signal cannot be considered as solely reflecting ABP or providing an accurate high-fidelity signal of absolute ABP. Rather, baroreceptor afferent activity might be considered as coding changes in ABP, but in a manner that is influenced by other factors as well. This issue is important when considering the role of the baroreceptor reflex in the long-term regulation of arterial pressure. In recent years, studies have begun to address the role of specific ion channels involved in barosensitivity of the baroreceptors. Most of this research has focused on the degerin/epithelial Naþ channel (Deg/ENaC) family of ion channels, and the current data suggest that this family of channels is responsible for the key mechanoelectrical transduction events (Figure 1(a)). Deg/ENaC subunits are expressed by barosensitive neurons, and the mechanosensitivity of these neurons is inhibited by the Deg/ENaC blocker, amiloride. Recent data in knockout mice also suggest a role of Deg/ENaC subunits, primarily 1 and 2, in barosensitivity. However, the Deg/ENaC family does not comprise the only channel types at the baroreceptive endings that are involved in baroreceptor activity. Transient receptor potential (TRP) channels have also been suggested to be part of the sensory transduction process, but they are likely involved more as modulators of the primary barosensitive channels. Although TRP channels impart mechanosensitivity in certain other systems, this does not appear to be the case for arterial baroreceptors.
260 Blood Pressure: Baroreceptors
Artery
Nodose or petrosal ganglion
Baroreceptor ending Action potential trigger zone
ABP Other channels and receptors
Deg/ENaC
Aortic depressor or carotid sinus nerve
To NTS
b
Adapted to low pressure
Adapted to high pressure
~75 mmHg Normal resting ~125 mmHg ~100 mmHg Aortic arch or carotid sinus pressure
CSN activity % of control maximum
Baroreceptor afferent firing rate
a
150
+ PGI2 100 + Pla
50
75
c
100
125
Carotid sinus pressure (mmHg)
Figure 1 Schematic of a baroreceptor afferent neuron (a), showing the mechanosensitive channels (Deg/ENaC, degerin/epithelial Naþ channel) on the endings at the blood vessel (ABP, arterial blood pressure), the generation of action potentials at the action potential trigger zone, and the transmission into the nucleus tractus solitarius (NTS). The firing rate of baroreceptor afferent nerves is increased with increasing blood pressure, but this relationship is modified by adaptation to higher or lower pressures (b) or response to chemical agents such as prostaglandin I2 (PGI2) or platelets (Pla) (c). (b) Adapted from Munch PA, Andresen MC, and Brown AM (1983) Rapid resetting of aortic baroreceptors in vitro. American Journal of Physiology 244: H672–H680. (c) Based on Chapleau MW, Cunningham JT, Sullivan MJ, et al. (1995) Structural versus functional modulation of the arterial baroreflex. Hypertension 26: 341–347.
Depolarization of baroreceptor endings resulting from stretch, and modified by a variety of other influences, results in the generation of action potentials carried along the axons of these pseudounipolar neurons that ultimately project to the NTS.
Effector Systems of Arterial Baroreceptor Reflexes The term ‘arterial baroreceptor reflex’ is used to refer to a variety of physiological responses elicited by
Blood Pressure: Baroreceptors 261 Arterial blood pressure; vascular resistance Heart rate and contractility Renin−Angiotensin system Baroreceptor input
Renal function
Central nervous system
Vasopressin secretion Oxytocin secretion ACTH secretion Drinking
Figure 2 Baroreceptor reflex effector systems. Changes in baroreceptor afferent activity reflexively influence many outputs of the brain relevant to cardiovascular regulation. ACTH, adrenocorticotropic hormone.
changes in baroreceptor afferent activity. While the baroreceptor reflex is often used in specific reference to the reflexive change in ABP and heart rate brought about by changing autonomic outflow to the heart and vasculature, there are a large number of physiological responses resulting from changes in baroreceptor afferent input, and they would each appropriately be termed a baroreceptor reflex. For example, decreases in ABP sensed by arterial baroreceptors elicit an increase in vasopressin (antidiuretic hormone) secretion from the posterior pituitary and an increase in thirst (as reflected by increased fluid ingestion). Thus, baroreceptor reflexes can be viewed as having autonomic, endocrine, and behavioral effectors, all of which interact to promote cardiovascular homeostasis (Figure 2). At the core of baroreceptor reflexes are the changes in sympathetic outflow, directed at the vasculature and the heart, and in parasympathetic (vagal) outflow, directed at the heart. Changes in baroreceptor afferent activity evoke reflexive changes in autonomic activity to the heart and sympathetic activity to many (but not all) vascular beds. Baroreceptor reflex control of autonomic activity to the heart provides a rapid means of adjusting cardiac output to match ABP. Imposed increases in ABP, detected by arterial baroreceptors, reflexively decrease heart rate (and cardiac output) by increasing parasympathetic activity and decreasing sympathetic activity. Conversely, decreases in ABP elicit the opposite responses (Figure 3). However, these two directions of responses should not be considered simply symmetrical responses. Rather, the decrease in cardiac output elicited by increased ABP is more related to increased parasympathetic activity, whereas the increase in cardiac output elicited by decreased ABP is more related to an increase in sympathetic activity, at least in some species. For example, in rats, the bradycardia caused by acute increases in
ABP can be largely blocked by drugs that interfere with the parasympathetic nervous system. Changes in baroreceptor afferent activity markedly alter sympathetic nerve activity directed toward certain vascular beds, particularly those impacting total peripheral resistance. Thus, whereas baroreceptors readily influence sympathetic activity directed toward renal, mesenteric, splanchnic, and muscle vascular beds, they have limited impact on the cutaneous or cerebral circulations. Increased baroreceptor afferent activity can powerfully inhibit sympathetic vasomotor outflow, whereas decreased baroreceptor afferent activity powerfully excites it. While these influences of baroreceptor activity on autonomic outflow directed to the heart and blood vessels might be at the core of baroreceptor reflex responses, several other baroreceptor-evoked responses also contribute to cardiovascular homeostasis (Figure 2). Several of these responses are considered here to illustrate specific points. One of the most powerful regulators of renin secretion from the juxtaglomerular cells of the kidney is the sympathetic innervation of these cells, and this sympathetic innervation is controlled in large part by baroreceptor input. Thus, decreases in ABP result in decreased arterial baroreceptor input to brain and in turn result in increases in sympathetic stimulation of the juxtaglomerular cells and increased renin secretion. The resulting generation of angiotensin II produces a variety of physiological effects, ranging from increased constriction of blood vessels to increased sodium reabsorption by the kidneys and increased fluid intake. Thus, arterial baroreceptors, by influencing renal renin secretion, have a wide influence on systemic physiology. Arterial baroreceptors also influence secretion of posterior pituitary hormones. Decreased ABP sensed by
Increasing
262 Blood Pressure: Baroreceptors
SNS
Vasoconstriction
Baroreceptor afferent activity Resting Decreasing
HR, CO PNS
SNS
Vasoconstriction HR, CO
PNS
Decreasing
Increasing Resting Arterial blood pressure
Figure 3 Relationship between arterial blood pressure, baroreceptor afferent activity, and cardiovascular autonomic outflow. SNS, sympathetic nervous system; PNS, peripheral nervous system; HR, heart rate; CO, cardiac output.
arterial baroreceptors increases vasopressin secretion from the posterior pituitary, with readily understandable influences on cardiovascular homeostasis: increased fluid retention by the kidneys and increased arterial vasoconstriction. Increases in ABP momentarily inhibit the activity of vasopressin-secreting cells (a response that has been used as a defining characteristic of magnocellular vasopressin neurons), but this effect does not appear to be sustained long enough to have any physiological impact. Arterial hypotension also causes secretion of the other major posterior pituitary hormone, oxytocin. While the physiological significance of hypotension-evoked oxytocin secretion is not clear, recent studies indicate that this hormone promotes renin secretion from the kidney, at least in rats. In contrast to vasopressin-secreting cells, increases in ABP appear to have no effect on oxytocin-secreting cells. Changes in ABP, sensed by arterial baroreceptors, influence drinking behavior. Decreases in ABP stimulate fluid intake, an effect that appears to be mediated entirely via arterial baroreceptor-evoked renin secretion with the resulting increase in blood levels of angiotensin II acting on the brain to stimulate drinking. In contrast, increases in ABP inhibit drinking behavior and this effect appears to be mediated by baroreceptorstimulated neuronal pathways in the brain. In summary, changes in the afferent activity of arterial baroreceptors reflexively elicit a variety of autonomic, endocrine, and behavioral responses included in cardiovascular homeostasis. While many of these responses occur in opposite fashion to increases and decreases in ABP, the mechanisms responsible for these different effects might be quite distinct.
Central Pathways and Processing Input to the central nervous system from arterial baroreceptors is through the NTS in the dorsomedial medulla. Within the NTS, baroreceptor afferents synapse with second-order sensory neurons, and at this stage the information begins to get integrated and relayed. The baroreceptor afferents are excitatory to the second-order neurons, likely using glutamate as the primary neurotransmitter. Neural transmission at this initial synapse can be blocked by glutamate receptor antagonists, as can baroreceptor reflexes when such drugs are applied to the NTS. The neural pathways subserving baroreceptor reflex control of parasympathetic and sympathetic responses have been well studied and this circuitry is well established (Figure 4). Neurons in the NTS, likely the second-order sensory neurons, innervate parasympathetic cardiac preganglionic neurons, most of which are present in the nucleus ambiguus. The synapse between the second-order sensory neuron and the parasympathetic preganglionic neuron is excitatory and likely to use glutamate as a neurotransmitter. The baroreceptor reflex circuitry linking the NTS with the sympathetic preganglionic neurons in the intermediolateral cell column in the thoracolumbar spinal cord is somewhat more complex and necessarily involves an inhibitory interneuron, because increases in baroreceptor input decrease sympathetic activity. Barosensitive glutamatergic NTS neurons, at least some of which are second-order sensory neurons, innervate neurons in the caudal ventrolateral medulla (CVLM) and excite g-aminobutyric acid (GABA)ergic
Blood Pressure: Baroreceptors 263
CNS
(+) Baroreceptor afferents
(+)
Cardiac vagal preganglionic neurons
Heart
NTS (+)
CVLM
(−)
RVLM
(+) Sympathetic preganglionic neurons
Heart and blood vessels Figure 4 Central nervous system baroreceptor pathway linking baroreceptor afferents to sympathetic and parasympathetic outflow. Plus (þ) and minus () symbols refer to excitatory synapses and inhibitory synapses, respectively.
neurons in this region. The GABAergic CVLM neurons innervate sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) that innervate sympathetic vasomotor preganglionic neurons in the spinal cord. Thus, activation of baroreceptor afferents inhibits sympathetic vasomotor outflow by a pathway involving an excitatory projection from NTS to CVLM, an inhibitory projection from CVLM to RVLM, and an excitatory projection from RVLM to sympathetic preganglionic neurons. Available evidence supports glutamate being the primary neurotransmitter at each of the excitatory synapses in this reflex pathway and GABA being the neurotransmitter at the inhibitory link from CVLM to RVLM. At each of the sites in this pathway, inputs from other brain regions have the capacity to modify baroreceptor reflex responses, and most brain-evoked responses that influence cardiovascular function have some influence on baroreceptor reflex processing. Central nervous system pathways mediating other baroreceptor-evoked responses are less well characterized. Hypotension-evoked secretion of vasopressin from the posterior pituitary gland involves activation of the magnocellular vasopressin neurons of the paraventricular and supraoptic hypothalamic nuclei, likely by a pathway involving the ventrolateral medulla. Presumably hypotension-evoked excitation of magnocellular oxytocin neurons is via similar pathways, but this has not been extensively studied. The inhibition of vasopressin neurons by acute increases in ABP is mediated by distinctly different pathways from the NTS to hypothalamus (again illustrating
the asymmetry between responses evoked by activating vs. unloading of baroreceptors). As for the central neural pathways involved in baroreceptor-mediated influences on drinking, hypotension-evoked drinking involves activation of the sympathetic innervation of the kidney juxtaglomerular cells, with the resulting generation of angiotensin II. This angiotensin II then acts on neurons in the subfornical organ, a forebrain region lacking a blood–brain barrier, to activate brain circuits involved in drinking. In contrast, increases in ABP inhibit drinking via central neural pathways from the NTS that have not been studied in any detail. The extensive nature of central baroreceptor reflex circuits is readily demonstrated by studies showing numerous brain regions expressing immediate-early genes such as c-fos in response to arterial baroreceptor activation or unloading. All of the regions directly involved in the aforementioned baroreceptor responses express immediate-early genes under conditions in which they would be expected to be activated by baroreceptor manipulations, but many other regions, presumably involved in higher order integration of baroreceptor responses, also express immediateearly genes in these studies.
Role of Arterial Baroreceptors in Cardiovascular Regulation Arterial baroreceptors provide a dynamic signal to the brain regarding changes in ABP and elicit reflex responses to maintain ABP within a narrow range.
264 Blood Pressure: Baroreceptors
Baroreceptor reflexes are essential for normal cardiovascular homeostasis and stabilize ABP at normal levels on a rapid time frame. Studying the impact of destruction of arterial baroreceptors on cardiovascular regulation has provided useful information on their function. Elimination of baroreceptor signals carried in the aortic depressor nerve and carotid sinus nerve results in a rapid increase in ABP and heart rate, reflecting the marked decrease in baroreceptor afferent signal to brain. Over the course of several days, ABP returns to a normal average level, but the variability around this normal average is markedly increased. A conclusion that can be drawn from such observations is that arterial baroreceptor reflexes are not critical for the maintenance of a normal average level of ABP, but they are essential for stabilizing ABP. These results from baroreceptor-denervated animals have also been used to support the notion that baroreceptor reflexes are not important in the long-term control of blood pressure, but this conclusion has been challenged by more recent studies showing that chronic stimulation of arterial baroreceptor afferents can have a sustained influence on ABP.
Cardiopulmonary Baroreceptors In addition to the baroreceptors positioned to sense ABP, there are also baroreceptors in the atria, and veins leading to them, referred to as cardiopulmonary baroreceptors. These baroreceptors sense stretch in the atria, which, because of the distensible nature of the atria, and veins leading to them, reflects blood volume. Thus, hypovolemia decreases stretch on these receptors and this leads reflexively to a number of responses aimed at restoring blood volume. Responses initiated by unloading cardiopulmonary baroreceptors include increased vasopressin secretion, increased renin secretion, and increased thirst. Nonhypotensive hypovolemia, as can be caused by moderate hemorrhage or removal of isotonic plasma volume by various experimental procedures, elicits each of these responses. As noted previously, each of
these responses is also characteristic of hypotension in the absence of hypovolemia, but the response to unloading of arterial and cardiopulmonary baroreceptors at the same time, as might be produced by hypotensive hemorrhage, is much greater than are responses produced by either stimulus in isolation. See also: Autonomic Disorders; Autonomic Failure; Autonomic Nervous System: Cardiovascular Control; Autonomic Nervous System: Central Cardiovascular Control; Autonomic Nervous System; Cardiovascular Function: Central Nervous System Control; Circumventricular Organs; Energy Homeostasis: Visceral Control; Heart Rate Variability: A Neurovisceral Integration Model; Parasympathetic Nervous System; Pituitary Gland (Cell Types, Mediators, Development); Sympathetic Nervous System; Vasopressin/Oxytocin and Receptors.
Further Reading Chapleau MW, Cunningham JT, Sullivan MJ, et al. (1995) Structural versus functional modulation of the arterial baroreflex. Hypertension 26: 341–347. Chapleau MW, Li Z, Meyrelles SS, et al. (2001) Mechanisms determining sensitivity of baroreceptor afferents in health and disease. Annals of the New York Academy of Sciences 940: 1–19. Dampney RA, Polson JW, Potts PD, et al. (2003) Functional organization of brain pathways subserving the baroreceptor reflex: Studies in conscious animals using immediate early gene expression. Cellular and Molecular Neurobiology 23: 597–616. Guyenet PG (2006) The sympathetic control of blood pressure. Nature Reviews Neuroscience 7: 335–346. Lohmeier TE, Hildebrandt DA, Warren S, et al. (2005) Recent insights into the interactions between the baroreflex and the kidneys in hypertension. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 288: R828–R836. Munch PA, Andresen MC, and Brown AM (1983) Rapid resetting of aortic baroreceptors in vitro. American Journal of Physiology 244: H672–H680. Stricker EM and Sved AF (2002) Controls of vasopressin secretion and thirst: Similarities and dissimilarities in signals. Physiology & Behavior 77: 731–736. Sved AF, Ito S, Madden CJ, et al. (2001) Excitatory inputs to the RVLM in the context of the baroreceptor reflex. Annals of the New York Academy of Sciences 940: 247–258.
Blood Pressure: Baroreceptors A F Sved, University of Pittsburgh, Pittsburgh, PA, USA ã 2009 Elsevier Ltd. All rights reserved.
Introduction For normal functioning of the cardiovascular system it is essential that arterial blood pressure (ABP) be highly regulated within the normal range. Usually, ABP is tightly regulated, and fluctuations in ABP on a minuteto-minute or hour-to-hour time frame are minimal. As with most homeostatic systems, the key parameter, in this case ABP, is controlled, at least in large part, by a powerful negative feedback reflex. The arterial baroreceptor reflex, the major negative feedback reflex controlling ABP, is composed of afferent nerves sensitive to changes in ABP that convey information to the central nervous system (CNS), outputs of the CNS that can impact ABP, and the central neural pathways connecting these inputs and outputs. This article describes the afferent limb of this reflex, the efferent components, and then the central neural systems connecting the inputs and outputs and providing a complex neural circuitry for the integration of these reflexes with the physiological status of the organism.
Arterial Baroreceptors The afferent component of the baroreceptor reflex is composed of pressure-sensitive receptors associated with two major blood vessels, the aortic arch and the carotid sinus, and their projections into the CNS. The blood pressures in these two major arteries are arguably the most critical to the organism, because they represent, respectively, whole-body perfusion pressure and perfusion pressure of the brain. The afferents from the aortic arch form the aortic depressor nerve, which joins with the vagus nerve in the neck. The cell bodies of these afferents, as well as other vagal afferent fibers, are present in the nodose ganglion. The baroreceptor afferents from the carotid sinus, along with chemosensitive afferents from this region, form the carotid sinus nerve, which joins with the glossopharyngeal nerve. The cell bodies of these afferents, as well as other glossopharyngeal afferents, are present in the petrosal ganglion. These baroreceptor afferents all project into the CNS and terminate in the dorsal medial medulla in a distinct region of the nucleus tractus solitarius (NTS). A few studies have suggested the presence of arterial baroreceptors in the coronary circulation, but if they exist they do not have the profound influence on
cardiovascular regulation that can be readily shown for the aortic and carotid baroreceptors. Arterial baroreceptors are stretch receptors that are activated (and therefore fire more action potentials) when ABP increases and distends the blood vessel wall (Figure 1). As with stretch receptors in other tissues, the response of these afferents adapts to prolonged stretch; in the case of baroreceptors, this adaptation, or resetting, begins to occur within minutes of a sustained change in blood pressure (Figure 1(b)). Thus, baroreceptor afferent firing codes acute changes in pressure rather than a specific pressure. It is important to keep in mind that ABP is a pulsatile parameter, and baroreceptor afferent activity follows this pressure wave and provides the brain with a dynamic and pulsating signal. In addition to being directly sensitive to changes in pressure, various local and circulating factors (e.g., endothelin, prostacyclins) also influence the firing rates of baroreceptor afferent nerves (Figure 1(c)). Thus, while changes in ABP clearly influence the baroreceptor signal provided to the brain, this signal cannot be considered as solely reflecting ABP or providing an accurate high-fidelity signal of absolute ABP. Rather, baroreceptor afferent activity might be considered as coding changes in ABP, but in a manner that is influenced by other factors as well. This issue is important when considering the role of the baroreceptor reflex in the long-term regulation of arterial pressure. In recent years, studies have begun to address the role of specific ion channels involved in barosensitivity of the baroreceptors. Most of this research has focused on the degerin/epithelial Naþ channel (Deg/ENaC) family of ion channels, and the current data suggest that this family of channels is responsible for the key mechanoelectrical transduction events (Figure 1(a)). Deg/ENaC subunits are expressed by barosensitive neurons, and the mechanosensitivity of these neurons is inhibited by the Deg/ENaC blocker, amiloride. Recent data in knockout mice also suggest a role of Deg/ENaC subunits, primarily 1 and 2, in barosensitivity. However, the Deg/ENaC family does not comprise the only channel types at the baroreceptive endings that are involved in baroreceptor activity. Transient receptor potential (TRP) channels have also been suggested to be part of the sensory transduction process, but they are likely involved more as modulators of the primary barosensitive channels. Although TRP channels impart mechanosensitivity in certain other systems, this does not appear to be the case for arterial baroreceptors.
260 Blood Pressure: Baroreceptors
Artery
Nodose or petrosal ganglion
Baroreceptor ending Action potential trigger zone
ABP Other channels and receptors
Deg/ENaC
Aortic depressor or carotid sinus nerve
To NTS
b
Adapted to low pressure
Adapted to high pressure
~75 mmHg Normal resting ~125 mmHg ~100 mmHg Aortic arch or carotid sinus pressure
CSN activity % of control maximum
Baroreceptor afferent firing rate
a
150
+ PGI2 100 + Pla
50
75
c
100
125
Carotid sinus pressure (mmHg)
Figure 1 Schematic of a baroreceptor afferent neuron (a), showing the mechanosensitive channels (Deg/ENaC, degerin/epithelial Naþ channel) on the endings at the blood vessel (ABP, arterial blood pressure), the generation of action potentials at the action potential trigger zone, and the transmission into the nucleus tractus solitarius (NTS). The firing rate of baroreceptor afferent nerves is increased with increasing blood pressure, but this relationship is modified by adaptation to higher or lower pressures (b) or response to chemical agents such as prostaglandin I2 (PGI2) or platelets (Pla) (c). (b) Adapted from Munch PA, Andresen MC, and Brown AM (1983) Rapid resetting of aortic baroreceptors in vitro. American Journal of Physiology 244: H672–H680. (c) Based on Chapleau MW, Cunningham JT, Sullivan MJ, et al. (1995) Structural versus functional modulation of the arterial baroreflex. Hypertension 26: 341–347.
Depolarization of baroreceptor endings resulting from stretch, and modified by a variety of other influences, results in the generation of action potentials carried along the axons of these pseudounipolar neurons that ultimately project to the NTS.
Effector Systems of Arterial Baroreceptor Reflexes The term ‘arterial baroreceptor reflex’ is used to refer to a variety of physiological responses elicited by
Blood Pressure: Baroreceptors 261 Arterial blood pressure; vascular resistance Heart rate and contractility Renin−Angiotensin system Baroreceptor input
Renal function
Central nervous system
Vasopressin secretion Oxytocin secretion ACTH secretion Drinking
Figure 2 Baroreceptor reflex effector systems. Changes in baroreceptor afferent activity reflexively influence many outputs of the brain relevant to cardiovascular regulation. ACTH, adrenocorticotropic hormone.
changes in baroreceptor afferent activity. While the baroreceptor reflex is often used in specific reference to the reflexive change in ABP and heart rate brought about by changing autonomic outflow to the heart and vasculature, there are a large number of physiological responses resulting from changes in baroreceptor afferent input, and they would each appropriately be termed a baroreceptor reflex. For example, decreases in ABP sensed by arterial baroreceptors elicit an increase in vasopressin (antidiuretic hormone) secretion from the posterior pituitary and an increase in thirst (as reflected by increased fluid ingestion). Thus, baroreceptor reflexes can be viewed as having autonomic, endocrine, and behavioral effectors, all of which interact to promote cardiovascular homeostasis (Figure 2). At the core of baroreceptor reflexes are the changes in sympathetic outflow, directed at the vasculature and the heart, and in parasympathetic (vagal) outflow, directed at the heart. Changes in baroreceptor afferent activity evoke reflexive changes in autonomic activity to the heart and sympathetic activity to many (but not all) vascular beds. Baroreceptor reflex control of autonomic activity to the heart provides a rapid means of adjusting cardiac output to match ABP. Imposed increases in ABP, detected by arterial baroreceptors, reflexively decrease heart rate (and cardiac output) by increasing parasympathetic activity and decreasing sympathetic activity. Conversely, decreases in ABP elicit the opposite responses (Figure 3). However, these two directions of responses should not be considered simply symmetrical responses. Rather, the decrease in cardiac output elicited by increased ABP is more related to increased parasympathetic activity, whereas the increase in cardiac output elicited by decreased ABP is more related to an increase in sympathetic activity, at least in some species. For example, in rats, the bradycardia caused by acute increases in
ABP can be largely blocked by drugs that interfere with the parasympathetic nervous system. Changes in baroreceptor afferent activity markedly alter sympathetic nerve activity directed toward certain vascular beds, particularly those impacting total peripheral resistance. Thus, whereas baroreceptors readily influence sympathetic activity directed toward renal, mesenteric, splanchnic, and muscle vascular beds, they have limited impact on the cutaneous or cerebral circulations. Increased baroreceptor afferent activity can powerfully inhibit sympathetic vasomotor outflow, whereas decreased baroreceptor afferent activity powerfully excites it. While these influences of baroreceptor activity on autonomic outflow directed to the heart and blood vessels might be at the core of baroreceptor reflex responses, several other baroreceptor-evoked responses also contribute to cardiovascular homeostasis (Figure 2). Several of these responses are considered here to illustrate specific points. One of the most powerful regulators of renin secretion from the juxtaglomerular cells of the kidney is the sympathetic innervation of these cells, and this sympathetic innervation is controlled in large part by baroreceptor input. Thus, decreases in ABP result in decreased arterial baroreceptor input to brain and in turn result in increases in sympathetic stimulation of the juxtaglomerular cells and increased renin secretion. The resulting generation of angiotensin II produces a variety of physiological effects, ranging from increased constriction of blood vessels to increased sodium reabsorption by the kidneys and increased fluid intake. Thus, arterial baroreceptors, by influencing renal renin secretion, have a wide influence on systemic physiology. Arterial baroreceptors also influence secretion of posterior pituitary hormones. Decreased ABP sensed by
Increasing
262 Blood Pressure: Baroreceptors
SNS
Vasoconstriction
Baroreceptor afferent activity Resting Decreasing
HR, CO PNS
SNS
Vasoconstriction HR, CO
PNS
Decreasing
Increasing Resting Arterial blood pressure
Figure 3 Relationship between arterial blood pressure, baroreceptor afferent activity, and cardiovascular autonomic outflow. SNS, sympathetic nervous system; PNS, peripheral nervous system; HR, heart rate; CO, cardiac output.
arterial baroreceptors increases vasopressin secretion from the posterior pituitary, with readily understandable influences on cardiovascular homeostasis: increased fluid retention by the kidneys and increased arterial vasoconstriction. Increases in ABP momentarily inhibit the activity of vasopressin-secreting cells (a response that has been used as a defining characteristic of magnocellular vasopressin neurons), but this effect does not appear to be sustained long enough to have any physiological impact. Arterial hypotension also causes secretion of the other major posterior pituitary hormone, oxytocin. While the physiological significance of hypotension-evoked oxytocin secretion is not clear, recent studies indicate that this hormone promotes renin secretion from the kidney, at least in rats. In contrast to vasopressin-secreting cells, increases in ABP appear to have no effect on oxytocin-secreting cells. Changes in ABP, sensed by arterial baroreceptors, influence drinking behavior. Decreases in ABP stimulate fluid intake, an effect that appears to be mediated entirely via arterial baroreceptor-evoked renin secretion with the resulting increase in blood levels of angiotensin II acting on the brain to stimulate drinking. In contrast, increases in ABP inhibit drinking behavior and this effect appears to be mediated by baroreceptorstimulated neuronal pathways in the brain. In summary, changes in the afferent activity of arterial baroreceptors reflexively elicit a variety of autonomic, endocrine, and behavioral responses included in cardiovascular homeostasis. While many of these responses occur in opposite fashion to increases and decreases in ABP, the mechanisms responsible for these different effects might be quite distinct.
Central Pathways and Processing Input to the central nervous system from arterial baroreceptors is through the NTS in the dorsomedial medulla. Within the NTS, baroreceptor afferents synapse with second-order sensory neurons, and at this stage the information begins to get integrated and relayed. The baroreceptor afferents are excitatory to the second-order neurons, likely using glutamate as the primary neurotransmitter. Neural transmission at this initial synapse can be blocked by glutamate receptor antagonists, as can baroreceptor reflexes when such drugs are applied to the NTS. The neural pathways subserving baroreceptor reflex control of parasympathetic and sympathetic responses have been well studied and this circuitry is well established (Figure 4). Neurons in the NTS, likely the second-order sensory neurons, innervate parasympathetic cardiac preganglionic neurons, most of which are present in the nucleus ambiguus. The synapse between the second-order sensory neuron and the parasympathetic preganglionic neuron is excitatory and likely to use glutamate as a neurotransmitter. The baroreceptor reflex circuitry linking the NTS with the sympathetic preganglionic neurons in the intermediolateral cell column in the thoracolumbar spinal cord is somewhat more complex and necessarily involves an inhibitory interneuron, because increases in baroreceptor input decrease sympathetic activity. Barosensitive glutamatergic NTS neurons, at least some of which are second-order sensory neurons, innervate neurons in the caudal ventrolateral medulla (CVLM) and excite g-aminobutyric acid (GABA)ergic
Blood Pressure: Baroreceptors 263
CNS
(+) Baroreceptor afferents
(+)
Cardiac vagal preganglionic neurons
Heart
NTS (+)
CVLM
(−)
RVLM
(+) Sympathetic preganglionic neurons
Heart and blood vessels Figure 4 Central nervous system baroreceptor pathway linking baroreceptor afferents to sympathetic and parasympathetic outflow. Plus (þ) and minus () symbols refer to excitatory synapses and inhibitory synapses, respectively.
neurons in this region. The GABAergic CVLM neurons innervate sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) that innervate sympathetic vasomotor preganglionic neurons in the spinal cord. Thus, activation of baroreceptor afferents inhibits sympathetic vasomotor outflow by a pathway involving an excitatory projection from NTS to CVLM, an inhibitory projection from CVLM to RVLM, and an excitatory projection from RVLM to sympathetic preganglionic neurons. Available evidence supports glutamate being the primary neurotransmitter at each of the excitatory synapses in this reflex pathway and GABA being the neurotransmitter at the inhibitory link from CVLM to RVLM. At each of the sites in this pathway, inputs from other brain regions have the capacity to modify baroreceptor reflex responses, and most brain-evoked responses that influence cardiovascular function have some influence on baroreceptor reflex processing. Central nervous system pathways mediating other baroreceptor-evoked responses are less well characterized. Hypotension-evoked secretion of vasopressin from the posterior pituitary gland involves activation of the magnocellular vasopressin neurons of the paraventricular and supraoptic hypothalamic nuclei, likely by a pathway involving the ventrolateral medulla. Presumably hypotension-evoked excitation of magnocellular oxytocin neurons is via similar pathways, but this has not been extensively studied. The inhibition of vasopressin neurons by acute increases in ABP is mediated by distinctly different pathways from the NTS to hypothalamus (again illustrating
the asymmetry between responses evoked by activating vs. unloading of baroreceptors). As for the central neural pathways involved in baroreceptor-mediated influences on drinking, hypotension-evoked drinking involves activation of the sympathetic innervation of the kidney juxtaglomerular cells, with the resulting generation of angiotensin II. This angiotensin II then acts on neurons in the subfornical organ, a forebrain region lacking a blood–brain barrier, to activate brain circuits involved in drinking. In contrast, increases in ABP inhibit drinking via central neural pathways from the NTS that have not been studied in any detail. The extensive nature of central baroreceptor reflex circuits is readily demonstrated by studies showing numerous brain regions expressing immediate-early genes such as c-fos in response to arterial baroreceptor activation or unloading. All of the regions directly involved in the aforementioned baroreceptor responses express immediate-early genes under conditions in which they would be expected to be activated by baroreceptor manipulations, but many other regions, presumably involved in higher order integration of baroreceptor responses, also express immediateearly genes in these studies.
Role of Arterial Baroreceptors in Cardiovascular Regulation Arterial baroreceptors provide a dynamic signal to the brain regarding changes in ABP and elicit reflex responses to maintain ABP within a narrow range.
264 Blood Pressure: Baroreceptors
Baroreceptor reflexes are essential for normal cardiovascular homeostasis and stabilize ABP at normal levels on a rapid time frame. Studying the impact of destruction of arterial baroreceptors on cardiovascular regulation has provided useful information on their function. Elimination of baroreceptor signals carried in the aortic depressor nerve and carotid sinus nerve results in a rapid increase in ABP and heart rate, reflecting the marked decrease in baroreceptor afferent signal to brain. Over the course of several days, ABP returns to a normal average level, but the variability around this normal average is markedly increased. A conclusion that can be drawn from such observations is that arterial baroreceptor reflexes are not critical for the maintenance of a normal average level of ABP, but they are essential for stabilizing ABP. These results from baroreceptor-denervated animals have also been used to support the notion that baroreceptor reflexes are not important in the long-term control of blood pressure, but this conclusion has been challenged by more recent studies showing that chronic stimulation of arterial baroreceptor afferents can have a sustained influence on ABP.
Cardiopulmonary Baroreceptors In addition to the baroreceptors positioned to sense ABP, there are also baroreceptors in the atria, and veins leading to them, referred to as cardiopulmonary baroreceptors. These baroreceptors sense stretch in the atria, which, because of the distensible nature of the atria, and veins leading to them, reflects blood volume. Thus, hypovolemia decreases stretch on these receptors and this leads reflexively to a number of responses aimed at restoring blood volume. Responses initiated by unloading cardiopulmonary baroreceptors include increased vasopressin secretion, increased renin secretion, and increased thirst. Nonhypotensive hypovolemia, as can be caused by moderate hemorrhage or removal of isotonic plasma volume by various experimental procedures, elicits each of these responses. As noted previously, each of
these responses is also characteristic of hypotension in the absence of hypovolemia, but the response to unloading of arterial and cardiopulmonary baroreceptors at the same time, as might be produced by hypotensive hemorrhage, is much greater than are responses produced by either stimulus in isolation. See also: Autonomic Disorders; Autonomic Failure; Autonomic Nervous System: Cardiovascular Control; Autonomic Nervous System: Central Cardiovascular Control; Autonomic Nervous System; Cardiovascular Function: Central Nervous System Control; Circumventricular Organs; Energy Homeostasis: Visceral Control; Heart Rate Variability: A Neurovisceral Integration Model; Parasympathetic Nervous System; Pituitary Gland (Cell Types, Mediators, Development); Sympathetic Nervous System; Vasopressin/Oxytocin and Receptors.
Further Reading Chapleau MW, Cunningham JT, Sullivan MJ, et al. (1995) Structural versus functional modulation of the arterial baroreflex. Hypertension 26: 341–347. Chapleau MW, Li Z, Meyrelles SS, et al. (2001) Mechanisms determining sensitivity of baroreceptor afferents in health and disease. Annals of the New York Academy of Sciences 940: 1–19. Dampney RA, Polson JW, Potts PD, et al. (2003) Functional organization of brain pathways subserving the baroreceptor reflex: Studies in conscious animals using immediate early gene expression. Cellular and Molecular Neurobiology 23: 597–616. Guyenet PG (2006) The sympathetic control of blood pressure. Nature Reviews Neuroscience 7: 335–346. Lohmeier TE, Hildebrandt DA, Warren S, et al. (2005) Recent insights into the interactions between the baroreflex and the kidneys in hypertension. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 288: R828–R836. Munch PA, Andresen MC, and Brown AM (1983) Rapid resetting of aortic baroreceptors in vitro. American Journal of Physiology 244: H672–H680. Stricker EM and Sved AF (2002) Controls of vasopressin secretion and thirst: Similarities and dissimilarities in signals. Physiology & Behavior 77: 731–736. Sved AF, Ito S, Madden CJ, et al. (2001) Excitatory inputs to the RVLM in the context of the baroreceptor reflex. Annals of the New York Academy of Sciences 940: 247–258.