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Baroreceptor Reflexes
C H A P T E R
33 Baroreceptor Reflexes Mark W. Chapleau Changes in blood pressure (BP) and/or blood volume are “sensed” within specific compartments of the cardiovascular system by “baroreceptors” (Fig. 33.1). Baroreceptors are mechanosensitive nerve endings that are activated by vascular and/or cardiac distension during increases in intraluminal BP. The activity of arterial baroreceptors innervating large arteries (primarily aortic arch and carotid sinuses) is increased when arterial BP rises, and decreased when BP falls. The changes in baroreceptor activity evoke rapid reflex adjustments that buffer or oppose the changes in arterial BP in a negative-feedback manner. Cardiopulmonary baroreceptors innervate the heart, vena cava, and pulmonary vasculature. Since the activity of cardiopulmonary baroreceptors correlates with intrathoracic (central) blood volume, these nerve endings are often referred to as “volume receptors” or “low-pressure” baroreceptors. The reflex adjustments triggered by changes in cardiopulmonary baroreceptor activity regulate blood volume in addition to influencing BP.
NEURAL PATHWAYS AND EFFECTOR MECHANISMS Arterial Baroreflex The neural pathways and effector mechanisms involved in baroreflex control of the circulation are summarized in Figures 33.1 and 33.2. The cell bodies (somata) of carotid sinus and aortic arch baroreceptor neurons are located in petrosal and nodose ganglia, respectively. The corresponding afferent baroreceptor activity is transmitted to the nucleus tractus solitarius (NTS) in the medullary brain stem via carotid sinus and glossopharyngeal nerves, and aortic depressor and vagus nerves, respectively. The baroreceptor inputs are integrated and relayed through a network of central nervous system (CNS) neurons controlling efferent parasympathetic nerve activity (paraSNA), sympathetic nerve activity (SNA), and release of the vasoconstrictor and antidiuretic peptide vasopressin (AVP) from the posterior pituitary gland (Figs 33.1 and 33.2). The multiple effector mechanisms by which these systems buffer increases in BP are depicted in Figure 33.2. The effector mechanisms operate in the opposite direction when arterial BP and baroreceptor activity are reduced.
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00033-0
BP-sensitive sensory nerves also innervate the juncture of the right carotid and right subclavian arteries (Fig. 33.1) and the coronary arteries. These nerves travel in the aortic depressor and vagus nerves with cell bodies located in the nodose ganglia. Activation of the coronary artery baroreflex modulates peripheral SNA and vascular resistance, but unlike carotid sinus and aortic arch baroreflexes, has little or no affect on HR.
Cardiopulmonary Baroreflex The cardiopulmonary region is innervated by multiple types of mechanosensitive and chemosensitive sensory nerves that affect autonomic and cardiovascular functions in a variety of ways (see Chapter 35). We focus here on vagal afferent neurons with cell bodies in the nodose ganglia and nerve endings in the heart, vena cava, and pulmonary vasculature that are sensitive to changes in central blood volume (Fig. 33.1). The electrophysiological properties of these sensory neurons, the CNS pathways engaged by their activation, and their influence on efferent effectors are similar to that of arterial baroreceptor neurons (see Figs 33.1 and 33.2), but not identical. While changes in cardiopulmonary baroreceptor activity during changes in central blood volume evoke powerful reflex changes in peripheral SNA, vascular resistance, and release of renin and AVP; the reflex has little affect on HR. The changes in SNA and vascular resistance contribute to orthostatic adjustments. Renal actions of SNA, the renin-angiotensinaldosterone system, and AVP leading to changes in Na and water reabsorption play a major role in regulation of blood volume.
DETERMINANTS OF AFFERENT BARORECEPTOR ACTIVITY Rate Sensitivity of Baroreceptors Baroreceptor activity is dependent not only on the mean level of BP, but also on the direction and rate of change in BP. Consequently, baroreceptor activity will increase or decrease to a greater extent when the change in BP occurs more rapidly leading to a more effective reflex compensation. Similarly, baroreceptor activity is higher
161
© 2012 Elsevier Inc. All rights reserved.
162
33. Baroreceptor Reflexes
FIGURE 33.1 Location of baroreceptors and neural pathways mediating baroreflex responses. (A) Arterial baroreceptor afferents innervate carotid sinuses, aortic arch and the right carotid artery-right subclavian artery juncture. Cardiopulmonary baroreceptors innervate veno-atrial juncture, atria, ventricles and pulmonary vasculature. The baroreflexes modulate paraSNA and SNA to numerous organ systems and vasopressin (AVP) release. Key targets involved in cardiovascular regulation are illustrated. (B) Major nuclei involved in baroreflex control. Increases in BP and baroreceptor activity activate excitatory neural projections from nucleus tractus solitarius (NTS) to preganglionic parasympathetic neurons in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX) resulting in increases in paraSNA and decreases in HR. Activation of excitatory projections from NTS to caudal ventrolateral medulla (CVLM) causes subsequent inhibition of premotor sympathetic neurons in rostral ventrolateral medulla (RVLM) that project to preganglionic sympathetic neurons in the intermediolateral (IML) column of the thoracolumbar spinal cord. Increased baroreceptor activity also inhibits secretion of AVP from magnocellular neurons in paraventricular nucleus (PVN) and supraoptic nucleus (SON) of hypothalamus. Other CNS regions interact with these areas to modulate baroreflexes.
FIGURE 33.2 Effector mechanisms mediating reflex responses to increases in baroreceptor activity. Increases in arterial BP and baroreceptor activity increase paraSNA, decrease SNA, and inhibit release of AVP leading to an array of cardiovascular, hormonal and renal responses. Decreases in arterial BP evoke directionally opposite reflex responses. A-V node, atrio-ventricular node; Ang II, angiotensin II; H2O, water.
III. AUTONOMIC PHYSIOLOGY
DECREASED BAROREFLEX SENSITIVITY IN DISEASE
during the systolic phase of the arterial pressure pulse and lower or absent during diastole. The phasic discharge of afferent activity facilitates reflex inhibition of SNA.
163
and autocrine/paracrine factors including norepinephrine, prostacyclin, serotonin, nitric oxide, and reactive oxygen species modulate baroreceptor sensitivity through actions on these ion channels and membrane pumps.
Large Artery Compliance Baroreceptors are not directly sensitive to BP, but rather are sensitive to mechanical deformation of the nerve endings during distension of the arterial wall. Therefore, large artery compliance (specifically of the carotid sinuses and aortic arch) is a major determinant of the baroreceptor sensitivity to changes in BP. Decreased arterial compliance contributes to decreased baroreceptor sensitivity in atherosclerosis, hypertension, and aging.
Neuronal Mechanisms Mediating Sensory Transduction The prevailing view is that baroreceptors are activated by the opening of mechanosensitive ion channels in the sensory terminals. The resulting depolarization, if of sufficient magnitude, will trigger action potential discharge upon opening of voltage-gated Na and K channels. The action potentials are propagated towards the CNS at frequencies related to the magnitude of deformation and depolarization of the sensory terminals. Evidence suggests that members of the epithelial sodium channel (ENaC) superfamily including acid-sensing ion channel 2 (ASIC2) are components of the mechanosensitive ion channel complex. Transient receptor potential (TRP) channels have also been implicated in baroreceptor sensory transduction and/ or signaling, perhaps functioning as a mechanosensor. A variety of voltage- and ligand-gated ion channels and membrane pumps modulate the membrane potential and excitability of baroreceptors including Kv1, Kv4, BK and KCNQ (M-type) K channels; tetrodotoxin-insensitive, voltage-gated Na channels; hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; serotonin 5HT3 receptor/ channels; and the Na/K–ATPase. Several neurohumoral
BAROREFLEX ADAPTATION AND RESETTING IN ACUTE HYPERTENSION Baroreceptor activity increases with a rise in arterial BP but declines over time if the acute hypertension is maintained. Furthermore, “post-excitatory depression” (PED) of baroreceptor activity occurs when BP decreases rapidly after a period of increased BP. Different mechanisms have been implicated in these two phenomena with opening of 4-aminopyridine sensitive K channels contributing to adaptation and activation of the Na/K–ATPase causing PED. Baroreceptor adaptation and PED contribute to acute resetting of the baroreceptor pressure-activity relationship to higher mean pressures in hypertension. The baroreceptor function curve is shifted in a parallel manner with little or no change in baroreceptor sensitivity (slope), and is usually accompanied by resetting of the arterial BP-HR relation (Fig. 33.3). Central mechanisms may exacerbate or oppose resetting of the baroreflex function curve. While baroreflex resetting compromises the ability to counter the sustained hypertension, it helps preserve the ability to buffer acute fluctuations in BP at the new higher prevailing level of BP.
DECREASED BAROREFLEX SENSITIVITY IN DISEASE Control of HR vs. SNA and BP, and Underlying Mechanisms Baroreflex sensitivity (BRS) for control of HR is consistently decreased in numerous pathological states including chronic hypertension, coronary artery disease,
FIGURE 33.3 Baroreceptor and baroreflex resetting during acute hypertension. An increase in mean arterial BP increases baroreceptor activity (left) and reflexively decreases HR (right). During a sustained increase in BP, baroreceptor activity decreases or adapts over time (left) and HR increases at the same level of BP (right). The baroreceptor and baroreflex function curves are shifted (reset) to higher BP during acute hypertension with preservation of the slope of the curves (sensitivity) (dashed lines).
III. AUTONOMIC PHYSIOLOGY
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33. Baroreceptor Reflexes
post-myocardial infarction, heart failure, diabetes mellitus, and obesity, and with aging. Afferent, central, and efferent mechanisms contribute to varying degrees to decreased BRS in these diseases. Chronic structural changes such as decreased large artery compliance and cardiac hypertrophy impair the afferent sensitivity of arterial and cardiopulmonary baroreceptors. In addition, neurohumoral activation and oxidative stress impair baroreflex function. For example, increased circulating levels of angiotensin II (Ang II) reset the baroreflex function curve to a higher mean level of arterial BP. This resetting is mediated by actions of Ang II on circumventricular organs that lack a blood–brain barrier (e.g., area postrema) and is independent of the rise in BP. Furthermore, Ang II acts at multiple central and peripheral sites in the nervous system to increase SNA, and decrease paraSNA and BRS. Aldosterone inhibits BRS by reducing afferent baroreceptor activity and by central actions. Factors released from activated platelets and reactive oxygen species decrease baroreceptor afferent sensitivity. Oxidative stress in the CNS contributes to increased SNA and BP in animal models of hypertension. Antioxidant therapies improve BRS in hypertension, heart failure, and in aging. In contrast to control of HR, the effects of cardiovascular disease and aging on arterial baroreflex control of SNA and BP are controversial with reports of both impaired and preserved BRS. Differences in results between studies can be explained in part by differences in: (i) the methods used to quantify changes in SNA and evaluate BRS; (ii) engagement of arterial vs. cardiopulmonary baroreflexes; (iii) control of SNA to different peripheral targets; (iv) severity of disease; and (v) experimental conditions (e.g., use of anesthesia). In most conditions, decreased BRS for parasympathetic control of HR usually precedes and/ or exceeds the decrease in BRS for sympathetic control. Structural damage to baroreceptor afferents, usually resulting from surgery or radiation, can cause “baroreflex failure” with loss of cardiovagal tone and severe, episodic periods of sympathetic-mediated hypertension (see Chapter 72). A similar phenotype is observed in patients with familial dysautonomia, a rare genetic disease with severe developmental sensory nerve defects (see Chapter 103).
Genetic Determinants of BRS Decreased BRS may be secondary to underlying cardiovascular disease or may precede and contribute to disease. BRS for control of HR is impaired in normotensive subjects with a family history of hypertension, and heritability of BRS has been confirmed in twin studies. Polymorphisms in several genes have been reported to be associated with BRS (see Chapter 34). Therefore, BRS screening in high risk patients identified by disease and/ or by the presence of specific polymorphisms may be advisable. The ability to measure BRS noninvasively from spontaneous fluctuations in systolic BP and pulse interval makes this clinical application feasible.
BRS: A DETERMINANT OF CARDIOVASCULAR RISK AND THERAPEUTIC TARGET Decreased BRS and Cardiovascular Risk Increased BP variability causes target organ damage, e.g., endothelial dysfunction, vascular and cardiac hypertrophy, kidney disease and cerebral vascular dysfunction. These insults lead to myocardial infarction, stroke, and heart and kidney failure. By minimizing BP variability and restraining SNA and BP, the arterial and cardiopulmonary baroreflexes reduce target organ damage. In addition to regulating BP, baroreflexes exert a major influence on the electrical properties of the heart through modulation of cardiac SNA and paraSNA. Myocardial infarction, heart failure, and diabetes are associated with decreased BRS for control of HR, cardiac arrhythmias, and sudden cardiac death. The decrease in BRS predicts occurrence of arrhythmias and mortality in patients suffering from these diseases suggesting a causal relationship.
BRS is a Therapeutic Target The strong inverse relationship between BRS and cardiovascular risk encourages targeting therapy to improve BRS. Baroreflexes may contribute to the benefit of standard antihypertensive therapies. For example, lowering of BP of hypertensive patients by pharmacological or dietary interventions rapidly resets the baroreflex function curve to lower mean arterial BPs. The baroreflex resetting helps stabilize BP at the new lower prevailing level of BP. Reversal of vascular and cardiac stiffening and hypertrophy with longer periods of antihypertensive treatment increases BRS. Antagonists of the renin-angiotensin- aldosterone system and antioxidants increase BRS independent of BP lowering, thus providing further reductions in cardiovascular risk. Recent findings have rejuvenated the concept of specific therapeutic targeting of baroreflex pathways in cardiovascular disease. Cholinesterase inhibitors promote increases in cardiovagal tone and BRS by increasing the concentration of the neurotransmitter acetylcholine at cholinergic synapses and sinoatrial node, and amplify cholinergic signaling in left ventricle. Administration of cholinesterase inhibitors and chronic electrical stimulation of the vagus nerve each result in novel downstream anti-inflammatory effects and increased survival post-myocardial infarction. A recent study examining effects of chronic vagus nerve stimulation in patients with heart failure has provided promising results. Chronic electrical stimulation of carotid sinus baroreceptors in dog models of hypertension and in patients with drug-resistant hypertension have demonstrated long-term efficacy in lowering BP and reducing target organ damage. Chronic carotid sinus baroreceptor stimulation has also been shown to improve cardiac function, decrease arrhythmias, and prolong survival in
III. AUTONOMIC PHYSIOLOGY
BRS: A Determinant of Cardiovascular Risk and Therapeutic Target
dog models of heart failure. Clearly, favorable effects of increasing baroreceptor activity extend far beyond shortterm control of BP.
Further Reading Brooks VL, Sved AF. Pressure to change? Re-evaluating the role of baroreceptors in the long-term control of arterial pressure. Am J Physiol Regul Integr Comp Physiol 2005;288:R815–8. Chapleau MW, Li Z, Meyrelles SS, Ma X, Abboud FM. Mechanisms determining sensitivity of baroreceptor afferents in health and disease. Ann NY Acad Sci 2001;940:1–19. Chapleau MW, Lu Y, Abboud FM. Mechanosensitive ion channels in blood pressure-sensing baroreceptor neurons. Hamill OP, editor. Current topics in membranes, Vol 59. : Elsevier Science; 2007. p. 541–67. Chapleau MW, Sabharwal R. Methods of assessing vagus nerve activity and reflexes. Heart Fail Rev 2011;16:109–27. Glazebrook PA, Ramirez AN, Schild JH, Shieh C-C, Doan T, Wible BA, et al. Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J Physiol 2002;541.2:467–82. Glazebrook PA, Schilling WP, Kunze DL. TRPC channels as signal transducers. Pflugers Arch 2005;451:125–30. Guyenet PG. The sympathetic control of blood pressure. Nature Rev Neurosci 2006;7:335–46. Hainsworth R. Reflexes from the heart. Physiol Rev 1991;71(3):617–58. Handa T, Katare RG, Kakinuma Y, Arikawa M, Ando M, Sasaguri S, et al. Anti-Alzheimer’s drug, donepezil, markedly improves long-term survival after chronic heart failure in mice. J Cardiac Fail 2009;15:805–11.
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Korner PI. Baroreceptor resetting and other determinants of baroreflex properties in hypertension. Clin Exp Pharmacol Physiol Suppl 1989;15:45–64. La Rovere MT, Bigger Jr. JT, Marcus FI, Mortara A, Schwartz PJ for the ATRAMI investigators. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. The Lancet 1998;351:478–84. Lu Y, Ma X, Sabharwal R, Snitsarev V, Morgan D, Rahmouni K, et al. The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation. Neuron 2009;64:885–97. Monahan KD, Eskurza I, Seals DR. Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men. Am J Physiol Heart Circ Physiol 2004;286:H2113–H2117. Parati G, Di Rienzo M, Mancia G. How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life. J Hypertens 2000;18:7–19. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, et al. Long term vagal stimulation in patients with advanced heart failure: First experience in man. Eur J Heart Fail 2008;10:884–91. Sun H, Li D-P, Chen S-R, Hittelman WN, Pan H-L. Sensing of blood pressure increase by transient receptor potential vanilloid 1 receptors on baroreceptors. J Pharmacol Exp Ther 2009;331:851–9. Taylor JG, Bisognano JD. Baroreflex stimulation in antihypertensive treatment. Curr Hypertens Rep 2010;12:176–81. Wladyka CL, Feng B, Glazebrook PA, Schild JH, Kunze DL. The KCNQ/ M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol 2008;586.3:795–802. Wright C, Drinkhill MJ, Hainsworth R. Reflex effects of independent stimulation of coronary and left ventricular mechanoreceptors in anaesthetized dogs. J Physiol 2000;528.2:349–58.
III. AUTONOMIC PHYSIOLOGY
33 Baroreceptor Reflexes Mark W. Chapleau Changes in blood pressure (BP) and/or blood volume are “sensed” within specific compartments of the cardiovascular system by “baroreceptors” (Fig. 33.1). Baroreceptors are mechanosensitive nerve endings that are activated by vascular and/or cardiac distension during increases in intraluminal BP. The activity of arterial baroreceptors innervating large arteries (primarily aortic arch and carotid sinuses) is increased when arterial BP rises, and decreased when BP falls. The changes in baroreceptor activity evoke rapid reflex adjustments that buffer or oppose the changes in arterial BP in a negative-feedback manner. Cardiopulmonary baroreceptors innervate the heart, vena cava, and pulmonary vasculature. Since the activity of cardiopulmonary baroreceptors correlates with intrathoracic (central) blood volume, these nerve endings are often referred to as “volume receptors” or “low-pressure” baroreceptors. The reflex adjustments triggered by changes in cardiopulmonary baroreceptor activity regulate blood volume in addition to influencing BP.
NEURAL PATHWAYS AND EFFECTOR MECHANISMS Arterial Baroreflex The neural pathways and effector mechanisms involved in baroreflex control of the circulation are summarized in Figures 33.1 and 33.2. The cell bodies (somata) of carotid sinus and aortic arch baroreceptor neurons are located in petrosal and nodose ganglia, respectively. The corresponding afferent baroreceptor activity is transmitted to the nucleus tractus solitarius (NTS) in the medullary brain stem via carotid sinus and glossopharyngeal nerves, and aortic depressor and vagus nerves, respectively. The baroreceptor inputs are integrated and relayed through a network of central nervous system (CNS) neurons controlling efferent parasympathetic nerve activity (paraSNA), sympathetic nerve activity (SNA), and release of the vasoconstrictor and antidiuretic peptide vasopressin (AVP) from the posterior pituitary gland (Figs 33.1 and 33.2). The multiple effector mechanisms by which these systems buffer increases in BP are depicted in Figure 33.2. The effector mechanisms operate in the opposite direction when arterial BP and baroreceptor activity are reduced.
Primer on the Autonomic Nervous System. DOI: 10.1016/B978-0-12-386525-0.00033-0
BP-sensitive sensory nerves also innervate the juncture of the right carotid and right subclavian arteries (Fig. 33.1) and the coronary arteries. These nerves travel in the aortic depressor and vagus nerves with cell bodies located in the nodose ganglia. Activation of the coronary artery baroreflex modulates peripheral SNA and vascular resistance, but unlike carotid sinus and aortic arch baroreflexes, has little or no affect on HR.
Cardiopulmonary Baroreflex The cardiopulmonary region is innervated by multiple types of mechanosensitive and chemosensitive sensory nerves that affect autonomic and cardiovascular functions in a variety of ways (see Chapter 35). We focus here on vagal afferent neurons with cell bodies in the nodose ganglia and nerve endings in the heart, vena cava, and pulmonary vasculature that are sensitive to changes in central blood volume (Fig. 33.1). The electrophysiological properties of these sensory neurons, the CNS pathways engaged by their activation, and their influence on efferent effectors are similar to that of arterial baroreceptor neurons (see Figs 33.1 and 33.2), but not identical. While changes in cardiopulmonary baroreceptor activity during changes in central blood volume evoke powerful reflex changes in peripheral SNA, vascular resistance, and release of renin and AVP; the reflex has little affect on HR. The changes in SNA and vascular resistance contribute to orthostatic adjustments. Renal actions of SNA, the renin-angiotensinaldosterone system, and AVP leading to changes in Na and water reabsorption play a major role in regulation of blood volume.
DETERMINANTS OF AFFERENT BARORECEPTOR ACTIVITY Rate Sensitivity of Baroreceptors Baroreceptor activity is dependent not only on the mean level of BP, but also on the direction and rate of change in BP. Consequently, baroreceptor activity will increase or decrease to a greater extent when the change in BP occurs more rapidly leading to a more effective reflex compensation. Similarly, baroreceptor activity is higher
161
© 2012 Elsevier Inc. All rights reserved.
162
33. Baroreceptor Reflexes
FIGURE 33.1 Location of baroreceptors and neural pathways mediating baroreflex responses. (A) Arterial baroreceptor afferents innervate carotid sinuses, aortic arch and the right carotid artery-right subclavian artery juncture. Cardiopulmonary baroreceptors innervate veno-atrial juncture, atria, ventricles and pulmonary vasculature. The baroreflexes modulate paraSNA and SNA to numerous organ systems and vasopressin (AVP) release. Key targets involved in cardiovascular regulation are illustrated. (B) Major nuclei involved in baroreflex control. Increases in BP and baroreceptor activity activate excitatory neural projections from nucleus tractus solitarius (NTS) to preganglionic parasympathetic neurons in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX) resulting in increases in paraSNA and decreases in HR. Activation of excitatory projections from NTS to caudal ventrolateral medulla (CVLM) causes subsequent inhibition of premotor sympathetic neurons in rostral ventrolateral medulla (RVLM) that project to preganglionic sympathetic neurons in the intermediolateral (IML) column of the thoracolumbar spinal cord. Increased baroreceptor activity also inhibits secretion of AVP from magnocellular neurons in paraventricular nucleus (PVN) and supraoptic nucleus (SON) of hypothalamus. Other CNS regions interact with these areas to modulate baroreflexes.
FIGURE 33.2 Effector mechanisms mediating reflex responses to increases in baroreceptor activity. Increases in arterial BP and baroreceptor activity increase paraSNA, decrease SNA, and inhibit release of AVP leading to an array of cardiovascular, hormonal and renal responses. Decreases in arterial BP evoke directionally opposite reflex responses. A-V node, atrio-ventricular node; Ang II, angiotensin II; H2O, water.
III. AUTONOMIC PHYSIOLOGY
DECREASED BAROREFLEX SENSITIVITY IN DISEASE
during the systolic phase of the arterial pressure pulse and lower or absent during diastole. The phasic discharge of afferent activity facilitates reflex inhibition of SNA.
163
and autocrine/paracrine factors including norepinephrine, prostacyclin, serotonin, nitric oxide, and reactive oxygen species modulate baroreceptor sensitivity through actions on these ion channels and membrane pumps.
Large Artery Compliance Baroreceptors are not directly sensitive to BP, but rather are sensitive to mechanical deformation of the nerve endings during distension of the arterial wall. Therefore, large artery compliance (specifically of the carotid sinuses and aortic arch) is a major determinant of the baroreceptor sensitivity to changes in BP. Decreased arterial compliance contributes to decreased baroreceptor sensitivity in atherosclerosis, hypertension, and aging.
Neuronal Mechanisms Mediating Sensory Transduction The prevailing view is that baroreceptors are activated by the opening of mechanosensitive ion channels in the sensory terminals. The resulting depolarization, if of sufficient magnitude, will trigger action potential discharge upon opening of voltage-gated Na and K channels. The action potentials are propagated towards the CNS at frequencies related to the magnitude of deformation and depolarization of the sensory terminals. Evidence suggests that members of the epithelial sodium channel (ENaC) superfamily including acid-sensing ion channel 2 (ASIC2) are components of the mechanosensitive ion channel complex. Transient receptor potential (TRP) channels have also been implicated in baroreceptor sensory transduction and/ or signaling, perhaps functioning as a mechanosensor. A variety of voltage- and ligand-gated ion channels and membrane pumps modulate the membrane potential and excitability of baroreceptors including Kv1, Kv4, BK and KCNQ (M-type) K channels; tetrodotoxin-insensitive, voltage-gated Na channels; hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; serotonin 5HT3 receptor/ channels; and the Na/K–ATPase. Several neurohumoral
BAROREFLEX ADAPTATION AND RESETTING IN ACUTE HYPERTENSION Baroreceptor activity increases with a rise in arterial BP but declines over time if the acute hypertension is maintained. Furthermore, “post-excitatory depression” (PED) of baroreceptor activity occurs when BP decreases rapidly after a period of increased BP. Different mechanisms have been implicated in these two phenomena with opening of 4-aminopyridine sensitive K channels contributing to adaptation and activation of the Na/K–ATPase causing PED. Baroreceptor adaptation and PED contribute to acute resetting of the baroreceptor pressure-activity relationship to higher mean pressures in hypertension. The baroreceptor function curve is shifted in a parallel manner with little or no change in baroreceptor sensitivity (slope), and is usually accompanied by resetting of the arterial BP-HR relation (Fig. 33.3). Central mechanisms may exacerbate or oppose resetting of the baroreflex function curve. While baroreflex resetting compromises the ability to counter the sustained hypertension, it helps preserve the ability to buffer acute fluctuations in BP at the new higher prevailing level of BP.
DECREASED BAROREFLEX SENSITIVITY IN DISEASE Control of HR vs. SNA and BP, and Underlying Mechanisms Baroreflex sensitivity (BRS) for control of HR is consistently decreased in numerous pathological states including chronic hypertension, coronary artery disease,
FIGURE 33.3 Baroreceptor and baroreflex resetting during acute hypertension. An increase in mean arterial BP increases baroreceptor activity (left) and reflexively decreases HR (right). During a sustained increase in BP, baroreceptor activity decreases or adapts over time (left) and HR increases at the same level of BP (right). The baroreceptor and baroreflex function curves are shifted (reset) to higher BP during acute hypertension with preservation of the slope of the curves (sensitivity) (dashed lines).
III. AUTONOMIC PHYSIOLOGY
164
33. Baroreceptor Reflexes
post-myocardial infarction, heart failure, diabetes mellitus, and obesity, and with aging. Afferent, central, and efferent mechanisms contribute to varying degrees to decreased BRS in these diseases. Chronic structural changes such as decreased large artery compliance and cardiac hypertrophy impair the afferent sensitivity of arterial and cardiopulmonary baroreceptors. In addition, neurohumoral activation and oxidative stress impair baroreflex function. For example, increased circulating levels of angiotensin II (Ang II) reset the baroreflex function curve to a higher mean level of arterial BP. This resetting is mediated by actions of Ang II on circumventricular organs that lack a blood–brain barrier (e.g., area postrema) and is independent of the rise in BP. Furthermore, Ang II acts at multiple central and peripheral sites in the nervous system to increase SNA, and decrease paraSNA and BRS. Aldosterone inhibits BRS by reducing afferent baroreceptor activity and by central actions. Factors released from activated platelets and reactive oxygen species decrease baroreceptor afferent sensitivity. Oxidative stress in the CNS contributes to increased SNA and BP in animal models of hypertension. Antioxidant therapies improve BRS in hypertension, heart failure, and in aging. In contrast to control of HR, the effects of cardiovascular disease and aging on arterial baroreflex control of SNA and BP are controversial with reports of both impaired and preserved BRS. Differences in results between studies can be explained in part by differences in: (i) the methods used to quantify changes in SNA and evaluate BRS; (ii) engagement of arterial vs. cardiopulmonary baroreflexes; (iii) control of SNA to different peripheral targets; (iv) severity of disease; and (v) experimental conditions (e.g., use of anesthesia). In most conditions, decreased BRS for parasympathetic control of HR usually precedes and/ or exceeds the decrease in BRS for sympathetic control. Structural damage to baroreceptor afferents, usually resulting from surgery or radiation, can cause “baroreflex failure” with loss of cardiovagal tone and severe, episodic periods of sympathetic-mediated hypertension (see Chapter 72). A similar phenotype is observed in patients with familial dysautonomia, a rare genetic disease with severe developmental sensory nerve defects (see Chapter 103).
Genetic Determinants of BRS Decreased BRS may be secondary to underlying cardiovascular disease or may precede and contribute to disease. BRS for control of HR is impaired in normotensive subjects with a family history of hypertension, and heritability of BRS has been confirmed in twin studies. Polymorphisms in several genes have been reported to be associated with BRS (see Chapter 34). Therefore, BRS screening in high risk patients identified by disease and/ or by the presence of specific polymorphisms may be advisable. The ability to measure BRS noninvasively from spontaneous fluctuations in systolic BP and pulse interval makes this clinical application feasible.
BRS: A DETERMINANT OF CARDIOVASCULAR RISK AND THERAPEUTIC TARGET Decreased BRS and Cardiovascular Risk Increased BP variability causes target organ damage, e.g., endothelial dysfunction, vascular and cardiac hypertrophy, kidney disease and cerebral vascular dysfunction. These insults lead to myocardial infarction, stroke, and heart and kidney failure. By minimizing BP variability and restraining SNA and BP, the arterial and cardiopulmonary baroreflexes reduce target organ damage. In addition to regulating BP, baroreflexes exert a major influence on the electrical properties of the heart through modulation of cardiac SNA and paraSNA. Myocardial infarction, heart failure, and diabetes are associated with decreased BRS for control of HR, cardiac arrhythmias, and sudden cardiac death. The decrease in BRS predicts occurrence of arrhythmias and mortality in patients suffering from these diseases suggesting a causal relationship.
BRS is a Therapeutic Target The strong inverse relationship between BRS and cardiovascular risk encourages targeting therapy to improve BRS. Baroreflexes may contribute to the benefit of standard antihypertensive therapies. For example, lowering of BP of hypertensive patients by pharmacological or dietary interventions rapidly resets the baroreflex function curve to lower mean arterial BPs. The baroreflex resetting helps stabilize BP at the new lower prevailing level of BP. Reversal of vascular and cardiac stiffening and hypertrophy with longer periods of antihypertensive treatment increases BRS. Antagonists of the renin-angiotensin- aldosterone system and antioxidants increase BRS independent of BP lowering, thus providing further reductions in cardiovascular risk. Recent findings have rejuvenated the concept of specific therapeutic targeting of baroreflex pathways in cardiovascular disease. Cholinesterase inhibitors promote increases in cardiovagal tone and BRS by increasing the concentration of the neurotransmitter acetylcholine at cholinergic synapses and sinoatrial node, and amplify cholinergic signaling in left ventricle. Administration of cholinesterase inhibitors and chronic electrical stimulation of the vagus nerve each result in novel downstream anti-inflammatory effects and increased survival post-myocardial infarction. A recent study examining effects of chronic vagus nerve stimulation in patients with heart failure has provided promising results. Chronic electrical stimulation of carotid sinus baroreceptors in dog models of hypertension and in patients with drug-resistant hypertension have demonstrated long-term efficacy in lowering BP and reducing target organ damage. Chronic carotid sinus baroreceptor stimulation has also been shown to improve cardiac function, decrease arrhythmias, and prolong survival in
III. AUTONOMIC PHYSIOLOGY
BRS: A Determinant of Cardiovascular Risk and Therapeutic Target
dog models of heart failure. Clearly, favorable effects of increasing baroreceptor activity extend far beyond shortterm control of BP.
Further Reading Brooks VL, Sved AF. Pressure to change? Re-evaluating the role of baroreceptors in the long-term control of arterial pressure. Am J Physiol Regul Integr Comp Physiol 2005;288:R815–8. Chapleau MW, Li Z, Meyrelles SS, Ma X, Abboud FM. Mechanisms determining sensitivity of baroreceptor afferents in health and disease. Ann NY Acad Sci 2001;940:1–19. Chapleau MW, Lu Y, Abboud FM. Mechanosensitive ion channels in blood pressure-sensing baroreceptor neurons. Hamill OP, editor. Current topics in membranes, Vol 59. : Elsevier Science; 2007. p. 541–67. Chapleau MW, Sabharwal R. Methods of assessing vagus nerve activity and reflexes. Heart Fail Rev 2011;16:109–27. Glazebrook PA, Ramirez AN, Schild JH, Shieh C-C, Doan T, Wible BA, et al. Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J Physiol 2002;541.2:467–82. Glazebrook PA, Schilling WP, Kunze DL. TRPC channels as signal transducers. Pflugers Arch 2005;451:125–30. Guyenet PG. The sympathetic control of blood pressure. Nature Rev Neurosci 2006;7:335–46. Hainsworth R. Reflexes from the heart. Physiol Rev 1991;71(3):617–58. Handa T, Katare RG, Kakinuma Y, Arikawa M, Ando M, Sasaguri S, et al. Anti-Alzheimer’s drug, donepezil, markedly improves long-term survival after chronic heart failure in mice. J Cardiac Fail 2009;15:805–11.
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Korner PI. Baroreceptor resetting and other determinants of baroreflex properties in hypertension. Clin Exp Pharmacol Physiol Suppl 1989;15:45–64. La Rovere MT, Bigger Jr. JT, Marcus FI, Mortara A, Schwartz PJ for the ATRAMI investigators. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. The Lancet 1998;351:478–84. Lu Y, Ma X, Sabharwal R, Snitsarev V, Morgan D, Rahmouni K, et al. The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation. Neuron 2009;64:885–97. Monahan KD, Eskurza I, Seals DR. Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men. Am J Physiol Heart Circ Physiol 2004;286:H2113–H2117. Parati G, Di Rienzo M, Mancia G. How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life. J Hypertens 2000;18:7–19. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, et al. Long term vagal stimulation in patients with advanced heart failure: First experience in man. Eur J Heart Fail 2008;10:884–91. Sun H, Li D-P, Chen S-R, Hittelman WN, Pan H-L. Sensing of blood pressure increase by transient receptor potential vanilloid 1 receptors on baroreceptors. J Pharmacol Exp Ther 2009;331:851–9. Taylor JG, Bisognano JD. Baroreflex stimulation in antihypertensive treatment. Curr Hypertens Rep 2010;12:176–81. Wladyka CL, Feng B, Glazebrook PA, Schild JH, Kunze DL. The KCNQ/ M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol 2008;586.3:795–802. Wright C, Drinkhill MJ, Hainsworth R. Reflex effects of independent stimulation of coronary and left ventricular mechanoreceptors in anaesthetized dogs. J Physiol 2000;528.2:349–58.
III. AUTONOMIC PHYSIOLOGY