Overview
The heart is innervated by parasympathetic and sympathetic fibers. The medulla oblongata is the primary site in the brain for regulating sympathetic and parasympathetic outflow to the heart and blood vessels. The hypothalamus and higher centers modify the activity of the medullary centers and are particularly important in regulating cardiovascular responses to emotion and stress (e.g., exercise, thermal stress).
The parasympathetic control of the heart is primarily mediated by the vagus nerve, which significantly influences the heart rate and rhythm. The vagus nerve originates in the brainstem at the medulla oblongata. [1] The nerve has three nuclei in the central nervous system associated with cardiovascular control: (1) the dorsal motor nucleus, (2) the nucleus ambiguus, and (3) the solitary nucleus. The parasympathetic output to the heart comes mainly from neurons in the nucleus ambiguus and to a lesser extent from the dorsal motor nucleus (see the image below). [2] The solitary nucleus, being an integrating hub for the baroreflex, receives sensory input about the state of the cardiovascular system.
Schematic illustration of arterial baroreceptor reflex. SNS = sympathetic nervous system.
Sympathetic innervation of the heart originates from preganglionic neurons located in the spinal cord's thoracic segments (T1-T4 or T5). These neurons project to postganglionic neurons in sympathetic ganglia, such as the stellate ganglia, which then innervate cardiac tissues. Sympathetic fibers increase the heart rate and contractility through norepinephrine (NE) release, acting on beta-adrenergic receptors on cardiomyocytes. [3]
The afferent fibers of the autonomic nervous system of the heart share the same pathway with gastrointestinal, genitourinary, baroreceptors, and chemoreceptors and transmit signals to the medulla by cranial nerves X and IX. The nucleus tractus solitarius (NTS) of the medulla receives sensory input from baroreceptors and chemoreceptors (see the image above).
Autonomic outflow from the medulla is divided principally into sympathetic and parasympathetic branches (see the image below). All the fibers forming the different cardiac plexus present synapse with the cervical plexus, brachial plexus, and intercostal nerves through communicating branches. These synapses have great importance in the presence of pain in certain cardiac pathologies. [2]
See also Heart Anatomy, Aortic Valve Anatomy, Mitral Valve Anatomy, Pulmonic Valve Anatomy, and Tricuspid Valve Anatomy.
Gross and Microscopic Anatomy
Gross anatomy
Sympathetic nervous system
Sympathetic nerves travel along arteries and other nerves and are found in the adventitia (e.g., outer wall) of blood vessels. Varicosities, which are small enlargements along the nerve fibers, are the site of neurotransmitter release. Sympathetic efferent nerves are present throughout the atria, ventricles (including the conduction system), and myocytes in the heart and also the sinoatrial (SA) and atrioventricular (AV) nodes. These adrenergic nerves release NE, which plays a crucial role in regulating heart rate and contractility. [1]
The preganglionic sympathetic fiber cell bodies are located in the lateral column of the spinal cord, extending to form synapses in the cervical and thoracic ganglia. [1] These fibers give origin to the three cervical ganglia and to the first three or four thoracic ganglia. [4, 5] The postganglionic fibers then project to various cardiac structures, influencing heart function. [1]
The cardiac branches of the superior ganglion or superior cardiac nerves (located at the C2 and C3 vertebrae) originate on the inferior portion of the mentioned ganglion. These superior cardiac nerves unite with nerves from other cervical ganglia en route to the cardiac plexus. The cervical ganglia are located along the carotid artery and in front of the scalene muscles of the neck.
The middle cervical ganglion is tiny and can be absent (it is located at the C6 vertebra, near the inferior thyroid artery). Its cardiac branch, the middle cardiac nerve, arises independently or emerges after the synapse with the inferior cervical ganglion. On the right side, it descends behind the subclavian artery to feed the cardiac plexus. On its way, it receives numerous branches from the vagus nerve. On the left side, the nerve enters the thorax posterior to the left subclavian artery, and it converges on the cardiac plexus.
The inferior cervical ganglion is located between the base of the transverse process of the last cervical vertebra and the first rib, on the medial side of the vertebral artery. Its cardiac branch, the inferior cardiac nerve, descends behind the subclavian artery and along the anterior surface of the trachea, finally joining the cardiac plexus. [4, 6]
The cardiac plexus is a network of sympathetic and parasympathetic fibers located at the base of the heart. It consists of a superficial part beneath the aortic arch and a deep part near the base of the heart. The sympathetic component originates from the cervical ganglia and T1-T4 or T5, while the parasympathetic input comes from the vagus nerve. [7]
Parasympathetic nervous system (vagus nerve)
The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the parasympathetic nervous system, which is responsible for regulating various involuntary bodily functions. [1] The name vagus comes from Latin and means "wandering." The vagus is a mixed nerve that has a role in sensory, motor, and secretory functions, and it contains approximately 80% sensory fibers. [8]
The vagus nerve exits the medulla oblongata between the olive and the inferior cerebellar peduncle and leaves the skull through the jugular foramen. It descends in the carotid sheath alongside the carotid artery and jugular vein, traversing from the brainstem to various organs in the neck, thorax, and abdomen. [9]
Unlike sympathetic innervation, which must first synapse within chain ganglia to supply the heart with postsynaptic fibers, the parasympathetic fibers synapse at the ganglia located directly on the heart and short postsynaptic fibers then supply the target organ. The parasympathetic nervous system mainly innervates the SA and AV nodes in the heart. The right vagus nerve predominantly influences the SA node, while the left vagus nerve has a more substantial effect on AV node conduction. [3]
Atrial muscle is also innervated by vagal efferents, whereas the ventricular myocardium is only sparsely innervated by vagal efferents. This selective innervation helps modulate cardiac output efficiently. Studies have revealed significant muscarinic receptor distribution and direct vagal influence on ventricular myocytes, affecting electrophysiology and contractility. This effect is achieved through interactions that counteract sympathetic activity, demonstrating a refined balance between the two autonomic systems. [10]
The vagus nerve reduces the heart rate by releasing acetylcholine at synapses within cardiac ganglia situated around the heart. This neurotransmitter binds to muscarinic receptors, leading to decreased heart rate and reduced force of contraction. [9]
Parasympathetic activity through the vagus nerve slows the heart rate, prolongs AV conduction, and reduces myocardial contractility during heightened sympathetic activity, a phenomenon known as "accentuated antagonism." Additionally, the vagus nerve's role in regulating arrhythmogenesis and protecting against ventricular fibrillation highlights its clinical importance. [10]
Natural variants
The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, significant overlap can exist in the anatomic distribution.
Studies have shown that despite this overlap, there are parallel yet functionally distinct pathways from the right and left vagi to the SA and AV nodal regions. This suggests a level of redundancy and adaptability in cardiac autonomic regulation. [11]
Microscopic anatomy
Alpha-adrenergic receptors are crucial in the regulation of cardiovascular functions. There are two primary types: alpha-1 (α1) receptors and alpha-2 (α2) receptors. [12]
The α1 receptors are located postsynaptically on the membrane of the effector cells such as vascular smooth muscle cells. They play a significant role in vasoconstriction by increasing intracellular calcium levels through the G-protein pathway, which activates phospholipase C, leading to smooth muscle contraction. In the heart, α1 receptors are distributed throughout the coronary microcirculation and are responsible for coronary vasoconstriction. [12]
The α2 receptors are located presynaptically on the cell membrane of the sympathetic nerve innervating the effector cells. They function as autoreceptors that inhibit the release of NE through a negative feedback mechanism involving Gi protein, which decreases cyclic AMP levels and reduces calcium influx. In coronary circulation, α2 receptors are more prevalent in arterioles and contribute to vasoconstriction during conditions such as coronary hypoperfusion. [13]
The following image demonstrates autonomic stimulation of the heart rate. [14]
Autonomic stimulation of the heart rate acts through G-protein coupled receptors (GPCR). Parasympathetic activation (vagus nerve) exerts an inhibitory action on the heart: it slows conduction from the sinus node, leading to bradycardia, and reduces conduction via the atrioventricular node. Activation by the sympathetic nervous system exerts an excitatory action on the heart: it stimulates sinus node and atrioventricular conduction, leading to faster heart rate. One pattern of signal transduction linking the autonomic nervous system to the intracellular effector is mediated through the cyclic adenosine monophosphate (cAMP) pathway. The muscarinic (M2) receptor, which is stimulated by the vagus nerve, binds acetylcholine and is coupled to the inhibitory G protein (Gi). The beta-adrenergic (B1) receptor, which is stimulated by the sympathetic nervous system, binds catecholamines and is coupled to the stimulatory G protein (Gs). When ligands bind to their respective GPCR, activated heterotrimeric G protein complexes dissociate from the GPCR and split into activated Gi and Gs subunits, which act on adenylyl cyclase. Gs stimulates adenyl cyclase to enhance cAMP production, whereas Gi proteins prevent cAMP production. The cAMP signaling cascade leads to an increased heart rate. Manipulation of this signaling pathway by gene therapy may be useful in treating cardiac arrhythmias.
Sympathetic and parasympathetic receptors are shown in the image below.
Pathophysiologic Variants
Sympathetic activation
Activation of sympathetic nerves during exercise, emotional stress, dehydration, or hemorrhage causes the vasoconstriction of arteries and veins mediated by alpha-adrenoceptors and increased heart rate (positive chronotropy), contractility (positive inotropy), rate of relaxation (increased lusitropy), and conduction velocity (positive dromotropy) by the beta-1 (β1) adrenoceptors.
Parasympathetic activation
The parasympathetic system effects are mediated by muscarinic receptors. The SA and AV nodes have extensive vagal innervation. Parasympathetic effects on inotropy are weak in the ventricle but relatively strong in the atria. This produces negative chronotropy and dromotropy in the heart as well as negative inotropy and lusitropy in the atria (the negative inotropic and lusitropic effects of vagal stimulation are relatively weak in the ventricles).
Chest pain and myocardial ischemia
The heart does not ache. However, chest pain is one of the most important symptoms of heart disease. A probable explanation is that metabolic changes suffered by the myocardial cells produce "irritation" of nerve fibers.
An imbalance between myocardial oxygen supply and demand leads to metabolic shifts in myocardial cells from aerobic to anaerobic metabolism. These changes result in the release of chemical mediators such as adenosine, bradykinin, and lactate, which stimulate sensory nerve endings in the myocardium and coronary vessels. [15]
The mechanism of referred pain is not clear, but the most probable explanation involves a final common pathway in the spinal cord with cerebral interpretation toward the somatic rather than the visceral location. Cardiac visceral sensory pain fibers follow the sympathetic efferent fibers, which supply the heart, back to the spinal cord; they have cell bodies located in thoracic dorsal root ganglia at the spinal level 1-4 or 5. Painful sensation mediated by visceral afferent fibers that enter the spinal cord at a particular level is referred to the somatic dermatome corresponding to that vertebral level.
Pain originating in the heart (visceral pain) is usually referred to the somatic body regions of the left upper limb, shoulder, neck/jaw and precordium. Interestingly, both sets of first order nerves (visceral afferent from heart & somatic sensory dermatomal) synapse is the dorsal horn of the spinal cord on second order neurons in the same vicinity. The most likely mechanism of referred pain would be visceral afferent pain fibers from heart releasing neurotransmitter in the dorsal horn of the spinal cord and these signaling molecules cross activating second order somatic afferent pathways.
The CNS does not clearly discern whether the pain is coming from the body wall or from the viscera, but the heart pain is most usually referred to somewhere on the body wall (i.e. substernal pain, left arm/hand pain, jaw pain) due to this cross signaling. Radiation to both arms is a stronger predictor of acute myocardial infarction. [16, 17]
The underlying neural remodeling in conditions such as myocardial ischemia can involve increased sympathetic activity and reduced parasympathetic modulation, contributing to altered pain perception. Studies highlight variations in autonomic innervation density across cardiac regions. Parasympathetic fibers are denser in the endocardium than the epicardium, with regional differences between ventricles. Sympathetic innervation predominates in the coronary arteries, especially smaller distal vessels. These patterns influence cardiac performance under both normal and ischemic conditions. [18]
Valsalva maneuver
The Valsalva maneuver provides a measure of sympathetic, vagal, and baroreceptor function. It involves a forced expiratory effort against a closed airway, leading to complex cardiovascular responses due to changes in intrathoracic and intra-abdominal pressures. These responses are regulated by various mechanisms, primarily aimed at controlling arterial blood pressure through baroreceptors, with contributions from pulmonary stretch receptors and chemoreceptors. [19] This maneuver has the following four phases:
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Phase 1 - Transient rise in arterial pressure and an associated decrease in the heart rate
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Phase 2 - Gradual fall in blood pressure, followed by recovery (an increase in heart rate accompanies this phase [during the expiratory phase of the maneuver])
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Phase 3 - Brief fall in blood pressure with an accompanying increase in heart rate occurring with the cessation of straining
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Phase 4 - Increase in blood pressure above the resting value (the "overshoot") and bradycardia
Phases 1 and 3 most likely reflect mechanical factors (e.g., intrathoracic pressure changes), whereas phases 2 and 4 are a consequence of sympathetic, vagal, and baroreflex interactions. [20, 21] Clinical variations in the response to this maneuver, such as exaggerated or blunted heart rate and blood pressure changes, can indicate underlying autonomic dysfunctions, including adrenergic failure or baroreflex abnormalities. Factors such as age, gender, effort duration, and medications can also influence these outcomes, highlighting the need for individualized interpretation in diagnostic settings. [22]
Neurocardiogenic (vasovagal) syncope
Neurocardiogenic syncope, also known as vasovagal reaction, is a common cause of syncope. [23] Neurally mediated (reflex) syncope refers to a reflex response causing vasodilatation and/or bradycardia (rarely tachycardia), leading to systemic hypotension and cerebral hypoperfusion. [24] The types of neurally mediated syncope include neurocardiogenic (vasovagal) syncope, carotid sinus syncope, situational syncope, and glossopharyngeal neuralgia.
The following three types of responses are seen: (1) cardioinhibitory response, (2) vasodepressor response, and (3) mixed response with both features. [25] It is likely that sensory inputs through vagal afferents, pain pathways, and central pathways (visual, temporal lobe, and other inputs) affect the NTS to cause sympathoinhibition and vagal efferent activation. The Bezold-Jarisch and carotid sinus reflexes may be involved. Patients may have increased muscle sympathetic nerve activity at rest and a blunted response to orthostatic stress. [26, 27]
Bezold-Jarisch reflex
The Bezold-Jarisch reflex is an eponym for a triad of responses (apnea, bradycardia, and hypotension) following the intravenous injection of Veratrum alkaloids in experimental animals. This observation was first reported in 1867 by von Bezold and Hirt and confirmed in 1938-1940 by Jarisch. [28]
The reflex originates in cardiac sensory receptors with nonmyelinated vagal afferent pathways (C fibers). The left ventricle, particularly the inferoposterior wall, is a principal location for these sensory receptors. Stimulation of these inhibitory cardiac receptors by stretch, chemical substances, or drugs increases parasympathetic activity and inhibits sympathetic activity. These effects promote reflex bradycardia, vasodilation, and hypotension, as well as modulate renin release and vasopressin secretion. [29]
Carotid sinus reflex
Blood pressure and heart rate are normally controlled in part by input from the baroreceptors located within the carotid sinus and aortic arch. An increase in blood pressure or pressure applied to the carotid sinus enhances the baroreceptor firing rate and activates vagal efferents, thereby slowing the heart rate and reducing the blood pressure.
Oculocardiac and trigeminocardiac reflexes
The oculocardiac reflex involves a decrease in heart rate and/or blood pressure in response to eyeball pressure. The reflex is thought to originate from the ophthalmic portion of the trigeminal nerve. Afferent stimuli move through the reticular formation and nuclei of the vagus nerve output and proceed via an efferent link through the vagus nerve to cardiovascular structures.
The trigeminocardiac reflex (TCR) is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, this could occur during craniofacial surgery, orbital fracture, balloon-compression rhizolysis of the trigeminal ganglion, and tumor resection in the cerebellopontine angle.
The proposed mechanism for the development of TCR is the sensory nerve endings of the trigeminal nerve send neuronal signals via the Gasserian (trigeminal) ganglion to the sensory nucleus of the trigeminal nerve, forming the afferent pathway of the reflex arc. The reaction subsides with cessation of the stimulus. Some patients may develop severe bradycardia, asystole, and hypotension, which require intervention. [30]
Sudden cardiac death
Diseases of cardiac nerves have been postulated to have a role in sudden cardiac death. Neural involvement may be the result of random damage to neural elements within the myocardium, or they may be primary, as in selective viral neuropathy. Secondary involvement can be a consequence of ischemic neural injury and has been postulated to result in autonomic destabilization, enhancing the propensity to arrhythmias. Nerve sprouting may be important. [31]
Postural tachycardia syndrome
Postural tachycardia syndrome (POTS) is an exaggerated increase in heart rate on tilt table testing or standing. The etiology of POTS is not clear, but the disorder may be heterogeneous. Abnormalities in autonomic regulation that may either be genetic or acquired are described (see Anatomy of the Autonomic Nervous System). Proposed mechanisms include partial sympathetic denervation leading to discordant cardiac and vascular sympathetic control, hypovolemia and impairment of the renin-angiotensin-aldosterone system, venous abnormalities, and baroreflex dysfunction. There is additional evidence of an attenuated vagal baroreflex response in POTS, as measured by changes in heart rate variability (HRV) in response to Valsalva and lower body negative pressure. [32, 33]
Beat-to-beat variability
The beat-to-beat variability in heart rate accompanying respiration at normal respiratory rates is predominantly mediated by the vagus nerve and is reduced or abolished by vagotomy, vagus nerve cooling, and muscarinic blockade. The determinants of the respiratory fluctuations in heart rate include a stretch reflex from the lungs and thoracic wall, changes in cardiac filling, arterial baroreceptor responses to blood pressure changes, changes in baroreflex sensitivity with respiratory phase, and respiratory center activity overflow to medullary vasomotor neurons.
The amplitude of the beat-to-beat variation with respiration (i.e., the maximum minus minimum heart rate difference, as measured in beats per minute [bpm]) and the E:I ratio (ratio of expiration to inspiration) are generally regarded as the simplest and most reliable measures of HRV in response to deep respiration. The maximum heart rate variation in response to deep breathing is a sensitive and specific index of autonomic function. This test is the best noninvasive test to assess cardiac vagal innervation.
Studies have highlighted the role of the vagus nerve in producing beat-to-beat HRV. Experiments have shown that vagal stimulation can cause significant HRV even after vagotomy, indicating that well-timed bursts of vagal activity are crucial for this variability. This supports the idea that HRV is not merely a reflection of heart rate but also an indicator of autonomic nervous system dynamics. [34]
Apneic facial immersion
In humans, the diving reflex has been studied as a tool to assess the autonomic nervous system. [35] The expected response in normal subjects results from a combination of facial immersion and breath holding. The expected effect is parasympathetic-mediated bradycardia and sympathetic-mediated peripheral vasoconstriction. [36]
Heart transplant
Suturing the ventricular nervous pathways or reestablishing the intrinsic linking of the cardiac electrical system is almost impossible. However, the rhythm is spontaneously reestablished, even when a cardiac pacemaker (in 10-20% of the cases) is eventually necessary. Because the vagus nerve is separated during the operation, the new heart beats at around 100 bpm until nerve regrowth occurs. This way, the heart rate maintains itself almost invariable, independent of somatic activity, and patients do not perceive ischemic pain.
Biofeedback
Biofeedback is the process of becoming aware of various physiologic functions using instruments that provide information on the activity of those same systems, with a goal of being able to manipulate them at will. Behavioral neurocardiac training with HRV biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. Whether the efficacy of this treatment can be improved with biofeedback of baroreflex gain is unknown. [37] Reduced HRV seems to indicate decreased cardiac vagal tone and elevated sympathetic activity in patients with anxiety and depression and would reflect deficit in the flexibility of emotional physiologic mechanisms.
A few studies have also revealed that biofeedback using respiratory control, relaxation, and meditation techniques can increase HRV. For now, insufficient data exist to determine if paced respiration or subjective relaxation is necessary or sufficient for the efficacy of HRV biofeedback. [38]
Carotid sinus hypersensitivity
Carotid sinus hypersensitivity is a common cause of syncope. The carotid sinus reflex arc is composed of an afferent limb arising from mechanoreceptors in the internal carotid artery that transmit impulses through cranial nerve IX to the medulla and terminate in the NTS in the vagal nucleus and the vasomotor center. The efferent limb innervates the SA and AV nodes via the vagus nerve and the parasympathetic ganglia and also inhibits sympathetic nervous tone to the heart and blood vessels.
Neurohormonal adaptation in heart failure
Sympathetic nervous system activation is a compensatory mechanism in heart failure with inotropic and chronotropic activity. Sympathetic activation is associated with pathologic ventricular remodeling, increased arrhythmias, sudden death, and increased mortality in patients with chronic heart failure. Preliminary human studies suggest a positive effect of statins on the sympathovagal balance in patients with heart failure. [39]
Autonomic failure syndrome (orthostatic hypotension)
Orthostatic hypotension (OH) is a common cardiovascular disorder, with or without signs of underlying neurodegenerative disease. OH is defined as a decrease of ≥ 20 mmHg in systolic blood pressure or ≥ 10 mmHg in diastolic blood pressure within 2 minutes of standing. Its prevalence depends on age, ranging from 5% in patients younger than 50 years to 30% in those older than 70 years. OH may complicate the treatment of hypertension, heart failure, and coronary artery disease; cause disabling symptoms, syncope, and traumatic injuries; and substantially reduce quality of life.
In healthy individuals, approximately 25-30% of circulating blood volume is found within the thoracic cavity while supine. Almost immediately, with the transition from supine to upright position, a gravity-mediated displacement of nearly 500 mL of blood away from the chest to the distensible venous capacitance system below the diaphragm (venous pooling) occurs. This results in a rapid decrease in central blood volume and a subsequent reduction in ventricular preload, stroke volume, and mean blood pressure. In the vascular system, a reference quantitative determinant of these changes is the venous hydrostatic indifference point (HIP), when pressure is independent of posture. In humans, the venous HIP is approximately at the diaphragmatic level, whereas the arterial HIP lies close to the level of the left ventricle. The venous HIP is dynamic and is significantly affected by venous compliance and muscular activity.
Upon standing, contractions of lower limb muscles, along with the presence of venous valves, provide an intermittent unidirectional flow, moving the venous HIP toward the right atrial level. Respiration may also increase venous return because deep inspiration results in both a decline in thoracic pressure and an increase in intra-abdominal pressure, which lowers retrograde flow due to compression of both the iliac and femoral veins. To provide appropriate perfusion pressure to critical organs, an effective set of the neural regulatory system is promptly activated upon standing.
The sympathetic nervous system is fast-acting and primarily modulated by mechanoreceptors and, to a smaller degree, by chemoreceptors. Arterial baroreceptors (high-pressure receptors) are located in the carotid sinus and the aortic arch and — by conveying baroceptive impulses via the carotid sinus and aortic depressor nerves to the brainstem, notably in the nucleus of the solitary tract — determine tonic inhibition of vasomotor centers. In contrast, cardiopulmonary baroreceptors (volume receptors) are located in the great veins and cardiac chambers and detect changes in the filling of central venous circulation but are not essential for orthostatic cardiovascular homeostasis. A sudden drop in blood pressure in the carotid sinus and the aortic arch triggers baroreceptor-mediated compensatory mechanisms within seconds, resulting in increased heart rate, myocardial contractility, and peripheral vasoconstriction. An additional local axon reflex, the veno-arteriolar axon reflex, results in constriction of arterial flow to the muscles, skin, and adipose tissue, leading to almost half of the increase in vascular resistance in the limbs upon standing. Ultimately, orthostatic stabilization is normally achieved in roughly 1 min or less.
During prolonged quiet standing, in addition to venous pooling, transcapillary filtration in the subdiaphragmatic space further reduces both central blood volume and cardiac output by approximately 15-20%. This transcapillary shift equilibrates after approximately 30 min of upright posture, which can result in a net fall in plasma volume of up to 10% over this time. Continued upright posture also results in the activation of neuroendocrine mechanisms, such as the renin-angiotensin-aldosterone system, which may vary in intensity, depending on the volume status of the patient. Still, the most important homeostatic response to prolonged orthostatic stress appears to be the carotid baroreflex-mediated increase of peripheral vascular resistance. The inability of any one of these factors to perform adequately or coordinately may result in a failure of the system to compensate for an initial or sustained postural challenge. This may produce a transient or persistent state of hypotension, which, in turn, can lead to symptomatic cerebral hypoperfusion and loss of consciousness, either in the early or late phase of orthostatic challenge. [40, 41]
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Schematic illustration of arterial baroreceptor reflex. SNS = sympathetic nervous system.
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Sympathetic and parasympathetic efferents.
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Autonomic stimulation of the heart rate acts through G-protein coupled receptors (GPCR). Parasympathetic activation (vagus nerve) exerts an inhibitory action on the heart: it slows conduction from the sinus node, leading to bradycardia, and reduces conduction via the atrioventricular node. Activation by the sympathetic nervous system exerts an excitatory action on the heart: it stimulates sinus node and atrioventricular conduction, leading to faster heart rate. One pattern of signal transduction linking the autonomic nervous system to the intracellular effector is mediated through the cyclic adenosine monophosphate (cAMP) pathway. The muscarinic (M2) receptor, which is stimulated by the vagus nerve, binds acetylcholine and is coupled to the inhibitory G protein (Gi). The beta-adrenergic (B1) receptor, which is stimulated by the sympathetic nervous system, binds catecholamines and is coupled to the stimulatory G protein (Gs). When ligands bind to their respective GPCR, activated heterotrimeric G protein complexes dissociate from the GPCR and split into activated Gi and Gs subunits, which act on adenylyl cyclase. Gs stimulates adenyl cyclase to enhance cAMP production, whereas Gi proteins prevent cAMP production. The cAMP signaling cascade leads to an increased heart rate. Manipulation of this signaling pathway by gene therapy may be useful in treating cardiac arrhythmias.
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Sympathetic and parasympathetic neurotransmitters and receptors.
