Features of the sympathetic nervous system

Historical and Conceptual Overview

The term sympathetic nervous system originates in the second-century teaching of Galen that the peripheral nerves, conduits for distributing the animal spirit in the body, enable concerted, coordinated (i.e., sympathetic) functioning of body organs. The notion of the sympathetic nervous system, therefore, antedated by approximately 14 centuries Harvey's demonstration of the circulation of the blood.

The sympathetic nervous system is a major component of the autonomic nervous system. In the late nineteenth century, Langley introduced the phrase autonomic nervous system to refer to nerves emanating from cell bodies in ganglia alongside the spinal column and in the gastrointestinal-tract walls. Langley defined three components: sympathetic, with preganglionic cells in the thoracolumbar spinal cord; parasympathetic (a word he coined), with preganglionic cells in the brain stem or sacral spinal cord; and enteric, with preganglionic cells near or in the target organs. The nerves of these systems were thought to differ from those of the somatic nervous system, not only in terms of anatomy but also in terms of function. Somatic nerves mediate conscious, observable changes in skeletal muscle contraction and therefore movement, whereas autonomic nerves mediate unconscious, largely unobservable changes in smooth muscle contraction independently (autonomously) of the central nervous system.

The early-twentieth century American physiologist Walter B. Cannon introduced the word homeostasis. Cannon added a hormonal component to the autonomic nervous system when he theorized that the sympathetic nervous system and the adrenal gland worked together as a unit to maintain homeostasis in emergencies. In the 1930s, he even formally proposed that the sympathetic nervous system used the same chemical messenger – adrenaline – as did the adrenal gland (in 1946, von Euler correctly identified the sympathetic neurotransmitter in mammals as norepinephrine). Accumulating evidence supports the independent regulation of the sympathetic nervous and adrenomedullary hormonal systems, refuting the concept of a unitary sympathoadrenal system. Nevertheless, Cannon's views about the unitary function of the neural and hormonal components of the sympathoadrenal system prevail in stress research.

Sweating, whether to control body temperature (thermoregulatory), evoked by eating spicy food (gustatory), or accompanying fear or anxiety (emotional), is mediated by the sympathetic cholinergic system, in which acetylcholine rather than norepinephrine is the chemical messenger. The autonomic nervous system, therefore, can be viewed as having five components: sympathetic noradrenergic, sympathetic cholinergic, parasympathetic cholinergic, adrenomedullary, and enteric.

Sympathetic Nervous System

The SNS is an evolutionary response to stress. In times of danger, the SNS, through its main effector molecules, norepinephrine and epinephrine, increase heart rate, cardiac output, and increase blood flow to important stress response organs such as skeletal muscle. The SNS is, however, a short-term response and chronic activation leads to adrenergic receptor downregulation, persistent tachycardia, increased myocardial oxygen demand, and myocyte necrosis. Thus when the acute response of the SNS becomes a chronic response, SNS activity ultimately leads to further cardiac damage. In humans with heart disease, increased norepinephrine concentrations are a significant risk factor for mortality. Increased SNS activity is likely one of the earliest systemic responses to cardiac injury. In the emergent patient with low-output heart failure or CHF, temporary augmentation of already heightened SNS activity is occasionally needed to treat the acute event, but long-term stimulation of the SNS is not an objective of chronic heart failure therapy.

1 Introduction

PSNS development, from the induction of NC through the overt differentiation of sympathetic ganglia, can be readily observed within the first 5 days of zebrafish development (An et al., 2002). During this time, dynamic changes in both the numbers and the distribution of sympathetic cells within the SCG can be easily visualized by th mRNA whole-mount in situ hybridization. At 2 dpf, bilateral rows containing approximately 5–10 th-positive cells are ventrally located near the dorsal aorta. By 5 dpf, the number of th-positive cells have increased fivefold and coalesced into a V-shaped ganglia, including some appearing to migrate ventrally toward the kidney, which may represent putative adrenal chromaffin cells (An et al., 2002). Thus, the evaluation of SCG formation at 3- and 5 dpf represents an excellent assay for early PSNS development that can be used in combination with forward genetic screens to detect novel mutations affecting different stages of PSNS development. Assaying the SCG would also be able to confirm mutations found to affect very early NC development. Such mutagenesis screens have been performed and examples of the different mutant classes that have been isolated thus far are discussed below.

Aging and the Sympatho–Adrenal System

The sympathetic nervous system (SNS) plays an essential role in the maintenance of physiological homeostasis in general and arterial blood pressure in particular. This appears to be the case both under basal (resting) conditions and in response to acute stress. Postganglionic sympathetic neurons innervating the heart and resistance vessels help to control cardiac output, arterial blood pressure, and regional vascular conductance, thereby ensuring the proper perfusion of vital organs. SNS stimulation of adrenalin (epinephrine) release from the adrenal medulla contributes significantly to the regulation of cardiovascular function and regulates energy metabolism. The SNS also has a key role in the regulation of internal body temperature. Impairment of SNS function has been implicated in the development of a variety of common medical conditions, including hypertension, congestive heart failure, sudden cardiac death, insulin resistance (metabolic) syndrome, and obesity. Thus, understanding the mechanisms of SNS dysfunction in these conditions is of major clinical significance.

The current literature supports the view that basal SNS activity increases with advancing age in healthy adult humans. Elevation in SNS activity appears to be region specific, targeting skeletal muscle and the gut rather than other organs innervated by the SNS such as the kidney. The SNS tone of the heart is increased, due primarily to reduced neuronal noradrenalin reuptake. In contrast, basal and stress-associated adrenalin secretion from the adrenal medulla is reduced markedly in human aging. Despite decreased secretion, plasma adrenalin concentrations are relatively unchanged due to a concomitant reduction in plasma clearance of adrenalin. The mechanisms underlying these age-associated changes in sympatho–adrenal function have not been established. Evolving research suggests that the increase in basal peripheral SNS activity with age is associated with elevated forebrain noradrenergic activity. These studies support the hypothesis that increased central nervous system sympathetic activity may underlie peripheral increases in SNS tone noted in studies of aged humans. The situation in other animal models appears to be rather different. In particular, whereas reduced peripheral baroreflex inhibition appears to be an important primary change with aging in animal studies, baroreceptor function in aged humans appears to be relatively preserved.

Reduced arterial compliance is a well-described feature of aging. It is less clear whether neuromuscular function of the venous system is altered by aging. Age-associated changes in venous compliance have been difficult to document, although some studies in humans have shown that aging reduces venous compliance and capacity. The constrictor response of the human dorsal hand vein to the α-adrenoceptor agonists noradrenalin and phenylephrine is unchanged. However, aging is associated with a reduced dilator response to the β-adrenoceptor agonist isoprenalin, and this may have clinical implications in patients who require these agents for blood pressure support. In summary, adult human aging is associated with significant changes in SNS physiological function and regulation that likely have clinical implications.

Central Nervous System Integration

SNS and PNS outflow is coordinated in the cardiovascular centers of the medulla. The dorsolateral medulla initiates responses that raise blood pressure, and the ventromedial medulla initiates responses that lower blood pressure. Medullary cardiovascular centers receive descending input from cerebral cortex, thalamus, hypothalamus, and diencephalon (Fig. 8-12).

A variety of afferent inputs impact cardiovascular control. Arterial baroreceptors regulate both sympathetic and parasympathetic activity. Cardiopulmonary volume receptors selectively control renal sympathetic nerves and also antidiuretic hormone release. Peripheral chemoreceptors of the aortic body and carotid body mediate effects of blood gas changes on the SNS. Central chemoreceptors respond to high CO2 with general sympathetic activation, as seen in the central nervous system (CNS) ischemic response and in Cushing's reflex. The hypothalamus has some direct effects, notably body temperature—sensitive control of cutaneous circulation. Output from the cerebrum normally is pressor but occasionally is depressor, e.g., blushing and fainting. Pain fibers can elicit diverse cardiovascular responses: skin pain often is pressor and visceral pain often is depressor.

Association between RLS/PLMs and sympathetic activation

Sympathetic nervous system (SNS) activity may contribute to generating the periodicity of PLMs. Two patients with insomnia who were found to have PLMs on PSG, also complained of cold feet. After a plethysmographic assessment demonstrated blunted pulses, warming of the lower extremity improved the pulses suggesting vasoconstriction as a mediator of the pulse abnormality. Treatment with phenoxybenzamine, a post-synaptic α-1 blocker, resulted in improvement of symptoms of cold feet as well as the PLMs suggesting sympathetic nervous system involvement in the vascular constriction as well as the periodicity of the PLMs. The authors pointed out that the SNS inherent periodicity of 20–40 s reflected that typically seen with PLMs (Ware et al., 1988). In addition, patients with RLS have decreased cardiovagal baroreceptor gain and increased calf vascular resistance, which may be mediated by the sympathetic nervous system (Bertisch et al., 2016).

In patients with restless legs syndrome, both systolic and diastolic blood pressures rise following a periodic limb movement during sleep with the peak occurring about 6–7 s following the limb movement. The average change in SBP was 16.7 mmHg when the limb movement was associated with a cortical arousal, and 11.2 mmHg when the limb movement was not. The consistent association between rise in blood pressure and limb movements supports the hypothesis that periodic limb movements are a component of an autonomic surge (Siddiqui et al., 2007). Another analysis of blood pressure changes associated with PLMs also found increases in systolic and diastolic pressures independent of whether micro-arousals were present, or not. Increases in blood pressures were noted several heartbeats after the PLM occurred, and were greater when micro-arousals were associated with the PLMs, than when they were not. The responses in blood pressures were greater with advancing age, longer history of RLS, and by longer duration of the associated micro-arousal (Pennestri et al., 2007).

PLMs have been shown to associate with hypertension severity. In one study that grouped patients according to the severity of their hypertension, those with more severe hypertension demonstrated statistically more PLMs than those with less severe hypertension. Age influenced the occurrence of PLMs, with patients over 50 years-old demonstrating more PLMs, and those with PLMs demonstrating a higher mean age than those without PLMs, but not the association between PLMs and hypertension. The presence, or absence of arousals did not affect the association between PLMs and hypertension severity (Espinar-Sierra et al., 1997).

5.18.5 Conclusions

SNS plays an intriguing role in maintaining pain in certain conditions. Complex regional pain syndromes are prime example of such states. Selective sympathetic blocks are commonly used to diagnose a subset of patients with a predominant sympathetically maintained pain state. In order to avoid false-positive diagnosis, at least two different diagnostic tests should be implicated on separate days to confirm the diagnosis. Treatment options that have shown some promising results include local anesthetic sympathetic blocks, SCS, radiofrequency techniques, and surgical sympathectomy in early stages. Visceral pain of pancreatic origin responds well to chemical neurolytic blocks. More randomized trials are warranted to prove long-term efficacy of neuromodulation as well as neurodestructive techniques.

SNS and the SAM Axis

The SNS influences the cardiovascular system, the gastrointestinal (GI) tract, respiration, renal, endocrine, and other systems, while the parasympathetic nervous system contributes by “withdrawing” and inhibiting the SNS. The SNS response is mediated by the locus coeruleus (LC)/noradrenergic system, comprising the noradrenergic cells of the medulla and pons. The CE projects to the brain stem to increase noradrenaline (NA) release from sympathetic nerve endings, sympathetic activation, and activation of the adrenal medulla, resulting in increased adrenaline and NA levels, arousal, and vigilance, that is, enhanced processing of external cues. The SAM system releases catecholamines (mostly adrenaline) into the bloodstream while the SNS with cholinergic preganglionic fibers releases NA from postganglionic axons. SNS innervation of peripheral organs is mediated by efferent preganglionic fibers, with cell bodies in the intermediolateral column of the spinal cord. These synapse in the sympathetic ganglia with postganglionic neurons, which innervate the vascular smooth muscle, heart, skeletal muscles, gut, kidney, fat, etc. Blood pressure and heart rate are elevated and energy resources are diverted to the musculature and away from vegetative functions.

At the same time, the hypothalamus is activated by the amygdala (largely indirectly; Herman et al., 2003) to release corticotropin-releasing hormone (CRH), and HPA activation ensues. Thus the two arms of the stress response system are both closely connected with amygdala and brain-stem function. Through its projections to the amygdala, the SNS enhances long-term storage of aversive emotional memories in the hippocampus and striatum. Noradrenergic responses to stressors may be modulated by higher centers such as the mesocortical/mesolimbic systems (influencing affect and anticipation); the amygdala and hippocampus, modulating the stress output (initiation, propagation, and termination of the response); and the arcuate nucleus, modulating pain.

Noradrenalin

Sympathetic nervous system tone is known to be enhanced in subjects with high hostility scores (Williams, 1994). Singer et al (1990) showed for the first time that administration of omega-3 PUFAs (EPA 1.8 g+DHA 1.1 g per day) for 36 weeks reduced plasma noradrenaline (NA) levels in male patients with mild essential hypertension. We have previously investigated the effect of omega-3 PUFAs in two different studies with healthy volunteers (both university students) and found that administration of omega-3 PUFAs for 8–9 weeks reduced plasma NA concentrations (Sawazaki et al., 1999; Hamazaki et al., 2005). However, this was not supported by short-term (1 month) intervention studies with omega-3 PUFAs (Hughes et al., 1991; Mills et al., 1990). Changes in central NA levels by omega-3 PUFAs might explain the relationship between these fatty acids and aggression.

Elevated Sympathetic Tone and Local Nerve Fiber Loss

The sympathetic nervous system with its two effector arms, the adrenal medulla and peripheral sympathetic nerve fibers, is the major regulatory component of glycogenolysis, gluconeogenesis, and lipolysis. While the adrenal medulla is more the general stimulator of splanchnic organs, sympathetic nerve fibers can stimulate distinct adipose tissue regions in the body. Provision of energy-rich fuels by the sympathetic nervous system depends on β2-adrenergic receptor signaling. For example, catecholamines via β2-adrenergic receptors activate the hormone-sensitive lipase in order to breakdown triglycerides into glycerol (used in gluconeogenesis) and free fatty acids. The α2-adrenergic subtype of the receptor exerts antilipolytic effects.1578 Thus, an elevated systemic activity of the sympathetic nervous system supports lipolysis, gluconeogenesis, and glycogenolysis. In addition, a high firing rate of sympathetic nerve fibers to adipose tissue would support local lipolysis. This would happen in the presence of high noradrenaline concentrations that exert β-adrenergic effects (≥ 10- 7 mol/l).

Importantly, many chronic inflammatory systemic diseases are accompanied by increased levels of circulating proinflammatory cytokines and an elevated activity of the sympathetic nervous system, which can be a substantial risk factor for cardiovascular disease.1166–1169, 1591–1593 The circulating cytokines directly stimulate the sympathetic nervous system in the hypothalamus and locus coeruleus. In addition, hyperinsulinemia is related to increased sympathetic nervous system activity because insulin stimulates the sympathetic nervous system.1594 Chronic inflammatory systemic diseases are accompanied by hyperinsulinemia and the reasons for this phenomenon have been discussed above.

Under consideration of systemic energy regulation in chronic inflammatory systemic diseases, the somewhat higher activity of the sympathetic nervous system is important to sustain allocation of energy-rich fuels to the immune system and to maintain systemic circulation. Indeed, denervation of the sympathetic nervous system largely decreased inflammation in animal models.1042, 1116, 1595 The aggravating influence of late denervation of the sympathetic nervous system, recently demonstrated,1116 is most probably not related to sympathetic nerve fibers but, possibly, to the manipulation of anti-inflammatory tyrosine hydroxylase-positive sympathetic cells in inflamed tissue (see also Chapter II).607, 1121, 1122

It is important to recognize that many components of the immune system such as macrophages, dendritic cells, neutrophils, NK cells, and T helper type 1 cells are inhibited via β2-adrenergic stimulation. The parallel activation of β2-adrenergic receptors to stimulate lipolysis on one hand and to inhibit immune function on the other seems to be contradictory because the sympathetic nervous system should serve the activated immune system. The two contrasting functions of adrenergic neurotransmitters can be explained by compartmentalization (Figure 43). If sympathetic nerve fibers are lost in inflamed tissue but remain present in the adipose tissue, the two sympathetic functions can happen in parallel. Indeed, sympathetic nerve fibers get rapidly lost in inflamed tissue of patients with rheumatoid arthritis and animals with experimental arthritis and in the activated spleen and lymph nodes in arthritic animals.606, 1042, 1044, 1119 However, sympathetic nerve fibers remain present in adjacent adipose tissue near the inflamed tissue and surrounding the draining lymph node.1573 This compartmentalization allows parallel lipolysis (β2) and immune activation (α2 or α1) (Figure 43).

In conclusion, elevated systemic sympathetic activity as the consequence of an “energy appeal reaction” and local retraction of sympathetic nerve fibers are of importance to serve an acutely activated immune system either in inflamed tissue or in draining lymph nodes/spleen. It also serves water retention via activation of the renin-angiotensin-aldosterone system (next section), which is a pretty negative signal due to volume expansion and the proinflammatory influence of angiotensin II (see Chapter II). All these mechanisms were positively selected for short-lived inflammatory episodes, but they are deleterious in chronic inflammatory systemic disease.