Physiology - An Illustrated Review

4. Autonomic Nervous System

The autonomic nervous system (ANS) is a branch of the peripheral nervous system (PNS). ANS neurons innervate smooth muscle, cardiac muscle, and glands to maintain homeostasis. The ANS is not under voluntary control.

The other branches of the PNS are the somatic nervous system and the enteric nervous system.

– The somatic nervous system innervates skeletal muscle and is discussed in Chapter 6.

– The enteric nervous system innervates nerve plexuses in the gut and is discussed in Chapter 19.

4.1 Organization of the Autonomic Nervous System

The ANS has a parasympathetic and sympathetic division. Preganglionic neurons of both divisions originate in the central nervous system (CNS) but emerge from different regions. Preganglionic neurons are lightly myelinated B fibers; postganglionic neurons are unmyelinated C fibers with slower conduction velocity. Table 4.1 summarizes the main features of each division, and they are illustrated in Fig. 4.1.



Quadriplegia is caused by spinal cord injury at a high level. A ventilator may be required if the injury involves C3−C5, as these spinal nerves control the diaphragm (via the phrenic nerve), which is the major muscle that allows us to breathe. However, quad-riplegic patients can survive because the cranial nerves (ANS preganglionic parasym-pathetic nerves) remain intact and can coordinate vital bodily functions despite the patient’s having no voluntary control from below the level of injury.


Horner syndrome

Horner syndrome may occur due to an interruption of the sympathetic supply to the face through disease of the brainstem or thoracolumbar region of the spinal cord, for example, by stroke, tumors, carotid artery dissection (tearing on the lining of the artery), or spinal cord injury; or it may be idiopathic (cause not known). It causes pupillary constriction (miosis), a sunken eye (enophthalmos), drooping of the upper eyelid (ptosis), and ipsilateral loss of sweating (anhydrosis) on the affected side of the face. Treatment for this disease is directed at the underlying cause.


Fig. 4.1 image The autonomic nervous system.

The autonomic nervous system has a parasympathetic division and a sympathetic division. Parasympathetic preganglionic neurons arise in the cranial nerve nuclei or in the sacral region of the spinal cord. They are relatively long compared with the parasympathetic postganglionic neurons. Sympathetic preganglionic neurons, which arise in the thoracolumbar region of the spinal cord, are relatively short compared with the postganglionic neurons. Both pre- and postganglionic parasympathetic neurons release acetylcholine as their neurotransmitter substance. Sympathetic preganglionic neurons also release acetylcholine, but postganglionic neurons release norepinephrine. The exception to this is sweat glands, which are innervated by sympathetic postganglionic fibers that release acetylcholine.


4.2 Neurotransmitters

Neurotransmitters that act in both the CNS and ANS are also discussed in Chapter 2.


Synthesis. Acetylcholine is synthesized via the combination of acetate from acetyl coenzyme A (acetyl-CoA) and choline and is catalyzed by the enzyme choline acetyltransferase. The uptake of choline into the presynaptic terminal is the rate-limiting step in acetylcholine synthesis.

Release. Depolarization of the preganglionic membrane by an action potential causes increased Ca2+influx into the presynaptic terminal and the release of acetylcholine (Fig. 4.2).

Degradation. The breakdown of acetylcholine is rapid via a specific enzyme, acetylcholinesterase, to produce acetate and choline. Acetylcholinesterase is located in neuronal membranes and red blood cells. Pseudocholinesterases (nonspecific) and butyrylcholinesterases, which are more widely distributed, can also hydrolyze acetylcholine.

Fig. 4.2 image Acetylcholine: release and degradation.

Acetylcholine is stored in vesicles in the axoplasm of presynaptic nerve terminals. These vesicles are anchored via the protein synapsin to the cytoskeletal network, thus allowing for the concentration of vesicles near the presynaptic membrane while preventing fusion with the membrane. An action potential causes Ca2+ influx into the axoplasm of the presynaptic terminal through voltage-gated channels. Ca2+ then activates protein kinases that phosphorylate synapsin. This causes the vesicles to become free of the cytoskeleton, dock at the active zone, fuse with the presynaptic membrane, and release acetylcholine into the synaptic gap. Acetylcholine attaches to receptors on the postsynaptic membrane and exerts its effects. Acetylcholine is then hydrolyzed by acetylcholinesterase, with reuptake of the choline component into the presynaptic terminal. See page 38 for discussion of acetylcholine’s effects on muscarinic cholinergic receptors (M1, M2, M3).



Synthesis. Norepinephrine is synthesized from the precursor amino acid tyrosine by hydroxylation to dihydroxyphenylalanine (dopa) in postganglionic neurons of the sympathetic division. Dopa is decarboxylated to dopamine, which is oxidized to norepinephrine and packaged in vesicles.

Ascorbic acid redox reactions

Ascorbic acid (vitamin C) is involved in many processes in the body, including collagen and bile acid synthesis, activation of neuroendocrine hormones (e.g., gastrin, corticotropin-releasing hormone [CRH], and thyrotropin-releasing hormone [TRH]), iron absorption, and detoxification (via stimulation of cytochrome P450 enzymes in the liver. Ascorbic acid is oxidized to dehydroascorbic acid via an extremely reactive intermediate, semidehydro-L-ascorbate. The hydrogen ions that are liberated in this oxidation are able to act as donors in hydroxylation reaction throughout the body (which accounts for some of its effects). One such reaction is when ascorbic acid acts as a cofactor for dopamine-β-hydroxylase in the synthesis of norepinephrine and epinephrine.


Release. When stimulated by an action potential, the presynaptic membrane is depolarized, Ca2+ influx increases levels in the presynaptic terminal, and vesicles of norepinephrine are released. Norepinephrine then binds to adrenergic receptors on target cells (Fig. 4.3).

Fig. 4.3 image Synthesis and termination of norepinephrine (NE) and adrenergic transmission.

Postganglionic sympathetic nerve terminals possess varicosities that enable the nerves to lie in close proximity to effector organs. NE synthesis and storage in vesicles occur in these varicosities. An action potential at the nerve terminal causes the influx of Ca2+ and the subsequent release of NE into the synaptic cleft. NE then binds to adrenergic receptors on effector organs, thus exerting its physiological effect. Note that NE has little effect on the β2 adrenergic receptor, whereas epinephrine, synthesized in the adrenal medulla, acts at all adrenergic receptors. Approximately 70% of NE is taken back up into the presynaptic nerve terminal and repackaged in vesicles or it is inactivated by monoamine oxidase (MAO). In the heart, NE is inactivated by MAO or catecholamine-O-methyltransferase (COMT). See pages 38 and 39 for discussion of norepinephrine’s effects on α- and β-adrenergic receptors. (cAMP, cyclic adenosine monophosphate; PKA, protein kinase A)


Degradation. Termination of action of norepinephrine is primarily by reuptake (60−90%) into the nerve terminal. Secondary degradation is by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

4.3 Neurotransmitter Receptors

Neurotransmitter receptors and signal transduction are also discussed in Chapter 1.

Cholinergic Receptors

Acetylcholine receptors fall into two classes: nicotinic receptors and muscarinic receptors.

Nicotinic Receptors

Nicotinic receptors are ligand-gated ion channels that are activated by acetylcholine or nicotine. Receptor activation leads to opening of Na+ and K+ channels (Fig. 4.4) and excitation.

Fig. 4.4 image Acetylcholine receptors.

The nicotinic receptor consists of five protein subunits. Binding of acetylcholine to the two α subunits is thought to change its conformation, permitting the central pore to open and allowing the influx of ions into the cell. The muscarinic receptor is coupled to intracellular G proteins, which may then transduce excitatory effects via phospholipase C or inhibitory/excitatory effects via adenylate cyclase.



– Postganglionic neurons in autonomic ganglia of both the parasympathetic and sympathetic divisions

– Motor end-plates of skeletal muscles at the neuromuscular junction (NMJ)

– Chromaffin cells in the adrenal medulla

Myasthenia gravis

Myasthenia gravis is an autoimmune disease in which there are too few functioning acetylcholine receptors at the neuromuscular junction. P atients with this condition often present in young adulthood with easy fatiguability of muscles, which may progress to permanent muscle weakness. Treatment involves using neostigmine or similar agents to prolong the action of released acetylcholine.


Muscarinic Receptors

Muscarinic receptors are metabotropic and are coupled to G proteins. They are activated by acetylcholine and muscarine.

– They are present on the targets of all postganglionic parasympathetic neurons (see each receptor subtype for the location where they are predominantly found and their effects).

M1 receptors

– Location: CNS

– Signal transduction mechanism: Gq activation followed by ↑ inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG)

– Effect: Excitatory

M2 receptors

– Location: Heart

– Signal transduction mechanism: Giactivation followed by ↓ cyclic adenosine monophosphate (cAMP)

– Effect: Inhibitory (decreased heart rate and velocity of contraction)

M3 receptors

– Location: Smooth muscle, glands

– Signal transduction mechanism: Gq activation followed by ↑ IP3 and DAG

– Effect: Excitatory (increased contraction of smooth muscle; increased secretion from glands)

Adrenergic Receptors

Adrenergic receptors are divided into α receptors (α1 and α2) and β receptors (β1, β2, and β3). Both norepinephrine and epinephrine activate adrenergic receptors, but the sensitivity varies within the receptor subtypes.

α1 receptors

– Location: Vascular smooth muscle

– Neurotransmitter sensitivity: Equal sensitivity to norepinephrine and epinephrine.

– Signal transduction mechanism: Gq activation followed by ↑ IP3 and DAG

– Effect: Excitatory (contraction of vascular smooth muscle)

α2 receptors

– Location: Autoreceptors at presynaptic terminals of sympathetic neurons

– Neurotransmitter sensitivity: More sensitive to epinephrine than norepinephrine

– Signal transduction mechanism: Gi activation followed by ↓ cAMP

– Effect: Inhibitory (block the release of norepinephrine from presynaptic terminals)

β1 receptors

– Location: Sinoatrial (SA) node, atrioventricular (AV) node, and cardiac ventricular muscle

– Neurotransmitter sensitivity: Equally sensitive to both norepinephrine and epinephrine

– Signal transduction mechanism: Gs activation followed by ↑ cAMP

– Effect: Excitatory (increased heart rate, force, and velocity of contraction)

β2 receptors

– Location: Bronchial smooth muscle

– Neurotransmitter sensitivity: More sensitive to epinephrine than norepinephrine

– Signal transduction mechanism: Gs activation followed by ↑ cAMP

– Effect: Relaxation (dilation) of bronchial smooth muscle

β3 receptors

– Location: Adipose tissue

– Neurotransmitter sensitivity: More sensitive to epinephrine than norepinephrine

– Signal transduction mechanism: Gs activation followed by ↑ cAMP

– Effect: Excitatory

Table 4.2 summarizes ANS receptors and their signal transduction mechanisms.


4.4 Physiologic Effects of the Autonomic Nervous System

Dual and Single Innervation

Dual Innervation. Most organs receive innervation from both the parasympathetic and sympathetic neurons. The two divisions usually work in opposition to each other. For example, sympathetic activity increases heart rate, whereas parasympathetic activity reduces heart rate.

Single Innervation. Some autonomic effectors receive input from only one division of the ANS. For example, sweat glands receive only cholinergic innervation from the sympathetic division, and ciliary muscles of the eye receive only parasympathetic innervation.

Fig. 4.5 image Physiologic responses of the autonomic nervous system.

This figure shows the effects of parasympathetic and sympathetic stimulation on organs throughout the body. Most organs are innervated by both systems with opposing effects. However, blood vessels, for example, are only innervated by sympathetic postganglionic neurons. (CNS, central nervous system; VIP, vasoactive intestinal peptide.)



Autonomic Tone

Under normal conditions, there is a low-level tonic firing in both the parasympathetic and sympathetic divisions. This autonomic tone is determined by higher autonomic centers in the brainstem. This continuous tonic firing allows the ANS to produce a response by reducing background neuronal activity to an organ. For example, vascular smooth muscle is controlled by sympathetic outflow. Therefore, a reduction in tonic sympathetic outflow results in vasodilation. Tonic activity is overridden in the emergency response when the entire sympathetic nervous system is activated as a unit.

Figure 4.5 provides a comprehensive chart of the effects of the parasympathetic and sympathetic nervous systems on organs throughout the body.

4.5 Drugs Affecting the Autonomic Nervous System

Cholinergic agonist drugs are termed parasympathomimetics, as they mimic the actions of acetylcholine.

– Direct-acting parasympathomimetics bind directly to cholinergic receptors.

– Indirect-acting parasympathomimetics inhibit the enzyme acetylcholinesterase and thus increase the concentration of acetylcholine.

Cholinergic antagonist drugs block neuronal and muscle nicotinic receptors, along with muscarinic receptors.

– Ganglionic blocking agents block nicotinic receptors at autonomic ganglia (but not nicotinic receptors at the neuromuscular junction).

– Depolarizing neuromuscular blocking agents persistently depolarize nicotinic receptors at the NMJ, leading to receptor desensitization.

– Nondepolarizing neuromuscular blocking agents block nicotinic receptors at the NMJ without depolarization.

– Muscarinic receptor antagonists block muscarinic receptors throughout the body and therefore have low organ specificity.

Table 4.3 provides a summary of cholinergic agonist and antagonist drugs.


Adrenergic agonist drugs are termed sympathomimetics, as they mimic the actions of norepinephrine and epinephrine.

– Catecholamines are endogenous sympathomimetics that directly stimulate specific adrenergic receptors.

– Direct sympathomimetics are synthetic agents that directly stimulate specific adrenergic receptors.

– Indirect sympathomimetics stimulate the release of stored norepinephrine from presynaptic nerve terminals or block the reuptake of norepinephrine (many do both).

Adrenergic antagonist drugs block specific adrenergic receptors.

– Alpha blockers block specific α receptors.

– Beta blockers block specific β receptors.

Table 4.4 lists the adrenergic agonist and antagonist drugs and the receptors where they are active.


4.6 Central Autonomic Control

The hypothalamus selectively activates components of the endocrine system and the autonomic and somatic nervous systems to maintain homeostasis. It initiates appropriate behavioral responses to stimuli such as stress, reproduction, exercise, heat, and cold. It also monitors body water and plasma glucose. The neuroendocrine functions of the hypothalamus are described in Chapter 23.

Temperature Regulation

The preoptic region and adjacent anterior nuclei of the hypothalamus contain a thermostat for establishing the set point temperature (~37°C/98.6°F), the core temperature that the system attempts to maintain.

Mechanisms of temperature regulation

If the core temperature falls below the set point, then the following mechanisms may be induced by the posterior hypothalamus (Fig. 4.6):

– Somatic nervous system activation induces shivering. Shivering generates heat by causing adenosine triphosphate (ATP) hydrolysis in the contractile apparatus of skeletal muscle.

– Thyroid hormones may be released, which generates heat by increasing the activity of Na+−K+ ATPase.

– Sympathetic nervous system activation causes vasoconstriction of blood vessels to the skin, resulting in heat conservation.

If the core temperature rises above the set point, then the following mechanisms may be induced by the anterior hypothalamus:

– Sympathetic cholinergic activation of sweat glands (via muscarinic receptors) increases heat loss by evaporation of water from the skin.

– Lowered sympathetic adrenergic activity causes dilation of blood vessels to the skin, resulting in heat loss by convection and radiation.

Countercurrent exchange of heat

In countercurrent exchange of heat, the fluid within two tubes flows in opposite directions. Because a temperature gradient is present in all parts of the tube, heat is exchanged along the entire length. The result of countercurrent heat exchange is thermal equilibrium. The body uses this property to minimize heat loss from the surface of the skin, as heat is transferred from arterial blood to venous blood. This facilitates maintenance of a stable core temperature. Countercurrent exchange of heat is analogous to the countercurrent exchange of water and the countercurrent multiplier in the loop of Henle (see pp. 178-181Fig. 17.4).


Fig. 4.6 image Neural factors affecting thermoregulation.

Sensors within the hypothalamus, the skin, and the spinal cord sense temperature. The hypothalamus regulates body temperature by coordinating the activity of heat loss and heat-generating/conservation mechanisms, which stimulate adjustments in the body to maintain an appropriate temperature.


Pathophysiology of Temperature Regulation

Fever. Fever is produced by endogenous pyrogens (e.g., interleukin-1) released by cells of the immune system in response to infective bacteria. These pyrogens act on the anterior hypothalamus to increase prostaglandin synthesis, which in turn stimulates the thermoregulatory center to reset the set point to a higher temperature. Because body temperature is cooler than the set point, body temperature increases (by heat production and conservation of heat loss) until it stabilizes at the new, elevated set point temperature. When the fever breaks and the set point returns to 37°C (98.6°F), the patient vasodilates and sweats to lose heat until the body temperature returns to normal.

Inflammatory mediators

Cytokines, which are secreted primarily by activated macrophages, are important mediators of inflammation. The most important inflammatory mediators are interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Local effects include induction of adhesion mole cule expression on vascular endothelium (promoting cell adherence), increased vascular permeability (promoting influx of serum components), and activation of lymphocytes. Systemic effects include increased leukocyte production, fever, and induction of an acute phase response. Other important cytokines are interleukin-8 (IL-8), a potent chemotactic factor for recruitment of neutrophils, basophils and T cells, and interleukin-12 (IL-12), which activates NK cells and promotes differentiation of T cells into T-helper (TH) cells.


Nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs (NSAIDs), for example, aspirin and ibuprofen, inhibit the cyclooxygenase enzymes, COX-1 and COX-2. These enzymes catalyze the formation of prostaglandin H2, which is the precursor for prostaglandin, prostacyclin, and thromboxane synthesis. Aspirin inhibits the cyclooxygenase enzymes by acetylating a single serine residue. This is an irreversible covalent modification that inactivates both COX-1 and COX-2. Other NSAIDs are competitive inhibitors of the cyclooxygenases. COX-1 maintains the normal lining of the stomach and is involved in kidney and platelet function. Inhibition of COX-1 is responsible for many of the side effects of NSAIDs. COX-2 is induced by inflammation. COX-2 inhibition is thought to lead to the analgesic, antipyretic, and antiinflammatory effects of aspirin and the other NSAIDs.


For suppressing fever, aspirin is effective therapy because it inhibits cyclooxygenase and therefore inhibits prostaglandin synthesis. In doing so, aspirin lowers the set point temperature and will cause activation of the heat loss mechanisms. Steroids may also be used because they block the release of arachidonic acid (the precursor of prostaglandins) from membrane phospholipids.

Heat exhaustion. Heat exhaustion occurs when the body overheats, causing profuse sweating. This may result in a drop in blood pressure and fainting. Treatment for this condition involves rehydration and resting in a cool place.

Heat stroke. Heat stroke represents a failure of heat loss mechanisms but not a change in set point. In this case, a person in a hot environment fails to adequately mobilize cutaneous vasodilation and sweating. People experiencing heat stroke must be drastically cooled (placed in a bathtub of ice water), or the core temperature will continue to rise, resulting in death.

Febrile convulsions

Febrile convulsions are seizures associated with elevated body temperature. They are the most common type of seizure in children, affecting 2 to 5% between the ages of 6 months and 5 years, with the peak incidence at 18 months. These seizures are not associated with trauma, infection, metabolic disturbances, or history of seizures, and most last < 10 minutes. More serious illnesses must be ruled out, but the treatment of simple febrile seizures with anticonvulsants is generally not recommended, as the potential drug toxicities associated with these medications outweigh the relatively minor risks associated with the convulsion.


Malignant hyperthermia

Malignant hyperthermia is a rare complication of anesthesia with any volatile anesthetic, particularly halothane. The anesthetic produces a substantial increase in skeletal muscle oxidative metabolism, which consumes oxygen (O2) and causes a buildup of carbon dioxide (CO2). The body also loses its capacity to regulate temperature, which rises rapidly (e.g., 1°C [1.8°F]/5 min). This can lead to circulatory collapse and death. Signs include muscular rigidity with accompanying acidosis, increased O2 consumption, hypercapnia (increased CO2), tachycardia (increased heart rate), and hyperthermia. Malignant hyperthermia may be treatable if dantrolene (a drug that reduces muscular contraction and the hyper-metabolic state) is given promptly.


Hypothermia. Hypothermia results from exposure to cold temperatures when the capacity to generate body heat is inadequate to maintain the core temperature. Death can occur by myocardial fibrillation (uncoordinated, chaotic contractions of cardiac muscle).

Feeding Behavior and Satiety

Feeding behavior is controlled by a reciprocal interaction between the lateral feeding center of the hypothalamus, which controls hunger, and the ventromedial satiety center of the hypothalamus.

– The lateral nucleus of the hypothalamus contains glucose receptors, which are sensitive to changes in blood glucose. These “glucostats” probably initiate feeding behavior.

– Gastric distention activates the ventromedial nucleus satiety center to terminate feeding behavior.

Water Balance

The anterior hypothalamus controls water balance by controlling the excretion of water by the kidney and creating the sensation of thirst.

– In water deficit, hypothalamic osmoreceptors are activated by the increased osmolality of extracellular fluid. Pressure-sensitive receptors in the great veins are also activated by the decrease in osmotic pressure. These stimulate the supraoptic and paraventricular nuclei of the hypothalamus to release antidiuretic hormone (ADH) from the posterior pituitary. ADH causes salt and water retention in the kidney (see Chapter 17).

– The activation of osmoreceptors in the subfornical organ, located in the diencephalon but outside the blood–brain barrier, causes the release of central angiotensin II. Angiotensin II activates the lateral nucleus of the hypothalamus, which initiates thirst.

Table 4.5 summarizes the functions of the hypothalamus and the effects of lesions in certain regions.