THE AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system controls the function of the heart, blood vessels, viscera,
and smooth muscle, and serves to maintain a stable internal environment despite
exposure to a constantly changing external environment. There are several differences
between the control mediated by the autonomic nervous system, compared to that
mediated by the somatic neurons which innervate skeletal muscle.
A. Activity of somatic nerves is under voluntary control; activity of autonomic
neurons is generally involuntary.
B. The target organ of somatic neurons, skeletal muscle, is quiescent in the
absence of neuronal stimulation; the target organs of autonomic neurons usually
show spontaneous activity which is modulated by stimulation.
C. Autonomic neurons are organized into ganglia and plexi. Sensory information is
carried by afferent autonomic pathways to CNS, where the controlling and
integrating centers for most autonomic functions are located. Efferent pathways
carry information from CNS to ganglia located outside the CNS, and from the
ganglia on to the visceral effector organs.
The autonomic nervous system is composed of 2 divisions, the parasympathetic and
sympathetic nervous systems. The sympathetic preganglionic axons leave the
intermediate spinal cord with the ventral roots from the first thoracic segment to the 3rd
lumbar segment. The parasympathetic preganglionic axons originate in the midbrain,
medulla, and sacral part of the spinal cord. Many end organs are innervated by both
sympathetic and parasympathetic fibers that usually act in an antagonist manner to
control organ function. The adrenal medulla, the central portion of the adrenal gland, is
a part of the sympathetic system and contains secretory (chromaffin) cells that release
catecholamines (mainly epinephrine) in response to neuronal stimulation. Classically,
the sympathetic system is considered to be dominant during times of stress, when the
organism is in a "fight or flight" situation. The sympathetic system can be stimulated to
undergo widespread discharge in times of stress, causing increased heart rate and
blood pressure, dilation of pupils and bronchioles, increased concentration of blood
sugar and shifting of the blood from skin and viscera to skeletal muscle, increasing the
ability of the organism to respond. The parasympathetic system dominates when the
organism is restoring or conserving energy during rest or sleep. The parasympathetic
system usually undergoes discharge at discrete sites. In general, sympathetic ganglia
innervate many targets, while parasympathetic ganglia lie close to their targets, and a
given parasympathetic ganglion only innervates one effector organ.
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Preganglionic axons of sympathetic neurons using ACh as a neurotransmitter form
synapses on ganglionic neurons that have ganglionic nicotinic AChR. The ganglionic
neurons send postganglionic fibers to their target organs, where they usually release
norepinephrine. There are two exceptions to this general rule. Most sweat glands are
innervated by cholinergic sympathetic fibers (although sweating palms are caused by
adrenergic sympathetic fibers). There are also cholinergic sympathetic fibers in the
skeletal muscle vasculature, but these are thought to have negligible physiological
significance. Preganglionic axons of parasympathetic neurons also use ACh as a
neurotransmitter and form nicotinic synapses on ganglionic neurons. The postganglionic
fibers of these neurons also use ACh as a neurotransmitter and form cholinergic
synapses via the muscarinic (mAChR) on the target organ.
In addition to the release of either ACh or norepinephrine, most postganglionic
autonomic nerve terminals contain and are able to release peptides and other
neuroactive substances such as purines. While it is believed that these compounds may
act either as "cotransmitters" or as "neuromodulators," the precise physiological role of
these substances remains to be elucidated.
II. Effects of Autonomic Stimulation on Organ Function
Parasympathetic activity slows the heart rate by hyperpolarization and slowing of
the diastolic depolarization in the sino-atrial node and reduces contractile force in
the atria by shortening the atrial action potential.
Sympathetic activity increases heart rate by increasing rate of diastolic
depolarization and increases contractile force by increasing Ca++ influx during
the action potential. Note that while the sympathetic nervous system innervates
all regions of the heart, there is very little parasympathetic innervation of the
B. Smooth Muscle in General:
Parasympathetic activity causes contraction or increased rhythmic activity of
Sympathetic activity causes relaxation or decreased rhythmic activity of smooth
Exception: Sympathetic activity contracts vascular smooth muscle except in
skeletal muscle arteries and veins, where both contraction and dilation can occur.
(This seemingly contradictory statement will be explained later, after you learn
about the different types of adrenergic receptors.)
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Effect of Stimulation and Parasympathetic Systems
S-A Node Increased rate Decreased rate
Atria Increased contractility Decreased contractility
A-V Node Increased conduction velocity Decreased conduction velocity
Ventricles Increased contractility ------------------------------
Iris Mydriasis Miosis
Ciliary Muscle Relaxation (for far vision) Contraction (for near vision)
Lacrimal Glands ------------------------------ Secretion
Lungs Bronchial dilation Bronchial constiction
Sweat Glands Secretion ------------------------------
Liver Glycogen breakdown ------------------------------
GI Tract Inhibition of peristalsis and Stimulation of peristalsis and
Colon and Bladder Inhibition of peristalsis Contraction
Salivary Glands Some secretion Secretion
Arterioles Vasoconstriction ------------------------------
(except skeletal muscle)
Veins Vasoconstriction ------------------------------
These effects are usually observed following stimulation of the respective systems. The actual
effect observed will depend on the overall neurogenic tone at the time of stimulation. In an
untreated individual, arterioles, veins, and sweat glands have mainly sympathetic tone, and the
heart, eye, salivary glands, GI tract, and bladder have mainly parasympathetic tone.
C. Exocrine Glands in General:
Parasympathetic activity usually stimulates secretion. Sympathetic activity can
either reduce, stimulate, or have no effect on secretion, depending on the
Parasympathetic activity causes miosis (pupillary constriction) by causing
contraction of the iris sphincter muscle.
Sympathetic activity causes mydriasis (pupillary dilation) by causing
contraction of the iris dilator muscle.
Parasympathetic activity stimulates contraction of the ciliary muscle
causing increased curvature of the lens for near vision.
Sympathetic activity causes relaxation of the ciliary muscle, decreasing
curvature of the lens for far vision.
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III. Synaptic Transmission in Autonomic Ganglion
A. Sympathetic Ganglion
Synaptic transmission in the mammalian superior cervical ganglion has been
extensively studied. Stimulation of the preganglionic fibers leads to a complex
series of changes in the membrane potential of the postganglionic neuron: (1) an
initial large depolarization (EPSP) due to activation of the ganglionic nicotinic
AChR of the postganglionic neuron; (2) a small hyperpolarization (slow IPSP)
due to the activity of an interneuron; (3) a small depolarization (slow EPSP), due
to activation of mAChR on the postganglionic neuron. The fast EPSP is
responsible for transmission through the ganglion; the PSPs serve to modulate
B. Parasympathetic Ganglia
Much less is known about synaptic transmission in parasympathetic ganglia.
Electrophysiological studies of parasympathetic ganglia in amphibian heart
suggest the presence of a fast EPSP due to activation of nAChR, and a slow
IPSP, due to activation of mAChR. Thus, while transmission through
parasympathetic ganglia may be simpler than that through sympathetic ganglia,
the main pathway for synaptic transmission in each case uses ACh.
There are many similarities between synaptic transmission at neuromuscular
junctions and autonomic ganglia. The synthesis, storage and release of ACh
take place in preganglionic cholinergic terminals of autonomic ganglia via
processes similar to those already described at the neuromuscular junction. The
nerve terminal contains many synaptic vesicles which release ACh by
exocytosis. As at the neuromuscular junction, none of the drugs affecting these
processes are used clinically to affect autonomic neurotransmission.
The postsynaptic ganglionic AChR are also localized to the subsynaptic
membrane; after denervation, the postsynaptic neurons become supersensitive
to ACh and new receptors appear in nonsynaptic regions. Activation of the
receptors causes a transient increase in membrane permeability to Na+ which
desensitizes in the continued presence of agonists. While there are thus a
number of similarities between the nicotinic receptor in skeletal muscle and in
autonomic ganglia, the two receptors differ markedly in their specificity for ligand
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IV. Ganglionic Stimulating Drugs
There are 2 classes of ganglionic stimulants.
1. Nicotinic Drugs
These drugs act as agonists which activate and then desensitize the AChR.
Low concentrations of these drugs stimulate nicotinic receptors sympathetic and
parasympathetic ganglia and in the adrenal medulla. Higher concentrations
cause blockade in both types of ganglia. The final effect can thus be a
summation of opposing effects. Because of their broad and somewhat
unpredictable actions the ganglionic stimulants are not widely used clinically.
However, because of the widespread consumption of nicotine from tobacco, its
use in insecticides and its high level of toxicity, it is important. At low doses
nicotine has sympathomimetic cardiovascular effects (increased heart rate and
increased force of contraction, elevating blood pressure) and parasympathetic
G.I. effects (increased intestinal tone of motility). In addition, nicotine is lipid
soluble and can produce complex central effects, tremors, stimulation of
respiration, and at high doses, convulsions.
Nicotine is thought to be the second most widely used addicting drug used in the
U.S.A. (caffeine is first). Abrupt cessation of smoking by a nicotine-dependent
smoker can result in headaches, tremors, visual disorders, irritability, etc. A
nicotine-containing gum and transdermal patches are available to help smokers
reduce nicotine dependence gradually while breaking the smoking habit. Nursing
women or people with cardiovascular problems should not use nicotine.
2. Muscarinic Drugs
Drugs which stimulate mAChR (muscarine, pilocarpine, etc.) cause stimulation of
sympathetic ganglia via the late EPSP. For most of these agents, these effects
are usually masked by muscarinic effects on the cardiovascular system.
There is, however, an experimental drug called McN-A-343, which appears to
preferentially stimulate mAChR in the symapthetic ganglia and in the adrenal
medulla and not mAChR in target organs such as the heart or vascular smooth
muscle. (As will be discussed later, this is because there are pharmacologically
distinct subtypes of muscarinic receptors). Thus, McN-A-343 can produce
vasoconstriction which is blocked by atropine.
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V. Ganglionic Blockers
Hexamethonium, mecamylamine, pentolinium, TEA, and trimethaphan act as
competitive antagonists – they block ganglionic transmission by binding to the
AChR without a change in the membrane potential of the ganglionic cells. The prototype
of the ganglionic blockers, hexamethonium, is the 6 carbon version of the depolarizing
neuromuscular junction blocker decamethonium. Hexamethonium is a very weak
blocker at the neuromuscular junction but much more potent at autonomic ganglia. The
ganglionic blockers block both parasympathetic and sympathetic ganglia. Their actual
effect depends therefore on whether the predominant autonomic tone in an untreated
individual is parasympathetic or sympathetic.
The effects on organs with predominantly sympathetic tone are:
(1) arterioles and veins – causes vasodilation
(2) sweat glands – decrease sweating
The effects on organs with predominantly parasympathetic tone are:
(1) heart – tachycardia
(2) eye – pupillary dilation and cycloplegia
(3) salivary glands – dry mouth
(4) GI tract – relaxation of intestinal muscle, constipation
(5) bladder – difficulty in emptying the bladder
Ganglionic blockers in the past were used as hypotensive agents, but are now rarely
used, except in emergency treatment of hypertensive crises and to produce controlled
hypotension during certain surgical procedures. The hypotensive effects are due to the
dilation of most arteries and veins in skin and viscera leading to a decrease in total
systemic vascular resistance.
The side effects of the ganglion blockers are due to their effects on other organs as
described above: visual problems, constipation, etc. More severe reactions include
marked hypotension and paralysis of the bowel and bladder.
VI. Readings: (G & G, Ninth Edition) Chapter 6; Chapter 9: pp. 191-197; Chapter 24: pp.
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