The Autonomic Nervous System

Definitions:
Autonomic nervous system (aka visceral nervous system): portion of the
peripheral nervous system that acts as a control system functioning primarily
below the level of consciousness. Controls heart rate, digestion, respiration rate,
salivation, perspiration, diameter of the pupils, and sexual arousal. Divided into
the parasympathetic and sympathetic nervous system (and the nonadrenergic
noncholinergic system). Includes visceral efferent and general visceral afferent
pathways.
Parasympathetic nervous system: portion of the autonomic nervous system,
sends fibers to cardiac muscle, smooth muscle, and glandular tissue. Functions to
rest and digest
Sympathetic nervous system: portion of the autonomic nervous system which
functions to mobilize the bodys resources during stress and constantly at a basal
level to maintain homeostasis. Functions as fight or flight
Visceral efferent pathways: two neurons and a synapse within an autonomic
ganglion. Cell bodies of the preganglionic neurons are in the brainstem or spinal
cord (CNS), cell bodies of the postganglionic neurons are in peripheral autonomic
ganglia. Preganglionic neurons are myelinated.

Anatomy of the autonomic nervous system (for the over-achievers)

Sympathetic nervous system
Originates from the thoracolumbar segments of the spinal cord (T1-L4)
All preganglionic neurons follow the same pathway
o Ventral root spinal nerve ramus comminucans sympathetic trunk
o T1-L4 contain myelinated preganglionic neurons and unmyelinated
postganglionic neurons
o Axons from preganglionic neurons synapse in autonomic ganglia
o Cell bodies of the preganglionic neurons located in the interomediolateral
nucleus
o Nerve endings in the adrenal medulla: preganglionic sympathetic nerve
fibers pass through without synapsing from the intermediolateral horn
through the sympathetic chain then through splanchnic nerves and finally
into the adrenal medulla
End directly on modified neuronal cells that secrete mainly
epinephrine and norepinephrine into the blood stream
Secretory cells embryologically are derived from nervous tissue
and are actually themselves postganglionic neurons
Parasympathetic nervous system
Originates from the brainstem and from the sacral segments of the spinal cord
Preganglionic neurons synapse in discrete autonomic ganglia except in case of
vagus nerve
o Vagus nerve synapses on terminal ganglia located within plexuses within
the visceral organ being innervated

Sacral preganglionic neurons are located in the intermediate gray matter of s1-s3
in the carnivore
o Preganglionic axons run through lumbosacral plexus to pelvic nerve to
synapse on pelvic ganglia within pelvic plexus.
o Postganglionic axons innervate pelvic viscera including the colon
o 50% of the axons in the pelvic neuron are GVA
Vagal parasympathetic (contains about 75% of parasympathetic nerve fibers)
preganglionic neurons arise from the parasympathetic nucleus of the vagus nerve.
o In the thorax, preganglionic neurons leave the vagus to innervate terminal
ganglia in the heart and lungs
o Bilaterally preganglionic neurons enter the abdomen through the vagus
trunk
Dorsal and ventral vagus trunk
Axons reach terminal ganglia of abdominal viscera by running in
nerve plexi on celiac and cranial mesenteric vessels
80% of the axons within the vagus nerve are afferent
Brainstem parasympathetic nuclei give rise to preganglionic neurons that run in to
oculomotor nerve (pupillary sphincter and ciliary muscles of the eye), facial nerve
(lacrimal, nasal, and submandibular glands), and glossopharyngeal nerve (parotid
and zygomatic glands)

Basic Characteristics of the Autonomic nervous system

Nerve fibers secrete mainly one or the other of two synaptic transmitters:
o Acetylcholine (cholinergic fibers)
o Norepinephrine (adrenergic fibers)
o All preganglionic neurons are cholinergic in both the sympathetic and
parasympathetic systems
o All or almost all of the postganglionic neurons of the parasympathetic
system are also cholinergic
o Most of the postganglionic sympathetic neurons are adrenergic

Exceptions: piloerector muscles of hair, sweat glands, a few of

the blood vessels
Mechanisms of Ach and NE secretion from postganglionic nerve endings
o When an action potential spreads over the terminal fibers,
depolarization increases the permeability of the fiber membrane to
calcium, allowing them to diffuse into the nerve terminals.
o Calcium ions interact with secretory vesicles that are adjacent to
membrane causing them to fuse with membrane and to empty to
exterior
Synthesis of Ach
o Ach is synthesized in the terminal endings of cholinergic nerve fibers
o Most of synthesis occurs in axoplasm outside the vesicles
o Ach is transported to the interior of vesicles and stored in concentrated
form until release
o Once secreted, persists in the tissue for a few seconds and then is splint
into an acetate ion and choline by acetylcholinesterase.
o Choline is then transmitted back to the nerve ending and used again for
synthesis of new acetylcholine by combining with Acetyl-CoA through
choline acetyl transferase.
Synthesis of Norepinephrine
o Begins in the axoplasm of terminal nerve endings of adrenergic nerve
fibers, completed inside the secretory vesicles.
tyrosinedopadopaminetransport of dopamine into
vesiclesdopaminenorepinephrine
in the adrenal medulla one additional step
o norepinephrineepinephrine through
methylation
o After secretion of norepinephrine by the terminal nerve endings its
removed from secretory site through three mechanisms
Reuptake into adrenergic nerve endings through active
transport process
50-80% of removal
diffusion away from nerve terminal into surrounding body
fluids and into blood
accounts for most of rest of removal
destruction of small amounts by tissue enzymes
MOA, catechol-o-methyl transferase
o Usually NE secreted into tissue remains active for only a few seconds
NE/epi secreted by adrenal medulla remain active until they
diffuse into tissue and are destroyed by catechol-O-methyl
transferase (mostly in the liver)
When secreted into the blood, NE/epi remain active 10-30
seconds and activity diminishes over 1 minute to several
minutes.

Receptors on effector organs

o Changing membrane permeability
Receptor protein is an integral part of the cell membrane
Conformation change in structure opens or closes an ion
channel
o Altering intracellular enzymes
Enzyme often attached to receptor protein
Ex: binding of NE with its receptor on the outside of many
cells increases activity of adenylyl cyclase in inside of
cellcauses formation of cAMP, cAMP can initiate
intracellular actions
Types of Receptors
Acetylcholine
Muscarinic activated by muscarine (toxin from toadstools) and Ach
o Found on all effector cells stimulated by the postganglionic neurons of the
parasympathetic nervous system and on those stimulated by the
postganglionic cholinergic neurons of the sympathetic nervous system
Nicotinic activated by nicotine and Ach
o Found at the synapses between the preganglionic and postganglionic
neurons of both parasympathetic and sympathetic nervous system
o Also present at many non-autonomic nerve endings such as NMJ in
skeletal muscle
Adrenergic
Alpha receptors norepinephrine excites mainly alpha receptors, also excited by
epi. Some actions are excitatory, some inhibitory
o Alpha1
o Alpha2
Beta receptors excited to a lesser extent my NE, excited more by epi. Some are
excitatory, some are inhibitory
o Beta1
o Beta2
o Beta3

Receptor

Agonist
potency
order

Selected
action
of agonist

Mechanism

Smooth muscle
contraction

Gq:
phospholipase C
(PLC) activated,
IP3 and calcium
up

Agonists

Antagonists

(Alpha-1 agonists)
1:
A, B, D

2:
A, B, C

Epinephrine
norepinephrin
e >>
isoprenaline

Epinephrine Smooth muscle

norepinephrin constriction and
e >>
neurotransmitter
isoprenaline
inhibition

Gi: adenylate
cyclase
inactivated,
cAMP down

Noradrenaline,
Phenylephrine,
Methoxamine,
Cirazoline,
Xylometazoline

(Alpha-1 blockers)
Alfuzosin, Doxazosin,
Phenoxybenzamine,
Phentolamine, Prazosin,
Tamsulosin, Terazosin

(Alpha-2 agonists)

(Alpha-2 blockers)

Dexmedetomidine,
Medetomidine,
Romifidine,
Clonidine,
Detomidine,
Lofexidine, Xylazine,
Tizanidine,
Guanfacine, Amitraz

Phentolamine
Yohimbine
Idazoxan
Atipamezole

Isoprenaline >
epinephrine =
norepinephrin
e

Heart muscle
contraction

Gs: adenylate
cyclase
activated,
cAMP up

Isoprenaline >
epinephrine
>> NE

Smooth muscle
relaxation

Gs: adenylate
cyclase
activated,
cAMP up (also
Gi, see 2)

Isoprenaline =
norepinephrin
e>
epinephrine

Enhance
lipolysis

Gs: adenylate
cyclase
activated,
cAMP up

Noradrenaline,
Isoprenaline,
Dobutamine

(Beta blockers)
Metoprolol, Atenolol,
Propranolol

Albuterol, Bitolterol,
mesylate, Formoterol,
Isoprenaline,
Levalbuterol,
Metaproterenol,
Salmeterol,
Terbutaline, Ritodrine

(Beta blockers)
Butoxamine, Propranolol

L-796568 [2],
Amibegron,
Solabegron

SR 59230A

Function of the adrenal medulla

Stimulation of the sympathetic nerves to the adrenal medulla causes large
quantities of epinephrine and NE to be released into the circulating blood
80% of secretion is epi, 20% is NE
Same effects on different organs as effects caused by direct sympathetic
stimulation except that the effects last 5-10 times as long
NE causes constriction of essentially all blood vessels, increased activity of heart,
inhibition of GI, dilation of pupils, etc
Epi causes almost all the same effects as NE but are different in a few ways:
o Epi has a greater effect on cardiac stimulation (because of greater effect on
beta receptors)
o Causes only weak constriction of blood vessels in muscles
Important because NE greatly increases total peripheral resistance
and elevates arterial pressure where epi raises arterial pressure to a
lesser extent but increases cardiac output more.
o Epi has 5-10 times greater metabolic effect as NE.
Epi secreted from adrenal medulla can increase metabolic rate by
up to 100%
Sympathetic and parasympathetic tone
Both sympathetic and parasympathetic systems are continually active at basal
rates
Allows a single nervous system both to increase and to decrease the activity of a
stimulated organ
o Ex: sympathetic tone normally keeps almost all the systemic arterioles
constricted to about their maximum diameter. By increasing
sympathetic tone, vessels constrict even more and if tone is decreased,
vessels can dilate more (more detail later)

Normal resting adrenal medulla also continuously secretes epinephrine and NE to

maintain BP
Autonomic reflexes
Cardiovascular autonomic reflex: help to control BP and HR
o Baroreceptor reflex when stretched by high pressure, send signals to
brainstem, inhibit sympathetic impulses allowing for pressure to fall back
into normal (discussed more in detail later)
GI reflex: upper part of GI and rectum controlled by reflexes. Ex: smell of food
initiates signals from nose and mouth to vagal, glossopharyngeal, and salivatory
nuclei of brainstem get secretion of gastric juices before food even enters the
mouth.
Emptying of urinary bladder
Sexual reflexes
Regulation of pancreatic secretion, GB emptying, kidney excretion of urine,
sweating, BG, and other visceral functions
Stress response of sympathetic nervous system
Increases arterial pressure
Increases blood flow to active muscles concurrent with decreased blood flow to
organs such as GI tract, kidney that are not needed for rapid motor activity
Increased rates of cellular metabolism throughout the body
Increased BG concentration
Increased glycolysis in the liver and muscle
Increased muscle strength
Increased mental activity
Increased rate of blood coagulation
Autonomic control centers in brain stem and hypothalamus:
Control autonomic functions such as arterial pressure, heart rate, breathing rate,
glandular secretion in GI tract, GI peristalsis, degree of contraction of urinary
bladder
Signals from the hypothalamus and even from cerebrum can affect the activities
of almost all of the brainstem autonomic control centers
Control of heart rate
Impulse for control of heart rate normally originates in the sinus node because the
self-excitatory rate is faster here than in the AV node or the Purkinje system.
The heart is supplied with both sympathetic and parasympathetic nerves
o The parasympathetic nerves (vagi) go mainly to the SA and AV nodes, but
also to some of the muscle in the atria
o Very little vagi travels to the muscles of the ventricles
o The sympathetic nerves are distributed to all parts of the heart, with a large
portion to the ventricular muscle
Vagal (parasympathetic stimulation) to the heart
o Stimulation of the parasympathetic nerves to the heart cause release of
Ach at vagal endings

o Ach released from vagus nerve binds to muscarinic receptors and decrease
cAMP
Two major effects of Ach on heart
Decrease the rate of rhythm of the sinus node
Decreases the excitability of the AV junctional fibers which
slows the transmission of the cardiac impulse into the
ventricles
Ach release at vagal nerve endings increases the permeability of
the fiber membranes to potassium, allows rapid leakage of K+ out
of conductive fibers leading to increased negativity inside the
fibers (hyperpolarization) makes excitable tissue much less
excitable.
In the sinus node, state of hyperpolarization decreases the resting
membrane potential of the sinus nodal fibers to a more negative
level. With the more negative resting membrane potential, it takes
the sodium influx longer to reach threshold for excitation, slowing
rhythmicity.

o Weak to moderate vagal stimulation can slow the heart to normal

o Strong vagal stimulation can stop the rhythmical excitation by the sinus
node or block the transmission of the impulse through the AV junction.
The ventricles can stop beating for 5-10 seconds before the Purkinje fibers
develop an escape rhythm

Sympathetic stimulation of heart

Work primarily on the AV node, norepinephrine binds to beta receptors and leads
to increased cAMP.
Three changes occur with sympathetic stimulation
o Increases the rate of sinus nodal discharge
o Increases the rate of conduction as well as level of excitability in all
portions of the heart
o Increases the force of contraction of all the cardiac musculature (atrial and
ventricular)
Mechanism for change with sympathetic cardiac stimulation
o Stimulation of sympathetic nerves releases hormone norepinephrine at
nerve endings
o Precise mechanism on cardiac mm fibers not entirely known
May increase the permeability of the fiber membrane to sodium
and calcium ions
In sinus node, increase sodium permeability causes more positive
resting membrane potential, resulting in an increased rate of
upward drift of the membrane potential to threshold for selfexcitation
In AV node, increased sodium permeability makes it easier for the
action potential to excite each succeeding portion of the
conduction fiber, decreasing the conduction time from atria to
ventricles.
Increase in permeability to calcium ions changes contractile
strength
Control of blood pressure and circulation
The sympathetic nervous system has primary control over circulation.
Sympathetic vasomotor nerve fibers exit spinal cord through all the thoracic
and first one or two lumbar spinal nerves and enter into a sympathetic chain
on either side of the vertebral column.
o From the sympathetic chain, they can pass by two paths into circulation
Specific sympathetic nerves that innervate mainly the vasculature
of internal viscera and heart
Immediately into peripheral portions of the spinal nerves and
distributed to the vasculature of peripheral areas
Sympathetic innervation of the blood vessels
o Innervation of the small arteries and arterioles allows sympathetic
stimulation to increase the resistance to blood flow, thereby decreasing the
rate of blood flow through tissues
o Innervation of large vessels (especially veins) makes it possible for
sympathetic stimulation to decrease the volume of these vessels,
translocating blood into heart
Sympathetic vasoconstrictor system

o The sympathetic system to vessels contain primarily vasoconstrictor nerve

fibers and only a few vasodilator nerve fibers.
o Sympathetic vasoconstrictor effect is most powerful in kidneys, gut,
spleen, and skin and less powerful in brain and skeletal muscle.
The vasomotor center
o Located bilaterally in the reticular substance of the medulla and lower
third of the pons
o Transmits parasympathetic impulses through vagus nerve to heart and
sympathetic impulses through cord and peripheral sympathetic nerves to
all or most of vessels of body.
o Contains several important centers
Vasoconstrictor area bilaterally in anterolateral portion of upper
medulla distribute their fibers to all levels of the spinal cord to
excite vasoconstrictor neurons of the sympathetic nervous system
Vasodilator area bilaterally in anterolateral portions of the lower
half of the medulla fibers from these neurons project upward to
vasoconstrictor area and inhibit vasoconstrictor activity leads to
vasodilation
Sensory area bilaterally in tractus solitarius in posterolateral
portions of medulla and lower pons neurons receive sensory
nerve signals through vagus and glossopharyngeal nerves help
control activities of both vasoconstrictor and vasodilator areas (ex:
baroreceptor reflex controlling BP)
Sympathetic vasoconstrictor tone
o Under normal conditions, vasoconstrictor area of vasomotor center
transmits signals causing continuous slow firing of these fibers at a rate of
0.5-2 impulses per second (sympathetic vasoconstrictor tone) to maintain
the partial state of contraction of blood vessels previously discussed.
o Loss of sympathetic tone can result in a MARKED decrease in BP due to
loss of vasoconstrictor tone
Vasomotor center control over heart activity
o Lateral portions of vasomotor center transmit excitatory impulses through
the sympathetic nerve fibers to the heart to control rate and contractility as
discussed above
o Medial portion of vasomotor center transmits parasympathetic impulses
through the vagus nerve to heart to decrease rate as discussed above
Control of the vasomotor center
o Reticular substance of pons, mesencephalon, and diencephalons excite or
inhibit the vasomotor center
o Hypothalamus can control vasoconstrictor system by exerting excitatory
or inhibitory effects on vasomotor center
o Cerbral cortex can also control vasomotor center
Simulation of motor cortex excites vasomotor center
Stimulation of other areas can either excite or inhibit depending on
location, intensity, etc

Control of arterial pressure

To control BP, the vasoconstrictor and cardioaccelerator functions of the
sympathetic nervous system are recruited together, and the parasympathetic
system is inhibited causing three simultaneous changes:
o Almost all arterioles of body constrict increases TPR, increasing arterial
pressure
o Veins and other large vessels of circulation are strongly constricted
displacing blood out of large peripheral blood vessels toward the heart,
increasing the volume of blood in heart chambers end result is greater
force of heart beat and increased BP
o Heart itself is directly stimulated by autonomic nervous system to enhance
cardiac pumping (rate and contractile force)
Very rapid can increase pressure within 5-10 seconds to twice normal
Baroreceptor reflex
o The most known nervous mechanism for arterial pressure control
o Reflex is initiated by stretch receptors located in the walls of several large
systemic arteries
Most abundant in the wall of the internal carotid arteries (Carotid
sinus) and aortic arch
o Feedback system used to achieve appropriate response based on stretch
Baroreceptor signals enter the tractus solitarius of the medulla and
secondary signals inhibit the vasoconstrictor center and excite the
parasympathetic center (when they are stretched too much aka
perceive elevated BP)
Net effect is vasodilation of veins and arterioles throughout
circulatory system and decreased heart rate and strength of
contraction.
o Baroreceptors are not that important in long term regulation of BP
They reset in 1-2 days to whatever pressure level they are exposed
to
Resetting prevents barorecptor reflex from functioning as a control
system for MAP longer than a few days (need to control the renalbody fluid- pressure control system)
Chemoreceptor reflex
o Chemosensitive cells that sense lack of oxygen, carbon dioxide excess,
hydrogen ion excess
o Located in two carotid bodies and aortic bodies adjacent to the aorta
o Signals transmitted from chemoreceptors into vasomotor center excite it
and elevate BP back to normal.
o Not a powerful arterial pressure controller in the normal range (arent
really stimulated until BP falls below 80 mmHg)
Central nervous system ischemic response
o When blood flow to the vasomotor center in the brain becomes decreased
severely enough to cause cerebral ischemia, the neurons in the vasomotor
center respond and become strongly excited

Believed to be caused by failure of the slowly flowing blood to

carry CO2 away from the vasomotor center
Build up of lactic acid may also play a roll
o Degree of sympathetic vasoconstriction caused by cerebral ischemia is so
great that some of the peripheral vessels may become completely
collapsed (ex: anuric after this response due to decreased/absent kidney
flow)
Cushing reaction
o Special type of CNS ischemic response that results from increased
pressure of CSF around brain
o Increased CSF pressure becomes that of arterial pressure increased
resistance to blood flow cerebral ischemia response increased arterial
pressure

Disorders of the Autonomic Nervous System

Dysautonomia
Widespread dysfunction of the autonomic nervous system
Felines, Canines all breeds/ages
More common in Europe, but has been reported in US and other countries
Clinical findings
o Cats initially mildly obtunded and anorectic, often have upper respiratory
signs or diarrhea
o Definite signs can have a peracute to chronic onset
o See dilated nonresponsive pupils, ptosis, third eyelid protrusion, dry
rhinarium, reduced lacrimal secretions, esophageal dysfunction with
regurgitation and constipation
o May also see dry oral mm, bradycardia, urinary or fecal incontinence, anal
areflexia, occasionally pelvic limb proprioceptive deficits in cats
(shouldnt really be a feature of Dysautonomia)
Sympathetic and parasympathetic dysfunction
Necropsy lesions
o Megaesophagus, diphtheritic mucous membranes, atonic bladder, retention
of fecal material
o Chromatolysis and neuronal degeneration of pre and postganglionic
sympathetic and parasympathetic neurons
o Specific distribution of chromatolytic autonomic and somatic lower motor
neurons found in brain stem and spinal cord
Diagnostics:
o Histopath for definitive
o Pilocarpine to cornea causes profound miosis within 10-15 minutes due to
denervation hypersensitivity (should have no effect on a healthy cat)
o Dilute phenylephrine reverses ptosis and protruding third eyelid
Treatment and prognosis

o Supportive care
o Feeding method appropriate for ME
o Evacuate bladder manually, artificial tears
o Treat constipation
o Effects of sympathomimetics questionable
o Some cats spontaneously recover but prognosis is poor if severely affected
o Prognosis is grave for dogs
Literature
o JSAP 2008 Gajanayake IM myasthenia and dysautonomia in a dog
Immune component only speculative based on positive Ach
receptor titers
o J Fel Med Surg 2008 Dysautonomia in US Cats
9 cases, regional distribution Missouri/Kansas
o JAVMA 2002 Dysautonomia in dogs
65 cases, rural dogs predisposed, reported all year round but
increased incidence in Feb/March
Endemic disease in Kansas
o Vet Rec 2003 Outbreak in closed colony of cats
6 of 8 cats in a closed colony develop, and the two that didnt had
abnormal esophageal motility
o JAAHA 2002 Dysautonomia in a family of GSHP
4 of 5 puppies in a litter develop