Study
Objectives
- To define receptors, autonomic neurotransmitters and blocking drugs, homeostasis,
receptors and related concepts.
- To describe the anatomy and the physiology of the sympathetic and the parasympathetic
nervous system, the visceral afferent system, the enteric nervous system,
transmitter mechanisms in autonomic ganglia and at peripheral receptors, the
bladder emptying, the pupillary reflexes.
- To explain the central autonomic control, the autonomic control of temperature, appetite,
thirst, the subsynaptic autonomic mechanisms, emotional disorders, the Kluver-
Bucy-syndrome.
- To use the above concepts in problem solving and case histories.
Principles
- The autonomic
nervous system mediates neural control of the internal milieu despite
substantial environmental changes.
- Cannons law: The
peristalsis in the small intestine is polarised, so it always proceeds in the
oral-aboral direction.
Definitions
are adrenergic and cholinergic substances (Table 6-1 and
6-3).
Autonomic
blocking drugs (sympatholytics and parasympatholytics) block the normal
effect of sympathetic and parasympathetic neurotransmitters.
Cholinergic
receptors are nicotinic (with a fast EPSP within ms) and muscarinic (with a slow EPSP lasting several seconds). Both cholinergic receptors are
transmembrane proteins and both open an ion channel in the protein.
Homeostasis refers
to all processes helping to keep in internal milieu of the body constant
despite environmental alterations.
Mydriasis refers
to dilatation of the pupil by sympathetic stimulation of the dilatator muscle.
Miosis refers
to contraction of the sphincter muscle (parasympathetic) resulting in a small
pupil.
Receptors for
neurotransmitters are specific cellular components, who react with a
neurotransmitter, a hormone or a drug (agonist) to produce a biological
response in the cell.
SIF cells are small intensity fluorescent cells, which possess muscarinic
receptors and contain vesicles filled with dopamine. Adequate stimulation
releases dopamine, which interacts with dopamine receptor (D2) on
the postsynaptic cell body and modulates the effect of acetylcholine. The
modulation takes place through a permeability increase for small ions (K+ out and Cl- into the cell), hyperpolarizing the cell
membrane.
The nicotinic
receptor responds to acetylcholine with a rapid influx of Na+,
whereby the membrane is depolarised.
The muscarinic
receptor. In the muscarinic M1 receptor, IP3 is
second messenger and increases cytosolic Ca2+. Activation of the M2 receptor implies activation of an inhibitory G-protein, which inhibits
adenylcyclase. The result is reduced concentration of cAMP, which operates in
smooth muscle contraction, with secretion from glands or with a slow EPSP.
Essentials
This paragraph
deals with 1. The autonomic system in general, 2.
The sympathetic system, and
3. The parasympathetic system.
1.
The Autonomic System In General
The autonomic
system directly influences smooth muscles, glands and the heart through
its two subdivisions, the sympathetic and the parasympathetic system. The two
subdivisions function in a dynamic balance aiming at homeostasis.The enteric
nervous system is lying within the walls of the gastrointestinal tract and
includes neurons in the pancreas, liver and gallbladder, thus being an entity in
itself. However, the enteric nervous system is clearly an important part of the
autonomic nervous system that controls gastrointestinal motility, secretion and
bloodflow.The central
autonomic systemThe central
autonomic nervous system outflow arises in the hypothalamus, the brainstem, and
the spinal cord. The motor and premotor cortex, the cingulate gyrus and the
hypothalamus can modulate the function of the autonomic medullary control
neurons in the lateral horn of the grey matter. Circulatory changes during
exercise and in various stressful situations are influenced or governed by the
cortex and deeper brain nuclei. The central autonomic system also modulates
release of certain peptides and catecholamines that affect both blood volume as
well as the total peripheral vascular resistance.The cerebral
cortex assimilates all inputs of visual, olfactory, labyrinthine, locomotor
origin, as well as from other specialised sensors (stretch receptors, chemo-,
baro-, osmo-, and thermo-receptors).The integration of
these inputs into an appropriate response takes place in the hypothalamus and in
the ponto-medullary centres. From here the efferent signals pass to the
periphery via the sympathetic and the parasympathetic pathways.The primary
afferent projections from the baroreceptors reach the solitary tract nucleus (STN),
and from here we have connections to the important dorsal motor nucleus of the
vagus (DMNV in Fig. 6-4). A high baroreceptor activity stimulates the DMNV, so
that the vagal inhibition of the heart is increased. More importantly, the high
baroreceptor activity inhibits the sympathetic drive to the heart and vessels
thus reducing blood pressure (Fig. 6-4).The central
autonomic structures co-operate in situations of survival character: Fright,
flight or fight- response, feeding and drinking in starvation, reproduction and
sexual satisfaction for continuation of life, thermoregulation at extreme
temperatures and emotional behaviour in crises.
The
Fright -Flight Or Fight Response
Aggression and
defence responses are elicited in emergency situations. The sympatho-adrenergic
system gives rise to the fright, flight or fight-reactions in acutely stressful
situations. The sympathetic reactions dominate over the parasympathetic and the
subject is aggressive or anxious. The brain releases corticotrophin-releasing
factor to the hypothalamic-pituitary portal system. The hypothalamic-pituitary
axis secretes adenocorticotropic hormone, the cardiac rate and contractile force
increases, the blood is distributed from viscera to the active skeletal muscles
by visceral vasoconstriction and preferential vasodilatation. The subject
hyperventilates, the gastrointestinal activity is reduced, and there is
increased glycogenolysis and lipolysis. The airways dilatate, and the adrenal
medullary (catecholamines) and cortical secretion (cortisol) increases. This
response is seen in humans exposed to psychological-emotional stress. Stress in
general is comprised of severe emotional and physical burdens (fear, pain,
hypoxia, hypothermia, hypoglycaemia, hypotension etc).Cannons emergency
reaction is an immediate sympatho-adrenergic response to life-threatening
situations, with both sympatho-adrenergic and parasympathetic overactivity. The
last phenomenon includes vagal cardiac arrest with involuntary defecation and
urination.Feeding and
drinkingBilateral
destruction of the ventromedial hypothalamic nuclei leads to hyperphagia and
failure of body weight control. Such animals become obese, and they have high
plasma [insulin].Bilateral lesions
in the lateral hypothalamic regions cause a temporary hypophagia.The cells of the
ventromedial nuclei have a special affinity for glucose, and these cells are
responsible for insulin secretion from the pancreatic b-cells.
Signals from the dorsal motor nucleus of the vagal nerve increase insulin
secretion, and sympathetic stimulation inhibits the release of insulin. The
ventromedial nuclei seem to function like a glucostat.Stimulation and
ablations of the limbic system affect food intake. Obviously from clinical
practice, psychological factors, emotional disturbances, motivations and
conditioned behaviour are all affecting our drive for food intake.Concerning the
control of food intake see also Chapter 20 and 27.Sexual behaviourHypothalamic and
other limbic system co-operation are responsible for a wide variety of autonomic
and somatic phenomena associated with emotions. Stimulation of the midbrain
septum yields pleasurable sensations and sexual drive in patients. The
dorsomedial nucleus of the hypothalamus is probably a major sex centre
responsible for the sexual act. Stimulation of the ventromedial and preoptic
regions also releases sexual activities. See also Chapter
29.
The
Thermocontrol
Thermoreceptors
can initiate generalised reactions to heat and cold. The signals from both
superficial and deep thermoreceptors must act through the hypothalamus to arouse
appropriate, generalised reactions.Cooling or heating
the denervated lower extremities of spinal men evoked vasoconstriction and
shivering or vasodilatation and sweating of the innervated upper body shortly
after cooled or warmed arterial blood reached the brain. The anterior
hypothalamus is responsible for sensing blood temperature variations. The
anterior hypothalamus, in particular the preoptic area, has been shown to
contain numerous heat-sensitive cells and less cold-sensitive receptors. Such
central thermoreceptors are also found at other levels of the CNS. After
destruction of the hypothalamus, the midbrain reticular formation takes over the
temperature control. Sections eliminating both the hypothalamus and the
mesencephalon leave the medulla and spinal cord to control temperature. The
posterior hypothalamus does not contain thermoreceptors. Concerning
thermocontrol see also Chapter 21.The brain and the
immune defence systemInternal and
external stress affects the prefrontal cortex, whereby the limbic system with
the hypothalamus is activated. Hypothalamic nuclei release corticotropin-releasing
hormone (CRH) to the portal blood. The blood reaches the adenohypophysis, where
CRH triggers the release of adenocorticotropic hormone (ACTH), endorphins and
met-enkephalin. ACTH works through different pathways in order to protect the
body. ACTH stimulates the adrenal cortex to release corticosteroids, which
produce immuno-suppression. Immuno-suppression reduces the number of
inflammatory effector cells, including helper T cells and killer cells.On the other hand,
cancer therapists assume that relaxed lifestyle and positive reinforcement may
have stimulated the immune defence in some patients with malignant diseases, and
explain miraculous remissions. Higher brain centres may even affect the
reticuloendothelial production of killer cells through the peripheral nerves to
the lymph nodes and bone marrow. See also Chapter 32
.![peripheral autonomic nervous system](images/fp6-1s.jpg)
Fig.
6-1: The
peripheral autonomic nervous system. b -receptors
stimulate glycogenolysis in the liver and lipolysis in lipid tissues. Autonomic nerves are
composed of two neurons termed the preganglionic and the Postganglionic neuron
based on anatomical location relative to the ganglion. A preganglionic neuron
has its cell body in the spinal cord or brainstem and is modulated by higher
centres and by spinal reflexes (Fig. 6-1). The preganglionic axon leaves the CNS
from the cranial, thoracic, lumbar or sacral regions and synapse in the
autonomic ganglia with the cell body of the postganglionic neuron. The
postganglionic neurons innervate the effector organs (Viscera).Viscera function
involuntarily and their activity must be modulated by the autonomic nervous
system with excitatory or inhibitory signals. All autonomic nerves have ganglia
outside the CNS in contrast to the somatic nervous system, where neural
connections are located entirely within the CNS. Most somatic nerves that
control motor function are myelinated and have a high conduction velocity,
whereas most postganglionic neurons are unmyelinated with a low conduction
velocity. However, the preganglionic neurons are mostly myelinated with a high
conduction velocity (Fig. 6-1). Receptors for
neurotransmitters are specific cellular components, whose interaction with
the neurotransmitter, a hormone or a drug produces a biological response in the
cell. Acetylcholine (ACh) is the transmitter between the pre- and the post-ganglionic neurons,
not only in the sympathetic nervous system, but also in the parasympathetic
system. The cholinergic receptors are nicotinic or muscarinic. The cholinergic
receptors of the ganglia and in the somatic motor endplate are nicotinic.
Nicotine and acetylcholine activate nicotinic cholinergic receptors. When the
action potential arrives at the preganglionic fibre, acetylcholine is released
from its terminals and diffuses across the synaptic cleft to bind to the
specific nicotinic receptors on the membrane of the postganglionic neuron.
Nicotinic receptors are linked to cation channels lined with negative charges.
These channels open enough to allow mainly hydrated Na+ to enter the
cell rapidly (for about 1 ms) and depolarise the membrane (Fig. 6-2).
![The nicotinic cholinergic receptor](images/fp6-2s.jpg)
Fig.
6-2: The
nicotinic cholinergic receptorThe resulting
current elicits an excitatory postsynaptic potential (EPSP).
Repolarisation is also fast (ms).Acetylcholine is
also the neurotransmitter for the sympathetic innervation of sweat glands, and
they are completely blocked by atropine. The acetylcholine receptors of
the sweat glands are muscarinic, since acetylcholine and muscarine
(Fig. 6-3) activate them.
![The muscarinic cholinergic receptor](images/fp6-3s.jpg)
Fig.
6-3: The
muscarinic cholinergic receptorThese slowly
working surface-receptors are linked to a long lasting cascade of events
starting with binding of the hormone to the receptor, activation of G-proteins
(see Chapter 7), enzyme activation, production of second-messengers, protein
kinase activation, and phosphorylation of specific proteins such as channels.
All these processes are simplified in Fig. 6-4, and the result is opening of K+-channels,
with efflux of K+, so the membrane is hyperpolarised. In this
example, acetylcholine is an inhibitory transmitter.
2.
The Sympathetic Nervous System
The preganglionic
sympathetic nerve fibres originate in small multipolar neurons in the lateral
horn of the grey matter in the thoracic and lumbar spinal cord. The central
sympathetic outflow converges on these preganglionic neurons. Their axons are
thin myelinated fibres that leave the spinal cord through the ventral root. The
preganglionic fibres then leave the spinal nerve forming myelinated white rami
communicantes, through which they reach the nearest ganglion in the
paravertebral ganglia of the paired sympathetic trunk. Typically, each fibre
will end here forming synapses with up to 20 postganglionic neurons. A few
preganglionic fibres pass the sympathetic trunk without interruption to form the
splancnic nerves that reach the three unpaired prevertebral ganglia (coeliac =
solar plexus, superior mesenteric and inferior mesenteric) of the lower
intestinal and urinary organs. Most sympathetic ganglia are remote from the
organ supplied. The postganglionic fibres are all unmyelinated, and they leave
the sympathetic trunk through the grey rami communicantes and thus reach the
effectors supplied by the sympathetic system. The effectors are the smooth
muscles of all organs (blood vessels, viscera, lungs, hairs, pupils), the heart
and glands (sweat glands, salivary and other digestive glands). In addition, the
sympathetic postganglionic fibres innervate adipocytes, hepatocytes and renal
tubular cells.The
sympatho-adrenergic system is a functional and phylogenetic unit of the
sympathetic system and the adrenal medulla. The adrenal medulla is a modified
sympathetic ganglion. Any increase in sympathetic activity increase the
secretion of adrenaline and noradrenaline from the medulla into the circulation.
The preganglionic fibres to the adrenal medulla pass all the way to the special
postganglionic cells in the adrenal medulla. The synapse is cholinergic
(nicotinic) as it is for all preganglionic synapses. The postganglionic cells of
the adrenal medulla have developed to cells filled with chromaffine granules,
and are called chromaffine cells. These cells do not conduct signals, but
synthesise adrenaline (and noradrenaline) which is released into the blood.
Sympathetic stimulation triggers the conversion of tyrosine to
dihydroxyphenylalanine (DOPA). A non-specific decarTableylase catalyses the
conversion of DOPA to dopamine, which is taken up by the chromaffine granules in
the cells. The granules contain the crucial enzyme, dopamine b-hydroxylase.
This enzyme is activated by sympathetic stimulation, and catalyses the formation
of noradrenaline from dopamine.A few granules
store noradrenaline (NA), while the remaining granules liberate NA to the
cytosol, where NA is methylated by phenylethanolamine N-methyltransferase to
adrenaline. Adrenaline is taken up by chromaffine granules and stored as the
predominant adrenal hormone.
Adrenergic
Receptors
The sympathetic
system exerts either excitatory or inhibitory actions through adrenergic
receptors. Adrenergic receptors are membrane-receptors. The dual response
to adrenergic stimulation was known before Ahlquist in 1948 proposed that
adrenergic receptors could be divided into two groups, a-
and b- receptors, on the basis of blocking drugs (Table
6-1). The basic idea of Ahlquist is that noradrenaline (NA) act predominantly on vasoconstricting a-receptors, and isoprenaline
(Iso) predominantly on vasodilatating b-receptors.
Both types of receptors are stimulated by adrenaline (Ad).
Table
6-1:
Adrenergic receptor subtypes.
The symbol
> indicates the rank order of sensitivity. |
|
Adrenergic
receptors |
|
a-receptors |
b-receptors |
Stimulated
by: |
NA>Ad |
|
Iso>Ad ³NA |
Blocked by |
Phenoxybenzamine |
|
Propranolol |
|
a-receptors |
b-receptors |
|
|
a 1-receptors |
a 2-receptors |
b 1-receptors |
b 2-receptors |
|
Stimulated
by |
NA>Ad |
NA>Ad |
Iso>Ad=NA |
Iso>Ad>NA
Salbutamol |
Blocked by |
Prazosin |
|
Metoprolol |
Butoxamine |
The rank order of
sensitivity of a series of chemically similar compounds for activating a
receptor (agonists) or inhibiting the receptor response (antagonists) is
considered diagnostic of the receptor subtype. More and more closely related
subtypes are distinguished, so there is already three subtypes for each of the
following receptors: a1ABC-receptors, a2ABC-receptors,
and b123-receptors.1. The a-receptors
are blocked by Phenoxybenzamine and Phentolamine.The a1-receptors
are located on the surface of target cells (vascular smooth muscle, sphincter
muscles of the gastrointestinal tract and bladder, and radial iris muscles).
They are highly sensitive to NA, less sensitive to Ad, and almost insensitive to
isoprenaline (Table 6-1).The a1-receptors
act through phospholipase C and through intracellular [Ca2+]
elevation. Ca2+ binds to calmodulin in the cytosol. The complex
activates protein kinase, which catalyses the phosphorylation of proteins. They
become enzymatically active, and trigger vasoconstriction.In contrast, the
presynaptic a2-receptors are located on
the presynaptic membrane (sympathetic end bulbs). NA released into the synaptic
cleft diffuses to the a1-receptors on the
target cells, but part of the NA diffuses back to the a2-receptors
on the presynaptic nerve terminals. Here, NA activates membrane adenylcyclase,
reducing [cAMP] in the cells, and thus inhibiting release of more NA from the
vesicles by negative feedback. Hence, a function of a2-receptors
is auto-inhibitory feedback. These receptors are also found in gastric smooth
muscle cells and the b-cells of pancreatic islets.
Stimulation decreases gastric motility and attenuates insulin secretion.2. The b-receptor
is blocked by propranolol (Table 6-1).The b-receptors
are located on effector cells that are most sensitive to isoprenaline, but less
so to Ad and NA. All b-receptors act through
activation of adenylcyclase and cAMP. b1-receptors
are equally sensitive to NA and Ad, whereas b2-receptors
are more sensitive to Ad than to NA (Table 6-1). b1-receptors
are located in the myocardium - primarily on pacemaker cells. The b1-receptors
of the heart are stimulated by NA which increases cAMP production with increased
chronotropic (increased heart rate) and inotropic effect (increased force).
Heart patients use Cardioselective b1-blockers
such as Metoprolol, because Metoprolol decreases cardiac arrhythmias and
tachycardia. b2-receptors
are found primarily on bronchiolar smooth muscle cells, vascular smooth muscle,
uterine smooth muscle, salivary glands, the intestine and the liver. When NA
binds to b2-receptors, it causes
inhibition of the target organ. Therefore, NA causes vasodilatation,
bronchodilatation and uterine relaxation. Similarly, sympatomimetics such as b2-stimulators
(salbutamol) increase cAMP production, resulting in bronchodilatation, increased
salivary secretion, uterine relaxation and enhanced hepatic glucose output. b2-stimulators
are used to eliminate bronchial asthma attacks. Butoxamine is a selective b2-blocker.
Table 6-2: Responses elicited in effector organs by sympathetic and parasympathetic
activation |
Effector
organ |
Adrenergic
response |
Cholinergic
response |
Heart |
|
|
Rate of
contraction |
Increase, b 1 |
Decrease, M2 |
Force of
contraction |
Increase, b 1 |
Decrease, M2 |
Arteries and
arterioles |
|
|
in
myocardium |
Vasodilatation, b 2 (a 1constr) |
Vasodilatation,
M |
in skeletal
muscles |
Vasodilatation, b 2 |
|
in lungs |
Vasodilatation, b 2 |
|
Bronchial
muscles |
Bronchodilatation, b 2 |
Bronchoconstriction,
M |
Gastrointestinal |
|
|
motility |
Decrease, a 2 (b 2,b 3) |
Increase, M |
sphincters |
Contraction, a |
Relaxation,
M |
secretion |
Decrease, a |
Increase, M1 |
Exocrine
glands |
|
|
Salivary |
Small
secretion, a 1 |
Secretion, M2 |
Lacrimal |
|
Secretion, M2 |
Digestive |
Decreased
secretion, a |
Secretion, M2 |
Airway |
|
Secretion, M |
Sweat |
Secretion, a 1 |
Secretion, M |
Pancreatic
acini |
Decreased
secretion, a |
Secretion, M |
Langerhans
islets |
Decreased
secretion, a 2 Increased secretion, b 2 |
|
Lipid cells |
Lipolysis, b 1 b 3 |
|
Liver
glycogenolysis |
Increase, a 1 b 2 |
|
Eye |
|
|
Ciliary
muscle |
Relax., b (far vision) |
Contraction,
M (near vision) |
Dilatator
muscle of pupil |
Contract., a 1 (Mydriasis) |
|
Sphincter
muscle of pupil |
|
Contraction,
M (Miosis) |
Kidney |
Renin
secretion, b 2 |
|
Ureter-motility |
Increase, a 1 |
|
Urinary
bladder |
|
|
detrusor |
Relaxation, b |
Contraction,
M |
sphincter |
Contraction, a 1 |
Relaxation,
M |
Genital
organs |
|
|
male |
Ejaculation, a 1 |
Erection, M |
uterus
(pregnant) |
Contraction, a 1 |
|
Adrenal
medulla |
|
Secretion, N |
The near-vision
response is also called the convergence response. Near vision -even with only
one eye - triggers accommodation and pupillary contraction (Table
6-1). The
ciliary muscle and the pupillary sphincter muscle are innervated of the
parasympathetic oculomotor nerve, and the two muscles (with M-receptors)
contract simultaneously for near vision. This leads to increased refractive
power or accommodation, and to pupillary contraction (miosis).When a person
closes his eyelids the pupils enlarge, and when he opens the pupils again the
pupils become smaller. This is due to the pupillary light reflex, where retinal
ganglion cells are stimulated by light, send signals through the optic nerve to
the olivary pretectal nucleus neurons. These light-sensitive neurons are
connected to the parasympathetic preganglionic neurons in the oculomotor
Edinger-Westphal nuclei on both sides. The light reflex contracts the pupillary
sphincter muscle. Argyll-Robertson’s pupillary syndrome refers to small,
light-refractive pupils with maintained convergence response to near vision. The
syndrome is seen in neurosyphilis, when the pupillary light reflex is spoiled by
interruption of the fibres from brachium to the olivary pretectal nucleus
neurons.Sympathetic
preganglionic neurons in the intermediolateral cell column of segment T1-T2,
send ascending axons to the superior cervical ganglion. Postganglionic axons
follow the ciliary nerve into the eye. The nerve terminals end on a 1- receptors on the dilatator pupillae muscle, and noradrenaline is
neurotransmitter. The sympathetic fibres also contain vasoconstrictors to the
facial skin and stimulate facial sweat glands (see Horners syndrome).Catecholamines are
substances consisting of catechol (an aromatic structure with two hydroxyl
groups) linked to an amine. The synthesis is described in Chapter
29.Catecholamines
increase heart rate and cardiac output by stimulation of the adrenergic b1-receptors
in the myocardium. Catecholamines, released by the adrenal medulla, support the
sympathetic system by modifying the circulation during exercise. During exercise
the blood is directed to the working muscles from other parts. Noradrenergic
nerve fibres innervate blood vessels all over the body. Sympathetic innervation
accounts for vascular tone and vasoconstriction.The most important
exercise response in humans is a tremendous vasodilatation in the vascular bed
of muscles. The vasodilatation is probably due to a decrease in the a-adrenergic
tone of muscular arterioles, and to the action of adrenaline on b2-receptors.Catecholamines
dilatate the bronchial airways by stimulating adrenergic b2-receptors.
They increase both tidal volume and respiratory frequency. The result is
increased ventilation. Catecholamines acting on b1-receptors
cause increased cardiac output. Catecholamines relax the smooth muscles of the
digestive tract (b2-receptors), but
contract the sphincters. Catecholamines stimulate metabolism (by activation of
the thyroid hormone, T3) and lipolysis. Adrenaline stimulates hepatic
glycogenolysis via b2-receptors.Finally,
adrenaline stimulates the ascending reticular system (ie, the reticular
activating system or RAS) in the brain stem, thus keeping us alert and causing
arousal reactions with desynchronisation of the EEG (Chapter
10).The resistance
vessels of the striated muscles in hunting predators (and perhaps in humans) are
also innervated by another system. This is the cholinergic, sympathetic
vasodilator system. It is capable of a rapid and appropriate bloodflow response
during hunting.Acute stress
activates the splancnic nerves and liberates large amounts of adrenaline from
the medulla. Diabetics who are developing acute hypoglycaemia, secrete large
amounts of catecholamines. Acute muscular activity starts a large catecholamine
secretion in exercising persons.Besides
catecholamines, ACTH is also released during stress by increasing hypothalamic
signals. ACTH stimulates the glucocorticoid and to some extent the
mineralocorticoid secretion through cAMP. Small amounts of glucocorticoids are
permissive for the actions of catecholamines.Plasma
catecholamines are rapidly removed from the blood and have a half-life in plasma
of less than 20 s. This is the combined result of rapid uptake by tissues and
inactivation in the liver and vascular endothelia (see Chapter
29).
The
Autonomic Control Of The Cardiovascular System
The brainstem is
the primary site for the autonomic cardiovascular control.High-pressure
baroreceptors are distension-activated stretch receptors located in the walls of
the carotid sinus and the aortic arch. Increased arterial blood pressure
increases the signal frequency in the sensory baroreceptor neurons that project
into the medullary cardiovascular centre (ie, the solitary tract nucleus,
nucleus ambiguus and the dorsal motor nucleus of the vagus, DMNV). Impulses
generated in the baroreceptor neurons with increasing blood pressure, activate
the vagal efferents to the heart and inhibit the sympathetic tone towards the
heart. As a consequence the heart rates and force of contraction decreases.
Impulses generated in cardiac baroreceptors by cardiac filling, also activate
the force of contraction (Fig. 6-4).The postganglionic
fibres from the 3 upper cervical ganglia of the sympathetic trunk pass to the
heart as the cardiac nerves to the cardiac plexus.
![Autonomic control of blood pressure](images/fp6-4s.jpg)
Fig.
6-4: The
autonomic control of blood pressure and heart rate.The sympathetic
effect is dominant. Increased sympathetic activity constricts the veins, which
increases cardiac output by augmenting cardiac filling. Arteriolar constriction
reduces cardiac output by increasing the arterial blood pressure (ie, afterload).
Other sensory inputs from skeletal muscles, lungs, gastrointestinal viscera,
hypothalamus and forebrain help to co-ordinate the autonomic cardiovascular
responses related to exercise, respiration, and feeding and temperature control.
Hormones, such as angiotensin II, can also modulate the autonomic responses
through neurons in the circumventricular organs of the brain, These organs (such
as the area postrema) lack the blood-brain barrier.The sympathetic
system innervates the sinus node, the coronary vessels and the myocardial
syncytium. Each fibre ends in many terminals, and from the terminals the
transmitter noradrenaline is released to the b2 -receptors of the smooth muscle cells of the coronary vessels and of the
myocardium (Fig. 6-4). As a result of increased sympathetic tone, the
contractility of the myocardium is increased. Thus, the end systolic volume falls
from its usual volume- as an example from 70 ml to 40 ml, and the end
diastolic volume increases due to increased venous return of blood from 140
to 180 ml. Hereby, the stroke volume is increased from 70 to 140
ml of blood in the example. A combination of the doubling of stroke volume
with a threefold increase in heart rate, results in a 6-fold rise in
cardiac output.Sympathetic
stimulation depolarizes the sinus node, so that the threshold potential is
reached faster than normal. Hereby, the heart rate is increased, and may reach
220 beats/min in young persons. Such a high frequency is due to a maximal
sympathetic activation of the heart combined with a reduction of
the vagal tone.
Sympathetic
Activation
Activation of
noradrenergic fibres leads to peripheral sympathetic vasoconstriction, so
that blood is shunted to central areas. The heart is stimulated through b1-receptors
so that its frequency and contractility is increased. Other organs are also
stimulated to make the person fit for fight or flight in any stressful
situation.The postganglionic
sympathetic fibres have noradrenaline and ATP containing vacuoles in their nerve
terminals. Hence, they release noradrenaline and ATP. The noradrenaline is
produced in the chromaffine granules of the neuron.
![Sympathetic ganglionic synapse](images/fp6-5s.jpg)
Fig.
6-5: A
sympathetic ganglionic synapse with a small intensity fluorescent cell (SIF
cell).Acetylcholine is
released from the preganglionic cell and binds to nicotinic receptors on the
postganglionic cell. Acetylcholine also binds to small SIF cells (Fig. 6-5) with
muscarinic receptors and vesicles that contain dopamine. Dopamine interacts with
dopamine receptors (D2 and D4) on the postganglionic cell and modulates
ganglionic transmission by increased permeability to small ions and hyperpolarisation.Liberation of
noradrenaline and ATP to the blood does not only lead to constriction of
arterioles and arterial vessels, but also constriction of veins and venules.
Without venous constriction, the large venous compliance would cause an
inordinate amount of blood to be stored in the veins upon sympathetic arteriolar
constriction. The consequence would be decreased venous return, which decreases
cardiac output and perfusion of vital organs.Activation of
presynaptic purine receptors by adenosine inhibits adrenaline release from the
postganglionic terminals innervating the blood vessels. This results in massive
vasodilatation.Exercise and
stress demand mobilisation of energy to muscles and heart. Activation of b2-receptors
in the arteriolar wall by circulating catecholamines from the medulla also
contributes to vasodilatation in the striated muscles. The total peripheral
vascular resistance is reduced during exercise to 20-30% of resting values.During stress the
cutaneous circulation is reduced at first, but then the cutaneous bloodflow
rises due to the increased heat production. The brain vessels are only modestly
constricted by sympathetic stimulation.
3.
The Parasympathetic System
The
parasympathetic system has two subdivisions. The cranial division in the
brainstem innervates the blood vessels of the head and neck and of many Thoraco-abdominal
viscera. The sacral division in the sacral cord innervates the smooth muscles of
the walls of the viscera and their glands (the large intestine, liver, kidney,
spleen, the bladder and the genitals).The
parasympathetic system only innervates a small percentage of the resistance
vessels. Only arteries in the brain and of the penis, the clitoris, and the
labia minora receive parasympathetic innervation. Hence, the parasympathetic
system has a minimal effect on the arterial blood pressure.Parasympathetic
fibres travelling in the vagus nerve are of utmost importance in affecting the
cardiac rate. Vagal fibres innervate the sino-atrial- and the atrio-ventricular-nodes
as well as the atrial muscle walls.The
parasympathetic system also innervates the tear and the salivary glands, and the
muscles within the eye.Excitation of the
vagus decreases heart rate and atrial contractile force, increases intestinal
motility, contracts the gall bladder and bronchi, and relaxes the sphincters of
the gastrointestinal tract. The vagal decrease in heart rate is due to the
rhythm shift to special P cells, which have a slow rate of depolarisation.
Acetylcholine (ACh) is liberated on the cardiac cell membranes, ACh-activated K+ - channels are opened (via cholinergic receptors and G-regulatory proteins), and
K+ leaks out of the cells, thus opposing the pacemaker current. Vagal
stimulation slows down the AV-conduction, causing the co-ordination of atrial
and ventricular rhythm to be disrupted. Vagal stimulation can lead to death.
Thus external massage of the carotid sinus can cause collar death by greatly
increasing vagal stimulation.The effect of
acetylcholine released in the autonomic ganglia can be simulated by nicotine.
Conversely, the effect of acetylcholine released by parasympathetic nerve
terminals at the target organs can be simulated by muscarine. These observations
suggest the presence of two different types of cholinergic receptors.
Cholinergic receptors are activated by ACh and by metacholine (MeCH).
Table
6-3:
Cholinergic receptor subtypes. ACh stands for acetylcholine, CCh for
carbacholine, MeCH for metacholine, DMPP for dimethylphenylpiperazine, and
HHSD for hexahydrosiladifenol |
Cholinergic
receptors |
|
Nicotinic |
|
Muscarinic |
|
Stimulated
by: |
Nicotine,
ACh, MeCH, DMPP |
|
Muscarine,
ACh, CCh MeCH |
|
Blocked by: |
Hexa-
and decamethonium d-tubocurarine |
|
Atropine,
scopolamine |
|
Two types of
nicotinic receptors |
|
Three
muscarinic subtypes |
|
Ganglionic |
Neuromuscular |
|
M1, M2 M3 |
Stimulated
by |
Nicotine,
ACh
DMPP |
Nicotine,
ACh |
|
|
Blocked by: |
Hexamethonium
d-tubocurarine |
Decamethonium
Atropine |
Pirenzepine
Gallamine HHSD |
Atropine
Dicyclomine |
The most important
ganglionic blocking drug for blockade of both sympathetic and parasympathetic
transmission is hexamethonium (Table 6-3).Cholinergic
receptors are located in all autonomic ganglia (nicotinic type), in
postganglionic terminals at target organs with parasympathetic innervation (muscarinic
type), and in the motor endplate (nicotinic type).Nicotinic
receptors are those activated by acetylcholine, nicotine and nicotinic agonists
(ex. dimethylphenylpiperazine, DMPP). Nicotine stimulates all autonomic ganglia
simultaneously. Hence, sympathetic vasoconstriction in the limbs and viscera is
accompanied by increased gastrointestinal activity and slowing of the heart via
the vagus. Nicotinic receptors are blocked completely by d-tubocurarine, and
hexa- or decamethonium (Table 6-3). The motor endplate has a different type of
nicotinic receptor than the ganglions, since its receptors are not blocked by
hexamethonium, but are blocked by d-tubocurarine and decamethonium (Table 6-3).Acetylcholine,
muscarine and muscarinic agonists (pilocarpine and carbacholine, CCh), activate
muscarinic receptors. At least 5 different muscarinic receptor molecules have
been identified (M1, M2, M3 ..). Activation of
the M1 type is illustrated in Fig. 6-3. Activation of the M2 type activates an inhibitory G-protein, which inhibits adenylcyclase. Muscarinic
receptor activation is linked to G-protein activation and second-messenger
systems.The dominating
receptors in the heart are the M3 receptors mainly in the coronary
circuit and the M2 receptors elsewhere. The typical effects of
acetylcholine are hyperpolarisation and reduced spontaneous depolarisation of
the sinusoidal cells leading to reduced pacemaker activity. Besides, the cardiac
contractility and conduction velocity are reduced (Dhein et al, 2001).Muscarinic
receptors are blocked completely by atropine, and by antimuscarinic drugs such
as homatropine and scopolamine (Table 6-3). These drugs do not block the
nicotinic effect of ACh on the postganglionic neurons or on the motor endplate.
- The
sympathetic system consists of short preganglionic and long postganglionic
nerve fibres. The parasympathetic system contains long preganglionic and
short postganglionic fibres.
- The
chemical transmitter at the target organ is noradrenaline in the sympathetic
and acetylcholine in the parasympathetic system.
- The
sympathetic system contains adrenergic receptors (a and b), whereas the parasympathetic system has
cholinergic receptors (muscarinic or muscarinergic and nicotinic or
nicotinergic).
- Activation
of the cholinergic system serves anabolic functions (ie, stay and play),
whereas activation of the noradrenergic system serves catabolic functions (ie,
fight, fright or flight).
- Activation
of a1-receptors increases
intracellular [Ca2+], which leads to phosphorylation of protein
kinases and thus to a response. Activation of a2-receptors
triggers an inhibition of the membrane adenylcyclase, reducing [cAMP] in the
cells. b1- and b2-receptors
activate adenylcyclase, which increases cAMP production in the cell.
Muscarinic receptors are completely blocked by atropine. Activation of M1-receptors
increases intracellular [Ca2+]. Activation of M2 inhibits adenylcyclase, and through an inhibitory G-protein reduces the
formation of cAMP.
Pathophysiology
This paragraph
deals with 1. Mushroom poisoning, 2. Carbamate and organo-phosphate
poisoning,
3. Xerophtalmia and xerostomia, 4. Tachycardia and bradycardia, 5. Smoking, 6. Phaeochromocytoma, 7. Primary or essential
hypertension, 8. Horners syndrome, 9. The Kluver- Bucy-syndrome and emotional disorders. - Altzheimers disease and
Parkinson’s disease are also related to the autonomic nervous system and
described in Chapter 7.
1.
Mushroom Poisoning Among the
poisonous mushrooms at least two are related to the autonomic nervous system: Amanita palterina (false
blusher) contains a substance with atropine-effect, which completely blocks the
muscarinic cholinergic receptors. Atropine-effects are described below. Amanita muscaria (red fly agaric) contains atropine-like substances, muscarine and other
hallucinogens. Atropine-effects are prominent: Motor unrest, delirium (red fly
agaric was used by the Vikings to run berserk), mouth dryness, pupillary
dilatation, and tachycardia. Some cases are dominated by muscarine-effects:
Glandular secretion (sweat, saliva, tear-flow), miosis, eye pains, bradycardia,
cramps, respiratory failure, lung oedema, and coma. Muscarinic symptoms are
treated with slow intravenous injection of atropine (1 mg in 1 ml). -
Ventilation with the mouth-to mouth-method may become fatal for the rescuer.
2.
Carbamate And Organo-Phosphate Poisoning These substances (carbaryle,
dimethoate, melathion, parathion etc) are used as insecticides in agriculture.
They are anti-cholinesterases so they accumulate acetylcholine in the tissues.
The clinical picture is due to the muscarinic and nicotinic effects of
acetylcholine. The muscarine-effects are described above. Other symptoms are
nausea, vomiting, muscle weakness, paresthesia, bronchospasm, shock and
respiratory arrest. Atropine (1 mg iv.) is given repeatedly to obtain complete
atropine blockade beginning with pupillary dilatation. Artificial ventilation is
often imperative. Cholinesterase- reactivators are tried in desperate
situations.
3. Xerophtalmia
and xerostomia Xerophtalmia and
xerostomia is dryness of the conjunctiva and the cornea, and
dryness of the mouth, respectively. Most of these disorders are of unknown
origin (ie essential or primary), although an autonomic cause may be suspected.
Xerophtalmia and xerostomia occurs in connection with anaesthesia due to the use
of atropine-like substances in order to reduce secretion.
4.
Tachycardia and bradycardia. A balance between
the parasympathetic and the sympathetic system normally determines cardiac
rhythm. The parasympathetic system predominates. A relative dominance of the
sympathetic tone towards the heart leads to tachycardia (ie, a heart rate above
80 beats per min), and a further relative dominance of the parasympathetic
system leads to bradycardia (ie, a heart rate below 50 beats per min).
Fluctuations of the autonomic tone leads to phasic changes of the sinus node
activity. During inspiration, the parasympathetic dominance falls and the heart
rate becomes rapid, whereas during expiration parasympathetic dominance
increases and the heart slows down. This phenomenon is found in children, and it
can even be found in healthy subjects of high age. The phenomenon is called
sinus arrhythmia.
5.
Smoking Cigarette smoking
is common among teen-agers, and more girls than boys of 15 years smoke
cigarettes. Activation of nicotinic cholinergic receptors is fast and
does not require G proteins. Nicotinic receptors stimulated by acetylcholine
open a Na+-channel and depolarise the cell membrane. Nicotine
stimulates nicotinic receptors on the postganglionic neuron of all autonomic
ganglia.The number of
cigarettes smoked and the number of years smoked seem to increase the number of
nicotinic cholinergic receptors in brain tissue. Smoker’s dependency may
depend upon the number of nicotinic receptors. Smokers, deprived of the usual
daily dose of nicotine in cigarettes, become depressed in mood, they feel stress
and they are un-concentrated. This is called abstinence and the cause is lack of
nicotine. The mood of the smoker is immediately improved by smoking. Although
smoking is nicotine addiction, nicotine seems to be one of the less dangerous
molecules in smoke. Polycyclic aromatic hydrocarbons and nitrosamines are potent
carcinogens and mutagens. Such substances release proteinases from granulocytes
and macrophages, whereby elastin is destroyed resulting in multi-site lung
degeneration or emphysema. The life-threatening dangers are due to cancer and
atherosclerosis: Lung cancer, chronic bronchitis and emphysema, cerebral stroke,
ischaemic heart disease, peripheral vascular disease, bladder cancer, and memory
problems. Male smokers have an increase in the number of abnormal spermatozoa,
and pregnant female smokers have an increase in neonatal mortality. Female
smokers above 30 years using anti-pregnancy pills have a 40-fold higher risk of
cerebral stroke than their non-smoking control group.
6.
Phaeochromocytoma Some patients
suffer from attacks of severe hypertension due to adrenaline hypersecretion. The
hypertension is caused by release of large amounts of adrenaline from a medullary
tumour of chromaffine cells. The attacks are sometimes fatal. The diagnosis
is important, because the patient can be cured by surgical abolition of the
tumour.
7.
Primary or essential hypertension in general
begins as a condition with sympathetic overactivity (see Chapter
9).
8.
Horner’s syndrome refers to a
condition with miosis, facial vasodilatation and loss of facial sweating and
enophtalmus due to damage of the sympathetic nerve supply from the
T1-T2-segments to the eye and facial skin.
9.
The Kluver- Bucy-syndrome refers to an emotional
disorder with bilateral temporal lobe lesions. The temporal cortex,
hippocampus and the amygdaloid body are damaged. Mental blindness (visual
agnosia) is the inability to recognise objects seen. Besides mental blindness,
the syndrome consists of loss of short-term memory, and hypersexual behaviour
incompatible with normal social adaptation. The hypersexual behaviour is related
to the visual agnosia.
Self-Assessment
Multiple Choice Questions
I. Each of the
following five statements have True/False options:
-
Altzheimers
disease is a primary cortical brain atrophy with premature ageing of the
brain. Lack of the acetylcholine-producing enzyme choline acetyltransferase
and of acetylcholine is characteristic.
-
Mushroom
poisoning can be dominated by muscarine-effects: Glandular secretion (sweat,
saliva, tear-flow), miosis, eye pains, bradycardia, cramps, respiratory
failure, lung oedema, and coma.
-
Cannons law: The
peristalsis in the small intestine is polarised, so it always proceeds in the
aboral-oral direction.
-
Cannons
emergency reaction is an immediate sympatho-adrenergic response to life
dangerous situations, with both sympatho-adrenergic and parasympathetic
overactivity. The last phenomenon includes vagal cardiac arrest with
involuntary defecation and urination.
-
The sympathetic
system contains adrenergic receptors (a and b),
whereas the parasympathetic system has cholinergic receptors (muscarinic or
muscarinergic and nicotinic or nicotinergic).
II. Each of the
following five statements have True/False options:
-
A. Mydriasis
refers to contraction of the pupil by sympathetic stimulation.
-
B. SIF cells are
small intensity fluorescent cells, which possess muscarinic receptors and
contain vesicles filled with dopamine. Adequate stimulation releases
dopamine, which interacts with dopamine receptor (D2) on the
postsynaptic cell body and modulates the effect of acetylcholine.
-
C. Apraxia refers
to a condition with lack of ability to recognise and interpret a sensory
stimulus.
-
D. Phenoxybenzamine
and phentolamine block the a-receptor.
-
E. Adrenaline
stimulates the ascending reticular system in the brain stem, thus keeping us
alert.
-
Each of the
following five statements have True/False options:
-
Argyll-Robertson’s
pupillary syndrome with small, light-refractive pupils and maintained
convergence response to near vision is a typical sign in acute syphilis.
-
Besides
catecholamines, ACTH is also released during stress by increasing
hypothalamic signals. ACTH stimulates the glucocorticoid and to some extent
the mineralocorticoid secretion through cAMP.
-
All autonomic
nerves have ganglia outside the CNS in contrast to the somatic nervous
system.
-
When
stimulated nicotinic receptors work through a slow cascade of events.
-
Catecholamines
dilatate the bronchial airways.
6.
Case History
A 19-year-old
female is in hospital with a cranial lesion caused by a fall from her horse. The
following clinical signs are found: 1) speech troubles and hoarseness, 2)
swallowing problems and paresis of the soft palate, 3) rapid heart rate, and 4)
dilatation of the stomach with vomiting.
Lesion of a
certain cranial nerve can explain all symptoms and signs.
1. What is the
name of the nerve?
2. What is
special about this particular lesion?
Try to solve the
problems before looking up the answers .
Highlights
- The autonomic
nervous system mediates neural control of the internal milieu despite
substantial environmental changes. The autonomic system directly influences
smooth muscles, glands and the heart through its two subdivisions, the
sympathetic and the parasympathetic system. The two subdivisions function in a
dynamic balance aiming at homeostasis.
- The sympathetic
system consists of short preganglionic and long postganglionic nerve fibres.
The parasympathetic system contains long preganglionic and short
postganglionic fibres.
- The chemical
transmitter at the target organ is noradrenaline in the sympathetic and
acetylcholine in the parasympathetic system.
- Carbamate and
organo-phosphate poisoning. These substances (carbaryle, dimethoate,
melathion, parathion etc) are used as insecticides. They are
anti-cholinesterases, so they accumulate acetylcholine. The clinical picture
of poisoning is due to the muscarinic and nicotinic effects of acetylcholine.
Atropine (1 mg iv.) is given repeatedly to obtain complete atropine blockade
beginning with pupillary dilatation.
- The sympathetic
system contains adrenergic receptors (a and b),
whereas the parasympathetic system has cholinergic receptors (muscarinic or
muscarinergic and nicotinic or nicotinergic).
- Activation of
the cholinergic system serves anabolic functions (i.e., stay and play),
whereas activation of the noradrenergic system serves catabolic functions
(i.e., fight, fright or flight).
- Activation of a1-receptors
increases intracellular [Ca2+], which leads to phosphorylation of
protein kinases and thus to a response.
- Activation of a2-receptors
triggers an inhibition of the membrane adenylcyclase, reducing [cAMP] in the
cells.
- b
1-
and b2-receptors activate adenylcyclase,
which increases cAMP production in the cell.
- Muscarinic
receptors are completely blocked by atropine. Activation of M1-receptors
increases intracellular [Ca2+]. Activation of M2 inhibits adenylcyclase, and through an inhibitory G-protein reduces the
formation of cAMP.
- The intrinsic
enteric nervous system consists of two sets of nerve plexi. The submucosal
(Meissner) plexus mainly regulates digestive glands, whereas the myenteric
(Auerbach) plexus, located between the longitudinal and the circular muscle
layers, is primarily connected with gut motility.
- Sympathetic
activity (excitement or pain) causes a large pupil, and parasympathetic
activity (light or near- sight) causes a small pupil.
- Parasympathetic
activity controls salivation, gastrointestinal functions (with the enteric
nervous system), emptying of the bladder and defaecation.
- The limbic
system including the hypothalamus controls vital autonomic functions and
emotional behaviour.
Further
Reading
Brodal, A (1981) Neurological
anatomy. Oxford University Press, New York.
Dhein
S, Vann Koppen C J, and O-E Brodde. Muscarinic receptors in the mammalian
heart. Pharm Rev 44, No3, 2001.
Loewy, A.D. and
K.M. Spyer (editors). "Central Regulation of Autonomic Functions." Oxford
University Press, N-Y., 1990.
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