von lateinisch: vegetus - rüstig, lebhaft, munter
Englisch: vegetative
"autonomic„
[Greek: auto = self; nomos = rule]
means self-rule/self-govern.
autonomos (gr): auto = self, nomos = regulate
vegetus (lat) = vivid, lively
vegetative (adj.)
from 1893, ….. having only such functions which perform
involuntarily or unconsciously and thus are likened to the processes
of vegetable growth.
The autonomic nervous system regulates
bodily functions by integrating sensory,
motor, humoral and behavioural changes
of the organism.
“Homeostasis”
(a term coined by Walter B. Cannon in 1926) The maintenance of steady states in the body
and the physiological processes through which
they are regulated.
ISOHYDRIA
ISOIONIA
ISOTONIA
HOMOIOTHERMIA
Walter Bradford Cannon
(1871– 1945)
Physiology of th autonomic neervous system AUTONOMIC NERVES INNERVATE:
SMOOTH MUSCLE
GLANDS
HEART
Claude Bernard
n. auricularis
magnus transection of
n. auricularis magnus
(vasoconstrictio) vasodilatatio
Discovery of the sympathetic vasomotor tone
It is dangerous to fall in love with a hypothesis and
not willing to take no for an answer (P. Medawar)
”Introduction a la medecine experimentale, 1865”
Functional anatomy of the
autonomic nervous system
SOMATIC AUTONOMIC
MOTOR
(efferent)
SENSORY
(afferent)
SYMPATHETIC
(efferent)
PARASYMPATHETIC
(efferent)
ENTERAL
LANGLEY’S CLASSIFICATION OF THE PERIPHERAL NERVOUS SYSTEM
THORACOLUMBAR SYMPATHETHIC
Th1-12, L1-2/3
CRANIOSACRAL PARASYMPATHETIC
III, VII, IX, X cranial nerves
S2-4
1
1
Kontroll
2 2
3
3
Walter Holbrook GASKELL
1847-1914
Pioneers of autonomic nervous system research
Wilhelm Feldberg
1900-1993
Henry Hallett Dale
1875 – 1968
Walter Bradford Cannon
1871-1945
Ulf S. von Euler
1905-1983
GASKELL ~1885
Anatomy of the autonomic
nervous system
LANGLEY ~1900
Use of nicotine to explore the
anatomical/functional organization
of autonomic ganglia
Nicotiana tobacum
STÖHR: ”Eine Nikotinanatomie
werde ich nie anerkennen.”
ZNS
PNS
MOTOR SENSORY AUTONOMIC
CNS
PNS
pregangl.
postgangl.
preggl. postggl.
1:30, 1:180
diffuse effect
1:2 [n. vagus 1:7000]
localized effect ('one-to-few’)
Psy
Sy
Fulton: anatomical basis of functional differences
ratio index [ggl. ciliare; ggl. cervicale superius]
('one-to-many')
Nucleus salivatorius superior (VII)
N. salivatorius inferior (IX)
Nucleus Edinger-Westphal (III)
N. motorius dorsalis nervi vagi (X)
N. ambiguus (X)
The parasympathetic
division of the autonomic
nervous system
= Th5(6)-9(10)
= Th10-11
The sympathetic division
of the autonomic nervous
system
Nucleus intermediolateralis
pars funicularis (PF)
pars principalis (PP)
pars intercalatus (PI)
n. centralis autonomicus (CA)
PF
PP
PI CA
EFFERENTS:
PILOMOTOR,
SUDOMOTOR,
VASOMOTOR
Segmental organization of the spinal cord
Preganglionic neurons in the intermediolateral column of the thoracic spinal cord
Retrograde labelling from sympathetic chain ganglia Retrograde labelling from the adrenal medulla
(Fluorogold) (True blue)
Fluorescent dye
divergence
convergence
ggl. coeliacum
substance P
Integrative functions of
prevertebral ganglia.
Viscero-visceral reflexes.
enteric nervous system
Ax
IRIS
URETER (EM)
ARTERIA
ARTERIA
GL SUBMAND
Adrenergic innervation of the heart
Innervation of the ductus deferens [Falck-Hillarp-Method]
Fluoreszcensmikroszkópia GCS
IRIS
STRUCTURE OF THE
AUTONOMIC GROUND PLEXUS
Electron microscopy Fluorescence microscopy
: partial sympathetic (GCS) denervation N-A HILLARP
Uterine adrenergic innervation
(physiological denervation during pregnancy [plasticity])
The axons of the preganglionic neurons contact the postganglionic neurons via a synapse in the autonomic ganglia.
The SYMPATHETIC PREGANGLIONIC neurons are located in the Th1-12
and the L1-3 THORACOLUMBAR segments of the spinal cord.
The PARASYMPATHETIC PREGANGLIONIC neurons are located in the
autonomic nuclei of cranial nerves III, VII, IX és X, and the S2-4 segments
of the sacral cord.
SMOOTH MUSCLE, GLANDS AND THE HEART are innervated by
postganglionic axons through the AUTONOMIC GROUND PLEXUS.
The adrenal medulla is innervated by preganglionic neurons/axons.
Anatomical organization of the
autonomic nervous system
Role of Ach in ganglionic transmission
FELDBERG CANNON
KIBIAKOV
LOEWI
Dream, William Blake
Electric stimulation
Of the vagus nerve
Perfusion fluid
Electric stimulation
Perfusate
Otto LOEWI’S experiment proved the chemical nature of the
transmission of the nerve impulse
HR
HR
Otto LOEWI 1873-1961
Nobel-prize, 1936 Skizze und Beschreibung der humoralen Übertragung
von Otto Loewi für seinen Sohn Guido, etwa 1950.
"If a nerve by a stimulus gets an impulse
this impulse is propagated within the nerve
and is transmitted to the respec tive effective
organs (heart, muscle, gland) innervated by
the nerve. The question arose by which means
the impulse coming from the nerve is transmitted
to the effector organ. I was able to solve this
question by proving that the impulse running
down within the nerve liberates from its endings
chemical substances (Acetylcholine or Adrenaline
respectively) which in their turn influence the
effector organ exactly like the stimulation of the
nerve. With other words the influence of nervous
stimulation on an organ is not a direct one but
an indirect one mediated to the organ by
chemical substances released by the nerve
stimulation in its endings."
:
Fühner - Dale - Feldberg
Ach bioassay
(high sensitivity of leech
muscle to Ach)
leech
sample
Contraction of leech muscle
in the presence of Ach
Ach
Experimental evidence demonstrates
the transmitter role of Ach in vivo
Muscle contraction elicited by intraartrial injection of acetylcholine
(a. radialis – m. opponens pollicis)
George H. Acheson, John L. Langohr, and John B. Stanbury SENSITIVITY OF SKELETAL MUSCLE TO INTRA-ARTERIAL
ACETYLCHOLINE IN NORMAL AND MYASTHENIC MAN. J Clin Invest. 27: 439–445, 1948.
Mette P. Sonne et al., Impaired endothelial function and insulin action
in first-degree relatives of patients with type 2 diabetes mellitus
Metabolism Clinical and Experimental 58 (2009) 93–101
FDR: first-degree relatives
+Ach +Ach
diabetes
(FDR)
Healthy control
Effect of intraarterially injected acetylcholine
on forearm blood flow: a measure of endothelial function
CON
FDR
Synthesis and metabolism of acetylcholine (Ach)
[Fig. by Gabriella Kékesi]
Ulf von EULER
1905-1983
Noradrenalin’s
transmitter role
Prostaglandines
Substance P
Nobel-Prize, 1970
The ability of noradrenaline (re)uptake
identifies noradrenergic nerve terminals
Synthesis and metabolism of catecholamines
[Fig. by Gabriella Kékesi]
A myocardialis beta-receptorok számának
csökkenése a szívműködés súlyos
funkcionális zavarainak indikátora.
Figure 2. (a) Measurement of pre- and postsynaptic sympathetic innervation of
the heart. Cardiac images in a patient suffering from hypertrophic obstructive
cardiomyopathy. Left: Presynaptic sympathetic innervation measured with
11C-labeled hydroxyephedrine ([11C]HED). Right: b-Adrenoceptor density
measured with 11C-labeled (S)-CGP 12177 ([11C]CGP). (b) Left:
Catecholamine re-uptake in patients with hypertrophic cardiomyopathy (HCM)
and control individuals, measured as volume of distribution (Vd, mL/g) of
[11C]HED (means are indicated by the horizontal lines). Right: Maximum
number of available binding sites (Bmax
, pmol/g) forb-adrenoceptors in
patients with HCM and control individuals, measured usi
ng [11C]CGP (means are indicated by the horizontal lines).
[11C]HED : presynaptic marker
[11C]CGP : beta receptor marker (non selective beta
antagonist)
HCM: hypertrophias cardiomyopathia
Diagram illustrating the [11C]-labelled hydroxyephedrine
(HED) transport model. NE, neuroeffector; U-1, uptake-1.
Imaging of myocardial receptors:
applications in the evaluation of
cardiac disease Heart Metab. 2008; 41:16–20 Studies in patients have demonstrated diffuse
down-regulation of beta-adrenoceptor density in
hypertrophic cardiomyopathy and in congestive
heart cardiac failure, two disorders where there is
evidence of elevated levels of sympathetic
activation.
PRE POST
Catecholamine
re-uptake
Adrenergic receptor
density
PET
sympathicus vs parasympathicus
adrenerg vs cholinerg
transzmission
HH Dale, 1933
" it seemed to me desirable to have a terminology enabling
us to refer to a nerve fibre in terms of the chemical
transmission of its effects, without reference to its
anatomical origin; and, on this functional basis, I11
proposed to refer to nerve fibres and their impulses as
“cholinergic” or “adrenergic”, as the case might be."
[Dale, Nobel Lecture, 1936]
When the sympathetic chain was
stimulated, so that beads of sweat
appeared on the hairless pads, the
venous fluid collected during the
stimulation acquired a stimulant
action on the leech muscle
corresponding to a content of 2.5-l0
µg of acetylcholine per litre.
The general rule that postganglionic
fibres in the parasympathetic parts
of the system are cholinergic, and
that those in the sympathetic part of
the system are adrenergic, still
holds; but there are exceptions to
this rule…
Sweat glands are innervated
by sympathetic cholinergic
postganglionic nerves
Ach
Ach
NA
Ach
nicotinic Ach receptors
nicotinic Ach receptors
muscarinic Ach receptors
nikotinos Ach receptorok
M1,2,3 1,2, 1,2,3
nikotinic Ach receptors
Ach
Ach
NA
Ach
muscarinic Ach receptors
nikotinic Ach receptors
1,2, 1,2,3
M1,2,3
II. Peptides
Co-transzmitter, Co-localization, Co-release
Transmitters of the
autonomic nervous system
Atropin-rezisztant vasodilatation in the cat submandibular gland
Eserin = physostigmin: Acetylcholinesterase inhibitor
Eserin = physostigmin: Acetylcholinesterase inhibitor
Atropin-rezisztant vasodilatation in the cat submandibular gland
Effect of NPY on the noradrenaline- and
electrical stimulation-evoked vasoconstriction
Frequency-dependent release
of neurotransmitters
Low frequency stimulation:
release of small molecule (classical)
transmitters (Ach, NA)
High frequency stimulation:
additional release of peptides
III. Nitric oxide (NO)
Transmitters of the
autonomic nervous system
Alfred Nobel
1833-1896
R. Furchgott
F. Murad
L. Ignarro
sildenafil cyclic-GMP-specific
phosphodiesterase type 5 (PDE5)
DALE’S PRINCIPLE (1934)
THE SAME TRANSMITTER(S) IS (ARE) RELEASED
FROM ALL NERVE TERMINALS OF THE NEURON
ONE NEURON, ONE TRANSMITTER
Neurotransmitters of the autonomic nervous system
Preganglionic neurons: Acetycholine
VIP
Postganglionic neurons: Sympathetic Parasympathetic
Noradrenaline Acetylcholine
ATP VIP
NPY NO
(Adrenaline)
Presynaptic modulation of
neurotransmitter release
Presynaptic modulation of neurotransmitter release
Presynaptic modulation of neurotransmitter release
Presynaptic modulation of neurotransmitter release
- transmitter-inaktiváció (reuptake) zavar - fokozott kalcium-permeabilitás
DENERVATION HYPERSENSITIVITY
Increased sensitivity of the denervated tissue towards
its own transmitter (and related agents).
- transmitter-inaktiváció (reuptake) zavar - fokozott kalcium-permeabilitás
DENERVATION HYPERSENSITIVITY
Increased sensitivity of the denervated tissue towards
its own transmitter (and related agents).
* increased number of receptors (de novo synthesis)
* impaired transmitter-inactivation (re-uptake)
* increased number of smooth muscle gap junctions
* increased calcium permeability
Pre- vs postganglionic sympathectomy
Paradox pupil
Horner’s syndrome
Functional characteristics of the
autonomic nervous system
„The sympathetics are like the loud and soft pedals,
modulating all the tones together, while the
parasympathetics are like the separate keys”
Cannon,
Walter Bradford
1871-1945 sympathetikos (gr)
Sympathetic: generalized activation of effectors
Parasympathetic: individual activation of effectors
PSy: Trophotrop (trophos - nourish)
Energy conservation,
Emptying of hollow viscera
Sy: Ergotrop (energy release - activation)
Stress-situatons: stress, fear, pain, rage, bleeding
Cannon: fight or flight
„The sympathetics are like the loud and soft pedals,
modulating all the tones together, while the
parasympathetics are like the separate keys”
CANNON:
Tonic activity of autonomic nerves:
* sympathetic tone of blood vessels
* vagal parasympathetic tone of the heart
* vagal parasympathetic bronchomotor tone
(rest: 1-3 Hz; activation: 10-30 Hz)
Sympathetic and parasympathetic
innervation of organs and tissues
[Cannon, W.B. The wisdom of the body]
antagonistic actions: visceral smooth muscle
(GI-tract, urinary bladder)
cardiac muscle
only sympathetic innervation: blood vessels, sweat glands
except: pia mater, erectile tissues
only parasympathetic innervation: bronchial smooth muscle (!)
salivary gland secretion is stimulated by sympathetic and parasympathetic nerves
Neurohumoral regulation of blood vessel tone:
Sympathetic vasoconstrictor tone endothelial NO (dilatation)
Cannon, Walter Bradford,
1871-1945
Tonic activity of autonomic nerves:
* sympathetic tone of blood vessels
* vagal parasympathetic tone of the heart
* vagal parasympathetic bronchomotor tone
(rest: 1-3 Hz; activation: 10-30 Hz)
British Heart_Journal, I975, 37, 6I26i8.
Sinus node function in the denervated human heart. Effect of digitalis
D. J. Goodman,2 R. M. Rossen, R. Ingham,3 A. K. Rider, and D. C. Harrison
Resting heart rate after heart transplantation
Role of vagus tone in the
regulation of heart rate
transmitter-inaktiváció (reuptake) zavara
fokozott kalcium-permeabilitás
Underaction of the sympathetic system:
Total sympathectomy:
Increased sensitivity towards cold
Increased sensitivity towards hypoglycemia (insulin)
Infertility (man)
Fatigue
Hypotension (initial)
Sympathectomy (e.g. for treatment of Raynaud disease)
transient vasodilatation
anhydrosis
Familiar dysautonomia
Sympathetic denervation:
Denervation supersensitivity
(Immunosympathectomy –NGF
Chemical sympathectomy – 6-OHDA)
Horner syndrome results from damage to the sympathetic nerves of the face.
Typically, only one side of the face is affected. Signs and symptoms are subtle but
include decreased pupil size and droping of the upper eyelid.
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Horner’s Syndrom: Ptosis, Myosis, Enophthalmus
HORNER’s syndrome:
ptosis (m. tarsalis)
miosis (m. dil. pup.)
enophthalmus (m. orbitalis)
dry skin (sudomotor inn.)
Pre- vs Post-
ggl. denervatio
Paradox pupilla
Pre- vs Post-
ggl. denervation
Paradox pupil
OVERACTION OF THE SYMPATHETICS
Hyperhydrosis, craniofacial hyperhydrosis
Raynaud’s disease: cold acral regions (vasoconstriction)
mental sweating: palm, plantar skin, axillary region
Generalized sympathetic activation:
exercise
stress
fear
cold
tiredness
blood loss
Raynaud7 first described a clinical condition consisting
of episodic digital cyanosis and pallor induced by cold or
emotional stimuli in 1862. This phenomenon was believed
to be an abnormal vasospastic response mainly as a result of
an overactive sympathetic nervous system. On the basis of
this theory, cervicothoracic sympathectomy was performed
as a surgical treatment for Raynaud’s phenomenon.1,8-10
Raynaud-disease: vasoconstriction and cyanosis due to increased
sympathetic activity in the fingers produced by cold or emotion.
Therapy: ETS (endoscopic thoracic surgery) removal of T2-T4
sympathetic ganglia (sympathectomy).
Consequence: vasodilatation in the affected region and
reflex (compensatory) sweating (trunk)
Cannon’s sympathetic alarm reaction
increased firing of tonically active sympathetic (vasomotor) fibres
activation of sy fibres which are quiet (inactive) at rest:
sudomotor
pilomotor
adrenal medullary activation
muscle vasodilators
activation of muscle vasodilators
activation of vasoconstrictors (splanchnic)
increased skeletal muscle blood flow (shift, redistribution)
increased cardiac output
increased heart rate
increased cardiac muscle contractility (positive inotrop)
bronchodilatation
Adrenalin: 0,2 g/kg/min
Noradrenalin: 0,05 g/kg/min
Adrenal medullary activation
80% adrenaline, 20% noradrenaline
A vs NA
cardiac effect (beta1)
increase in heart rate, contractility
weak constriction of skeletal muscle blood vessels
slight increase in peripheral vascular resistance
bronchodilatation
increased cardiac output
metabolic effects
increased hepatic glycogenolysis
increased skeletal muscle glycogenolysis
increase in blood sugar
increase in blood FFA
Adrenal medullary activation
AUTONOMIC
INNERVATION OF
INDIVIDUAL ORGANS
Constriction
Skeletal muscle Dilatation (adrenaline)
Skeletal muscle Dilatation (cholinergic)
Pial vessels Dilatation
Blood vessels of erectile tissues Dilatation
Constriction
(palm, mental ≈)