autonomos (gr): auto = self, nomos = regulate · chemical substances (acetylcholine or adrenaline...

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 ≈)