Norepinephrine

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an

Norepinephrine
organic chemical in the catecholamine family that functions in the brain and
body as a hormone and neurotransmitter. The name "noradrenaline", derived
from Latin roots meaning "at/alongside the kidneys", is more commonly used in
the United Kingdom; in the United States, "norepinephrine", derived from Greek
roots having that same meaning, is usually preferred.[1] "Norepinephrine" is also
the international nonproprietary name given to the drug.[2] Regardless of which
name is used for the substance itself, parts of the body that produce or are
affected by it are referred to as noradrenergic.

The general function of norepinephrine is to mobilize the brain and body for
action. Norepinephrine release is lowest during sleep, rises during wakefulness,
and reaches much higher levels during situations of stress or danger, in the so-
called fight-or-flight response. In the brain, norepinephrine increases arousal and
alertness, promotes vigilance, enhances formation and retrieval of memory, and
focuses attention; it also increases restlessness and anxiety. In the rest of the
body, norepinephrine increases heart rate and blood pressure, triggers the release Clinical data
of glucose from energy stores, increases blood flow to skeletal muscle, reduces Synonyms NE, NA,
blood flow to the gastrointestinal system, and inhibits voiding of the bladder and
gastrointestinal motility.
Noradrenaline,
(R)-(–)-
In the brain, noradrenaline is produced in nuclei that are small yet exert powerful Norepinephrine,
effects on other brain areas. The most important of these nuclei is the locus
l-1-(3,4-
coeruleus, located in the pons. Outside the brain, norepinephrine is used as a
Dihydroxyphenyl)-2-
neurotransmitter by sympathetic ganglia located near the spinal cord or in the
aminoethanol
abdomen, and it is also released directly into the bloodstream by the adrenal
glands. Regardless of how and where it is released, norepinephrine acts on target Physiological data
cells by binding to and activating adrenergic receptors located on the cell Source locus coeruleus;
surface.
tissues sympathetic nervous
system; adrenal
A variety of medically important drugs work by altering the actions of
medulla
noradrenaline systems. Noradrenaline itself is widely used as an injectable drug
Target system-wide
for the treatment of critically low blood pressure. Beta blockers, which counter tissues
some of the effects of noradrenaline, are frequently used to treat glaucoma, Receptors α1, α2, β1, β3
migraine, and a range of cardiovascular problems. Alpha blockers, which
Agonists sympathomimetic
counter a different set of noradrenaline effects, are used to treat several
drugs, clonidine,
cardiovascular and psychiatric conditions. Alpha-2 agonists often have a
isoprenaline
sedating effect, and are commonly used as anesthesia-enhancers in surgery, as
well as in treatment of drug or alcohol dependence. Many important psychiatric Antagonists Tricyclic
drugs exert strong effects on noradrenaline systems in the brain, resulting in antidepressants, beta
side-effects that may be helpful or harmful. blockers,
antipsychotics
Precursor dopamine
 Biosynthesis dopamine β-
Contents
monooxygenase
Structure Metabolism MAO-A; COMT
Biochemical mechanisms
Biosynthesis Identifiers
Degradation IUPAC name
Functions (R)-4-(2-amino-1-hydroxyethyl)benzene-1,2-di
Cellular effects ol
Sympathetic nervous system
Central nervous system CAS Number 51-41-2 (http://www.c

Pharmacology ommonchemistry.org/
Beta blockers ChemicalDetail.aspx?
Alpha blockers ref=51-41-2)
Alpha-2 agonists
PubChem 439260 (https://pubch
Stimulants and antidepressants CID
em.ncbi.nlm.nih.gov/c
Diseases and disorders
ompound/439260)
Sympathetic hyperactivation
Pheochromocytoma IUPHAR/BPS 505 (http://www.guidet
Stress opharmacology.org/G
ADHD
RAC/LigandDisplayFo
Autonomic failure
rward?ligandId=505)
Comparative biology and evolution
DrugBank DB00368 (https://ww
History
w.drugbank.ca/drugs/
References
DB00368)
ChemSpider 388394 (http://www.ch
Structure emspider.com/Chemic
al-Structure.388394.ht
Norepinephrine is a catecholamine and a phenethylamine.[3] Its structure differs
ml)
from that of epinephrine only in that epinephrine has a methyl group attached to
its nitrogen, whereas the methyl group is replaced by a hydrogen atom in
KEGG C00547 (http://www.k
norepinephrine.[3] The prefix nor- is derived as an abbreviation of the word egg.jp/entry/C00547)
"normal", used to indicate a demethylated compound.[4] CompTox DTXSID5023378 (http
Dashboard
(EPA) s://comptox.epa.gov/d
ashboard/DTXSID502
3378)
ECHA 100.000.088 (https://e
InfoCard cha.europa.eu/substa
nce-information/-/subs
tanceinfo/100.000.08
8)
Chemical and physical data
Formula C8H11NO3
Molar mass 169.180 g·mol−1
 Norepinephrine structure Epinephrine structure
Catechol structure

Biochemical mechanisms

Biosynthesis
Biosynthetic pathways for catecholamines and trace amines in the human brain[5][6][7]

AADC PNMT

L-Phenylalanine Phenethylamine N-Methylphenethylamine

AAAH
N-Methyltyramine
PNMT

AADC

L-Tyrosine p-Tyramine DBH

brain minor p-Octopamine

AAAH CYP2D6 pathway

PNMT
AADC
primary
pathway
L-DOPA Dopamine

Synephrine
DBH COMT

PNMT

Epinephrine Norepinephrine 3-Methoxytyramine

Norepinephrine is synthesized from dopamine in the human body by the dopamine β-hydroxylase
(DBH) enzyme.
Norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and
postganglionic neurons of the sympathetic nervous system. While the conversion of tyrosine to dopamine occurs predominantly
in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-monooxygenase occurs predominantly inside
neurotransmitter vesicles.[8] The metabolic pathway is:

Phenylalanine → Tyrosine → L-DOPA → Dopamine → Norepinephrine[8]

Thus the direct precursor of norepinephrine is dopamine, which is synthesized indirectly from the essential amino acid
phenylalanine or the non-essential amino acid tyrosine.[8] These amino acids are found in nearly every protein and, as such, are
provided by ingestion of protein-containing food, with tyrosine being the most common.

Phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen (O2) and
tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with
tetrahydrobiopterin, O2, and probably ferrous iron (Fe2+) as cofactors.[8] L-DOPA is converted into dopamine by the enzyme
aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate as a cofactor.[8] Dopamine
is then converted into norepinephrine by the enzyme dopamine β-monooxygenase (formerly known as dopamine β-hydroxylase),
with O2 and ascorbic acid as cofactors.[8]

Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-
adenosyl-L-methionine as cofactor.[8]

Degradation
In mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by
either of the enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT.[9] From there the breakdown can proceed
by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of
which are thought to be biologically inactive and are excreted in the urine.[10]

Norepinephrine degradation.[10] Metabolizing enzymes are shown in boxes.

Functions
Cellular effects
Like many other biologically active substances, Adrenergic receptors in the mammal brain and body[10]
norepinephrine exerts its effects by binding to Family Receptor Type Mechanism
and activating receptors located on the surface
Increase IP3 and calcium by
of cells. Two broad families of norepinephrine α1 Gq-coupled.
activating phospholipase C.
receptors have been identified, known as alpha Alpha
Decrease cAMP by
and beta adrenergic receptors.[10] Alpha α2 Gi/Go-coupled.
inhibiting adenylate cyclase.
receptors are divided into subtypes α1 and α2;
β1
beta receptors into subtypes β1, β2, and β3.[10]
Increase cAMP by
Beta β2 Gs-coupled.
All of these function as G protein-coupled activating adenylate cyclase.
receptors, meaning that they exert their effects β3
via a complex second messenger system.[10]
Alpha-2 receptors usually have inhibitory effects, but many are located pre-synaptically (i.e., on the surface of the cells that
release norepinephrine), so the net effect of alpha-2 activation is often a decrease in the amount of norepinephrine released.[10]
Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.[10]

Storage, release, and reuptake

Inside the brain norepinephrine functions as a
neurotransmitter, and is controlled by a set of
mechanisms common to all monoamine
neurotransmitters. After synthesis,
norepinephrine is transported from the cytosol
into synaptic vesicles by the vesicular
monoamine transporter (VMAT).[11]
Norepinephrine is stored in these vesicles
until it is ejected into the synaptic cleft,
typically after an action potential causes the
vesicles to release their contents directly into
the synaptic cleft through a process called
exocytosis.[10]

Once in the synapse, norepinephrine binds to

and activates receptors. After an action
potential, the norepinephrine molecules
quickly become unbound from their receptors.
Norepinephrine (labeled "noradrenaline" in this drawing) processing
They are then absorbed back into the in a synapse. After release norepinephrine can either be taken up
presynaptic cell, via reuptake mediated again by the presynaptic terminal, or broken down by enzymes.
primarily by the norepinephrine transporter
(NET).[12] Once back in the cytosol,
norepinephrine can either be broken down by monoamine oxidase or repackaged into vesicles by VMAT, making it available for
future release.[11]

Sympathetic nervous system

Norepinephrine is the main neurotransmitter used by the sympathetic nervous system, which consists of about two dozen
sympathetic chain ganglia located next to the spinal cord, plus a set of prevertebral ganglia located in the chest and abdomen.[13]
These sympathetic ganglia are connected to numerous organs, including the eyes, salivary glands, heart, lungs, liver, gallbladder,
stomach, intestines, kidneys, urinary bladder,
reproductive organs, muscles, skin, and
adrenal glands.[13] Sympathetic activation of
the adrenal glands causes the part called the
adrenal medulla to release norepinephrine (as
well as epinephrine) into the bloodstream,
from which, functioning as a hormone, it
gains further access to a wide variety of
tissues.[13]

Broadly speaking, the effect of norepinephrine

on each target organ is to modify its state in a
way that makes it more conducive to active
body movement, often at a cost of increased
energy use and increased wear and tear.[14]
This can be contrasted with the acetylcholine-
mediated effects of the parasympathetic
nervous system, which modifies most of the
same organs into a state more conducive to
rest, recovery, and digestion of food, and
usually less costly in terms of energy
expenditure.[14]

The sympathetic effects of norepinephrine

include:
Schema of the sympathetic nervous system, showing the
In the eyes, an increase in production
of tears, making the eyes more sympathetic ganglia and the parts of the body to which they connect.
moist,[15] and pupil dilation through
contraction of the iris dilator.
In the heart, an increase in the amount of blood pumped.[16]
In brown adipose tissue, an increase in calories burned to generate body heat (thermogenesis).[17]
Multiple effects on the immune system. The sympathetic nervous system is the primary path of interaction
between the immune system and the brain, and several components receive sympathetic inputs, including the
thymus, spleen, and lymph nodes. However the effects are complex, with some immune processes activated
while others are inhibited.[18]
In the arteries, constriction of blood vessels, causing an increase in blood pressure.[19]
In the kidneys, release of renin and retention of sodium in the bloodstream.[20]
In the liver, an increase in production of glucose, either by glycogenolysis after a meal or by gluconeogenesis
when food has not recently been consumed.[20] Glucose is the body's main energy source in most conditions.
In the pancreas, increased release of glucagon, a hormone whose main effect is to increase the production of
glucose by the liver.[20]
In skeletal muscles, an increase in glucose uptake.[20]
In adipose tissue (i.e., fat cells), an increase in lipolysis, that is, conversion of fat to substances that can be used
directly as energy sources by muscles and other tissues.[20]
In the stomach and intestines, a reduction in digestive activity. This results from a generally inhibitory effect of
norepinephrine on the enteric nervous system, causing decreases in gastrointestinal mobility, blood flow, and
secretion of digestive substances.[21]
Noradrenaline and ATP are sympathetic co-transmitters. It is found that the endocannabinoid anandamide and the cannabinoid,
WIN 55,212-,2 can modify the overall response to sympathetic nerve stimulation, and indicate that prejunctional CB1 receptors
mediate the sympatho-inhibitory action. Thus can cannabinoids inhibit both the noradrenergic and purinergic components of
sympathetic neurotransmission.[22]

Central nervous system

The noradrenergic neurons in the brain form a neurotransmitter system, that,
when activated, exerts effects on large areas of the brain. The effects are
manifested in alertness, arousal, and readiness for action.

Noradrenergic neurons (i.e., neurons whose primary neurotransmitter is

norepinephrine) are comparatively few in number, and their cell bodies are
confined to a few relatively small brain areas, but they send projections to many
other brain areas and exert powerful effects on their targets. These noradrenergic
cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who Brain areas containing noradrenergic
assigned them labels starting with the letter "A" (for "aminergic").[23] In their neurons.
scheme, areas A1 through A7 contain the neurotransmitter norepinephrine (A8
through A14 contain dopamine). Noradrenergic cell group A1 is located in the
caudal ventrolateral part of the medulla, and plays a role in the control of body fluid metabolism.[24] Noradrenergic cell group A2
is located in a brainstem area called the solitary nucleus; these cells have been implicated in a variety of responses, including
control of food intake and responses to stress.[25] Cell groups A5 and A7 project mainly to the spinal cord.[26]

The most important source of norepinephrine in the brain is the locus coeruleus, which contains noradrenergic cell group A6 and
adjoins cell group A4. The locus coeruleus is quite small in absolute terms—in primates it is estimated to contain around 15,000
neurons, less than one millionth of the neurons in the brain—but it sends projections to every major part of the brain and also to
the spinal cord.[27]

The level of activity in the locus coeruleus correlates broadly with vigilance and speed of reaction. LC activity is low during sleep
and drops to virtually nothing during the REM (dreaming) state.[28] It runs at a baseline level during wakefulness, but increases
temporarily when a person is presented with any sort of stimulus that draws attention. Unpleasant stimuli such as pain, difficulty
breathing, bladder distension, heat or cold generate larger increases. Extremely unpleasant states such as intense fear or intense
pain are associated with very high levels of LC activity.[27]

Norepinephrine released by the locus coeruleus affects brain function in a number of ways. It enhances processing of sensory
inputs, enhances attention, enhances formation and retrieval of both long term and working memory, and enhances the ability of
the brain to respond to inputs by changing the activity pattern in the prefrontal cortex and other areas.[29] The control of arousal
level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.[28]

There is great similarity between situations that activate the locus coeruleus in the brain and situations that activate the
sympathetic nervous system in the periphery: the LC essentially mobilizes the brain for action while the sympathetic system
mobilizes the body. It has been argued that this similarity arises because both are to a large degree controlled by the same brain
structures, particularly a part of the brainstem called the nucleus gigantocellularis.[27]

Pharmacology
A large number of important drugs exert their effects by interacting with norepinephrine systems in the brain or body. Their uses
include treatment of cardiovascular problems, shock, and a variety of psychiatric conditions. These drugs are divided into:
sympathomimetic drugs which mimic or enhance at least some of the effects of norepinephrine released by the sympathetic
nervous system; sympatholytic drugs, in contrast, block at least some of the effects.[30] Both of these are large groups with
diverse uses, depending on exactly which effects are enhanced or blocked.[30]
Norepinephrine itself is classified as a sympathomimetic drug: its effects when given by intravenous injection of increasing heart
rate and force and constricting blood vessels make it very useful for treating medical emergencies that involve critically low
blood pressure.[30] Surviving Sepsis Campaign recommended norepinephrine as first line agent in treating septic shock which is
unresponsive to fluid resuscitation, supplemented by vasopressin and epinephrine. Dopamine usage is restricted only to highly
selected patients.[31]

Beta blockers
These are sympatholytic drugs that block the effects of beta adrenergic receptors while having little or no effect on alpha
receptors. They are sometimes used to treat high blood pressure, atrial fibrillation and congestive heart failure, but recent reviews
have concluded that other types of drugs are usually superior for those purposes.[32][33] Beta blockers may be a viable choice for
other cardiovascular conditions, though, including angina and Marfan syndrome.[34] They are also widely used to treat glaucoma,
most commonly in the form of eyedrops.[35] Because of their effects in reducing anxiety symptoms and tremor, they have
sometimes been used by entertainers, public speakers and athletes to reduce performance anxiety, although they are not medically
approved for that purpose and are banned by the International Olympic Committee.[36][37]

However, the usefulness of beta blockers is limited by a range of serious side effects, including slowing of heart rate, a drop in
blood pressure, asthma, and reactive hypoglycemia.[35] The negative effects can be particularly severe in people who suffer from
diabetes.[32]

Alpha blockers
These are sympatholytic drugs that block the effects of adrenergic alpha receptors while having little or no effect on beta
receptors.[38] Drugs belonging to this group can have very different effects, however, depending on whether they primarily block
alpha-1 receptors, alpha-2 receptors, or both. Alpha-2 receptors, as described elsewhere in this article, are frequently located on
norepinephrine-releasing neurons themselves and have inhibitory effects on them; consequently blockage of alpha-2 receptors
usually results in an increase in norepinephrine release.[38] Alpha-1 receptors are usually located on target cells and have
excitatory effects on them; consequently blockage of alpha-1 receptors usually results in blocking some of the effects of
norepinephrine.[38] Drugs such as phentolamine that act on both types of receptors can produce a complex combination of both
effects. In most cases when the term "alpha blocker" is used without qualification, it refers to a selective alpha-1 antagonist.

Selective alpha-1 blockers have a variety of uses. Because one of their effects is to relax the muscles in the neck of the bladder,
they are often used to treat benign prostatic hyperplasia, and to help with the expulsion of bladder stones. Alpha-blockers also
likely help people pass their kidney stones.[39] Their effects on the central nervous system make them useful for treating
generalized anxiety disorder, panic disorder, and posttraumatic stress disorder.[40] They may, however, have significant side-
effects, including a drop in blood pressure.[38]

Some antidepressants function partly as selective alpha-2 blockers, but the best-known drug in that class is yohimbine, which is
extracted from the bark of the African yohimbe tree.[41] Yohimbine acts as a male potency enhancer, but its usefulness for that
purpose is limited by serious side-effects including anxiety and insomnia.[41] Overdoses can cause a dangerous increase in blood
pressure.[41] Yohimbine is banned in many countries, but in the United States, because it is extracted from a plant rather than
chemically synthesized, it is sold over the counter as a nutritional supplement.[42]

Alpha-2 agonists
These are sympathomimetic drugs that activate alpha-2 receptors or enhance their effects.[43] Because alpha-2 receptors are
inhibitory and many are located presynaptically on norepinephrine-releasing cells, the net effect of these drugs is usually to
reduce the amount of norepinephrine released.[43] Drugs in this group that are capable of entering the brain often have strong
sedating effects, due to their inhibitory effects on the locus coeruleus.[43] Clonidine, for example, is used for the treatment of
anxiety disorders and insomnia, and also as a sedative premedication for patients about to undergo surgery.[44] Xylazine, another
drug in this group, is also a powerful sedative and is often used in combination with ketamine as a general anaesthetic for
veterinary surgery—in the United States it has not been approved for use in humans.[45]

Stimulants and antidepressants

These are drugs whose primary effects are thought to be mediated by different neurotransmitter systems (dopamine for
stimulants, serotonin for antidepressants), but many also increase levels of norepinephrine in the brain. Amphetamine, for
example, is a stimulant that increases release of norepinephrine as well as dopamine.[46] Monoamine oxidase inhibitors are
antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin. In some cases it is difficult to
distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters.

Diseases and disorders

A number of important medical problems involve dysfunction of the norepinephrine system in the brain or body.

Sympathetic hyperactivation
Hyperactivation of the sympathetic nervous system is not a recognized condition in itself, but it is a component of a number of
conditions, as well as a possible consequence of taking sympathomimetic drugs. It causes a distinctive set of symptoms including
aches and pains, rapid heartbeat, elevated blood pressure, sweating, palpitations, anxiety, headache, paleness, and a drop in blood
glucose. If sympathetic activity is elevated for an extended time, it can cause weight loss and other stress-related body changes.

The list of conditions that can cause sympathetic hyperactivation includes severe brain injury,[47] spinal cord damage,[48] heart
failure,[49] high blood pressure,[50] kidney disease,[51] and various types of stress.

Pheochromocytoma
A pheochromocytoma is a rarely occurring tumor of the adrenal medulla, caused either by genetic factors or certain types of
cancer. The consequence is a massive increase in the amount of norepinephrine and epinephrine released into the bloodstream.
The most obvious symptoms are those of sympathetic hyperactivation, including particularly a rise in blood pressure that can
reach fatal levels. The most effective treatment is surgical removal of the tumor.

Stress
Stress, to a physiologist, means any situation that threatens the continued stability of the body and its functions.[52] Stress affects
a wide variety of body systems: the two most consistently activated are the hypothalamic-pituitary-adrenal axis and the
norepinephrine system, including both the sympathetic nervous system and the locus coeruleus-centered system in the brain.[52]
Stressors of many types evoke increases in noradrenergic activity, which mobilizes the brain and body to meet the threat.[52]
Chronic stress, if continued for a long time, can damage many parts of the body. A significant part of the damage is due to the
effects of sustained norepinephrine release, because of norepinephrine's general function of directing resources away from
maintenance, regeneration, and reproduction, and toward systems that are required for active movement. The consequences can
include slowing of growth (in children), sleeplessness, loss of libido, gastrointestinal problems, impaired disease resistance,
slower rates of injury healing, depression, and increased vulnerability to addiction.[52]

ADHD
Attention deficit hyperactivity disorder is a psychiatric condition involving problems with attention, hyperactivity, and
impulsiveness.[53] It is most commonly treated using stimulant drugs such as methylphenidate (Ritalin), whose primary effect is
to increase dopamine levels in the brain, but drugs in this group also generally increase brain levels of norepinephrine, and it has
been difficult to determine whether these actions are involved in their clinical value. There is also substantial evidence that many
people with ADHD show biomarkers involving altered norepinephrine processing.[54] Several drugs whose primary effects are on
norepinephrine, including guanfacine, clonidine, and atomoxetine, have been tried as treatments for ADHD, and found to have
effects comparable to those of stimulants.[55][56]

Autonomic failure
Several conditions, including Parkinson's disease, diabetes and so-called pure autonomic failure, can cause a loss of
norepinephrine-secreting neurons in the sympathetic nervous system. The symptoms are widespread, the most serious being a
reduction in heart rate and an extreme drop in resting blood pressure, making it impossible for severely affected people to stand
for more than a few seconds without fainting. Treatment can involve dietary changes or drugs.[57]

Comparative biology and evolution

Norepinephrine has been reported to exist in a wide variety of animal species,
including protozoa,[58] placozoa and cnidaria (jellyfish and related species),[59]
but not in ctenophores (comb jellies), whose nervous systems differ greatly from
those of other animals.[60] It is generally present in deuterostomes (vertebrates,
etc.), but in protostomes (arthropods, molluscs, flatworms, nematodes, annelids,
etc.) it is replaced by octopamine, a closely related chemical with a closely
related synthesis pathway.[58] In insects, octopamine has alerting and activating
functions that correspond (at least roughly) with the functions of norepinephrine Chemical structure of octopamine,
in vertebrates.[61] It has been argued that octopamine evolved to replace which serves as the homologue of
norepinephrine in many invertebrate
norepinephrine rather than vice versa; however, the nervous system of
species
amphioxus (a primitive chordate) has been reported to contain octopamine but
not norepinephrine, which presents difficulties for that hypothesis.[58]

History
Early in the twentieth century Walter Cannon, who had popularized the idea of a sympathoadrenal system preparing the body for
fight and flight, and his colleague Arturo Rosenblueth developed a theory of two sympathins, sympathin E (excitatory) and
sympathin I (inhibitory), responsible for these actions.[62] The Belgian pharmacologist Zénon Bacq as well as Canadian and US-
American pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter.[62] In 1939,
Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate
body.[63][64] In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a
neurotransmitter.[65] He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and
adduced evidence that it is the sympathin of Cannon and Rosenblueth.

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