Norepinephrine

Norepinephrine
Norepinephrine structure with descriptor.svg
Noradrenaline 3D ball.png
Systematic (IUPAC) name
4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
Clinical data
Trade names Levarterenol, Levophed, Norepin
AHFS/Drugs.com
monograph
Licence data US FDA:link
Pregnancy
category
AU: B3
US: C
Legal status
AU: Prescription Only (S4)
CA: -only
UK: POM
US: -only
Routes Intravenous
Pharmacokinetic data
Metabolism Hepatic
Excretion
Urine (84-96%)
Identifiers
CAS number 51-41-2 Yes
ATC code
C01CA03
PubChem
CID 439260
DrugBank
DB00368
ChemSpider 388394 Yes
UNII X4W3ENH1CV Yes
KEGG D00076 Yes
ChEBI CHEBI:18357 Yes
ChEMBL
CHEMBL1437 Yes
Synonyms
Noradrenaline
(R)-()-Norepinephrine
l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol
Chemical data
Formula
C8H11NO3
Molecular mass
169.18 g/mol
SMILES[show]
InChI[show]
Physical data
Density1.3970.06 g/cm3
Melting point 217 C (423 F) (decomposes)
Boiling point 442.6 C (828.7 F) 40.0C
Yes (what is this?) (verify)
Norepinephrine (INN) (abbreviated norepi or NE), also called noradrenaline (BAN) (abbreviated NA,
NAd, or norad), or 4,5--trihydroxy phenethylamine is a catecholamine with multiple roles
including those as a hormone and a neurotransmitter.[1] It is the hormone and neurotransmitter
most responsible for vigilant concentration in contrast to its most chemically similar hormone,
dopamine, which is most responsible for cognitive alertness.[2]

Medically it is used in those with severe hypotension. It does this by increasing vascular tone (tension
of vascular smooth muscle) through -adrenergic receptor activation.
Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. The
terms noradrenaline (from the Latin) and norepinephrine (from the Greek) are interchangeable,
with noradrenaline being the common name in most parts of the world. However the U.S. National
Library of Medicine[3] has promoted norepinephrine as the favored name. It was discovered by Ulf
von Euler in 1946.[4]
One of the most important functions of norepinephrine is its role as the neurotransmitter released
from the sympathetic neurons to affect the heart. An increase in norepinephrine from the
sympathetic nervous system increases the rate of contractions in the heart.[5] As a stress hormone,
norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are
controlled.[6] Norepinephrine also underlies the fight-or-flight response, along with epinephrine,
directly increasing heart rate, triggering the release of glucose from energy stores, and increasing
blood flow to skeletal muscle. It increases the brain's oxygen supply.[7][broken citation]
Norepinephrine is synthesized from dopamine by dopamine -hydroxylase in the secretory granules of
the medullary chromaffin cells.[8] It is released from the adrenal medulla into the blood as a
hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous
system, where it is released from noradrenergic neurons in the locus coeruleus. The actions of
norepinephrine are carried out via the binding to adrenergic receptors.
Contents [hide]
1 Medical uses
2 Physiological effects
2.1 Norepinephrine system
2.2 Role in cognition
2.3 Fasting
2.4 Macronutrient intake
3 Drug interactions
3.1 Synthesis modulators
3.2 Release modulators
3.3 Receptor binding modulators
3.4 Termination modulators
3.5 Alzheimers Disease
4 Chemistry
5 Mechanism
5.1 Biosynthesis
5.2 Vesicular transport
5.3 Release
5.4 Receptor binding
5.5 Termination
6 Nutritional sources
7 See also
8 References
9 External links
Medical uses[edit]
Norepinephrine is used as a vasopressor medication for patients with critical hypotension. It is given
intravenously and acts on both 1 and 2 adrenergic receptors to cause vasoconstriction. Its effects

are often limited to the increasing of blood pressure through agonist activity on 1 and 2
receptors, and causing a resultant increase in peripheral vascular resistance. At high doses, and
especially when it is combined with other vasopressors, it can lead to limb ischemia and limb death.
Norepinephrine is used mainly to treat patients in vasodilatory shock states such as septic shock
and neurogenic shock, while showing fewer adverse side-effects compared to dopamine
treatment.[9]
Physiological effects[edit]
Norepinephrine is released when a host of physiological changes are activated by a stressful event.
In the brain, this is caused in part by activation of an area of the brain stem called the locus coeruleus
(LC). This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic
neurons project bilaterally (send signals to both sides of the brain) from the locus coeruleus along
distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal
cord, forming a neurotransmitter system.
Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to
transmit the fight-or-flight response in each tissue, respectively. The adrenal medulla can also
contribute to such post-ganglionic nerve cells, although they release norepinephrine into the blood.
Norepinephrine system[edit]
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 influences
on the reward system.
The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The
axons of the neurons in the locus coeruleus act on adrenergic receptors in:
Amygdala
Cingulate gyrus
Cingulum
Hippocampus
Hypothalamus
Neocortex
Spinal cord
Striatum
Thalamus
Some Brainstem nuclei
Cerebellum
On the other hand, axons of neurons of the lateral tegmental field act on adrenergic receptors in
hypothalamus, for example.
This structure explains some of the clinical uses of norepinephrine, since a modification of this system
affects large areas of the brain.
Role in cognition[edit]
Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase the alteration
detection rate (frequency at which an alteration was selected) in multiple-cue probability learning
during tasks involving giving predictive cues (such as auditory or visual), and thereby enhance
subsequent learning.[10] A. J. Yu et al. developed a Bayesian framework to examine NE release in
instances of "unexpected uncertainty", wherein a drastic alteration in sensory information produces

a large disparity between top-down expectations and what actually occurs.[11] The model predicts
that NE levels spike when the predictive context is switched, then subside. It has also been shown
that lesions of the locus coeruleus impair this attentional shift.[11]
Similarly, several studies have implicated the LC-NE system in eliciting the P300, a cortical eventrelated potential that responds to environmental stimuli with behaviorally relevant, motivational, or
attention-grabbing properties.[12][13][14][15][16] The P300 may reflect updating of prior
knowledge regarding stimuli relevant for accurate and efficient decision making. Several studies
have searched for a P300 generator within the brain and have ultimately concluded that the
potential must have a source that is distributed, synchronous and localized in cortex.[17] This
definition is ideally satisfied both functionally and anatomically by the LC neuromodulatory system.
Given its broad projection pattern and the correlation between NE release and increased sensory
signal transmission,[18] it seems likely that noradrenergic cortical release is the neuronal mechanism
of the P300.
Examination of the LCs tonic firing pattern has led to speculation that it is important for the
exploratory behavior essential for learning relations between sensory input, decision processing,
motor output, and behavioral feedback.[19] Tonic activation within the range of 05 Hz has been
shown to correlate with levels of drowsiness, accurate task performance, and, when slightly more
elevated, distractibility and erratic task performance. Furthermore, phasic activation of the LC is
observed in response to both highly salient, unconditioned and task-relevant stimuli. The phasic
response occurs after stimulation and precedes a behavioral response in a time-locked fashion.[20]
As such, phasic activation of the LC-NE system is proposed to enhance signal processing and
behavioral responses specifically to task-relevant stimuli. Given the contrasting functional roles of
LC tonic and phasic activity, it is plausible that projections from this brain region are important for
maintaining a balance between exploratory and goal-directed behaviors that regulate probabilistic,
environmental learning and corresponding decision making.
The LC-NE system receives convergent input from the orbitofrontal (OFC) and anterior cingulate
cortices (ACC). The OFC has been associated with evaluation of reward. For example, Tremblay et
al. found that the response magnitude of single-units in this region is varied with the hedonic value
of a stimulus.[21] Additionally, neurons in this region are activated by rewarding stimuli, but not by
identification of the stimulus nor corresponding response-preparation. Activation of the ACC
appears to reflect some evaluation of cost-benefit. Several studies show ACC activation in response
to performance error, negative feedback, or monetary loss.[22][23][24] Additionally, ACC responds
to task difficulty.[25] Therefore, ACC activation may serve to integrate evaluations of task difficulty
with corresponding outcome information to gauge the benefits of taking an action in regards to a
particular environmental stimulus. Conceivably, the functions of the ACC and OFC are directly
related to decision-making, and their projections to LC may modulate the phasic release of NE in
order to gain-modulate cortical responses to decision outcomes.
LC-NE may play a significant role in synchronizing cortical activity in response to a decision process.
In computational modeling of decision, the most accurate and efficient decision mechanisms are
mathematically defined random walk or drift-diffusion processes that utilize single-layer neural
networks to calculate the disparity in evidence between two options.[26] NE release gated by the
LC-NE system is elicited after neurons processing sensory information have presumably reached a
decision threshold.[27] Thus, the phasic burst can alter activation in all cortical processing layers in
a temporally dependent manner, essentially collapsing the vast information-processing circuit to the
outcome of a single-decision layer. Brown et al. found that the addition of a phasic LC mechanism
was sufficient to yield optimal performance from a single-layer decision network.[28]

Fasting[edit]
A study has shown that fasting leads to increased levels of norepinephrine (NE) in the blood for up to
4 days of fasting.[29]
Macronutrient intake[edit]
Glucose intake was found to significantly increase plasma NE levels. In contrast, protein and fat intake
was found to have no effect.[30]
Drug interactions[edit]
Different medications affecting norepinephrine function have their targets at different points in the
mechanism, from synthesis to signal termination.
Synthesis modulators[edit]
-Methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for
tyrosine hydroxylase, and blocking this enzyme.
Vesicular transport modulators[edit]
This transportation can be inhibited by reserpine and tetrabenazine.[31]
Release modulators[edit]
Inhibitors of norepinephrine release
Substance[32] Receptor[32]
acetylcholine muscarinic receptor
norepinephrine (itself)/epinephrine 2 receptor
5-HT 5-HT receptor
adenosine
P1 receptor
PGE EP receptor
histamine
H2 receptor
enkephalin
receptor
dopamine
D2 receptor
ATP P2 receptor
Stimulators of norepinephrine release
Substance[32] Receptor[32]
epinephrine 2 receptor
angiotensin II AT1 receptor
Receptor binding modulators[edit]
Examples include alpha blockers for the -receptors, and beta blockers for the -receptors.
Termination modulators[edit]
Uptake modulators[edit]
Inhibitors[31] of uptake 1 include:
cocaine
tricyclic antidepressants
desipramine
serotonin-norepinephrine reuptake inhibitors
phenoxybenzamine
amphetamine
reboxetine
Inhibitors[31] of uptake 2 include:

normetanephrine
steroid hormones
phenoxybenzamine
Alzheimers Disease[edit]
The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally diffuses
from "varicosities". As such, it provides an endogenous anti-inflammatory agent in the
microenvironment around the neurons, glial cells, and blood vessels in the neocortex and
hippocampus.[33] Up to 70% of norepinephrine projecting cells are lost in Alzheimers Disease. It
has been shown that norepinephrine stimulates mouse microglia to suppress A-induced
production of cytokines and their phagocytosis of A, suggesting this loss might have a role in
causing this disease.[33]
Chemistry[edit]
Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-()-(R)norepinephrine. The prefix nor- indicates that norepinephrine is the next-lower homolog of
epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its
nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix
nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated
compound.[34][35][36]
Mechanism[edit]
Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It
performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors,
followed by the signal termination, either by degradation of norepinephrine or by uptake by
surrounding cells.
Biosynthesis[edit]
Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic
neurons of the sympathetic nervous system from the amino acid tyrosine. While the conversion
steps of L-tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of
dopamine to norepinephrine by dopamine -hydroxylase occurs predominantly in the
neurotransmitter vesicle.
Biosynthesis of norepinephrine
Vesicular transport[edit]
Between the decarboxylation and the final -oxidation, norepinephrine is transported into synaptic
vesicles. This is accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer.
This transporter has equal affinity for norepinephrine, epinephrine and isoprenaline.[31]
Release[edit]
To perform its functions, norepinephrine must be released from synaptic vesicles. Many substances
modulate this release, some inhibiting it and some stimulating it. An action potential reaches the
presynaptic membrane, which changes the membrane polarisation. Calcium ions thus enter,
resulting in vesicular fusion, releasing norepinephrine.
For instance, there are inhibitory 2 adrenergic receptors presynaptically that give negative feedback on
release by homotropic modulation.
Receptor binding[edit]
Main article: Adrenergic receptor

Norepinephrine performs its actions on the target cell by binding to and activating adrenergic
receptors. The target cell expression of different types of receptors determines the ultimate cellular
effect, and thus norepinephrine has different actions on different cell types.
Termination[edit]
Signal termination is a result of reuptake and degradation.
Uptake[edit]
Extracellular uptake of norepinephrine into the cytosol is done either presynaptically (uptake 1) or by
non-neuronal cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism
from the cytosol into synaptic vesicles.
Comparison of norepinephrine uptake
Uptake Transporter Vmax (n mol/g/min)[37]
KM[37]
Specificity[38] Location
Other substrates[38] Inhibitors [39]
Uptake 1
Norepinephrine transporter[39]
1.2
0.3
norepinephrine > epinephrine >
isoprenaline
presynaptic
methylnoradrenaline (nasal decongestant)
tyramine
guanethidine
Cocaine
Tricyclic antidepressants (e.g. desipramine)
Phenoxybenzamine
Amphetamine
Reboxetine
Uptake 2
100
250
epinephrine > norepinephrine > isoprenaline cell membrane of
non-neuronal cells[31]
dopamine
5-HT
histamine
normetanephrine
steroid hormones (e.g., corticosterone)
phenoxybenzamine
Vesicular
VMAT[39]
-[39] ~0.2[39]
norepinephrine > epinephrine > isoprenaline[39]
Synaptic vesicle membrane[39]
dopamine[39]
5-HT[39]
guanethidine[39]
MPP+[39]
Reserpine[39]
Tetrabenazine
Degradation[edit]
Norepinephrine degradation. Enzymes are shown in boxes.[40]
In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:
Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT)
3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO)
Vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid), also referred to as vanilmandelate or VMA
(via MAO)
3-Methoxy-4-hydroxyphenylethylene glycol, "MHPG" or "MOPEG" (via MAO)

Epinephrine (via PNMT)[41]

In the periphery, VMA is the major metabolite of catecholamines, and is excreted unconjugated in the
urine. A minor metabolite (although the major one in the central nervous system) is MHPG, which
is partly conjugated to sulfate or glucuronide derivatives and excreted in the urine.[42]
Nutritional sources[edit]
Shown here is the chemical structure of L-tyrosine. The biosynthesis of norepinephrine depends upon
the presence of L-tyrosine, an amino acid building-block of many proteins in meat, nuts, and eggs,
for example.
The synthesis of norepinephrine depends on the presence of tyrosine, an amino acid found in proteins
such as meat, nuts, and eggs. Dairy products such as cheese also contain high amounts of tyrosine
(the amino acid is named for "tyros", the Greek word for cheese). However, adult humans readily
synthesize tyrosine from phenylalanine, an essential amino acid. Tyrosine is the precursor to
dopamine, which in turn is a precursor to epinephrine and norepinephrine.