Norepinephrine
DB Bylund, University of Nebraska Medical Center, Omaha, NE, USA
KC Bylund, University of Rochester, Rochester, NY, USA
r 2014 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by David B Bylund, volume 3, pp 638–640, r 2003, Elsevier Inc.
Introduction
Norepinephrine (also called noradrenaline) is a neuro-
transmitter in both the peripheral and central nervous sys-
tems. Norepinephrine produces many effects in the body, the
most notable being those associated with the ‘fight or flight’
response to perceived danger. The effects of norepinephrine
and a related catecholamine, epinephrine (also called ad-
renaline), are mediated by the family of adrenergic receptors.
The chemical structure of norepinephrine, as shown in
Figure 1, indicates that it is a catecholamine because it has
both the catechol moiety (two hydroxyl groups on a benzene
ring) and an amine (NH2) group.
History
In the late 1940s, von Euler in Sweden and Holtz in Germany
identified norepinephrine as the neurotransmitter of the
mammalian sympathetic nerves and soon thereafter also
found it to be a normal constituent of mammalian brain.
Norepinephrine was subsequently shown to be a central
neurotransmitter that can be visualized in the brain by fluor-
escent and immunohistochemical techniques.
Neurochemistry of Norepinephrine
Biosynthesis of Catecholamines
Norepinephrine is synthesized in neurons starting with the
amino acid tyrosine, which is obtained from the diet and can
also be synthesized from phenylalanine. Tyrosine is converted
to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine
hydroxylase; DOPA in turn is converted to dopamine in the
cytoplasm. Dopamine, also a neurotransmitter, is taken up
into vesicles and converted to norepinephrine by the enzyme
dopamine b-hydroxylase. In the adrenal medulla and in a few
brain regions, norepinephrine is converted to epinephrine by
the enzyme phenylethanolamine N-methyltransferase. The
biosynthesis of the catecholamines is summarized in Figure 2.
HO OH
NH2
HO
Figure 1 Structure of norepinephrine.
614
Storage, Release, and Reuptake of Norepinephrine
Norepinephrine is stored in vesicles (also called storage
granules) in the nerve terminals, which concentrate it and
protect it from metabolism until it is released following nerve
stimulation. The major mechanism by which the effects of
norepinephrine are terminated is reuptake back into the nerve
terminal by a high-affinity transporter. This transporter is an
important site of drug action. Norepinephrine can also be
metabolized to inactive products. Inhibition of either of these
processes results in an increase in the synaptic level of nor-
epinephrine and a prolongation of its effects.
Metabolism of Norepinephrine
Norepinephrine is metabolized by the enzymes monoamine
oxidase and catechol-O-methyltransferase to 3-methoxy-4-
hydroxymandelic acid and 3-methoxy-4-hydroxyphenylglycol
(MHPG). The major metabolite found in the blood and urine
is MHPG, and levels of this metabolite have been frequently
used to assess the functional status of the noradrenergic
system in human subjects, although the validity of doing
so is questionable. However, serum and urine measurement
of norepinephrine, other catecholamines, and their metabol-
ites is instrumental in the diagnosis of the catecholamine-
secreting tumors: pheochromocytomas, neuroblastomas, and
paragangliomas.
Adrenergic Receptors
Types and Subtypes of Adrenergic Receptors
Adrenergic receptors (also called adrenoceptors) mediate the
effects of norepinephrine and epinephrine. Adrenergic recep-
tors were originally classified in 1948 into two major types,
a and b, based on their pharmacological characteristics (i.e.,
rank order potency of agonists in producing various effects).
The current classification scheme, which is based on both
pharmacological evidence and the molecular cloning of the
nine different adrenergic receptors, includes three major
Tyrosine hydroxylase DOPA decarboxylase
Tyrosine DOPA Dopamine
Dopamine
Phenylethanolamine
N-methlytransferase
-Hydroxylase
Epinephrine Norepinephrine
Figure 2 Biosynthesis of catecholamines.
Encyclopedia of the Neurological Sciences, Volume 3 doi:10.1016/B978-0-12-385157-4.00047-6
 Norepinephrine 615

types – a1, a2, and b – each of which is further divided into
three subtypes (Figure 3). Norepinephrine has similar affin-
ities for all nine of the subtypes, with the exception that it is
relatively weak (has low potency) at the b2 subtype.
the blood vessels of the skeletal muscles causes vasodilatation.
Norepinephrine and epinephrine, acting at b1-receptors, in-
crease the force and rate of contraction of the heart, whereas
epinephrine acting at b2-receptors causes bronchodilatation
and relaxation of smooth muscle in the uterus.

Location of Adrenergic Receptors

Although adrenergic receptors are found throughout the
body in tissues innervated both by the peripheral and central
nervous systems, a few locations are of special interest.
a1-Adrenergic receptors are found peripherally in some blood
vessels, whereas a2-receptors are located on platelets and on
nerve terminals in both the peripheral and central nervous
systems. In the heart, b1-receptors predominate, whereas in
the smooth muscles of the lungs, some blood vessels, and the
uterus, b2-receptors are relatively abundant.
Effects of Norepinephrine
Effects Mediated by the Autonomic Nervous System
The autonomic nervous system is divided into two com-
ponents – the sympathetic nervous system and the para-
sympathetic nervous system. The final (postganglionic) nerves
in the sympathetic system are adrenergic and thus release
norepinephrine at end organs. The adrenal medulla, which is
also part of the sympathetic system, releases epinephrine into
the circulation. Activation of the sympathetic system, as occurs
in response to perceived danger, results in the release of large
quantities of norepinephrine and epinephrine. Norepin-
ephrine acting at a1-receptors causes constriction of cutaneous
blood vessels, whereas epinephrine acting at b2-receptors in
Adrenergic receptors
 -2 -1
Adrenergic Adrenergic Adrenergic
-1 -2 -3 -1A -1B
-2A -2B -2C
Figure 3 Classification of adrenergic receptors.
Effects Mediated by the Central Nervous System
In the central nervous system, the cell bodies of noradrenergic
neurons are found primarily in the locus coeruleus in the
brainstem. These neurons, however, project widely throughout
the brain and spinal cord. The locus coeruleus, and
hence norepinephrine, is an important regulator of a variety
of physiological activities, including sleep/wake cycles, atten-
tion, orientation, mood, memory, and cardiovascular func-
tion, as well as autonomic and endocrine functions. Although
adrenergic receptors are found throughout the brain, a2-
receptors are of particular importance because they help
regulate the release of norepinephrine as well as many other
neurotransmitters.
Drugs that Mimic or Block the Effects of
Norepinephrine
Norepinephrine is rarely used clinically due to its rapid me-
tabolism and many sites of action. Drugs that evoke responses
similar to sympathetic nerve stimulation are called sym-
pathomimetic drugs. They produce their effects either directly,
by stimulating adrenergic receptors (adrenergic receptor
agonists), or indirectly, by promoting the release of norepin-
ephrine or by blocking its reuptake. Table 1 gives examples of
various sympathomimetic drugs, with their mechanisms of
action, the effects they produce, and common therapeutic
indications. A structural analog of norepinephrine, meta-
iodobenyzlguanidine (MIBG), is a guanethidine derivative
that is specifically taken up by the norepinephrine transporter,
and subsequently enters catecholamine storage granules.
-1D Radiolabeled MIBG (using 131I or 123I) is routinely used with
positron emission tomography (PET) in the diagnosis and
localization of catecholamine-secreting tumors, and higher
doses of 131I MIBG are also given in the treatment of advanced
neuroblastoma.

Table 1 Drugs that mimic the effects of norepinephrine

Receptor Examples of drugs Effect Therapeutic indication

a1 Phenylephrine Vasoconstriction Hypotension and nasal congestion

a2 Clonidine and brimonidine Lowers blood and intraocular pressure Hypertension and glaucoma
b1 Dobutamine Increases cardiac output Cardiogenic shock
b2 Albuterol, terbutaline, and ritodrine Relaxes smooth muscle in lung and Asthma and premature labor
uterus
Indirect acting Amphetamine Central nervous system stimulant Narcolepsy and hyperactivity
Indirect acting Desipramine and atomoxetine Blocks norepinephrine reuptake Depression and attention-deficit/
hyperactivity disorder (ADHD)
Indirect acting Phenelzine Inhibits norephinephrine metabolism Depression
by monoamine oxidase
616 Norepinephrine

Table 2 Drugs that block the effects of norepinephrine

Receptor Examples of drugs Effect Therapeutic indication

a1 Prazosin and terazosin Vasodilatation Hypertension and benign prostatic hypertrophy

a2 Mirtazapine Antidepressant Depression
b1, b2 Propranolol and timolol Decreases cardiac output and intraocular Hypertension, angina, glaucoma, migraine,
pressure tremors, and anxiety
b1 Atenolol and metoprolol Decreases cardiac output Hypertension

Drugs that block the responses to sympathetic nerve
stimulation and thus block the effects of norepinephrine are
called adrenergic receptor antagonists. In contrast to agonists,
they do not activate adrenergic receptors, but act by blocking
the effects of either released norepinephrine or an adminis-
tered adrenergic receptor agonist. Table 2 gives examples of
adrenergic receptor antagonists, with their receptor selectivity,
the effects they produce, and common therapeutic indications.
See also: Autonomic Nervous System; Overview. Heterotrimeric G
Proteins. Neurotransmitter Receptors. Neurotransmitters; Overview
Further Reading
Ahlquist RP (1948) A study of adrenotropic receptors. American Journal of
Physiology 153: 586–600.
Bylund DB, Eikenberg DC, Hieble JP, et al. (1994) IV. International Union of
Pharmacology nomenclature of adrenoceptors. Pharmacological Reviews 46:
121–136.
Cooper JR, Bloom FE, and Roth RH (1996) The Biochemical Basis of
Neuropharmacology, pp. 226–292. New York: Oxford University Press.
Crassous PA, Denis C, Paris H, and Senard JM (2007) Interest of alpha2-
adrenergic agonists and antagonists in clinical practice: Background, facts and
perspectives. Current Topics in Medicinal Chemistry 7: 187–194.
Docherty JR (2010) Subtypes of functional alpha-1 adrenoceptors. Cellular and
Molecular Life Sciences 67: 405–417.
Eisenhofer G, Kopin IJ, and Goldstein DS (2004) Catecholamine metabolism: A
contemporary view with implications for physiology and medicine.
Pharmacological Reviews 56: 331–349.
Grassi G (2009) Assessment of sympathetic cardiovascular drive in human
hypertension: Achievements and perspectives. Hypertension 54: 690–697.
Gyires K, Zadori ZS, Torok T, and Matyus P (2009) Alpha-2 adrenoceptor subtypes-
mediated physiological, pharmacological actions. Neurochemistry International
55: 447–453.
Hokfelt T, Johansson O, and Goldstein M (1984) Central catecholamine neurons as
revealed by immunohistochemistry with special reference to adrenaline neurons.
In: Björklund A and Hokfelt T (eds.) Handbook of Chemical Neuroanatomy,
Vol. 2, Part 1: Classical Transmitters in the CNS. Amsterdam: Elsevier.
Ilias I and Pacak K (2005) Diagnosis and management of tumors of the adrenal
medulla. Hormone and Metabolic Research 37: 717–721.
Kristensen AS, Andersen J, Jorgensen TN, et al. (2011) SLC6 neurotransmitter
transporters: structure, function, and regulation. Pharmacological Reviews 63:
585–640.
Rockman HA and Lefkowitz RJ (2011) Introduction to the series on novel aspects of
cardiovascular G-protein-coupled receptor signaling. Circulation Research 109:
202–204.
Relevant Websites
http://www.adrenoceptor.com
Adrenoceptor Online.
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=439260
Norepinephrine – Compound Summary.
http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=4
The IUPHAR Adrenoceptor Database.