Norepinephrine [1] Identifiers



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Norepinephrine

1

Norepinephrine



Norepinephrine

[1]

 Identifiers 

CAS number

(l) 51-41-2 (l)

 [2]


,  138-65-8

 [3]


(dl)

ChemSpider

388394

 [4]


 Properties 

Molecular formula

C

8

H



11

NO

3



Molar mass

169.18 g mol

−1

Melting point



L: 216.5–218 °C (decomp.)

D/L: 191 °C (decomp.)

Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Infobox references



Norepinephrine (INN) (abbreviated norepi or NE) or noradrenaline (BAN) (abbreviated NA or NAd) is a

catecholamine with multiple roles including as a hormone and a neurotransmitter.

[5]

As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled.



Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate,

triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine

can also suppress neuroinflammation when released diffusely in the brain from the locus ceruleus.

[6]


When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through α-adrenergic

receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its

direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called

reflex bradycardia.

Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.

[7] 


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. The actions of norepinephrine are carried out via the binding

to adrenergic receptors.



Norepinephrine

2

Etymology

The term "norepinephrine" is derived from the chemical prefix nor-, which 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, while the methyl group is replaced by a hydrogen atom in norepinephrine.

Chemistry

Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is 

L

-(−)-(R)-norepinephrine. The



prefix nor-, is derived from the German abbreviation for "N ohne Radikal" (N, the symbol for nitrogen, without

radical),

[8] 

referring to the absence of the methyl functional group at the nitrogen atom.



Origins

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 ceruleus. 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 ceruleus 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 be counted to such postganglionic

nerve cells, although they release norepinephrine into the blood.

Norepinephrine 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 alertness and arousal, and influences on the reward system.

Anatomically, 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

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 the system affects large

areas of the brain.



Norepinephrine

3

Mechanism

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

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:

• The first reaction is the hydroxylation into dihydroxyphenylalanine (L-DOPA) (DOPA =

3,4-DiHydroxy-L-Phenylalanine), catalyzed by tyrosine hydroxylase. This is the rate-limiting step.

• This is followed by decarboxylation into the neurotransmitter dopamine, catalyzed by pyridoxal phosphate &

DOPA decarboxylase.

• Last is the final β-oxidation into norepinephrine by dopamine beta hydroxylase, requiring ascorbate as a cofactor

(electron donor).

Tyrosine


Levodopa

Dopamine


Norepinephrine

Vesicular transport

Between the decarboxylation and the final β-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.

[9]

Release

To perform its functions, norepinephrine needs to be released from synaptic vesicles. Many substances modulate this

release, some inhibiting it and some stimulating it.

For instance, there are inhibitory α2 adrenergic receptors presynaptically, that gives negative feedback on release by

homotropic modulation.

Receptor binding

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

Signal termination is a result of reuptake and degradation.



Uptake

Extracellular uptake of norepinephrine into the cytosol is either done 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.



Norepinephrine

4

Comparison of norepinephrine uptake



 Uptake 

 Transporter 

V

max

(nmol/g/min)[10]

K

M

[10]

Specificity[11]

Location 

Other substrates[11]

Inhibitors [12]

Uptake 1

Norepinephrine

transporter[12]

1.2


0.3

norepinephrine >

epinephrine >

isoprenaline

presynaptic

methylnoradrenaline



(nasal decongestant)

tyramine



guanethidine

Cocaine


Tricyclic

antidepressants (e.g.

desipramine)

Phenoxybenzamine



Amphetamine



Uptake 2

100


250

epinephrine >

norepinephrine >

isoprenaline

cell membrane

of

non-neuronal



cells[9]

dopamine



5-HT


histamine

normetanephrine



steroid hormones

(e.g. corticosterone)

phenoxybenzamine



Vesicular

VMAT[12]


-[12]

~0.2[12] norepinephrine >

epinephrine >

isoprenaline[12]

Synaptic

vesicle


membrane[12]

dopamine[12]



5-HT[12]


guanethidine[12]

MPP+[12]


Reserpine[12]

Tetrabenazine



Degradation

Norepinephrine degradation. Enzymes are shown in boxes. [12]

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)



[13]

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 sytem) is MHPG, which is partly conjugated to sulfate or

glucuronide derivatives and excreted in the urine.

[12]


Norepinephrine

5

Noradrenergic agents



By indication

Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder, depression and hypotension.

Norepinephrine, as with other catecholamines, itself cannot cross the blood-brain barrier, so drugs such as

amphetamines are necessary to increase brain levels.



Attention-deficit/hyperactivity disorder

Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus. For

people with ADHD, psychostimulant medications such as methylphenidate (Ritalin/Concerta), dextroamphetamine

(Dexedrine), and Adderall (a mixture of dextroamphetamine and racemic amphetamine salts) are prescribed to help

increase levels of norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake

inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than dopamine. As a result,

Strattera has a lower abuse potential. However, it may not be as effective as the psychostimulants are with many

people who have ADHD. Consulting with a physician, physician assistant or nurse practitioner is needed to find the

appropriate medication and dosage. (Other SNRIs, currently approved as antidepressants, have also been used

off-label for treatment of ADHD.)



Depression

Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors

are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to

postsynaptic cells in the brain. There is some recent evidence implying that SNRIs may also increase dopamine

transmission.

[14] 


This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and

norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use.

If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic

transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be

partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex of the brain).

Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin

activity, but tend to produce unwanted side effects due to the nonspecific inactivation of histamine, acetylcholine and

alpha-1 adrenergic receptors. Common side effects include sedation, dry mouth, constipation, sinus tachycardia,

memory impairment, orthostatic hypotension, blurred vision and weight gain.

[15] 


For this reason, they have largely

been replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however

have little or no effect on norepinephrine, and the newer SNRIs described above, such as venlafaxine (Effexor) and

duloxetine (Cymbalta).



Hypotension

Norepinephrine is also used as a vasopressor medication (for example, brand name Levophed) for patients with

critical hypotension. It is given intravenously and acts on both α

and α



adrenergic receptors to cause

vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α

and α



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 mainly used to

treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival

benefit over dopamine.


Norepinephrine

6

By site of action

Different medications affecting norepinephrine function have their targets at different points in the mechanism, from

synthesis to signal termination.



Synthesis modulators

α-methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine

hydroxylase, and blocking this enzyme.

Vesicular transport modulators

This transportation can be inhibited by reserpine and tetrabenazine.

[9]

Release modulators

Inhibitors of norepinephrine release

Substance[16]

Receptor[16]

acetylcholine

muscarinic receptor

norepinephrine

(itself)/epinephrine

α2 receptor

5-HT


5-HT receptor

adenosine

P1 receptor

PGE


EP receptor

histamine

H2 receptor

enkephalin

δ receptor

dopamine


D2 receptor

ATP


P2 receptor

Stimulators of norepinephrine release

Substance[16] Receptor[16]

adrenaline

β2 receptor

angiotensin II

AT1 receptor

Receptor binding modulators

Examples include alpha blockers for the α-receptors, and beta blockers for the β-receptors.



Norepinephrine

7

Termination modulators



Uptake modulators

Inhibitors

[9] 

of uptake 1 include:



• cocaine

• tricyclic antidepressants

• desipramine

• phenoxybenzamine

• amphetamine

Inhibitors

[9] 

of uptake 2 include:



• normetanephrine

• steroid hormones

• phenoxybenzamine

Anti-Inflammatory agent role in Alzheimer’s Disease

The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses 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.

[6] 

Up to 70% of norepinephrine projecting



cells are lost in Alzheimer’s Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress

Aβ-induced production of cytokines and their phagocytosis of Aβ suggesting this loss might have a role in causing

this disease.

[6]


Nutritional sources

Shown here is the chemical structure of tyrosine.

The biosynthesis of norepinephrine depends upon

the presence of 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). Tyrosine

is the precursor to dopamine, which is in itself a precursor of

epinephrine and norepinephrine.

Serotonin, a neurotransmitter that is in many ways the opposite of the

catecholamines, is also directly synthesized from an amino acid

(tryptophan). However, tryptophan has a somewhat different process of

degradation. When serotonin is catabolized in the body, it does not

break down into useful substrates in the way that dopamine is further

degraded into epinephrine and norepinephrine. Instead, it breaks down into 5-hydroxyindoleacetic acid (5-HIA), an

organic acid which may be harmful in high amounts. Tryptophan can further be catabolized into kynurenate,

quinolinate, and picolinate, harmful substances that are generally regarded as markers of bodily inflammation.

Banana peels contain significant amounts of norepinephrine and dopamine.

[17]


Norepinephrine

8

See also

• Norepinephrine bitartrate

• Catecholaminergic polymorphic ventricular tachycardia



External links

• Mental Health: A report of surgeon general. Etiology of Anxiety Disorders 

[18]

• http:/


 

/

 



www.

 

biopsychiatry.



 

com/


 

nordop.


 

htm


References

[1] Merck Index, 11th Edition, 6612.

[2] http:/

 

/



 

www.


 

commonchemistry.

 

org/


 

ChemicalDetail.

 

aspx?ref=51-41-2



[3] http:/

 

/



 

www.


 

commonchemistry.

 

org/


 

ChemicalDetail.

 

aspx?ref=138-65-8



[4] http:/

 

/



 

www.


 

chemspider.

 

com/


 

388394


[5] "Norepinephrine definition" (http:/

 

/



 

dictionary.

 

reference.



 

com/


 

browse/


 

Norepinephrine). dictionary.reference.com. . Retrieved 2008-11-24.

[6] Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F,

Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through

norepinephrine. (http:/

 

/



 

www.


 

pnas.


 

org.


 

libproxy.

 

ucl.


 

ac.


 

uk/


 

content/


 

107/


 

13/


 

6058.


 

full.


 

pdf) Proc Natl Acad Sci U S A. 107:6058–6063

doi:10.1073/pnas.0909586107 PMID 20231476

[7] "Introduction to Autonomic Pharmacology" (http:/

 

/

 



www.

 

fleshandbones.



 

com/


 

readingroom/

 

pdf/


 

225.


 

pdf) (PDF). Elsevier International.

. Link redirected to commercial site!

[8] TIHKAL on "nor" (http:/

 

/

 



www.

 

drugsinfo.



 

net/


 

tihkal/


 

tihkal01.

 

html)


[9] Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167

[10] These values are from rat heart. Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill

Livingstone. ISBN 0-443-07145-4. Page 167

[11] Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page

167

[12] Unless else specified in boxes, then ref is: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's



pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

[13] "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502

[14] http:/

 

/



 

stahlonline.

 

cambridge.



 

org/


 

prescribers_drug.

 

jsf?page=0521683505c95_p539-544.



 

html.


 

therapeutics&

 

name=Venlafaxine&



title=Therapeutics

[15] http:/

 

/

 



www.

 

preskorn.



 

com/


 

columns/


 

9803.


 

html


[16] Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page

129


[17] Kanazawa, Kazuki; Hiroyuki Sakakibara (2000). "High content of Dopamine, a strong antioxidant, in Cavendish banana" (http:/

 

/



 

152.


 

1.

118.



 

33/


 

Files/


 

Journal of Agricultural and Food Chemistry 2000 48 (3) 844-848.

 

pdf) (PDF). Journal of Agriculture and Food Chemistry 48:



844–848. doi:10.1021/jf9909860. . Retrieved 8 November 2007.

[18] http:/

 

/

 



www.

 

surgeongeneral.



 

gov/


 

library/


 

mentalhealth/

 

chapter4/



 

sec2_1.


 

html


Article Sources and Contributors

9

Article Sources and Contributors



Norepinephrine  Source: http://en.wikipedia.org/w/index.php?oldid=385931198  Contributors: 1.1.1, 5 albert square, A314268, AC+79 3888, AStudent, AbinoamJr, Acdx, Ajaybsc, Albmont,

Alex.tan, Alexis Örtenholm, Alvis, Andrew73, Arcadian, Ashleyisachild, Azazilsgoat, Beetstra, Belovedfreak, Bensaccount, BobArctor, Bradleyosborn, C6541, CDN99, CUSENZA Mario,

Cacycle, Calvin 1998, Can't sleep, clown will eat me, Casforty, Cat Whisperer, Chaldor, Charles Gaudette, Chem-awb, Choij, Crazyvas, D Anthony Patriarche, Davidruben, Delegeferenda, Delta

G, Deltabeignet, Diberri, DocWatson42, DustWolf, ER MD, Edgar181, Eequor, El3ctr0nika, Erud, Evand, Eyu100, Fantumphool, Fenice, Flamingnerd, Fredrik, Freecat, Gcm, Gingerjess,

Goldenphoenix86, Harbinary, Heah, Heathniederee, Hede2000, Hoffmeier, Hopkapi, Iraqidude, Jfdwolff, Josh Cherry, JulesH, Jü, Kitvonnegut, Ktai, Kwijiboamigo, Leafyplant, LittleHow,

Looxix, Lukeblue9254, MSGJ, Magnus Manske, MarcoTolo, Markus451, Mashford, Master1228, Mav, MichaK, Michael Hardy, Michaelbusch, Michaledwardmarks, Mikael Häggström,

MisterSheik, Mrs.meganmmc, Nbauman, Nimur, Noobeditor, PFHLai, PL290, Parker007, Paul August, PeeJay2K3, Plandu, Ponzpons, Possum, Razorflame, Richardcavell, Rjwilmsi,

Roadnottaken, Romanm, RossMM, Rossmcd, Runefrost, SVI, Sayeth, Sbrools, Scientizzle, Shoy, Skittleys, SoCal, SuperTycoon, Tarotcards, Tarquin, Tea with toast, Teemu08, The Red, The

Right Honourable, The Son of Man, Thedeejay, Think outside the box, Tide rolls, TimGrin, TomRau, Tomchiukc, Varnav, Vojtech.dostal, Walkerma, WanderingHermit, Wickey-nl,

WriterHound, XanaDrew, Xxxx00, Роман Беккер, 242 anonymous edits



Image:Norepinephrine_structure_with_descriptor.svg'>Image Sources, Licenses and Contributors

Image:Norepinephrine structure with descriptor.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Norepinephrine_structure_with_descriptor.svg  License: Creative Commons

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User:Sbrools



Image:L-tyrosine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-tyrosine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Photohound

Image:3,4-Dihydroxy-L-phenylalanin (Levodopa).svg  Source: http://en.wikipedia.org/w/index.php?title=File:3,4-Dihydroxy-L-phenylalanin_(Levodopa).svg  License: Public Domain

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Image:L-Tyrosin - L-Tyrosine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:L-Tyrosin_-_L-Tyrosine.svg  License: Public Domain  Contributors: User:NEUROtiker

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Document Outline

  • Norepinephrine
    • Etymology
    • Chemistry
    • Origins
      • Norepinephrine system
    • Mechanism
      • Biosynthesis
      • Vesicular transport
      • Release
      • Receptor binding
      • Termination
        • Uptake
        • Degradation
    • Noradrenergic agents
      • By indication
        • Attention-deficit/hyperactivity disorder
        • Depression
        • Hypotension
      • By site of action
        • Synthesis modulators
        • Vesicular transport modulators
        • Release modulators
        • Receptor binding modulators
        • Termination modulators
        • Anti-Inflammatory agent role in Alzheimer’s Disease
    • Nutritional sources
    • See also
    • External links
    • References
  • License

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