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Norepinephrine
FromWikipedia,thefreeencyclopedia

Norepinephrine(INN)(abbreviatednorepiorNE),alsocallednoradrenaline(BAN)
(abbreviatedNA,NAd,ornorad),or4,5trihydroxyphenethylamineisacatecholamine
withmultiplerolesincludingthoseasahormoneandaneurotransmitter.[1]Itisthehormone
andneurotransmittermostresponsibleforvigilantconcentrationincontrasttoitsmost
chemicallysimilarhormone,dopamine,whichismostresponsibleforcognitivealertness.[2]

Norepinephrine

Medicallyitisusedinthosewithseverehypotension.Itdoesthisbyincreasingvasculartone
(tensionofvascularsmoothmuscle)throughadrenergicreceptoractivation.
Areasofthebodythatproduceorareaffectedbynorepinephrinearedescribedasnoradrenergic.
Thetermsnoradrenaline(fromtheLatin)andnorepinephrine(fromtheGreek)are
interchangeable,withnoradrenalinebeingthecommonnameinmostpartsoftheworld.
HowevertheU.S.NationalLibraryofMedicine[3]haspromotednorepinephrineasthefavored
name.ItwasdiscoveredbyUlfvonEulerin1946.[4]
Oneofthemostimportantfunctionsofnorepinephrineisitsroleastheneurotransmitter
releasedfromthesympatheticneuronstoaffecttheheart.Anincreaseinnorepinephrinefrom
thesympatheticnervoussystemincreasestherateofcontractionsintheheart.[5]Asastress
hormone,norepinephrineaffectspartsofthebrain,suchastheamygdala,whereattentionand
responsesarecontrolled.[6]Norepinephrinealsounderliesthefightorflightresponse,along
withepinephrine,directlyincreasingheartrate,triggeringthereleaseofglucosefromenergy
stores,andincreasingbloodflowtoskeletalmuscle.Itincreasesthebrain'soxygensupply.[7]
Norepinephrineissynthesizedfromdopaminebydopaminehydroxylaseinthesecretory
granulesofthemedullarychromaffincells.[8]Itisreleasedfromtheadrenalmedullaintothe
bloodasahormone,andisalsoaneurotransmitterinthecentralnervoussystemand
sympatheticnervoussystem,whereitisreleasedfromnoradrenergicneuronsinthelocus
coeruleus.Theactionsofnorepinephrinearecarriedoutviathebindingtoadrenergicreceptors.

Systematic(IUPAC)name
4[(1R)2amino1hydroxyethyl]benzene1,2diol

Clinicaldata
Tradenames

Levarterenol,Levophed,
Norepin

AHFS/Drugs.com monograph
Licencedata

USFDA:link

Pregnancy
category

AU:B3

Legalstatus

AU:PrescriptionOnly

Contents

US:C

(S4)
CA:only

1Medicaluses

UK:POM

2Physiologicaleffects

US:only

2.1Norepinephrinesystem

Routes

Intravenous
Pharmacokineticdata

2.2Roleincognition
2.3Fasting

Metabolism

Hepatic

2.4Macronutrientintake

Excretion

Urine(8496%)
Identifiers

3Druginteractions
3.1Synthesismodulators

CASnumber

51412

3.2Releasemodulators

ATCcode

C01CA03

3.3Receptorbindingmodulators

PubChem

CID439260

3.4Terminationmodulators

DrugBank

DB00368

3.5AlzheimersDisease

ChemSpider

388394

UNII

X4W3ENH1CV

5.1Biosynthesis

KEGG

D00076

5.2Vesiculartransport

ChEBI

CHEBI:18357

5.3Release

ChEMBL

CHEMBL1437

5.4Receptorbinding

Synonyms

Noradrenaline
(R)()Norepinephrine
l1(3,4Dihydroxyphenyl)2
aminoethanol

4Chemistry
5Mechanism

5.5Termination
6Nutritionalsources
7Seealso
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Chemicaldata

8References
9Externallinks

Medicaluses

Formula

C8H11NO3

Molecularmass

169.18g/mol

SMILES
InChI

Physicaldata

Norepinephrineisusedasavasopressormedicationforpatientswithcriticalhypotension.Itis
givenintravenouslyandactsonboth1and2adrenergicreceptorstocausevasoconstriction.

Density

1.3970.06g/cm3

Itseffectsareoftenlimitedtotheincreasingofbloodpressurethroughagonistactivityon1

Meltingpoint

217C(423F)(decomposes)

and2receptors,andcausingaresultantincreaseinperipheralvascularresistance.Athigh

Boilingpoint

doses,andespeciallywhenitiscombinedwithothervasopressors,itcanleadtolimbischemia
andlimbdeath.Norepinephrineisusedmainlytotreatpatientsinvasodilatoryshockstatessuch
assepticshockandneurogenicshock,whileshowingfeweradversesideeffectscomparedto
dopaminetreatment.[9]

442.6C(828.7F)40.0C
(whatisthis?)(verify)

Physiologicaleffects
Norepinephrineisreleasedwhenahostofphysiologicalchangesareactivatedbyastressfulevent.
Inthebrain,thisiscausedinpartbyactivationofanareaofthebrainstemcalledthelocuscoeruleus(LC).Thisnucleusistheoriginofmost
norepinephrinepathwaysinthebrain.Noradrenergicneuronsprojectbilaterally(sendsignalstobothsidesofthebrain)fromthelocuscoeruleus
alongdistinctpathwaystomanylocations,includingthecerebralcortex,limbicsystem,andthespinalcord,forminganeurotransmittersystem.
Norepinephrineisalsoreleasedfrompostganglionicneuronsofthesympatheticnervoussystem,totransmitthefightorflightresponseineach
tissue,respectively.Theadrenalmedullacanalsocontributetosuchpostganglionicnervecells,althoughtheyreleasenorepinephrineintothe
blood.

Norepinephrinesystem
Thenoradrenergicneuronsinthebrainformaneurotransmittersystem,that,whenactivated,exertseffectsonlargeareasofthebrain.Theeffects
aremanifestedinalertness,arousal,andinfluencesontherewardsystem.
Thenoradrenergicneuronsoriginatebothinthelocuscoeruleusandthelateraltegmentalfield.Theaxonsoftheneuronsinthelocuscoeruleusact
onadrenergicreceptorsin:
Amygdala
Cingulategyrus
Cingulum
Hippocampus
Hypothalamus
Neocortex
Spinalcord
Striatum
Thalamus
SomeBrainstemnuclei
Cerebellum
Ontheotherhand,axonsofneuronsofthelateraltegmentalfieldactonadrenergicreceptorsinhypothalamus,forexample.
Thisstructureexplainssomeoftheclinicalusesofnorepinephrine,sinceamodificationofthissystemaffectslargeareasofthebrain.

Roleincognition
Corticalnorepinephrine(NE)releaseduringattentionparadigms(patterns)canincreasethealterationdetectionrate(frequencyatwhichan
alterationwasselected)inmultiplecueprobabilitylearningduringtasksinvolvinggivingpredictivecues(suchasauditoryorvisual),andthereby
enhancesubsequentlearning.[10]A.J.Yuetal.developedaBayesianframeworktoexamineNEreleaseininstancesof"unexpecteduncertainty",
whereinadrasticalterationinsensoryinformationproducesalargedisparitybetweentopdownexpectationsandwhatactuallyoccurs.[11]The
modelpredictsthatNElevelsspikewhenthepredictivecontextisswitched,thensubside.Ithasalsobeenshownthatlesionsofthelocus
coeruleusimpairthisattentionalshift.[11]
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Similarly,severalstudieshaveimplicatedtheLCNEsysteminelicitingtheP300,acorticaleventrelatedpotentialthatrespondstoenvironmental
stimuliwithbehaviorallyrelevant,motivational,orattentiongrabbingproperties.[12][13][14][15][16]TheP300mayreflectupdatingofprior
knowledgeregardingstimulirelevantforaccurateandefficientdecisionmaking.SeveralstudieshavesearchedforaP300generatorwithinthe
brainandhaveultimatelyconcludedthatthepotentialmusthaveasourcethatisdistributed,synchronousandlocalizedincortex.[17]This
definitionisideallysatisfiedbothfunctionallyandanatomicallybytheLCneuromodulatorysystem.Givenitsbroadprojectionpatternandthe
correlationbetweenNEreleaseandincreasedsensorysignaltransmission,[18]itseemslikelythatnoradrenergiccorticalreleaseistheneuronal
mechanismoftheP300.
ExaminationoftheLCstonicfiringpatternhasledtospeculationthatitisimportantfortheexploratorybehavioressentialforlearningrelations
betweensensoryinput,decisionprocessing,motoroutput,andbehavioralfeedback.[19]Tonicactivationwithintherangeof05Hzhasbeen
showntocorrelatewithlevelsofdrowsiness,accuratetaskperformance,and,whenslightlymoreelevated,distractibilityanderratictask
performance.Furthermore,phasicactivationoftheLCisobservedinresponsetobothhighlysalient,unconditionedandtaskrelevantstimuli.The
phasicresponseoccursafterstimulationandprecedesabehavioralresponseinatimelockedfashion.[20]Assuch,phasicactivationoftheLCNE
systemisproposedtoenhancesignalprocessingandbehavioralresponsesspecificallytotaskrelevantstimuli.Giventhecontrastingfunctional
rolesofLCtonicandphasicactivity,itisplausiblethatprojectionsfromthisbrainregionareimportantformaintainingabalancebetween
exploratoryandgoaldirectedbehaviorsthatregulateprobabilistic,environmentallearningandcorrespondingdecisionmaking.
TheLCNEsystemreceivesconvergentinputfromtheorbitofrontal(OFC)andanteriorcingulatecortices(ACC).TheOFChasbeenassociated
withevaluationofreward.Forexample,Tremblayetal.foundthattheresponsemagnitudeofsingleunitsinthisregionisvariedwiththehedonic
valueofastimulus.[21]Additionally,neuronsinthisregionareactivatedbyrewardingstimuli,butnotbyidentificationofthestimulusnor
correspondingresponsepreparation.ActivationoftheACCappearstoreflectsomeevaluationofcostbenefit.SeveralstudiesshowACC
activationinresponsetoperformanceerror,negativefeedback,ormonetaryloss.[22][23][24]Additionally,ACCrespondstotaskdifficulty.[25]
Therefore,ACCactivationmayservetointegrateevaluationsoftaskdifficultywithcorrespondingoutcomeinformationtogaugethebenefitsof
takinganactioninregardstoaparticularenvironmentalstimulus.Conceivably,thefunctionsoftheACCandOFCaredirectlyrelatedtodecision
making,andtheirprojectionstoLCmaymodulatethephasicreleaseofNEinordertogainmodulatecorticalresponsestodecisionoutcomes.
LCNEmayplayasignificantroleinsynchronizingcorticalactivityinresponsetoadecisionprocess.Incomputationalmodelingofdecision,the
mostaccurateandefficientdecisionmechanismsaremathematicallydefinedrandomwalkordriftdiffusionprocessesthatutilizesinglelayer
neuralnetworkstocalculatethedisparityinevidencebetweentwooptions.[26]NEreleasegatedbytheLCNEsystemiselicitedafterneurons
processingsensoryinformationhavepresumablyreachedadecisionthreshold.[27]Thus,thephasicburstcanalteractivationinallcortical
processinglayersinatemporallydependentmanner,essentiallycollapsingthevastinformationprocessingcircuittotheoutcomeofasingle
decisionlayer.Brownetal.foundthattheadditionofaphasicLCmechanismwassufficienttoyieldoptimalperformancefromasinglelayer
decisionnetwork.[28]

Fasting
Astudyhasshownthatfastingleadstoincreasedlevelsofnorepinephrine(NE)inthebloodforupto4daysoffasting.[29]

Macronutrientintake
GlucoseintakewasfoundtosignificantlyincreaseplasmaNElevels.Incontrast,proteinandfatintakewasfoundtohavenoeffect.[30]

Druginteractions
Differentmedicationsaffectingnorepinephrinefunctionhavetheirtargetsatdifferentpointsinthemechanism,fromsynthesistosignal
termination.

Synthesismodulators
Methyltyrosineisasubstancethatintervenesinnorepinephrinesynthesisbysubstitutingtyrosinefortyrosinehydroxylase,andblockingthis
enzyme.
Vesiculartransportmodulators
Thistransportationcanbeinhibitedbyreserpineandtetrabenazine.[31]

Releasemodulators

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Inhibitorsofnorepinephrinerelease
Substance[32]
acetylcholine

Receptor[32]
muscarinicreceptor

norepinephrine(itself)/epinephrine 2receptor
5HT

5HTreceptor

adenosine

P1receptor

PGE

EPreceptor

histamine

H2receptor

enkephalin

receptor

dopamine

D2receptor

ATP

P2receptor

Stimulatorsofnorepinephrine
release
Substance[32]

Receptor[32]

epinephrine

2receptor

angiotensinII

AT1receptor

Receptorbindingmodulators
Examplesincludealphablockersforthereceptors,andbetablockersforthereceptors.

Terminationmodulators
Uptakemodulators
Inhibitors[31]ofuptake1include:
cocaine
tricyclicantidepressants
desipramine
serotoninnorepinephrinereuptakeinhibitors
phenoxybenzamine
amphetamine
reboxetine
Inhibitors[31]ofuptake2include:
normetanephrine
steroidhormones
phenoxybenzamine

AlzheimersDisease
Thenorepinephrinefromlocusceruleuscellsinadditiontoitsneurotransmitterrolelocallydiffusesfrom"varicosities".Assuch,itprovidesan
endogenousantiinflammatoryagentinthemicroenvironmentaroundtheneurons,glialcells,andbloodvesselsintheneocortexand
hippocampus.[33]Upto70%ofnorepinephrineprojectingcellsarelostinAlzheimersDisease.Ithasbeenshownthatnorepinephrinestimulates
mousemicrogliatosuppressAinducedproductionofcytokinesandtheirphagocytosisofA,suggestingthislossmighthavearoleincausing
thisdisease.[33]

Chemistry
Norepinephrineisacatecholamineandaphenethylamine.ThenaturalstereoisomerisL()(R)norepinephrine.Theprefixnorindicatesthat
norepinephrineisthenextlowerhomologofepinephrine.Thetwostructuresdifferonlyinthatepinephrinehasamethylgroupattachedtoits
nitrogen,whereasthemethylgroupisreplacedbyahydrogenatominnorepinephrine.Theprefixnorisderivedasanabbreviationoftheword
"normal",usedtoindicateademethylatedcompound.[34][35][36]
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Mechanism
Norepinephrineissynthesizedfromtyrosineasaprecursor,andpackedintosynapticvesicles.Itperformsitsactionbybeingreleasedintothe
synapticcleft,whereitactsonadrenergicreceptors,followedbythesignaltermination,eitherbydegradationofnorepinephrineorbyuptakeby
surroundingcells.

Biosynthesis
Norepinephrineissynthesizedbyaseriesofenzymaticstepsintheadrenalmedullaandpostganglionicneuronsofthesympatheticnervoussystem
fromtheaminoacidtyrosine.WhiletheconversionstepsofLtyrosinetodopamineoccurspredominantlyinthecytoplasm,theconversionof
dopaminetonorepinephrinebydopaminehydroxylaseoccurspredominantlyintheneurotransmittervesicle.

Vesiculartransport
Betweenthedecarboxylationandthefinaloxidation,norepinephrineistransportedintosynaptic
vesicles.Thisisaccomplishedbyvesicularmonoaminetransporter(VMAT)inthelipidbilayer.This
transporterhasequalaffinityfornorepinephrine,epinephrineandisoprenaline.[31]

Release
Toperformitsfunctions,norepinephrinemustbereleasedfromsynapticvesicles.Manysubstances
modulatethisrelease,someinhibitingitandsomestimulatingit.Anactionpotentialreachesthe
presynapticmembrane,whichchangesthemembranepolarisation.Calciumionsthusenter,resultingin
vesicularfusion,releasingnorepinephrine.
Forinstance,thereareinhibitory2adrenergicreceptorspresynapticallythatgivenegativefeedbackon
releasebyhomotropicmodulation.

Receptorbinding
Norepinephrineperformsitsactionsonthetargetcellbybindingtoandactivatingadrenergicreceptors.
Thetargetcellexpressionofdifferenttypesofreceptorsdeterminestheultimatecellulareffect,andthus
norepinephrinehasdifferentactionsondifferentcelltypes.

Termination
Signalterminationisaresultofreuptakeanddegradation.
Uptake

Biosynthesisofnorepinephrine

Extracellularuptakeofnorepinephrineintothecytosolisdoneeitherpresynaptically(uptake1)orbynon
neuronalcellsinthevicinity(uptake2).Furthermore,thereisavesicularuptakemechanismfromthecytosolintosynapticvesicles.

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Comparisonofnorepinephrineuptake
Uptake

Transporter

Vmax(n
mol/g/min)[37]

KM[37]

Specificity[38]

Location

Othersubstrates[38]

Inhibitors[39]
Cocaine

methylnoradrenaline
Uptake1

Norepinephrine
1.2
transporter[39]

0.3

norepinephrine
>epinephrine presynaptic
>isoprenaline

(nasaldecongestant)
tyramine
guanethidine

Tricyclic
antidepressants
(e.g.desipramine)
Phenoxybenzamine
Amphetamine
Reboxetine

normetanephrine
Uptake2

100

250

cell
epinephrine>
membraneof
norepinephrine
nonneuronal
>isoprenaline
cells[31]

dopamine

steroidhormones

5HT

(e.g.,

histamine

corticosterone)
phenoxybenzamine

Vesicular VMAT[39]

[39]

norepinephrine
Synaptic
>epinephrine
[39]
vesicle
~0.2
>
membrane[39]
[39]
isoprenaline

dopamine[39]
5HT[39]

Reserpine[39]

guanethidine[39]

Tetrabenazine

MPP+[39]

Degradation
Inmammals,norepinephrineisrapidlydegradedtovariousmetabolites.Theprincipal
metabolitesare:
Normetanephrine(viatheenzymecatecholOmethyltransferase,COMT)
3,4Dihydroxymandelicacid(viamonoamineoxidase,MAO)
Vanillylmandelicacid(3Methoxy4hydroxymandelicacid),alsoreferredtoas
vanilmandelateorVMA(viaMAO)
3Methoxy4hydroxyphenylethyleneglycol,"MHPG"or"MOPEG"(viaMAO)
Epinephrine(viaPNMT)[41]
Intheperiphery,VMAisthemajormetaboliteofcatecholamines,andisexcreted
unconjugatedintheurine.Aminormetabolite(althoughthemajoroneinthecentral
nervoussystem)isMHPG,whichispartlyconjugatedtosulfateorglucuronide
derivativesandexcretedintheurine.[42]

Norepinephrinedegradation.Enzymesareshownin
boxes. [40]

Nutritionalsources
Thesynthesisofnorepinephrinedependsonthepresenceoftyrosine,anaminoacidfoundinproteinssuchasmeat,nuts,andeggs.Dairyproducts
suchascheesealsocontainhighamountsoftyrosine(theaminoacidisnamedfor"tyros",theGreekwordforcheese).However,adulthumans
readilysynthesizetyrosinefromphenylalanine,anessentialaminoacid.Tyrosineistheprecursortodopamine,whichinturnisaprecursorto
epinephrineandnorepinephrine.

Seealso
Catecholaminergicpolymorphicventriculartachycardia
Historyofcatecholamineresearch

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33. HenekaMT,NadrignyF,RegenT,MartinezHernandezA,DumitrescuOzimekL,TerwelD,JardanhaziKurutzD,WalterJ,KirchhoffF,HanischUK,
KummerMP.(2010).LocusceruleuscontrolsAlzheimer'sdiseasepathologybymodulatingmicroglialfunctionsthroughnorepinephrine.
(http://www.pnas.org.libproxy.ucl.ac.uk/content/107/13/6058.full.pdf)ProcNatlAcadSciUSA.17:60586063doi:10.1073/pnas.0909586107
(https://dx.doi.org/10.1073%2Fpnas.0909586107)PMID20231476
34. SharmaB,SatishA,KumarR(1999).DictionaryofDrugs(http://books.google.com/?id=3JvArcoG2voC&printsec=frontcover#PPA166).Anmol
Publications.ISBN8126118202.
35. GaddumJH(June1956)."ThePrefix'Nor'inChemicalNomenclature".Nature177(1046):10461046.Bibcode:1956Natur.177.1046G
(http://adsabs.harvard.edu/abs/1956Natur.177.1046G).doi:10.1038/1771046b0(https://dx.doi.org/10.1038%2F1771046b0).
36. MatthiessenA,FosterGC(1868)."Researchesintothechemicalconstitutionofnarcotineandofitsproductsofdecomposition"(http://books.google.com/?
id=tKsOAAAAIAAJ&printsec=titlepage).JournaloftheChemicalSociety358.
37. Thesevaluesarefromratheart.Unlesselsespecifiedintable,thenrefis:Rang,H.P.(2003).Pharmacology.Edinburgh:ChurchillLivingstone.ISBN0
443071454.Page167
38. Unlesselsespecifiedintable,thenrefis:Rang,H.P.(2003).Pharmacology.Edinburgh:ChurchillLivingstone.ISBN0443071454.Page167
39. Unlesselsespecifiedinboxes,thenrefis:RodFlowerHumphreyP.RangMaureenM.DaleRitter,JamesM.(2007).Rang&Dale'spharmacology.
Edinburgh:ChurchillLivingstone.ISBN0443069115.
40. Figure114in:RodFlowerHumphreyP.RangMaureenM.DaleRitter,JamesM.(2007).Rang&Dale'spharmacology.Edinburgh:Churchill
Livingstone.ISBN0443069115.
41. "EndokrynologiaKliniczna"ISBN8320008158,page502
42. Chapter11in:RodFlowerHumphreyP.RangMaureenM.DaleRitter,JamesM.(2007).Rang&Dale'spharmacology.Edinburgh:Churchill
Livingstone.ISBN0443069115.

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