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14-September-2008 18:02:48 - Norepinephrine This article or section includes a list of references or external links, but its sources remain unclear because it has insufficient inline citations. You can improve this article by introducing more precise citations where appropriate. May 2008 The references used in this article may be clearer with a different or consistent style of citation, footnoting, or external linking. September 2007 Norepinephrine1 IUPAC name 4-2-Amino-1-hydroxyethyl benzene-1,2-diol Other names Noradrenaline Identifiers CAS number D: 149-95-1 L: 51-41-2 D/L: 138-65-8 Properties Molecular formula C8H11NO3 Molar mass 169.18 g/mol 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 is a catecholamine with dual roles as a hormone and a neurotransmitter. 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. However, when norepinephrine acts as a drug it will increase blood pressure by its prominent increasing effects on the vascular tone due stimulation of alpha-Receptors. This increase in vascular resistance is triggering a compensatory reflex that overcomes its direct stimulatory effects on the heart. The reflex, called the baroreceptor reflex, results in a drop in heart rate called reflex bradycardia. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.2 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. Contents 1 Origins 1.1 Norepinephrine system 2 Mechanism 2.1 Biosynthesis 2.2 Vesicular transport 2.3 Release 2.4 Receptor binding 2.5 Termination 2.5.1 Degradation 2.5.2 Uptake 3 Noradrenergic agents 3.1 By indication 3.1.1 Attention-deficit/hyperactivity disorder 3.1.2 Depression 3.1.3 Hypotension 3.2 By site of action 3.2.1 Synthesis modulators 3.2.2 Vesicular transport modulators 3.2.3 Release modulators 3.2.4 Receptor binding modulators 3.2.5 Termination modulators 3.2.5.1 Uptake modulators 4 Chemistry 5 Natural sources 6 References 7 External links 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. 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 from the amino acid tyrosine: The first reaction is the oxidation 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.3 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 Further reading: Adrenergic receptor Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. Unlike epinephrine, which activates all adrenergic receptors α1 α2 β1 β2, norepinephrine activates all but β2 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 both a result of degradation and reuptake. Degradation 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 3-Methoxy-4-hydroxymandelic acid VMA via MAO 3-Methoxy-4-hydroxyphenylethylene glycol, MHPG or MOPEG via MAO Epinephrine via PNMT4 VMA and MOPEG are the two major urinary metabolites of catecholamine metabolism. Uptake Uptake is either done presynaptically uptake 1 or by non-neuronal cells in the vicinity uptake 2. Comparison of norepinephrine uptake Uptake Rate nmol/g/min5 KM5 Specificity6 Location Other substrates6 Uptake 1 1.2 0.3 noradrenaline adrenaline isoprenaline presynaptic methylnoradrenaline nasal decongestant tyramine guanethidine Uptake 2 100 250 adrenaline noradrenaline isoprenaline cell membrane of non-neuronal cells3 dopamine 5-HT histamine 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 ADD/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 ADD/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 ADD/ADHD. Consulting with a physician 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 ADD/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.citation needed 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 have side effects due to the nonspecific activation of histamine and acetylcholine receptors. Side effects include tiredness, increased hunger, dry mouth, and blurred vision. For this reason, they have largely been replaced by newer selective reuptake drugs such as fluoxetine Prozac. 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 alpha-1 and alpha-2 adrenergic receptors to cause vasoconstriction. Its effect in vitro is often limited to the increasing of blood pressure through agonistic activity on alpha-1 and alpha-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. Thus, in many nursing and paramedic schools, the phrase Levophed'll leave them dead is used. 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. 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.3 Release modulators Inhibitors of norepinephrine release Substance7 Receptor7 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 Substance7 Receptor7 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. Termination modulators Uptake modulators Inhibitors3 of uptake 1 include: cocaine tricyclic antidepressants desipramine phenoxybenzamine amphetamine Inhibitors3 of uptake 2 include: normetanephrine steroid hormones phenoxybenzamine 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 of epinephrine. Natural sources Protein from such sources as meat, nuts and egg whites are broken down by the digestive system into amino acids such as l-tyrosine, a precursor to dopamine, which is in itself a precursor of norepinephrine. Similarly, l-tryptophan from protein is needed for serotonin production. Banana peels contain significant amounts of norepinephrine and dopamine.9 References The references used in this article may be clearer with a different or consistent style of citation, footnoting, or external linking. September 2007 ^ Merck Index, 11th ion, 6612. ^ Introduction to Autonomic Pharmacology. Elsevier International. ^ a b c d e Rang, H. P. 2003. Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167 ^ Endokrynologia Kliniczna ISBN 83-200-0815-8, page 502 ^ a b 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 ^ a b Unless else specified in table, then ref is: Rang, H. P. 2003. Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167 ^ a b c d Unless else specified in table, then ref is: Rang, H. P. 2003. Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 129 ^ TIHKAL on nor ^ Kanazawa, Kazuki; Hiroyuki Sakakibara 2000. High content of Dopamine, a strong antioxidant, in Cavendish banana. Journal of Agriculture and Food Chemistry 48: 844-848. Retrieved on 8 November 2007. Brunton, Lazo, Parker: Goodmn Gilman's The Pharmacological Basis of Therapeutics. McGraw Hill, 11th ion. pp. 248-249. External links Mental Health: A report of surgeon general. Etiology of Anxiety Disorders http://www.med.upenn.edu/astonjoneslab/epapers/A-JNeuropsycho5thGen.pdf http://www.biopsychiatry.com/nordop.htm v d e Phenethylamines 2C-B 2C-C 2C-D 2C-E 2C-I 2C-N 2C-T-2 2C-T-21 2C-T-4 2C-T-7 2C-T-8 3C-E 4-FMP Bupropion Cathine Cathinone Clenbuterol DESOXY Dextroamphetamine Methamphetamine Diethylcathinone Dimethylcathinone DOC DOB DOI DOM bk-MBDB Dopamine Br-DFLY Ephedrine Epinephrine Escaline Etafedrine Fenfluramine Levosalbutamol Levmetamfetamine MBDB MDA MDMA MDMC MDEA MDPV Mescaline Methcathinone Norepinephrine Phentermine Salbutamol Tyramine Venlafaxine v d e Endocrine system: hormones/endocrine glands Peptide hormones, Steroid hormones Hypothalamic-pituitary Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α FSH, LH, TSH, GH, prolactin, POMC ACTH, MSH, endorphins, lipotropin Adrenal axis Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA Thyroid axis Thyroid: thyroid hormone T3 and T4 - calcitonin - Parathyroid: PTH Gonadal axis Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin pregnancy Other end. glands Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin Non-end. glands Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Thymulin - Skeleton: Osteocalcin - Liver/other: Insulin-like growth factor IGF-1, IGF-2 Target-derived NGF, BDNF, NT-3 v d e Amines, alcohols: amino alcohols Ethanolamine Heptaminol Isoetarine Norepinephrine Propanolamine Sphingosine v d e Cardiac stimulants excluding cardiac glycosides C01C Adrenergic and dopaminergic agents Adrenergic agonists primarily β1 and mixed EPINEPHRINE Etilefrine Isoprenaline Norepinephrine Norfenefrine Phenylephrine Dobutamine Oxedrine Metaraminol Methoxamine Mephentermine Prenalterol Midodrine Arbutamine Dopamine agonists DOPAMINE Fenoldopam Both Dopexamine Ibopamine Octopamine Unknown/ungrouped Dimetofrine Gepefrine Cafedrine Theodrenaline Phosphodiesterase inhibitors PDE3I Amrinone Milrinone Enoximone Bucladesine Other cardiac stimulants Angiotensinamide Xamoterol Levosimendan Retrieved from http://en..org/wiki/Norepinephrine Categories: Catecholamines | NeurotransmittersHidden categories: Articles lacking in-text citations | references cleanup | All articles with statements | Articles with statements since February 2007 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages БългарÑ?ки Català Dansk Deutsch Þ‹Þ¨ÞˆÞ¬Þ€Þ¨Þ„Þ¦Þ?Þ° Eesti Español Français Hrvatski Italiano עברית Latina Lietuvių Magyar МакедонÑ?ки Nederlands 日本語 ‪Norsk bokmÃ¥l‬ Polski Português РуÑ?Ñ?кий SlovenÅ¡Ä?ina СрпÑ?ки / Srpski Suomi Svenska Türkçe This page was last modified on 24 August 2008, at 03:11
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