«Noradrenaline (NA), also called norepinephrine (NE) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. The name "noradrenaline", derived from Latin roots meaning "at/alongside the kidney", is more commonly used in the United Kingdom; in the United States, "norepinephrine," derived from Greek roots having that same meaning, is usually preferred. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.
The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility.
In the brain, noradrenaline is produced in nuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, and it is also released directly into the bloodstream by the adrenal glands. Regardless of how and where it is released, norepinephrine acts on target cell by binding to and activating noradrenergic receptors located on the cell surface.
A variety of medically important drugs work by altering the actions of noradrenaline systems. Noradrenaline itself is widely used as an injectable drug for the treatment of critically low blood pressure. Beta blockers, which counter some of the effects of noradrenaline, are frequently used to treat glaucoma, migraine, and a range of cardiovascular problems. Alpha blockers, which counter a different set of noradrenaline effects, are used to treat several cardiovascular and psychiatric conditions. Alpha-2 agonists often have a sedating effect, and are commonly used as anesthesia-enhancers in surgery, as well as in treatment of drug or alcohol dependence. Many important psychiatric drugs exert strong effects on noradrenaline systems in the brain, resulting in side-effects that may be helpful or harmful.
Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine 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.
Norepinephrine is synthesized from the amino acidtyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. While the conversion of tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-monooxygenase occurs predominantly inside neurotransmitter vesicles. The metabolic pathway is:
Thus the direct precursor of norepinephrine is dopamine, which is synthesized indirectly from the essential amino acid phenylalanine or the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, with tyrosine being the most common.
Phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen (O2) and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, and probably ferrous iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate as a cofactor. Dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase (formerly known as dopamine β-hydroxylase), with O2 and ascorbic acid as cofactors.
Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor.
In mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT. From there the breakdown can proceed by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of which are thought to be biologically inactive and are excreted in the urine.
Like many other biologically active substances, norepinephrine exerts its effects by binding to and activating receptors located on the surface of cell. Two broad families of norepinephrine receptors have been identified, known as alpha and beta adrenergic receptors. Alpha receptors are divided into subtypes α1 and α2; beta receptors into subtypes β1, β2, and β3. All of these function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Alpha-2 receptors usually have inhibitory effects, but many are located pre-synaptically (i.e., on the surface of the cell that release norepinephrine), so the net effect of alpha-2 activation is often a decrease in the amount of norepinephrine released. Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.
Inside the brain norepinephrine functions as a neurotransmitter, and is controlled by a set of mechanisms common to all monoamine neurotransmitters. After synthesis, norepinephrine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter (VMAT). Norepinephrine is stored in these vesicles until it is ejected into the synaptic cleft, typically after an action potential causes the vesicles to release their contents directly into the synaptic cleft through a process called exocytosis.» (wikipedia)
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