Norepinephrine ( NE ), also called noradrenaline ( NA ) or noradrenaline , is organic chemicals in the catecholamine family that function in the brain and body as hormones and neurotransmitters. The name "noradrenaline", derived from the Latin root meaning "on/next to the kidney", is more commonly used in the UK; in the United States, "norepinephrine," derived from a Greek root having the same meaning, is usually preferred. "Norepinephrine" is also an international nonproprietary name given to the drug. Regardless of the name used for the substance itself, the parts of the body that produce or are affected by it are referred to as noradrenergic .
In the brain, norepinephrine is produced in small nuclei but exerts powerful effects on other areas of the brain. The most important of these cores is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by a sympathetic ganglia located near the spinal cord or in the abdomen, and is also released directly into the bloodstream by the adrenal glands. Regardless of how and where it is released, norepinephrine acts on the target cell by binding and activating the noradrenergic receptor located on the cell surface.
The general function of norepinephrine is to mobilize the brain and body to act. The slowest release of Norepinephrine during sleep, increases during awake, and reaches a much higher level during stressful situations or hazards, in so-called fight-or-flight responses. In the brain, norepinephrine promotes arousal and alertness, increases alertness, improves memory formation and retention, and focuses attention; it also increases anxiety and anxiety. Throughout 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 bladder emptying and gastrointestinal motility.
Various important medical drugs work by altering the actions of the norepinephrine system. Norepinephrine itself is widely used as an injectable drug for the treatment of very low blood pressure. Beta blockers, which counteract some of the effects of norepinephrine, are often used to treat glaucoma, migraines, and various cardiovascular problems. Alpha blockers, which counteract a range of different norepinephrine effects, are used to treat some cardiovascular and psychiatric conditions. Alpha-2 agonists often have a sedative effect, and are commonly used as anesthesia-enhancing in surgery, as well as in the treatment of drug or alcohol dependence. Many important psychiatric drugs have a powerful effect on the norepinephrine system in the brain, which produces side effects that may be helpful or harmful.
Video Norepinephrine
Structure
Norepinephrine is catecholamine and phenethylamine. The structure is different from epinephrine only in epinephrine that has a methyl group attached to its nitrogen, while the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix or - is derived as an abbreviation of the word "normal", used to denote a demethylated compound.
Maps Norepinephrine
Biochemical mechanism
Biosynthesis
Norepinephrine is synthesized from amino acid tyrosine 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 mainly in the cytoplasm, the conversion of dopamine into norepinephrine by dopamine? -monooxygenase occurs mainly in the neurotransmitter vesicles. The metabolic pathway is:
- Phenylalanine -> Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine
So the direct precursor norepinephrine is dopamine, which is synthesized indirectly from the essential amino acid phenylalanine or non-essential amino acid tyrosine. These amino acids are found in almost every protein and, thus, are provided by the consumption of foods containing protein, with tyrosine being the most common.
Phenylalanine is converted into tyrosine by the enzyme of phenylalanine hydroxylase, with molecular oxygen (O 2 ) and tetrahydrobiopterin as the cofactor. Tyrosine is converted to L-DOPA by tyrosine hydroxylase enzyme, with tetrahydrobiopterin, O 2 , and possibly iron (Fe 2 ) as a cofactor. L-DOPA is converted to dopamine by the aromatic enzyme L -amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate as a cofactor. Dopamine is then converted to norepinephrine by dopamine enzyme? -monooxygenase (formerly known as dopamine? -hydroxylase ), with O 2 and ascorbic acid as a cofactor.
Norepinephrine itself can then be converted into epinephrine by the enzyme phenylethanolamine N -methyltransferase with S -addosyl- L -methionine as a cofactor.
Degradation
In mammals, norepinephrine is rapidly degraded into various metabolites. The initial step in the solution can be catalyzed by one of the monoamine oxidase enzymes (especially monoamine oxidase A) or COMT. From there the damage can be continued with various paths. The main end product is Vanillylmandelic acid or conjugated form of MHPG, both considered biologically inactive and excreted in the urine.
Function
Mobile effect
Like many other biologically active substances, norepinephrine has the effect of binding and activating receptors located on the cell surface. Two large families of norepinephrine receptors have been identified, known as alpha and beta adrenergic receptors. The alpha receptor is divided into subtypes? 1 and? 2 ; beta receptor becomes subtype? 1 ,? 2 , and? 3 . All of these functions as protein-coupled G receptors, which means that they use their effects through a complicated second messenger system. Alfa-2 receptors usually have inhibitory effects, but many are pre-synaptic (ie, on the surface of cells that release norepinephrine), so that the net effect of alpha-2 activation often decreases in the amount of norepinephrine released. The Alpha-1 receptors and the three types of beta receptors usually have an excitatory effect.
Storage, release and retrieve
In the brain's norepinephrine function as a neurotransmitter, and is controlled by a common set of mechanisms for all monoamine neurotransmitters. After synthesis, norepinephrine is transported from the cytosol into a synaptic vesicle by a vesicular monoamine transporter (VMAT). Norepinephrine is deposited in this vesicle until it is ejected into the synaptic cleft, usually after the action potential causes the vesicle to release its contents directly into the synaptic cleft through a process called exocytosis.
Once in the synapse, norepinephrine binds and activates the receptor. After the action potential, the norepinephrine molecule quickly becomes unbound from its receptor. They are then reabsorbed into presinaptic cells, via reuptake mediated primarily by norepinephrine (NET) transporters. Upon return to the cytosol, norepinephrine can be broken down by monoamine oxidase or repacked into vesicles by VMAT, making it available for future release.
Sympathetic nervous system
Norepinephrine is the main neurotransmitter used by the sympathetic nervous system, which consists of about two dozen ganglia of sympathetic chains located next to the spinal cord, plus a set of previtebral ganglia located on the chest and abdomen. These sympathetic ganglia are connected to various organs, including the eyes, salivary glands, heart, lungs, liver, gallbladder, stomach, intestine, kidney, bladder, reproductive organs, muscles, skin, and adrenal glands. Sympathetic activation of the adrenal glands causes a section called the adrenal medulla to release norepinephrine (and epinephrine) into the bloodstream, from which, functioning as a hormone, it gains further access to various tissues.
Broadly speaking, the norepinephrine effect on each target organ is to change its state in a way that makes it more conducive to active body movement, often with increased energy use costs and increased wear. This can be contrasted with the effects of acetylcholine mediated from the parasympathetic nervous system, which converts most of the same organ into a more conducive state for rest, recovery and digestion of food, and is usually cheaper in terms of energy expenditure.
The sympathetic effects of norepinephrine include:
- In the eye, increased tear production, making the eyes moist, and dilating the pupils through the iris dilator contraction.
- At heart, an increase in the amount of blood pumped.
- In brown adipose tissue, increased calories are burned to produce body heat.
- Many effects on the immune system. The sympathetic nervous system is the main route of interaction between the immune system and the brain, and some components receive sympathetic input, including thymus, spleen, and lymph nodes. But the effect is very complex, with some immune processes activated while others are inhibited.
- Inside the arteries, narrowing of blood vessels, causes an increase in blood pressure.
- In the kidney, release of renin and sodium retention in the bloodstream.
- In the liver, increased glucose production, either by glycogenolysis after meals or by gluconeogenesis when food has not been consumed. Glucose is the body's main energy source in most conditions.
- In the pancreas, an increase in glucagon release, a hormone whose main effect is to increase the production of glucose by the liver.
- In skeletal muscle, increased glucose uptake.
- In adipose tissue (i, e, fat cells), an increase in lipolysis, that is, the conversion of fat into a substance that can be used directly as a source of energy by muscles and other tissues.
- In the stomach and intestines, there is a decrease in digestive activity. This results from the inhibitory effect of norepinephrine in the enteric nervous system, leading to decreased gastrointestinal mobility, blood flow, and digestive secretion.
Central nervous system
The noradrenergic neurons in the brain form a system of neurotransmitters, which, when activated, effect on large areas of the brain. The effect is manifested in alertness, passion, and readiness to act.
Noradrenergic neurons (ie neurons whose main neurotransmitter is norepinephrine) are relatively small, and their cell body is limited to some relatively small areas of the brain, but they send projections to many other areas of the brain and have a strong effect on their targets. The noradrenergic cell group was first mapped in 1964 by Annica DahlstrÃÆ'¶m and Kjell Fuxe, who commissioned their label starting with the letter "A" (for "aminergic"). In their scheme, areas A1 through A7 contain norepinephrine neurotransmitters (A8 to A14 containing dopamine). Noradrenergic cell group A1 is located in the ventrolateral part of the tail of the medulla, and plays a role in the control of body fluid metabolism. The Noradrenergic A2 cell group is located in the brain stem area called the solitary nucleus; these cells have been implicated in various responses, including control of food intake and responses to stress. A5 and A7 cell groups project mainly to the spinal cord.
The most important source of norepinephrine in the brain is the locus coeruleus, which contains the noradrenergic cell group A6 and the adjoin of the A4 group of cells. The locus coeruleus is quite small in absolute terms - in primates it is estimated to contain about 15,000 neurons, less than a million neurons in the brain - but sends projections to every major part of the brain as well as to the spine. rope.
Activity levels at the coeruleus locus are highly correlated with alertness and reaction speed. LC activity is low during sleep and almost non-existent during REM (dreaming). It runs at the baseline level during waking, but increases temporarily when someone is presented with any kind of stimulus that attracts attention. Unpleasant stimuli such as pain, difficulty breathing, bladder distension, heat or cold result in greater improvement. Unpleasant conditions such as intense fear or severe pain are associated with very high levels of LC activity.
Norepinephrine released by the coeruleus locus affects brain function in several ways. It enhances the processing of sensory input, increases attention, promotes long-term memory formation and work and improves the brain's ability to respond to input by altering activity patterns in the prefrontal cortex and other areas. Passion level control is strong enough that drug induced suppression of LC has a strong sedative effect.
There is a great resemblance between the situation that activates the coeruleus locus in the brain and the situation that activates the sympathetic nervous system at the periphery: LC essentially mobilizes the brain to act while the sympathetic system mobilizes the body. It has been argued that this similarity arises because both are largely controlled by the same brain structure, especially the part of the brainstem called the gigantocellular nucleus.
Pharmacology
A large number of important drugs exert its effect by interacting with the norepinephrine system in the brain or body. Its use includes treatment of cardiovascular problems, shock, and various psychiatric conditions. These drugs are divided into: sympathomimetic drugs that mimic or enhance at least some of the effects of norepinephrine released by the sympathetic nervous system; sympatholytic drugs, by contrast, block at least some of the effects. Both are large groups with varying usage, depending on which effects are enhanced or blocked.
Norepinephrine itself is classified as a sympathomimetic drug: its effect when administered with intravenous injection increases heart rate and strength and constricts blood vessels making it very useful for treating medical emergencies involving low critical blood pressure. Persistent Sepsis Campaigns recommended norepinephrine as a first-line agent in treating septic shock that is unresponsive to fluid resuscitation, complemented by vasopressin and epinephrine. The use of dopamine is restricted only to highly selected patients.
Beta blocker
It is a sympatholytic drug that blocks the effects of beta-adrenergic receptors while having little to no effect on alpha receptors. They are sometimes used to treat high blood pressure, atrial fibrillation and congestive heart failure, but recent reviews have concluded that other types of drugs are usually superior to those ends. Beta blockers may be a viable option for other cardiovascular conditions, including angina and Marfan syndrome. They are also widely used to treat glaucoma, most often in the form of eye drops. Because of its effect in reducing the symptoms of anxiety and tremor, they are sometimes used by entertainers, public speakers and athletes to reduce performance anxiety, even though they are not medically approved for that purpose and prohibited by the International Olympic Committee.
However, the usefulness of beta blockers is limited by a variety of serious side effects, including slowing heart rate, decreased blood pressure, asthma, and reactive hypoglycemia. The negative effects can be very severe in people suffering from diabetes.
Alpha blocker
It is a sympatholytic drug that blocks the effects of the adrenergic alpha receptor while having little or no effect on the beta receptor. Drugs that fall into this group can have very different effects, however, depending on whether they primarily block alpha-1 receptors, alpha-2 receptors, or both. The alpha-2 receptors, as described elsewhere in this article, often lie in neurons releasing norepinephrine themselves and have an inhibitory effect on them; consequently blockage of alpha-2 receptors usually results in increased norepinephrine release. The alpha-1 receptors are usually located on target cells and have a stimulating effect on them; consequently blockage of alpha-1 receptors usually results in blocking some norepinephrine effects. Drugs such as phentolamine acting on both receptor types can produce a complex combination of both effects. In many cases when the term "alpha blocker" is used without qualification, it refers to a selective alpha-1 antagonist.
Selective alpha-1 inhibitors have various uses. Because one effect is relaxing the muscles in the bladder neck, they are often used to treat benign prostatic hyperplasia, and to aid the expulsion of bladder stones. The effects on the central nervous system make them useful for treating generalized anxiety disorders, panic disorders, and post-traumatic stress disorder. They may, however, have significant side effects, including a decrease in blood pressure.
Some antidepressants function in part as selective alpha-2 inhibitors, but the most famous drug in the class is yohimbine, which is extracted from the bark of the African yohimbe tree. Yohimbine acts as a potential male enhancer, but its usefulness for that purpose is limited by serious side effects including anxiety and insomnia. Overdose can cause a dangerous increase in blood pressure. Yohimbine is banned in many countries, but in the United States, because it is extracted from a plant rather than chemically synthesized, it is sold on the table as a nutritional supplement.
Alfa-2 agonist
This is a sympathomimetic drug that activates the alpha-2 receptor or enhances its effect. Because alpha-2 receptors are inhibitors and many are located presinaptically in the cells that release norepinephrine, the net effect of these drugs is usually to reduce the amount of norepinephrine released. Drugs in this group that are able to enter the brain often have a strong sedative effect, due to their inhibitory effect on the coeruleus locus. Clonidine, for example, is used for the treatment of anxiety disorders and insomnia, as well as premedication of sedatives for patients undergoing surgery. Xylazine, another drug in this group, is also a strong sedative and is often used in combination with ketamine as a general anesthetic for animal surgery - in the United States not yet approved for use in humans.
Stimulants and antidepressants
It is a drug whose primary effect is thought to be mediated by different neurotransmitter systems (dopamine for stimulants, serotonin for antidepressants), but many also increase norepinephrine levels in the brain. Amphetamine, for example, is a stimulant that increases the release of norepinephrine and dopamine. Monoamine oxidase inhibitors are antidepressants that inhibit norepinephrine metabolic degradation and serotonin. In some cases it is difficult to distinguish the norepinephrine mediation effect from effects associated with other neurotransmitters.
Diseases and disorders
A number of important medical problems involve the dysfunction of the norepinephrine system in the brain or body.
Sympathetic hyperactivity
Hyperactivity of the sympathetic nervous system is not a recognized condition in its own right, but is a component of a number of conditions, as well as the possible consequences of taking sympathomimetic drugs. It causes different symptoms including aches and pains, rapid heartbeat, high blood pressure, sweating, palpitations, anxiety, headaches, pallor, and decreased blood glucose. If sympathetic activity increases for a long time, it can lead to weight loss and other body changes related to stress.
A list of conditions that can lead to sympathetic hyperactivation include severe brain injury, spinal cord damage, heart failure, high blood pressure, kidney disease, and various types of stress.
Pheochromocytoma
Pheochromocytoma is a rare adrenal medulla tumor, caused by genetic factors or certain types of cancer. The consequence is an increase in the amount of norepinephrine and epinephrine released into the bloodstream. The most obvious symptoms are sympathetic hyperactive symptoms, including an increase in blood pressure that can reach fatal levels. The most effective treatment is surgical removal of the tumor.
Stress
Stress, for a physiologist, means any situation that threatens the stability of the body and its function. Stress affects a variety of body systems: the two most consistently activated are the hypothalamus-pituitary-adrenal axis and norepinephrine system, including the sympathetic nervous system and the locus coeruleus-centered system in the brain. Stressors of many types evoke increased noradrenergic activity, which mobilizes the brain and body to confront threats. Chronic stress, if continued for a long time, can damage many parts of the body. A significant part of the damage is due to the continuous effects of norepinephrine release, since the general function of norepinephrine directs resources away from maintenance, regeneration, and reproduction, and to the systems necessary for active movement. The consequences can include slowing growth (in children), sleeplessness, loss of libido, gastrointestinal problems, disease resistance disorder, slower healing rates of depression, and increased susceptibility to addiction.
ADHD
Attention deficit hyperactivity disorder is a psychiatric condition involving problems with attention, hyperactivity, and impulsivity. It is most often treated by stimulant drugs such as methylphenidate (Ritalin), whose primary effect is to increase dopamine levels in the brain, but the drugs in this group also generally increase the level of the norepinephrine brain, and it is difficult to determine whether this action is involved in the value clinical them. There is also substantial evidence that many people with ADHD exhibit "biomarkers" involving modified norepinephrine processing. Some drugs whose main effects are on norepinephrine, including guanfacine, clonidine, and atomoxetine, have been tried as treatments for ADHD, and are found to have effects that are comparable to those of stimulants.
Autonomous Failure
Some conditions, including Parkinson's disease, diabetes and so-called pure autonomic failure, can lead to the loss of neurons secreting norepinephrine in the sympathetic nervous system. The symptoms are widespread, the most serious of which is the decrease in heart rate and a remarkable drop in resting blood pressure, making it impossible for severely affected people to stand for more than a few seconds without fainting. Treatment may involve dietary changes or medications.
Comparative biology and evolution
Norepinephrine has been reported to exist in a variety of animal species, including protozoa, placozoa and cnidaria (jellyfish and related species), but not in ctenophores (jelly combs), whose nervous system is very different from other animals. It is commonly present in deuterostomes (vertebrates, etc.), but in protostomes (arthropods, mollusks, flatworms, nematodes, annelids, etc.) is replaced by octopamine, a chemical closely related to closely related synthesis pathways. In insects, octopamine has warned and activated the appropriate function (at least approximately) with the norepinephrine function in vertebrates. It has been argued that octopamine evolved to replace norepinephrine rather than otherwise ; However, the amphioxus nervous system (primitive chordate) has been reported to contain octopamine but not norepinephrine, which presents difficulties for the hypothesis.
History
In the early 20th century Walter Cannon, who popularized the idea of ​​a sympathetic system that prepares the body to fight and fly, and his partner, Arturo Rosenblueth, developed his two-sympathy theory, E. sympathizers./i> (stimulus) and my sympathy (inhibition), is responsible for this action. Belgian pharmacologist Zac non Bacq and Canadian and US-American pharmacologists between 1934 and 1938 suggested that noradrenaline may be a sympathetic transmitter. In 1939, Hermann Blaschko and Peter Holtz independently identified the mechanism of biosynthesis for norepinephrine in vertebrate bodies. In 1945 Ulf von Euler published the first of a series of papers that defined the role of norepinephrine as a neurotransmitter. He showed the presence of norepinephrine in tissues and preserved sympathetic brains, and added evidence that it was his sympathy Cannon and Rosenblueth.
References
Source of the article : Wikipedia
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