|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Mol. mass||169.18 g/mol|
|Melt. point||217 °C (423 °F) (decomposes)|
|Boiling point||442.6 °C (829 °F) ±40.0°C|
|(what is this?)|
Norepinephrine (INN) (abbreviated norepi or NE), also called noradrenaline (BAN) (abbreviated NA, NAd, or norad), or 4,5-β-trihydroxyphenethylamine is a catecholamine with multiple roles including those as a hormone and a neurotransmitter. It is the hormone and neurotransmitter most responsible for vigilant concentration in contrast to its most chemically similar hormone, dopamine, which is most responsible for cognitive alertness.
Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. The terms noradrenaline (from the Latin) and norepinephrine (from the Greek) are interchangeable, with noradrenaline being the common name in most parts of the world. However the U.S. National Library of Medicine has promoted norepinephrine as the favored name.
One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons to affect the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions in the heart. As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled. Norepinephrine also underlies the fight-or-flight response, along with epinephrine, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply.[broken citation]
Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in the secretory granules of the medullary chromaffin cells. 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 in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.
- 1 Medical uses
- 2 Physiological effects
- 3 Mechanism
- 4 Chemistry
- 5 Mechanism
- 6 Nutritional sources
- 7 References
- 8 External links
Norepinephrine is used for 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 α1 and α2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 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 used mainly to treat patients in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.
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 coeruleus (LC). 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 coeruleus 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 contribute to such post-ganglionic nerve cells, although they release norepinephrine into the blood.
The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are manifested in alertness, arousal, and influences on the reward system.
- Cingulate gyrus
- Spinal cord
- Some Brainstem nuclei
This structure explains some of the clinical uses of norepinephrine, since a modification of this system affects large areas of the brain.
Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase the alteration detection rate (frequency at which an alteration was selected) in multiple-cue probability learning during tasks involving giving predictive cues (such as auditory or visual), and thereby enhance subsequent learning. A. J. Yu et al. developed a Bayesian framework to examine NE release in instances of "unexpected uncertainty", wherein a drastic alteration in sensory information produces a large disparity between top-down expectations and what actually occurs. The model predicts that NE levels spike when the predictive context is switched, then subside. It has also been shown that lesions of the locus coeruleus impair this attentional shift.
Similarly, several studies have implicated the LC-NE system in eliciting the P300, a cortical event-related potential that responds to environmental stimuli with behaviorally relevant, motivational, or attention-grabbing properties. The P300 may reflect updating of prior knowledge regarding stimuli relevant for accurate and efficient decision making. Several studies have searched for a P300 generator within the brain and have ultimately concluded that the potential must have a source that is distributed, synchronous and localized in cortex. This definition is ideally satisfied both functionally and anatomically by the LC neuromodulatory system. Given its broad projection pattern and the correlation between NE release and increased sensory signal transmission, it seems likely that noradrenergic cortical release is the neuronal mechanism of the P300.
Examination of the LC’s tonic firing pattern has led to speculation that it is important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback. Tonic activation within the range of 0–5 Hz has been shown to correlate with levels of drowsiness, accurate task performance, and, when slightly more elevated, distractibility and erratic task performance. Furthermore, phasic activation of the LC is observed in response to both highly salient, unconditioned and task-relevant stimuli. The phasic response occurs after stimulation and precedes a behavioral response in a time-locked fashion. As such, phasic activation of the LC-NE system is proposed to enhance signal processing and behavioral responses specifically to task-relevant stimuli. Given the contrasting functional roles of LC tonic and phasic activity, it is plausible that projections from this brain region are important for maintaining a balance between exploratory and goal-directed behaviors that regulate probabilistic, environmental learning and corresponding decision making.
The LC-NE system receives convergent input from the orbitofrontal (OFC) and anterior cingulate cortices (ACC). The OFC has been associated with evaluation of reward. For example, Tremblay et al. found that the response magnitude of single-units in this region is varied with the hedonic value of a stimulus. Additionally, neurons in this region are activated by rewarding stimuli, but not by identification of the stimulus nor corresponding response-preparation. Activation of the ACC appears to reflect some evaluation of cost-benefit. Several studies show ACC activation in response to performance error, negative feedback, or monetary loss. Additionally, ACC responds to task difficulty. Therefore, ACC activation may serve to integrate evaluations of task difficulty with corresponding outcome information to gauge the benefits of taking an action in regards to a particular environmental stimulus. Conceivably, the functions of the ACC and OFC are directly related to decision-making, and their projections to LC may modulate the phasic release of NE in order to gain-modulate cortical responses to decision outcomes.
LC-NE may play a significant role in synchronizing cortical activity in response to a decision process. In computational modeling of decision, the most accurate and efficient decision mechanisms are mathematically defined random walk or drift-diffusion processes that utilize single-layer neural networks to calculate the disparity in evidence between two options. NE release gated by the LC-NE system is elicited after neurons processing sensory information have presumably reached a decision threshold. Thus, the phasic burst can alter activation in all cortical processing layers in a temporally dependent manner, essentially collapsing the vast information-processing circuit to the outcome of a single-decision layer. Brown et al. found that the addition of a phasic LC mechanism was sufficient to yield optimal performance from a single-layer decision network.
A study has shown that fasting leads to increased levels of norepinephrine (NE) in the blood for up to 4 days of fasting.
Glucose intake was found to significantly increase plasma NE levels. In contrast, protein and fat intake was found to have no effect.
A commonly-known side effect associated with schizo-affective patients, known as akathisia (commonly mistaken for schizophrenic symptoms), was found to be associated with increased levels of norepinephrine. Data supports the efficacy of novel antipsychotics that deal with the agonism of the NMDA glutamate receptors, associated with regulating uptake of norepinephrine, which, in turn, affects the trafficking of glutamate. This suggests that schizophrenia may, in fact, have a greater association with abnormal norepinephrine-reuptake kinetics than with dopamine, which may actually be responsible for a large part of the mechanism of glutamate release.
Different medications affecting norepinephrine function have their targets at different points in the mechanism, from synthesis to signal termination.
Vesicular transport modulators
|norepinephrine (itself)/epinephrine||α2 receptor|
|angiotensin II||AT1 receptor|
Receptor binding modulators
Inhibitors of uptake 1 include:
Inhibitors of uptake 2 include:
The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally diffuses 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. 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 ofcytokines and their phagocytosis of Aβ, suggesting this loss might have a role in causing this disease.
Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The prefix nor- 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, 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 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.
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.
To perform its functions, norepinephrine must be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it. An action potential reaches the presynaptic membrane, which changes the membrane polarisation. Calcium ions thus enter, resulting in vesicular fusion, releasing norepinephrine.
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.
Signal termination is a result of reuptake and degradation.
Extracellular uptake of norepinephrine into the cytosol is done either 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.
|Uptake||Transporter||Vmax (n mol/g/min)||KM||Specificity||Location||Other substrates||Inhibitors |
|Uptake 1||Norepinephrine transporter||1.2||0.3||norepinephrine > epinephrine > isoprenaline||presynaptic|
|Uptake 2||100||250||epinephrine > norepinephrine > isoprenaline||cell membrane of non-neuronal cells|
|Vesicular||VMAT||-||~0.2||norepinephrine > epinephrine > isoprenaline||Synaptic vesicle membrane|
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)
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 system) is MHPG, which is partly conjugated to sulfate or glucuronide derivatives and excreted in the urine.
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). However, adult humans readily synthesize tyrosine from phenylalanine, an essential amino acid. Tyrosine is the precursor to dopamine, which in turn is a precursor to epinephrine and norepinephrine.
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