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Catecholamines

Circulating catecholamines refer to ((epinephrine)) and nor-epinephrine.

A catecholamine is a monoamine neurotransmitter.

 

 

A catecholamine is an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.

 

 

Catecholamines cause general physiological changes that prepare the body for physical activity.

 

Catecholamines include: 

 

 

dopamine

 

 

norepinephrine (noradrenaline)

 

 

epinephrine (adrenaline)

Catecholamines have a half-life of a few minutes when circulating in the blood. 

Catecholamines can be degraded by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO).

MAOIs bind to MAO,  preventing it from breaking down catecholamines and other monoamines.

Catabolism of catecholamines is mediated by two main enzymes: catechol-O-methyltransferase (COMT) and cytosol of the cell and monoamine oxidase (MAO) which is located in the mitochondrial membrane. 

Catechol-O-methyltransferase (COMT) is present in the synaptic cleft.

The  catabolic process is mediated by either MAO or COMT which depends on the tissue and location of catecholamines, and alcohol dehydrogenase, aldehyde dehydrogenase and aldehyde reductase. 

The end product of epinephrine and norepinephrine is vanillylmandelic acid (VMA) which is excreted in the urine. 

Dopamine catabolism leads to the production of homovanillic acid (HVA).

 

They are derived from the amino acid tyrosine.

Catecholamine synthesis is usually considered to begin with tyrosine. 

Tyrosine is derived from dietary sources as well as synthesis from phenylalanine.

 

Phenylalanine and tyrosine amino acids are found in high concentrations in the blood and the brain. 

Tyrosine can be formed from dietary phenylalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. 

Insufficient amounts of phenylalanine hydroxylase result in phenylketonuria, a metabolic disorder that leads to intellectual deficits unless treated by dietary manipulation.

They are water-soluble and are 50% bound to plasma proteins in circulation.

 

Acute porphyria can cause elevated catecholamines.

Release of the neurohormones epinephrine and norepinephrine from the adrenal medulla  is part of the fight-or-flight response.

Tyrosine is created from phenylalanine by hydroxylation by the enzyme phenylalanine hydroxylase, 

and is also ingested directly from dietary protein. 

Catecholamine-secreting cells convert tyrosine serially to L-DOPA and then to dopamine. 

 

Tyrosine is converted into L-DOPA by tyrosine 3-hydroxylase.

L-DOPA is converted into dopamine by the enzyme aromatic amino acid decarboxylase (AADC), with pyridoxal phosphate as the cofactor. 

 

The enzyme tyrosine hydroxylase (TH) converts the amino acid L-tyrosine into 3,4-dihydroxyphenylalanine (L-DOPA). which is metabolized by aromatic L-amino acid decarboxylase to the transmitter dopamine. 

The decarboxylation of L-DOPA to dopamine is the final step in formation of the transmitter.

In neurons using norepinephrine or epinephrine as transmitters, the enzyme dopamine β-hydroxylase (DBH), that converts dopamine to yield norepinephrine, is also present. 

 

Dopamine is the first catecholamine synthesized from DOPA. 

 

The rate limiting step in catecholamine biosynthesis through the predominant metabolic pathway is the hydroxylation of L-tyrosine to L-DOPA.

The amino acids phenylalanine and tyrosine are precursors for catecholamines. 

Norepinephrine and epinephrine are derived from further metabolic modification of dopamine. 

Dopamine is a precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. 

Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase: with cofactors O2 and L-ascorbic acid.

Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine as the cofactor.

 

In neurons in which epinephrine is the transmitter, a third enzyme phenylethanolamine N-methyltransferase converts norepinephrine into epinephrine. 

 

Dopamine may be further converted to norepinephrine or converted to epinephrine.

 

Catecholamines are produced mainly by the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. 

 

Two catecholamines: norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation. 

Norepinephrine is a neuromodulator of the peripheral sympathetic nervous system.

Norepinephrine is also present in the blood from spillover from the synapses of the sympathetic system.

Dopamine, acts as a neurotransmitter in the central nervous system.

Dopamine is largely produced in neuronal cell bodies in two areas of the brainstem: the ventral tegmental area and the substantia nigra.

The substantia nigra contains neuromelanin-pigmented neurons. 

The neuromelanin-pigmented cell bodies of the locus coeruleus produce norepinephrine.  

 

 

Various stimulant drugs are catecholamine analogues.

 

 

L-Phenylalanine is converted into L-tyrosine by phenylalanine 4-hydroxylase.

Epinephrine is released by the adrenal medulla upon activation of preganglionic sympathetic nerves innervating this organ.

Epinephrine is produced in small groups of neurons in the human brain which express its synthesizing enzyme, phenylethanolamine N-methyltransferase;

 

 

These epinephrine producing neurons project from a nucleus that is adjacent (ventrolateral) to the area postrema and from a nucleus in the dorsal region of the solitary tract.DOPA

Activation of preganglionic sympathetic nerves occurs during times of stress.

Elevated catecholamine levels in blood are associated with stress.

 

 

Such stress  can be induced from psychological reactions, environmental stressors such as elevated sound levels, intense light, or low blood sugar levels.

 

 

When there are extremely high levels of catecholamines, catecholamine toxicity can occur in the central nervous system.

 

Catecholamine effects include:  increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system.

Some drugs, like tolcapone, which is a central COMT-inhibitor, raise the levels of all the catecholamines.

Catecholamines secreted into urine after being broken down, can be measured for the diagnosis of illnesses associated with catecholamine levels in the body.

 

Urine testing for catecholamine is used to detect pheochromocytoma.

 

 

Catecholamines are secreted by cells that are mostly in the nervous and the endocrine systems. 

 

 

The adrenal glands secrete catecholamines into the blood when there is physical or mental stress.

 

 

Adrenal catecholamine secretion is usually a healthy physiological response.

 

The, acute or chronic excess of circulating catecholamines can potentially increase blood pressure and heart rate levels and provoke deleterious effects. 

Tests for fractionated plasma free metanephrines or urine metanephrines are used to confirm or exclude certain diseases associated with hypertension and tachycardia that do not adequately respond to treatment.

The adrenaline and noradrenaline metabolites are called metanephrine and normetanephrine, respectively.

Blood tests are available to analyze the amount of catecholamines present in the body.

Catecholamine testing  provide information relative to tumors such as: pheocromocytoma, paraganglioma, and neuroblastoma. 

 

 

This trauma, due to stimulation or damage of nuclei in the brainstem, affects  the sympathetic nervous system.

Norepinephrine is also released by the adrenal medulla, and accounts for about 20% of its total catecholamine release.

The primary source of circulating norepinephrine is spillover from sympathetic nerves innervating blood vessels.

Increase heart rate through beta-adrenoreceptor stimulation.

Beta-adrenoreceptor and calcium channel blockers modulate this effect by inhibiting the signal cascade.

Most of the norepinephrine released by sympathetic nerves is taken back up by the nerves where it is metabolized, but a small amount of norepinephrine diffuses into the blood and circulates throughout the body.

At times of high sympathetic nerve activation, the amount of norepinephrine entering the blood increases.

Plasma catecholamine levels higher in patients with this Tako-Tsubo syndrome than in patients with ST-segment elevated myocardial infarction (Wittstein IS et al).

Catecholamines nor epinephrine and epinephrine induced platelet activation and can mediate endothelial and cardiomyocyte injury.

Catecholamine surges can induce myocyte injury via the cyclic adenosine monophosphate-mediated calcium overload.

Pheochromocytoma causes very high circulating levels of catecholamines that can lead to a hypertensive crisis.

Extremely high levels of catecholamine can also be caused by neuroendocrine tumors in the adrenal medulla: pheochromocytoma.

High levels of catecholamines can also be caused by monoamine oxidase A (MAO-A) deficiency, known as Brunner syndrome. 

MAO-A is one of the enzymes responsible for degradation of these neurotransmitters.

MAO-A deficiency increases the bioavailability of these neurotransmitters.

 

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