Catecholamines in Platelets

Test for Determining the Concentration of Catecholamines (Neurotransmitters) in Blood Platelets

Catecholamines in platelets

Neurotransmitters are the classic neuromessengers that are released rapidly by the presynaptic neuron, diffuse across the synaptic cleft, and have either an excitatory or an inhibitory effect on a postsynaptic neuron. There are three classes of neurotransmitters – biogenic amines, amino acids, and peptides. The biogenic amines (monoamine) consist of three catecholamines, which are structurally related to a group of organic compounds designated as catechols (norepinephrine, epinephrine, dopamine), an indolamine (serotonin), an ethylamine (histamine), and a quaternary amine (acetylcholine). In European nomenclature, norepinephrine and epinephrine are known as noradrenalin and adrenalin, respectively.

The principal catecholamines found in the body – norepinephrine, epinephrine, and dopamine – are formed by hydroxylation and decarboxylation of the amino acid tyrosine (Fig. 1). Some of the tyrosine is formed from phenylalanine, but most is of dietary origin. Serotonin is also formed in the body by hydroxylation and decarboxylation of the essential amino acid tryptophan (Fig. 2). After release from the specific neurons, epinephrine and norepinephrine are metabolized to biologically inactive products by oxidation and methylation. The former reaction is catalyzed by monoamine oxidase (MAO) and the latter by catechol-O-methyl transferase (COMT). Dopamine is metabolized to inactive compounds by MAO and COMT in a manner analogous to the inactivation of norepinephrine. Released serotonin is recaptured by an active reuptake mechanism and inactivated by MAO.

The biogenic amine neurotransmitters are well known to most psychiatrists, because they were the first neurotransmitters discovered and, therefore, have been the subject of research studies for the longest amount of time. Most of the standard psychiatric drugs have one or more of the biogenic amine neurotransmitters as their initial site of action.

Catecholamines influence virtually all tissues and many functions. In most instances, however, catecholamines are not the sole or exclusive regulators; they participate with other hormonal and neuronal systems in regulation of a multitude of diverse physiological processes, thus contributing to a redundancy that ensures both a great physiological reserve and the possibility of very fine or discriminatory control.

The effect of catecholamines on illness like cardiovascular, visceral, metabolic, etc., is well established. The catecholamine levels are increased after severe exercise, by emotional stress, and by smoking. Other diseases or conditions that may increase circulating or urinary catecholamines are hypothyroidism, diuretic therapy, heavy alcohol intake, hypoglycemia, hypoxia, severe acidosis, Cushing’s Syndrome, myocardial infarction, hemolytic anemia, essential hypertension and occasionally lymphoma or severe renal disease. On the other hand, symptoms like autism, attention deficit disorder, specific developmental delays in childhood, etc., show reduced circulating levels of catecholamines but a bimodal distribution of serotonin, i.e. one group with high levels of serotonin and another group with low levels of serotonin.

The actions of thyroid hormones and the catecholamines norepinephrine and epinephrine are intimately interrelated. Epinephrine increases the metabolic rate, stimulates the nervous system, and produces cardiovascular effects similar to those of thyroid hormone, although the duration of these actions is brief. Norepinephrine has generally similar actions. Thyroid hormones increase the number and affinity of β-adrenergic receptors in the heart and possibly in some other tissues, and the effects of thyroid hormones on the heart resemble those of β-adrenergic stimulation. Although circulating catecholamine levels are normal in hyperthyroidism, the cardiovascular effects, involuntary trembling, and sweating produced by thyroid hormones can be reduced or abolished by an operation on some portion of the sympathetic nervous system.

Interrelationship between methylation and catecholamine biosynthesis

The methylation process has a profound effect on the level of platelet catecholamines. For example, in the case of hypomethylation, platelet norepinephrine and histamine levels are usually high and epinephrine levels are low due to the lack of methylation process.

Why platelet catecholamine?

• In plasma, the concentration of catecholamines is extremely low and their estimation has required that methods be used at the limit of their sensitivity.
• Stress of venipuncture and upright posture can greatly affect plasma catecholamine levels. Also, it has been reported that plasma catecholamine values decrease rapidly if the red blood cells (RBCs) were not removed within five minutes after obtaining the specimen.
• Dopamine, epinephrine, and norepinephrine are present in human plasma and urine in the form of acid hydrolysable conjugates and some of the catecholamines are also bound to a specific protein. These are known as free and total amines.
• Platelets take up dopamine, epinephrine, and norepinephrine against a concentration gradient into the 5-HT storage organelles, and serotonin is present in highest concentration in the blood platelets.
• Platelet catecholamine levels provide a stable index of circulating plasma catecholamine concentration, and these are unaffected by acute elevations of plasma levels with physical and psychological stress.
• Urinary catecholamine concentrations reflect plasma and peripheral sympathetic nervous system activity, tonic stimulation of adrenal medulla, and metabolic breakdown of norepinephrine. Also, since free catecholamine excretion occurs by renal tubular mechanism, it is highly dependent on urinary pH being facilitated in an acid urine and retarded in an alkaline one.

Physiological conditions attributed to the function of individual biogenic amines and MAO

Platelet Epinephrine

It is derived almost exclusively from the adrenal medulla, and it represents the activity of the humoral arm of the sympathetic nervous system.

Platelet epinephrine levels provide valuable information for patients with

• Stressful situations such as hypoglycemia
• Essential hypertension
• Myocardial infarction
• Suspected tumor in adrenal glands
• Neuroblastoma
• Progressive Muscular Dystrophy and Myasthenia Gravis
• Physical exhaustion
• Hypothyroidism, diuretic therapy, and Cushing’s Syndrome

Platelet Norepinephrine

Platelet norepinephrine originates from sympathetic nerve endings, and it represents the neural arm of the sympathetic nervous system.

In what conditions might norepinephrine levels be informative?

• Failure of baroreceptor reflexes (a receptor that is stimulated by change in pressure, which is in the walls of blood vessels).
• Differentiates hypertension from pheochromocytoma – a tumor of chromaffin tissue of the adrenal medulla. Symptoms: headache, sweating, palpitations, apprehension, tremor, nausea, vomiting, flushing of the face, neuropathic pain, and pain in the chest and abdomen.
• Various autonomic nervous failures, such as Shy-Drager Syndrome – a progressive disorder that begins with symptoms of autonomic insufficiency including orthostatic hypotension, impotence in males, constipation, urinary urgency or retention and anhydrosis. These are followed by signs of generalized neurological dysfunction such as Parkinson-like disturbance and coarse tremors of legs.

Platelet Dopamine

The origin of platelet dopamine is unclear. However, it is released into the plasma from peripheral sympathetic nerves and the adrenal glands. It is an important sympathoadrenal neurohormone. Since virtually all of the dopamine is rapidly conjugated upon release, it is necessary to measure total (free and conjugated) dopamine.

Many conditions, particularly chronic ones, warrant investigating dopamine levels, such as the following:

• Orthostatic hypotension
• T-wave abnormalities (ECG) and arterial fibrillation
• Seizure with hypotension
• Stress-related hypertension
• Hypomagnesemia
• Impaired ejaculation and excessive urination at night
• Behavioral changes with respect to mania and depression
• Schizophrenia
• Tardive dyskinesia
• Parkinsonian symptoms

Platelet Serotonin

It is synthesized in the intestinal chromaffin cells or in central or peripheral neurons and is found in high concentrations in many body tissues, including the intestinal mucosa, pineal body, and central nervous system. It is present in highest concentrations in blood platelets and in the gastrointestinal tract.

An increased value may indicate:

• Cystic fibrosis
• Ovarian carcinoid tumor
• Tropical sprue
• Severe pain of sciatica or skeleton
• Smooth muscle spasm
• Bronchial adenoma, carcinoid type
• Malabsorption of food
• Celiac disease
• Whipple disease
• Stasis syndrome
• Chronic intestinal obstruction
• Oat cell cancer of respiratory system
• Prolonged alimentary hyperglycemia
• Prolonged insomnia
• Compromised MAO production or secretion
• Malignant lymphoma of stomach
• Accentuated manic phase of bipolar illness
• Autism spectrum disorder
• Attention deficit disorder

 

A decreased value may indicate:

• Depressive illness
• Small-intestinal resection
• Phenylketonuria (PKU)
• Hartnup's disease
• Mastocytosis
• Autism spectrum disorder
• Attention deficit disorder

 

A very high value may indicate:

• Ilial tumor
• Large carcinoid tumor
• Pancreatic tumor
• Duodenal tumor
• Biliary tumor
  
  Clinical alert: Platelet serotonin assay may detect some carcinoid missed by urinary serotonin and 5-HIAA assay.

Platelet Monoamine Oxidase

Increased activity may indicate:

• Hypothyroidism
• Emotional stress
• Smoking
• Dementia
• Hypertension
• Parkinsonism
• Depression
• Neuroblastoma
• Myocardial infarction
• Severe exercise
• Hypoglycemia
• Cushing’s Syndrome
• Ovulatory surge
• Diuretic therapy

 

Decreased activity may indicate:

• Hyperthyroidism
• Chronic schizophrenia
• Bipolar mania
• Chronic alcoholism
• Hypervitaminosis – D
• Radiation injuries
• Suicidal behavior
• Iron deficiency anemia
• Vitamin B2 deficiency
• Hyperbolic O₂ intoxication
• Administration of psychoactive drugs

References

1. Audhya TK. Advances in measurement of platelet catecholamines at subpicomol levels for diagnosis of depression and anxiety. Amer Assoc of Clin Chem, 51(6):248 (Abstract), 2005.
2. Audhya TK, Adams JB, Johansen L. Correlation of serotonin levels in CSF, platelets, plasma, and urine. Biochim Biophys Acta, 1820(10):1496-1501, 2012.
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4. Dequattro V, Campese VM, Myers M. Anatomy and Biochemistry of the Sympathetic Nervous System. In: DeGroot LJ ed. Endocrinology, Philadelphia, Saunders, 1989, 1717-1737.
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