Sinoatrial node

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Sinoatrial_node 

 

Sinoatrial node
Figure 1 shows the conduction system of the heart. The SA node is labelled 1.
Details
System	Electrical conduction system of the heart
Artery	Sinoatrial nodal artery
Identifiers
Latin	nodus sinuatrialis
Acronym(s)	SA node
MeSH	D012849
TA98	A12.1.06.003
TA2	3953
FMA	9477
Anatomical terminology

The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is a group of cells located in the wall of the right atrium of the heart. These cells have the ability to spontaneously produce an electrical impulse (action potential; see below for more details), that travels through the heart via the electrical conduction system (see figure 1) causing it to contract. In a healthy heart, the SA node continuously produces action potential, setting the rhythm of the heart and so is known as the heart's natural pacemaker. The rate of action potential production (and therefore the heart rate) is influenced by nerves that supply it.

Structure

The sinoatrial node is a banana-shaped structure that varies in size, usually between 10-30 millimeters (mm) long, 5–7 mm wide, and 1–2 mm deep.

Location

The SA node is located in the wall (myocardium) of the right atrium, laterally to the entrance of the superior vena cava in a region called the sinus venarum (hence sino- + atrial). It is positioned roughly between a groove called the crista terminalis located on the internal surface of the heart and the corresponding sulcus terminalis, on the external surface. These grooves run between the entrance of the superior vena cava and the inferior vena cava.

Microanatomy

Figure 2: Low magnification stained image of the SA node (center-right on image) and its surrounding tissue. The SA node surrounds the sinoatrial nodal artery, seen as the open lumen. Cardiac muscle cells of the right atrium can be seen to the left of the node, and fat tissue to the right.

The cells of the SA node are spread out within a mesh of connective tissue, containing nerves, blood vessels, collagen and fat. Immediately surrounding the SA node cells are paranodal cells. These cells have structures intermediate between that of the SA node cells and the rest of the atrium. The connective tissue, along with the paranodal cells, insulate the SA node from the rest of the atrium, preventing the electrical activity of the atrial cells from affecting the SA node cells. The SA node cells are smaller and paler than the surrounding atrial cells, with the average cell being around 8 micrometers in diameter and 20-30 micrometers in length (1 micrometer= 0.000001 meter). Unlike the atrial cells, SA node cells contain fewer mitochondria (the power plant of the cell), fewer myofibers (the contractile machinery of the cell), and a smaller sarcoplasmic reticulum (a calcium storage organelle that releases calcium for contraction). This means that the SA node cells are less equipped to contract compared to the atrial and ventricular cells.

Action potentials pass from one cardiac cell to the next through pores known as gap junctions. These gap junctions are made of proteins called connexins. There are fewer gap junctions within the SA node and they are smaller in size. This is again important in insulating the SA node from the surrounding atrial cells.

Blood supply

The sinoatrial node receives its blood supply from the sinoatrial nodal artery. This blood supply, however, can differ hugely between individuals. For example, in most humans, this is a single artery, although in some cases there have been either 2 or 3 sinoatrial node arteries supplying the SA node. Also, the SA node artery mainly originates as a branch of the right coronary artery; however in some individuals it has arisen from the circumflex artery, which is a branch of the left coronary artery. Finally, the SA node artery commonly passes behind the superior vena cava, before reaching the SA node; however in some instances it passes in front. Despite these many differences, there doesn’t appear to be any advantage to how many sinoatrial nodal arteries an individual has, or where they originate 

Venous drainage

There are no large veins that drain blood away from the SA node. Instead, smaller venules drain the blood directly into the right atrium.

Function

Pacemaking

The main role of a sinoatrial node cell is to initiate action potentials of the heart that can pass through cardiac muscle cells and cause contraction. An action potential is a rapid change in membrane potential, produced by the movement of charged atoms (ions). In the absence of stimulation, non-pacemaker cells (including the ventricular and atrial cells) have a relatively constant membrane potential; this is known as a resting potential. This resting phase ends when an action potential reaches the cell. This produces a positive change in membrane potential, known as depolarization, which is propagated throughout the heart and initiates muscle contraction. Pacemaker cells, however, do not have a resting potential. Instead, immediately after repolarization, the membrane potential of these cells begins to depolarise again automatically, a phenomenon known as the pacemaker potential. Once the pacemaker potential reaches a set value, the threshold potential, it produces an action potential. Other cells within the heart (including the Purkinje fibers and atrioventricular node) can also initiate action potentials; however, they do so at a slower rate and therefore, if the SA node is functioning properly, its action potentials usually override those that would be produced by other tissues.

Outlined below are the 3 phases of a sinoatrial node action potential. In the cardiac action potential, there are 5 phases (labelled 0-4), however pacemaker action potentials do not have an obvious phase 1 or 2.

Phase 4

Figure 3: Sinoatrial node action potential waveform, outlining major ion currents involved (downward deflection indicates ions moving into the cell, upwards deflection indicates ions flowing out of the cell).

This phase is also known as the pacemaker potential. Immediately following repolarization, when the membrane potential is very negative (it is hyperpolarised), the voltage slowly begins to increase. This is initially due to the closing of potassium channels, which reduces the flow of potassium ions (I_k) out of the cell (see phase 2, below). Hyperpolarization also causes activation of hyperpolarisation-activated cyclic nucleotide–gated (HCN) channels. The activation of ion channels at very negative membrane potentials is unusual, therefore the flow of sodium (Na⁺) and some K⁺ through the activated HCN channel is referred to as a funny current (I_f). This funny current causes the membrane potential of the cell to gradually increase, as the positive charge (Na⁺ and K⁺) is flowing into the cell. Another mechanism involved in pacemaker potential is known as the calcium clock. This refers to the spontaneous release of calcium from the sarcoplasmic reticulum (a calcium store) into the cytoplasm, also known as calcium sparks. This increase in calcium within the cell then activates a sodium-calcium exchanger (NCX), which removes one Ca²⁺ from the cell, and exchanges it for 3 Na⁺ into the cell (therefore removing a charge of +2 from the cell, but allowing a charge of +3 to enter the cell) further increasing the membrane potential. Calcium later reenters the cell via SERCA and calcium channels located on the cell membrane. The increase in membrane potential produced by these mechanisms, activates T-type calcium channels and then L-type calcium channels (which open very slowly). These channels allow a flow of Ca²⁺ into the cell, making the membrane potential even more positive.

Phase 0

This is the depolarization phase. When the membrane potential reaches the threshold potential (around -20 to -50 mV), the cell begins to rapidly depolarise (become more positive). This is mainly due to the flow of Ca²⁺ through L-type calcium channels, which are now fully open. During this stage, T-type calcium channels and HCN channels deactivate.

Phase 3

This phase is the repolarization phase. This occurs due to the inactivation of L-type calcium channels (preventing the movement of Ca²⁺ into the cell) and the activation of potassium channels, which allows the flow of K⁺ out of the cell, making the membrane potential more negative.

Nerve supply

Heart rate depends on the rate at which the sinoatrial node produces action potentials. At rest, heart rate is between 60 and 100 beats per minute. This is a result of the activity of two sets of nerves, one acting to slow down action potential production (these are parasympathetic nerves) and the other acting to speed up action potential production (sympathetic nerves).

The sympathetic nerves begin in the thoracic region of the spinal cord (in particular T1-T4). These nerves release a neurotransmitter called noradrenaline (NA). This binds to a receptor on the SA node membrane, called a beta-1adrenoceptor. Binding of NA to this receptor activates a G-protein (in particular a G_s-Protein, S for stimulatory) which initiates a series of reactions (known as the cAMP pathway) that results in the production of a molecule called cyclic adenosinemonophosphate (cAMP). This cAMP binds to the HCN channel (see above). Binding of cAMP to the HCN, increases the flow of Na⁺ and K⁺ into the cell, speeding up the pacemaker potential, so producing action potentials at a quicker rate, and increasing heart rate. An increase in heart rate is known as positive chronotropy.

The parasympathetic nerves supplying the SA node (in particular the Vagus nerves) originate in the brain. These nerves release a neurotransmitter called acetylcholine (ACh). ACh binds to a receptor called an M2 muscarinic receptor, located on the SA node membrane. Activation of this M2 receptor, then activates a protein called a G-protein (in particular G_i protein, i for inhibitory). Activation of this G-protein, blocks the cAMP pathway, reducing its effects, therefore inhibiting sympathetic activity and slowing action potential production. As well as this, the G-protein also activates a potassium channel, which allows K⁺ to flow out of the cell, making the membrane potential more negative and slowing the pacemaker potential, therefore decreasing the rate of action potential production and therefore decreasing heart rate. A decrease in heart rate is known as negative chronotropy.

The first cell to produce the action potential in the SA node isn’t always the same: this is known as pacemaker shift. In certain species of animals—for example, in dogs—a superior shift (i.e. the cell that produces the fastest action potential in the SA node is higher than previously) usually produces an increased heart rate whereas an inferior shift (i.e. the cell producing the fastest action potential within the SA node is further down than previously) produces a decreased heart rate.

Clinical significance

Sinus node dysfunction describes an irregular heartbeat caused by faulty electrical signals of the heart. When the heart's sinoatrial node is defective, the heart’s rhythms become abnormal – typically too slow or exhibiting pauses in its function or a combination, and very rarely faster than normal.

Blockage of the arterial blood supply to the SA node (most commonly due to a myocardial infarction or progressive coronary artery disease) can therefore cause ischaemia and cell death in the SA node. This can disrupt the electrical pacemaker function of the SA node, and can result in sick sinus syndrome.

If the SA node does not function, or the impulse generated in the SA node is blocked before it travels down the electrical conduction system, a group of cells further down the heart will become its pacemaker.

History

The sinoatrial node was first discovered by a young medical student, Martin Flack, in the heart of a mole, whilst his mentor, Sir Arthur Keith, was on a bicycle ride with his wife. They made the discovery in a makeshift laboratory set up in a farmhouse in Kent, England, called Mann's Place. Their discovery was published in 1907.

Adrenaline

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Adrenaline 

Epinephrine

Skeletal formula of adrenaline
Ball-and-stick model of the zwitterionic form of adrenaline found in the crystal structure
Clinical data
Trade names	EpiPen, Adrenaclick, others
Other names	Epinephrine, adrenaline, adrenalin
AHFS/Drugs.com	Monograph
MedlinePlus	a603002
License data	US DailyMed: EpiPen US FDA: Epinephrine
Pregnancy category	AU: A
Addiction liability	None
Routes of administration	IV, IM, endotracheal, IC, nasal, eye drop
ATC code	A01AD01 (WHO) B02BC09 (WHO) C01CA24 (WHO) R01AA14 (WHO) R03AA01 (WHO) S01EA01 (WHO)
Physiological data
Receptors	Adrenergic receptors
Metabolism	Adrenergic synapse (MAO and COMT)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	15–20%
Metabolism	Adrenergic synapse (MAO and COMT)
Metabolites	Metanephrine
Onset of action	Rapid
Elimination half-life	2 minutes
Duration of action	Few minutes
Excretion	Urine
Identifiers

IUPAC name
CAS Number	51-43-4
PubChem CID	5816
IUPHAR/BPS	479
DrugBank	DB00668
ChemSpider	5611
UNII	YKH834O4BH
KEGG	D00095
ChEBI	CHEBI:28918
ChEMBL	ChEMBL679
PDB ligand	ALE (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID5022986
ECHA InfoCard	100.000.090
Chemical and physical data
Formula	C9H13NO3
Molar mass	183.207 g·mol−1
3D model (JSmol)	Interactive image
Density	1.283±0.06 g/cm3 @ 20 °C, 760 Torr

SMILES

InChI

Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). Adrenaline is normally produced both by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an important role in the fight-or-flight response by increasing blood flow to muscles, output of the heart by acting on SA Node, pupil dilation response and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals and some single-celled organisms. Polish physiologist Napoleon Cybulski first isolated adrenaline in 1895.

Medical uses

As a medication, it is used to treat a number of conditions including anaphylaxis, cardiac arrest, and superficial bleeding. Inhaled adrenaline may be used to improve the symptoms of croup. It may also be used for asthma when other treatments are not effective. It is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin. Common side effects include shakiness, anxiety, and sweating. A fast heart rate and high blood pressure may occur. Occasionally it may result in an abnormal heart rhythm. While the safety of its use during pregnancy and breastfeeding is unclear, the benefits to the mother must be taken into account.

A case has been made for the use of adrenaline infusion in place of the widely accepted treatment of inotropes for preterm infants with clinical cardiovascular compromise. Although there is sufficient data which strongly recommends adrenaline infusions as a viable treatment, more trials are needed in order to conclusively determine that these infusions will successfully reduce morbidity and mortality rates among preterm, cardiovascularly compromised infants.

Physiological effects

The adrenal medulla is a minor contributor to total circulating catecholamines (L-DOPA is at a higher concentration in the plasma), though it contributes over 90% of circulating adrenaline. Little adrenaline is found in other tissues, mostly in scattered chromaffin cells, and in a small number of neurons which use adrenaline as a neurotransmitter. Following adrenalectomy, adrenaline disappears below the detection limit in the blood stream.

Pharmacological doses of adrenaline stimulate α₁, α₂, β₁, β₂, and β₃ adrenoceptors of the sympathetic nervous system. Sympathetic nerve receptors are classified as adrenergic, based on their responsiveness to adrenaline. The term "adrenergic" is often misinterpreted in that the main sympathetic neurotransmitter is noradrenaline, rather than adrenaline, as discovered by Ulf von Euler in 1946. Adrenaline does have a β₂ adrenoceptor-mediated effect on metabolism and the airway, there being no direct neural connection from the sympathetic ganglia to the airway.

The concept of the adrenal medulla and the sympathetic nervous system being involved in the flight, fight and fright response was originally proposed by Cannon. But the adrenal medulla, in contrast to the adrenal cortex, is not required for survival. In adrenalectomized patients hemodynamic and metabolic responses to stimuli such as hypoglycemia and exercise remain normal.

Exercise

One physiological stimulus to adrenaline secretion is exercise. This was first demonstrated by measuring the dilation of a (denervated) pupil of a cat on a treadmill, later confirmed using a biological assay on urine samples. Biochemical methods for measuring catecholamines in plasma were published from 1950 onwards. Although much valuable work has been published using fluorimetric assays to measure total catecholamine concentrations, the method is too non-specific and insensitive to accurately determine the very small quantities of adrenaline in plasma. The development of extraction methods and enzyme-isotope derivate radio-enzymatic assays (REA) transformed the analysis down to a sensitivity of 1 pg for adrenaline. Early REA plasma assays indicated that adrenaline and total catecholamines rise late in exercise, mostly when anaerobic metabolism commences.

During exercise, the adrenaline blood concentration rises partially from the increased secretion of the adrenal medulla and partly from the decreased metabolism of adrenaline due to reduced blood flow to the liver. Infusion of adrenaline to reproduce exercise circulating concentrations of adrenaline in subjects at rest has little haemodynamic effect, other than a small β₂-mediated fall in diastolic blood pressure. Infusion of adrenaline well within the physiological range suppresses human airway hyper-reactivity sufficiently to antagonize the constrictor effects of inhaled histamine.

A link between the sympathetic nervous system and the lungs was shown in 1887 when Grossman showed that stimulation of cardiac accelerator nerves reversed muscarine-induced airway constriction. In experiments in the dog, where the sympathetic chain was cut at the level of the diaphragm, Jackson showed that there was no direct sympathetic innervation to the lung, but that bronchoconstriction was reversed by release of adrenaline from the adrenal medulla. An increased incidence of asthma has not been reported for adrenalectomized patients; those with a predisposition to asthma will have some protection from airway hyper-reactivity from their corticosteroid replacement therapy. Exercise induces progressive airway dilation in normal subjects that correlates with work load and is not prevented by beta blockade. The progressive dilation of the airway with increasing exercise is mediated by a progressive reduction in resting vagal tone. Beta blockade with propranolol causes a rebound in airway resistance after exercise in normal subjects over the same time course as the bronchoconstriction seen with exercise induced asthma. The reduction in airway resistance during exercise reduces the work of breathing.

Emotional response

Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of adrenaline, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to adrenaline is fear. In an experiment, subjects who were injected with adrenaline expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects. The findings from this study demonstrate that there are learned associations between negative feelings and levels of adrenaline. Overall, the greater amount of adrenaline is positively correlated with an aroused state of negative feelings. These findings can be an effect in part that adrenaline elicits physiological sympathetic responses including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between adrenaline and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film. Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce adrenaline. Findings support the idea that adrenaline does have a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear.

Memory

It has been found that adrenergic hormones, such as adrenaline, can produce retrograde enhancement of long-term memory in humans. The release of adrenaline due to emotionally stressful events, which is endogenous adrenaline, can modulate memory consolidation of the events, ensuring memory strength that is proportional to memory importance. Post-learning adrenaline activity also interacts with the degree of arousal associated with the initial coding. There is evidence that suggests adrenaline does have a role in long-term stress adaptation and emotional memory encoding specifically. Adrenaline may also play a role in elevating arousal and fear memory under particular pathological conditions including post-traumatic stress disorder. Overall, "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects.” Studies have also found that recognition memory involving adrenaline depends on a mechanism that depends on β adrenoceptors. Adrenaline does not readily cross the blood–brain barrier, so its effects on memory consolidation are at least partly initiated by β adrenoceptors in the periphery. Studies have found that sotalol, a β adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered adrenaline on memory. These findings suggest that β adrenoceptors are necessary for adrenaline to have an effect on memory consolidation.

Pathology

Increased adrenaline secretion is observed in pheochromocytoma, hypoglycemia, myocardial infarction and to a lesser degree in essential tremor (also known as benign, familial or idiopathic tremor). A general increase in sympathetic neural activity is usually accompanied by increased adrenaline secretion, but there is selectivity during hypoxia and hypoglycaemia, when the ratio of adrenaline to noradrenaline is considerably increased. Therefore, there must be some autonomy of the adrenal medulla from the rest of the sympathetic system.

Myocardial infarction is associated with high levels of circulating adrenaline and noradrenaline, particularly in cardiogenic shock.

Benign familial tremor (BFT) is responsive to peripheral β adrenergic blockers and β₂-stimulation is known to cause tremor. Patients with BFT were found to have increased plasma adrenaline, but not noradrenaline.

Low, or absent, concentrations of adrenaline can be seen in autonomic neuropathy or following adrenalectomy. Failure of the adrenal cortex, as with Addison's disease, can suppress adrenaline secretion as the activity of the synthesing enzyme, phenylethanolamine-N-methyltransferase, depends on the high concentration of cortisol that drains from the cortex to the medulla.

Terminology

In 1901, Jōkichi Takamine patented a purified extract from the adrenal glands which was trademarked by Parke, Davis & Co in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline.

However, the pharmacologist John Abel had already prepared an extract from adrenal glands as early as 1897, and coined the name epinephrine to describe it (from the Greek epi and nephros, "on top of the kidneys"). In the belief that Abel's extract was the same as Takamine's (a belief since disputed), epinephrine became the generic name in the US, and remains the pharmaceutical's United States Adopted Name and International Nonproprietary Name (though the name adrenaline is frequently used).

The terminology is now one of the few differences between the INN and BAN systems of names. Although European health professionals and scientists preferentially use the term adrenaline, the converse is true among American health professionals and scientists. Nevertheless, even among the latter, receptors for this substance are called adrenergic receptors or adrenoceptors, and pharmaceuticals that mimic its effects are often called adrenergics. The history of adrenaline and epinephrine is reviewed by Rao.

Mechanism of action

Physiologic responses to adrenaline by organ

Organ	Effects
Heart	Increases heart rate; contractility; conduction across AV node
Lungs	Increases respiratory rate; bronchodilation
Liver	Stimulates glycogenolysis
Muscle	Stimulates glycogenolysis and glycolysis
Brain
Systemic	Vasoconstriction and vasodilation
	Triggers lipolysis
	Muscle contraction

Play media

7x speed timelapse video of fish melanophores responding to 200µM adrenaline

As a hormone, adrenaline acts on nearly all body tissues by binding to adrenergic receptors. Its effects on various tissues depend of the type of tissue and expression of specific forms of adrenergic receptors. For example, high levels of adrenaline causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.

Adrenaline is a nonselective agonist of all adrenergic receptors, including the major subtypes α₁, α₂, β₁, β₂, and β₃. Adrenaline's binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. β adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.

Adrenaline causes liver cells to release glucose into the blood, acting through both alpha and beta adrenergic receptors to stimulate glycogenolysis. Adrenaline binds to β₂ receptors on liver cells, which changes conformation and helps G_s, a heterotrimeric G protein, exchange GDP to GTP. This trimeric G protein dissociates to G_s alpha and G_s beta/gamma subunits. G_s alpha stimulates adenylyl cyclase, thus converting adenosine triphosphate into cyclic adenosine monophosphate (AMP). Cyclic AMP activates protein kinase A. Protein kinase A phosphorylates and partially activates phosphorylase kinase. Adrenaline also binds to α₁ adrenergic receptors, causing an increase in inositol trisphosphate, inducing calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin, which leads to further activation of phosphorylase kinase. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then breaks down glycogen leading to the production of glucose.

Adrenaline also has significant effects on the cardiovascular system. It increases peripheral resistance via α₁ receptor-dependent vasoconstriction and increases cardiac output by binding to β₁ receptors. The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures and therefore increase oxygen exchange at the cellular level. While adrenaline does increase aortic, cerebral, and carotid circulation pressure, it lowers carotid blood flow and end-tidal CO₂ or E_TCO₂ levels. It appears that adrenaline may be improving macrocirculation at the expense of the capillary beds where actual perfusion is taking place.

Measurement in biological fluids

Adrenaline may be quantified in blood, plasma or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults are normally less than 10 ng/L, but may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000–10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L.

Biosynthesis and regulation

The biosynthesis of adrenaline involves a series of enzymatic reactions.

In chemical terms, adrenaline is one of a group of monoamines called the catecholamines. Adrenaline is synthesized in the chromaffin cells of the adrenal medulla of the adrenal gland and a small number of neurons in the medulla oblongata in the brain through a metabolic pathway that converts the amino acids phenylalanine and tyrosine into a series of metabolic intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA by Tyrosine hydroxylase, this is the rate-limiting step. Then it is subsequently decarboxylated to give dopamine by DOPA decarboxylase (aromatic L-amino acid decarboxylase). Dopamine is then converted to noradrenaline by dopamine beta-hydroxylase which utilizes ascorbic acid (Vitamin C) and copper. The final step in adrenaline biosynthesis is the methylation of the primary amine of noradrenaline. This reaction is catalyzed by the enzyme phenylethanolamine N-methyltransferase (PNMT) which utilizes S-adenosyl methionine (SAMe) as the methyl donor. While PNMT is found primarily in the cytosol of the endocrine cells of the adrenal medulla (also known as chromaffin cells), it has been detected at low levels in both the heart and brain.

Biosynthetic pathways for catecholamines and trace amines in the human brain L-Phenylalanine L-Tyrosine L-DOPA Adrenaline Phenethylamine p-Tyramine Dopamine Noradrenaline N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH Epinephrine is produced in a small group of neurons in the human brain (specifically, in the medulla oblongata) via the metabolic pathway shown above.

Regulation

The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high or low ambient temperature. All of these stimuli are processed in the central nervous system.

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream. For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H⁺ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.

Unlike many other hormones adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis. Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious adrenaline administration, pheochromocytoma, and other tumors of the sympathetic ganglia.

Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase.

History

Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna ("adrenalin"), contained adrenaline and other catecholamines. American ophthalmologist William H. Bates discovered adrenaline's usage for eye surgeries prior to 20 April 1896. In 1897, John Jacob Abel (1857-1938), the father of modern pharmacology, finds a natural substance produced by the adrenal glands that he names epinephrine. The first hormone to be identified, it remains a crucial, firstline treatment for cardiac arrests, severe allergic reactions and other conditions. Japanese chemist Jōkichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900. In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen. Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.

Society and culture

Adrenaline junkie

An adrenaline junkie is somebody who engages in sensation-seeking behavior through "the pursuit of novel and intense experiences without regard for physical, social, legal or financial risk". Such activities include extreme and risky sports, substance abuse, unsafe sex, and crime. The term relates to the increase in circulating levels of adrenaline during physiological stress. Such an increase in the circulating concentration of adrenaline is secondary to activation of the sympathetic nerves innervating the adrenal medulla, as it is rapid and not present in animals where the adrenal gland has been removed. Although such stress triggers adrenaline release, it also activates many other responses within the central nervous system reward system which drives behavioral responses, so while the circulating adrenaline concentration is present, it may not drive behavior. Nevertheless, adrenaline infusion alone does increase alertness and has roles in the brain including the augmentation of memory consolidation.

Strength

Adrenaline has been implicated in feats of great strength, often occurring in times of crisis. For example, there are stories of a parent lifting part of a car when their child is trapped underneath.