Adrenaline

• 1. Introduction

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  Adrenaline, known as epinephrine across much of the United States, is present in a resting adult at less than 10 nanograms per litre of blood plasma. During times of stress, that level can climb 50-fold or more. The same molecule is also a medicine. It carries two official names, and the reason traces back to a trademark and a dispute between chemists around the year 1900. Where did this substance come from, and who first pinned it down? How does the body assemble it, send it to nearly every tissue, and then switch it off? And what does a surge of it do to breathing, to fear, and to what a person remembers?

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• 2. The Race To The Extract

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  In 1895, the Polish physiologist Napoleon Cybulski obtained extracts of the adrenal gland and called them nadnerczyna. They contained adrenaline along with other catecholamines.

  That same year, George Oliver, a general practitioner in North Yorkshire, joined forces with Edward Albert Schäfer of University College London. Their paper showed that adrenal extract raised blood pressure and heart rate, and that the active component came from the medulla rather than the cortex. This 1895 observation predates the 1902 discovery of secretin, which is why adrenaline can claim to be the first hormone.

  Before the 20th of April 1896, the American ophthalmologist William H. Bates had already found a use for the extract in eye surgery.

  In 1897, John Jacob Abel of Johns Hopkins University found a compound in adrenal extract with the molecular formula C17H15NO4. Abel was the first chairman of the first department of pharmacology in the United States, and is called the father of modern pharmacology.

  In 1900, the Japanese chemist Jōkichi Takamine worked with his assistant Keizo Uenaka to purify a principle 2000 times more active than Abel's. Its formula was C10H15NO3. Thomas Aldrich of the Parke-Davis Scientific Laboratory purified adrenaline independently in the same year. In 1901, Takamine isolated and purified the hormone from the adrenal glands of sheep and oxen.

  Hermann Pauly worked out the structure in 1903. In 1904, the German chemist Friedrich Stolz made adrenaline in the laboratory, and Henry Drysdale Dakin did the same independently. Stolz started from the ketone form of the molecule, called adrenalone. Both Pauly and Stolz judged Takamine's compound the active one and Abel's the inactive one.

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• 3. Two Names One Molecule

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  Takamine patented his purified adrenal extract in 1901, and the American firm Parke, Davis & Co trademarked it. The British Approved Name and the European Pharmacopoeia term became adrenaline. The word comes from the Latin ad, meaning on, and rēnālis, meaning of the kidney, which in turn comes from ren, kidney.

  Abel had prepared an adrenal extract as early as 1897, and he coined a rival name for it. His word, epinephrine, comes from the Ancient Greek epí, meaning upon, and nephrós, meaning kidney. Adrenaline was a registered trademark in the United States, and many assumed Abel's extract was the same as Takamine's. That assumption has since been disputed. Epinephrine therefore became the American generic name, and it remains the United States Adopted Name and the International Nonproprietary Name.

  The split between the INN and BAN naming systems is now one of the few places where they disagree. European health professionals and scientists mostly say adrenaline, while their American counterparts mostly say epinephrine. Even so, the receptors are called adrenergic receptors or adrenoceptors everywhere, and drugs that mimic the hormone are often called adrenergics.

  That word turns out to be slightly misleading. In 1946, Ulf von Euler showed that the main neurotransmitter of the sympathetic nervous system is noradrenaline, not adrenaline.

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• 4. Assembly And Release

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  More than 90 percent of the adrenaline in circulation comes from the adrenal medulla. A little more is found in scattered chromaffin cells and in a small number of neurons that use it as a neurotransmitter. After surgical removal of the adrenal glands, adrenaline falls below the detection limit in the bloodstream.

  Chemically, adrenaline is a monoamine and one of the catecholamines. It is built in the chromaffin cells of the medulla, and in a few neurons of the medulla oblongata in the brain, from the amino acids phenylalanine and tyrosine. The first step oxidizes tyrosine to L-DOPA using the enzyme tyrosine hydroxylase, and this is the rate-limiting step. DOPA decarboxylase then converts L-DOPA to dopamine. Dopamine beta-hydroxylase turns dopamine into noradrenaline, with help from vitamin C and copper. The last step methylates noradrenaline using the enzyme PNMT, which takes its methyl group from S-adenosyl methionine. PNMT sits mainly in the cytosol of chromaffin cells, though low levels have been detected in the heart and brain.

  The adrenal cortex plays a quiet part in that final step. Adrenocorticotropic hormone, or ACTH, prompts the cortex to release cortisol, and cortisol drains into the medulla and raises PNMT expression. ACTH and the sympathetic nervous system also boost the activity of tyrosine hydroxylase and dopamine beta-hydroxylase. Failure of the cortex, as in Addison's disease, can therefore suppress adrenaline, because PNMT depends on a high concentration of cortisol.

  Physical threat, excitement, noise, bright lights, and high or low temperatures are the main triggers of release. All of them are processed in the central nervous system. Signals travel along the splanchnic nerves to the medulla, where preganglionic fibres release acetylcholine onto nicotinic receptors. The cells depolarize, calcium flows in through voltage-gated channels, and chromaffin granules empty their contents into the blood. Both adrenaline and noradrenaline are released this way.

  The transporter VMAT1 shuttles noradrenaline out of the granules so PNMT can reach it. It also carries freshly made adrenaline back in for storage. Unlike many hormones, adrenaline exerts no negative feedback on its own synthesis. Its action ends through reuptake into nerve terminals, some dilution, and breakdown by monoamine oxidase and catechol-O-methyl transferase. The breakdown products are 3,4-Dihydroxymandelic acid and metanephrine. Without a feedback brake, surreptitious administration, pheochromocytoma and other tumors of the sympathetic ganglia can push levels abnormally high.

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• 5. Reaching Every Tissue

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  Five receptor subtypes respond to adrenaline: α1, α2, β1, β2 and β3. Adrenaline is a nonselective agonist, so it activates all of them. What happens next depends on which receptors a tissue carries. High levels relax the smooth muscle of the airways, yet the same levels make the smooth muscle around most arterioles contract.

  The liver shows the chain of events most clearly. Adrenaline binds a β2 receptor on a liver cell, and the receptor helps the G protein Gs swap GDP for GTP. The protein splits into a Gs alpha subunit and a Gs beta-gamma pair. Gs alpha stimulates adenylyl cyclase, which converts ATP into cyclic AMP. Cyclic AMP activates protein kinase A, which partially activates phosphorylase kinase.

  A second route runs through the α1 receptor. Binding there raises inositol trisphosphate and sends calcium ions into the cytoplasm. The calcium binds calmodulin, which pushes phosphorylase kinase further toward full activation. The enzyme then phosphorylates glycogen phosphorylase, which breaks down glycogen into glucose.

  Other tissues join in. Binding to α receptors inhibits insulin secretion by the pancreas and stimulates glycogen breakdown in liver and muscle. Binding to β receptors triggers glucagon secretion, more ACTH from the pituitary gland, and increased fat breakdown in adipose tissue. Together these effects raise blood glucose and fatty acids, the fuel cells need for energy.

  In the cardiovascular system, α1-driven vasoconstriction raises peripheral resistance, while β1 receptors raise cardiac output. The aim is higher coronary and cerebral perfusion pressures. Adrenaline lifts aortic, cerebral and carotid pressure, yet it lowers carotid blood flow and end-tidal CO2. It appears to improve microcirculation at the cost of the capillary beds where perfusion takes place.

  Walter Bradford Cannon first proposed that the adrenal medulla and the sympathetic nervous system drive the flight, fight and fright response. Yet the medulla, unlike the cortex, is not needed for survival. In patients who have lost their adrenal glands, the metabolic and circulatory responses to low blood sugar and to exercise stay normal.

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• 6. Exercise And Breath

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  A cat on a treadmill gave researchers their first proof that exercise releases adrenaline. They watched the dilation of a pupil that had been cut off from its nerve supply. A biological assay of urine samples later confirmed it. Chemical methods for measuring catecholamines in plasma appeared from 1950 onwards. Fluorimetric assays were too crude to detect the tiny amounts of adrenaline in plasma. Radio-enzymatic assays pushed sensitivity down to 1 picogram. Early results showed that adrenaline rises late in exercise, mostly once anaerobic metabolism begins.

  During exercise, blood adrenaline climbs for two reasons. The adrenal medulla secretes more, and reduced blood flow to the liver slows the hormone's breakdown. Infusing adrenaline into resting subjects at exercise-like concentrations has little effect on the circulation beyond a slight β2-mediated fall in diastolic blood pressure. Infusions well within the physiological range also calm airway hyper-reactivity enough to counter the constricting effect of inhaled histamine.

  The link between the sympathetic nervous system and the lungs goes back to 1887. In that year Grossman showed that stimulating cardiac accelerator nerves reversed airway constriction caused by muscarine. Later, Jackson cut the sympathetic chain at the diaphragm in dogs. He found no direct sympathetic supply to the lung, yet constricted airways still relaxed, because the adrenal medulla released adrenaline.

  Patients without adrenal glands do not show more asthma. Those prone to asthma gain some protection from their corticosteroid replacement therapy. In healthy people, exercise opens the airways progressively in step with workload, and beta-blockade does not prevent it. The opening comes from a steady fall in resting vagal tone, and the lower resistance reduces the work of breathing. After exercise, the beta-blocker propranolol causes airway resistance to rebound over the same time course as the constriction seen in exercise-induced asthma.

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• 7. Fear And Memory

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  In one experiment, volunteers were injected with adrenaline and then shown fear films. Compared with a control group, they showed more negative and fewer positive facial expressions. They also reported more intense fear and stronger negative memories. The researchers read this as a learned link between negative feelings and adrenaline levels. The hormone triggers sympathetic responses such as a faster heartbeat and shaking knees, and those sensations may be taken as fear whatever the film actually provoked.

  The effect was selective. In the same study, injected subjects were no more amused by an amusement film and no angrier at an anger film. A study of rodents that could or could not produce adrenaline pointed the same way. Adrenaline seems to help the brain encode emotionally arousing events, feeding the heightened arousal of fear.

  Adrenergic hormones can strengthen long-term memory after the fact in humans. Adrenaline released during an emotionally stressful event helps consolidate the memory, so that its strength tracks its importance. Adrenaline given after learning interacts with how aroused the person was at the start. The hormone may also heighten arousal and fear memory in pathological states, including post-traumatic stress disorder. One summary of the evidence states: "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects."

  The sotalol experiments show how this works. Adrenaline does not readily cross the blood-brain barrier, so its memory effects start at β adrenoceptors in the body's periphery. Sotalol, a β blocker that also stays out of the brain, cancels the memory boost from adrenaline given peripherally. That result suggests β adrenoceptors are necessary for adrenaline to affect consolidation.

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• 8. Treatment And Folklore

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  Anaphylaxis, cardiac arrest and superficial bleeding are the main conditions treated with adrenaline as a drug. Inhaled adrenaline can ease the symptoms of croup, and it may help in asthma when other treatments fail. It can be given into a vein, into a muscle, by inhalation, or just under the skin. Common side effects are shakiness, anxiety and sweating, and a fast heart rate and high blood pressure may follow. Occasionally it produces an abnormal heart rhythm. Its safety in pregnancy and breastfeeding is unclear, so the benefit to the mother must be weighed.

  Preterm infants with cardiovascular compromise are the subject of a more recent case. Some argue for adrenaline infusion in place of inotropes, the widely accepted treatment. The data look encouraging, but more trials are needed to show that infusions lower illness and death in these infants. In the eye, epinephrine can treat open-angle glaucoma, because it increases the outflow of aqueous humor and so lowers pressure inside the eye.

  Doctors also measure adrenaline in blood, plasma or serum. The test can aid diagnosis, monitor treatment, or identify the cause of a suspected poisoning. Patients with pheochromocytoma often show plasma levels of 1000-10,000 nanograms per litre. Giving adrenaline by injection to acute-care cardiac patients can produce levels of 10,000-100,000. High levels also appear after a myocardial infarction, particularly in cardiogenic shock. In essential tremor, patients have more adrenaline in plasma but not more noradrenaline, and the tremor responds to peripheral β blockers.

  Low oxygen and low blood sugar reveal something odd. The ratio of adrenaline to noradrenaline rises sharply, even though the wider sympathetic system is not especially active. The adrenal medulla must therefore act with some independence.

  An adrenaline junkie is described as someone who "has a compulsive desire for extreme excitement". The activities named include extreme and risky sports, substance abuse, unsafe sex and crime. The adrenaline surge is rapid, and it does not occur in animals whose adrenal glands have been removed. Stress also activates many other parts of the brain's reward system, and those drive behavior, so circulating adrenaline may not be the cause. Infusing adrenaline alone does raise alertness.

  Stories of great strength in a crisis often credit adrenaline. The best known tells of a parent lifting part of a car to free a child trapped underneath. Such tales are offered as evidence of what the body can endure under stress.

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