history of catecholamine research history of catecholamine research the catecholamines are a group of neurotransmitters composed of the endogenous substances dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine), as well as numerous artificially synthesized compounds such as isoprenaline, an anti-bradycardiac medication. their investigation constitutes a major chapter in the history of physiology, biochemistry, and pharmacology. adrenaline was the first hormone extracted from an endocrine gland and obtained in pure form, before the word hormone was coined. adrenaline was also the first hormone whose structure and biosynthesis was discovered. second to acetylcholine, adrenaline and noradrenaline were some of the first neurotransmitters discovered, and the first intercellular biochemical signals to be found in intracellular vesicles. the β-adrenoceptor gene was the first g protein-coupled receptor to be cloned. nerve fibers with noradrenaline in the iris adrenaline in the adrenal medulla forerunners british physician and physiologist henry hyde salter (1823–1871) included a chapter on treatment "by stimulants" in a book on asthma first published in 1860. he noted the benefits of strong coffee, presumably because it dispelled sleep, which favored asthma. even more impressive to him, however, was the response to "strong mental emotion": "the cure of asthma by violent emotion is more sudden and complete than by any other remedy whatever; indeed, i know few things more striking and curious in the whole history of therapeutics. (..) the cure (..) takes no time; it is instantaneous, the intersect paroxysm ceases on the instant." the retrospective interpretation is that the "cure″" was due to the release of adrenaline from the adrenal glands. at the same time, the french physician alfred vulpian also made discoveries about the adrenal medulla. material scraped from the adrenal medulla turned green when ferric chloride was added. this did not occur with the adrenal cortex nor with any other tissue. vulpian even came to the insight that the substance entered "le torrent circulator" ("the circulatory torrent"), as blood from the adrenal veins did give the ferric chloride reaction. members of university college london around 1895. schäfer in middle of front row, oliver in light coat. in the early 1890s, in the laboratory of oswald schmiedeberg in strasbourg, the german pharmacologist carl jacob (1857–1944) studied the relationship between the adrenal glands and the intestine. electrical stimulation of the vagus nerve or injection of muscarine elicited peristalsis. this peristalsis was promptly abolished by electrical stimulation of the adrenal glands. the experiment has been called "the first indirect demonstration of the role of the adrenal medulla as an endocrine organ actually a more sophisticated demonstration of the adrenal medullary function than the classic study of oliver and schafer". while this may be true, jacob did not envisage a chemical signal secreted into the blood to influence distant organs, the actual function of a hormone, but nerves running from the adrenals to the gut, "hemmungsbahnen für die darmbewegung". oliver and schäfer 1893–1894 george oliver was a physician practicing in the spa town of harrogate in north yorkshire. edward albert schäfer was professor of physiology at university college london. in 1918, he prefixed the surname of his physiology teacher, william sharpey, to his own to become edward albert sharpey schafer. the canonical story, told by henry hallett dale, who worked at university college london from 1902 to 1904, runs as follows: dr oliver, i was told, … had a liking and a ′flair′ for the invention of simple appliances, with which observations and experiments could be made on the human subject. dr oliver had invented a small instrument with which he claimed to be able to measure, through the unbroken skin, the diameter of a living artery, such as the radial artery at the wrist. he appears to have used his family in his experiments, and a young son was the subject of a series, in which dr oliver measured the diameter of the radial artery, and observed the effect upon it of injecting extracts of various animal glands under the skin. … we may picture, then, professor schafer, in the old physiological laboratory at university college, … finishing an experiment of some kind, in which he was recording the arterial blood pressure of an anaesthetized dog. … to him enters dr oliver, with the story of the experiments on his boy, and, in particular, with the statement that injection under the skin of a glycerin extract from calf’s suprarenal gland was followed by a definite narrowing of the radial artery. professor schafer is said to have been entirely skeptical, and to have attributed the observation to self-delusion. … he can hardly be blamed, i think; knowing even what we now know about the action of this extract, which of us would be prepared to believe that injecting it under a boy’s skin would cause his radial artery to become measurably more slender? dr oliver, however, is persistent; he … suggests that, at least, it will do no harm to inject into the circulation, through a vein, a little of the suprarenal extract, which he produces from his pocket. so professor schafer makes the injection, expecting a triumphant demonstration of nothing, and finds himself standing ′like some watcher of the skies, when a new planet swims into his ken,′ watching the mercury rise in the manometer with amazing rapidity and to an astounding height. despite this tale being reiterated many times, it is not beyond doubt. dale himself said that it was handed down at university college and showed some surprise that the constriction of the radial artery was measurable. of oliver's descendants, none recalled experiments on his son. dale's report of subcutaneous injections contradicts the concerned parties. oliver: “during the winter of 1893–4, while prosecuting an inquiry as to … agents that vary the caliber of … arteries … i found that the administration by the mouth of a glycerin extract of the adrenals of the sheep and calf produced a marked constrictive action on the arteries.” schafer: “in the autumn of 1893 there called upon me in my laboratory at university college a gentleman who was personally unknown to me. … i found that my visitor was dr. george oliver, <who> was desirous of discussing with me the results which he had been obtaining from the exhibition by the mouth of extracts from certain animal tissues, and the effects which these had in his hands produced upon the blood vessels of man.” systemic effects of orally given adrenaline are highly unlikely, so details of the canonical text may be legend. experiment by oliver und schäfer: an adrenal extract increases the blood pressure and contracts the spleen. on march 10, 1894, oliver and schafer presented their findings to the physiological society in london. a 47-page account followed a year later, in the style of the time without statistics, but with precise description of many individual experiments and 25 recordings on kymograph smoked drums, showing, besides the blood pressure increase, reflex bradycardia and contraction of the spleen. ″it appears to be established as the result of these investigations that the suprarenal capsules are to be regarded although ductless, as strictly secreting glands. the material which they form and which is found, at least in its fully active condition, only in the medulla of the gland, produces striking physiological effects upon the muscular tissue generally, and especially upon that of the heart and arteries. its action is produced mainly if not entirely by direct action.″ the reports created a sensation. oliver was fast to try adrenal extracts in patients, orally again and rather indiscriminately, from addison's disease, hypotension (″loss of vasomotor tone″), diabetes mellitus and diabetes insipidus to graves' disease (″exophthalmic goiter″). it seems he adhered to contemporary ideas of organotherapy, believing that powerful substances existed in tissues and ought to be discovered for medicinal use. he immediately went on to extract the pituitary gland and, again with schafer, discovered vasopressin. in 1903 adrenaline, meanwhile purified, was first used in asthma. the use was based, not on the bronchodilator effect, which was discovered later, but on the vasoconstrictor effect, which was hoped to alleviate the “turgidity of the bronchial mucosa” – presumably vascular congestion and edema. also as of 1903, adrenaline was added to local anesthetic solutions. the surgeon heinrich braun in leipzig showed that it prolonged the anesthesia at the injection site and simultaneously reduced ″systemic″ effects elsewhere in the body. independent discoverers a year after oliver and schafer, władysław szymonowicz (1869–1939) and napoleon cybulski of the jagiellonian university in kraków reported essentially similar findings and conclusions. in one aspect, they went beyond the work in england. they found that blood from the adrenal veins caused hypertension when injected intravenously in a recipient dog, whereas blood from other veins did not, showing that the adrenal pressor substance was in fact secreted into the blood and confirming vulpian. the polish authors freely acknowledged the priority of oliver and schäfer, and the british authors acknowledged the independence of szymonowicz and cybulski. the main difference was in the location of the action: to the periphery by oliver and schäfer but, erroneously, to the central nervous system by szymonowicz and cybulski. another year later, the us-american ophthalmologist william bates, perhaps motivated like oliver, instilled adrenal extracts into the eye and found that ″the conjunctiva of the globe and lids whitened in a few minutes″, correctly explained the effect by vasoconstriction, and administered the extracts in various eye diseases. chemistry in 1897, john jacob abel in baltimore partially purified adrenal extracts to what he called “epinephrin”, and otto von fürth in strasbourg to what he called “suprarenin”. the japanese chemist jōkichi takamine, who had set up his own laboratory in new york, invented an isolation procedure and obtained it in pure crystal form in 1901, and arranged for parke-davis to market it as ”adrenalin”, spelt without the terminal “e”. in 1903, natural adrenaline was found to be optically active and levorotary. in 1905 synthesis of the racemate was achieved by friedrich stolz at hoechst ag in höchst (frankfurt am main) and by henry drysdale dakin at the university of leeds. in 1906 the chemical structure was elucidated by ernst joseph friedmann (1877–1956) in strasbourg, and in 1908 the dextrorotary enantiomer was shown to be almost inactive by arthur robertson cushney (1866–1926) at the university of michigan, leading him to conclude that ″the ‘receptive substance’ affected by adrenalin″ is able to discriminate between the optical isomers and, hence, itself optically active. overall, 32 designations have been coined, of which “adrenaline”, preferred in the united kingdom, and “epinephrine”, preferred in the united states, persist as generic names in the scientific literature. adrenaline as a transmitter a new chapter was opened when max lewandowsky in 1899 in berlin observed that adrenal extracts acted on the smooth muscle of the eye and orbit of cats — such as the iris dilator muscle and nictitating membrane — in the same way as sympathetic nerve stimulation. the correspondence was extended by john newport langley and, under his supervision, thomas renton elliott in cambridge. in four papers in volume 31, 1904, of the journal of physiology elliott described the similarities organ by organ. his hypothesis stands in the abstract of a presentation to the physiological society of may 21, 1904, a little over ten years after oliver and schafer's presentation: ″adrenalin does not excite sympathetic ganglia when applied to them directly, as does nicotine. its effective action is localized at the periphery. i find that even after complete denervation, whether of three days’ or ten months’ duration, the plain muscle of the dilatator pupillae will respond to adrenalin, and that with greater rapidity and longer persistence than does the iris whose nervous relations are uninjured. therefore, it cannot be than adrenalin excites any structure derived from, and dependent for its persistence on, the peripheral neurone. ... the point at which the stimulus of the chemical excitant is received, and transformed into what may cause the change of tension of the muscle fiber, is perhaps a mechanism developed out of the muscle cell in response to its union with the synapsing sympathetic fiber, the function of which is to receive and transform the nervous impulse. "adrenalin" might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery.″ the abstract is the ″birth certificate″ of chemical neurotransmission. elliott was never so explicit again.