The Discovery of adrenaline
The first practical discovery of adrenaline by man occurred when one of our ancestral hominids while out for a stroll was unexpectedly surprised by a sabre-toothed tiger. Isolating and naming the compound were not uppermost in our man’s mind at the time and it was not until the late nineteenth century that progress was made in this area.
The first scientifically rigorous demonstration of the pressor effects of suprarenal extract was by George Oliver and Edward Schafer in 1894 at University College London [1]. In the present age of bespoke and off-the-shelf technology and equipment and commercially available kits it is worth going into these early laboratory experiments in some detail. To measure the effects of suprarenal extract on heart rate in dogs, cats and rabbits, the following apparatus was constructed:
‘A fine steel hook is caught in the epicardium of the auricle,and another in that of the ventricle; from these hooks fine cotton threads pass first over pulleys moving on a horizontal axis, and then vertically downwards, to be attached to long levers made of flat springy steel.
To the ends of the levers writing pens are attached; and the lever is so constructed that it yields to the least pull of the thread.
In order that the pull of the ventricle shall not affect directly the thread which is attached to the auricle, a metallic ring is passed through the aperture made in the thorax to expose the heart, and into the pericardial cavity between the auricle and ventricle; those of the right side of the heart having generally been used.
This ring serves sufficiently to fix the base, and to prevent the action of the one part from directly affecting the lever which is connected with the other. Sometimes in place of using this ring, the base of the ventricle, at the auriculoventricular boundary, has been held firmly by a clip. The extracts were administered by intravenous injection’.
Extracts of suprarenal glands were obtained by Oliver and Schafer from calves, sheep, guinea-pigs, cats, dogs and man. They were tested in vivo for pulse rate, respiration and temperature in cats, rabbits, guinea-pigs and a monkey (presumably whatever menagerie happened to be unlucky enough to be wandering around the grounds of the institute at the time).
The one consistent variable was an extremely potent effect of medullary (but not cortical) extract on heart rate and blood pressure consequent to arteriole contraction. Sub-cutaneous injection had no effect in most species except in rabbits who over-responded by dying. This observation of species differences in response to a drug is itself worthy of comment; if the sub-cut route had been tried first in rabbits, the investigators might have lost confidence and dropped the project.
Fortunately they were made of sterner stuff in those days, and tested the extract in a number of species (an approach much in abeyance now that rodents are the almost exclusive animal of choice for drug testing in basic science, and even they are becoming prohibitively expensive by the day).
Within the leisurely time frame given to Victorian scientists, when not constructing their own laboratory apparatus, Oliver and Schafer conducted comparative potency tests of their extract against other natural agents with known pressor activities such as ergot and digitalis. They also studied the effects of a range of physico-chemical challenges such as boiling, heat, acids, alkalis, and peptic digestion on biological activity.
These early experiments, and others by Moore at University College London [2], characterized some of the physical and biochemical properties of adrenal extract and laid the platform for purification of the active substance which was first achieved by John Abel in 1899 at Johns Hopkins University, Baltimore [3] and independently by the Japanese scientist Jokichi Takamine in his own laboratory in New York City [4] with the sponsorship of Parke-Davis & Co., and Thomas Aldrich (Parke-Davis & Co., Detroit, Michigan) [5]. It is interesting that, although both had strong Parke-Davis connections, neither Takamine nor Aldrich appeared to be aware of one another’s work.
Takamine obtained a stable crystalline compound of uniform composition with extremely potent vasopressor properties from the adrenal glands of sheep and oxen and named it Adrenalin. The patent taken out for Adrenalin by Takamine and Parke-Davis in 1900 was challenged on the grounds that natural compounds cannot be patented, but the decision went in favour of the patent holders. Therefore adrenaline made legal as well as scientific history. (Note: Takamine dropped the ‘e’ for purposes of securing the patent; British physiologists had for years been referring to the putative active compound in adrenal extracts as ‘adrenaline’).
Takamine determined the empirical formula as C10H15N03 and proposed physiological and medical uses. He was also prescient in that, on the basis of this discovery, and on previous observations by George Murray, a British physician in Newcastle-upon-Tyne that extract of ovine thyroid could correct thyroid deficiency in patients, he predicted that ‘the wonderful physiological action of the various glands may depend upon the effects of apparently simple chemical substances,’ thus stimulating the search for many other small tissue-specific compounds such as steroids and amines (and peptides) secreted for important physiological roles.
Both Abel, who published the wrong empirical formula in 1899, and Takamine were misled in that the adrenaline they thought they had purified was later shown to be contaminated with noradrenaline, which is why Takamine’s formula is slightly out. Abel did give the name epinephrin to the new compound, on the basis of a suggestion by Hyrtl that epinephris would be the most appropriate name for the supra-renal gland, and this stuck for American usage (but not for the other side of the Pond, which quite rightly settled with adrenaline for historical reasons). The correct empirical formula of C9H13NO3 was determined by Aldrich in 1901 [5].
Friedrich Stolz at Farbwerke Hochst, Germany, synthesized a ketone form of adrenaline (which he called adrenalone) in 1904, the first hormone to be synthesised in the laboratory [6]. Independently of Stolz, Henry Dakin at the University of Leeds UK also synthesised a ketone analogue of adrenaline which when injected intravenously into rabbits resulted in a very similar response in arterial pressure to that of the natural compound, albeit with lower potency [7]. The final step permitting large-scale production, the conversion of adrenalone to adrenaline, was achieved by Stolz in 1906.
The importance of using a purified or synthetic form of adrenaline in bioactivity studies was illustrated by the work of Carl Wiggers at the University of Michigan who first demonstrated a vasoconstrictor effect of purified adrenaline (obtained from Parke-Davis & Co.) on cerebral blood flow [8] when earlier experiments by several groups using crude adrenal extracts had failed to show any effect.
It was John Newport Langley at the University of Cambridge UK, whose observations along with those of Paul Ehrlich were to lay the foundations for the concept of drug receptors, who first observed in the cat [9] that the effects produced by suprarenal extract (he did not use purified adrenaline) are almost all such as are produced by stimulation of sympathetic nerves. ‘In many cases the effects produced by the extract and by electrical stimulation of the sympathetic nerve correspond exactly’.
This led to the proposal by his co-worker TR Elliott [10] that adrenaline might be the chemical compound secreted from sympathetic nerve terminals. George Barger and Henry Dale of the Wellcome laboratories in London UK tested a number of sympathomimetic compounds for bioactivity [11], using the contractile response of the cat uterus in vivo, an organ which is predominantly innervated by sympathetic nerves.
They also monitored effects on blood pressure via injections into the femoral vein and recording pressure in the carotid artery. They noted that sympathetic activity could be stimulated more potently by primary amines than by secondary amines including adrenaline, and considered, but for this reason discounted, the possibility that adrenaline could be the active compound secreted from sympathetic nerve terminals. Noradrenaline was not to be identified as the sympathetic neurotransmitter until the work of the Swedish physiologist Ulf von Euler in the 1940’s [12].
Despite the huge contribution of adrenaline to medicine, a Nobel Prize was never awarded for the early work, although other tissue-specific compounds such as insulin, cortisol and the hypothalamic releasing factors were duly feted later in the century, as indeed were the catecholamine receptor blockers, and von Euler won in 1970 for his work on noradrenaline. One can only speculate that in its incipient period the Nobel Committee had a superabundant backlog of candidate discoveries to consider in those heady days of scientific progress.
On a more general note, it is useful to meditate on how, through study of the history of science, we can not only gain precious insight into the ways in which that distant breed of worthy investigators went about their empirical business, but also, by returning to the seminal work of those whose patience and industry created the scientific mega-industry we work in today, give credit to those whose papers no longer appear in journal reference lists.
The history of science over the last century is as it was written and published at the time. Most academics are content to write as though anything that happened more than 20 years ago is of little interest, and is consigned to a footnote in a previous review. It is not a ‘black box’, and we should give due credit to our forebears whose acumen and diligence has allowed us to ‘stand on the shoulders of giants’.
Note: The reader’s attention is drawn to the erudite historical article by Horace Davenport [13]. Subsequent developments in this fascinating subject during the 20th century may be pursued in the review by MR Bennett [14].
Author(s) Affiliation
D Jessop – Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE), University of Bristol
A Grossman – Centre for Endocrinology, St Bartholomew”s Hospital, University of London, UK
References
- Oliver G, Schafer EA. The physiological effects of extracts of the suprarenal capsules. J Physiol 1895; 18:230-76.
- Moore B. On the chromogen and on the active physiological substance of the suprarenal gland. J Physiol 1897; 21:382-9.
- Abel JJ. On epinephrine, the active constituent of the suprarenal capsule and its compounds. J Physiol 1901; 27:237.
- Takamine J. The isolation of the active principle of the suprarenal gland. J Physiol 1902; 27: xxix-xxx.
- Aldrich TB. A preliminary report on the active principle of the suprarenal gland. Am J Physiol 1901; 5: 457-461.
- Stolz F Uber adrenalin und alkylaminoacetobrenzcatechin. Ber Dtsch Chem Ges 1904; 37:4149-54.
- Dakin HD. The synthesis of a substance allied to noradrenaline. Proc Roy Soc Lond Series B 1905; LXXVI:491-7.
- Wiggers C. On the action of adrenalin on the cerebral vessels. Am J Physiol 1905; 14:452-65.
- Langley JN. Observations on the physiological action of extracts of the supra-renal bodies. J Physiol 1901; 27:237-56.
- Elliott TR. On the action of adrenalin. J Physiol 1904; 32: xx-xxi.
- Barger G, Dale HH. Chemical structure and sympathomimetic action of amines. J Physiol 1910; 41:19-59.
- von Euler US. A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and noradrenaline. Acta Physiol Scand 1946; 12:73-97. www.the-aps.org/publications/tphys/legacy/1982/issue2/76.pdfBennett MR. One hundred years of adrenaline: the discovery of autoreceptors. Clin Auton Res 1999; 9:145-159.
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