History of catecholamines research

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The catecholamines (or catecholamines ) or catecholamines include the body's own substances dopamine , noradrenaline (norepinephrine) and adrenaline (epinephrine) as well as numerous artificially produced substances, among which isoprenaline is to be emphasized. Exploring them forms an important chapter in the history of physiology , biochemistry and pharmacology . Adrenaline was the first hormone extracted from an endocrine gland , the first to be shown in its pure form and the first to be clarified in its structure and biosynthesis , before the word “hormone” was coined. Along with acetylcholine, adrenaline and noradrenaline were the first neurotransmitters to be discovered and the first messenger substances to be found stored in intracellular vesicles . The β-adrenoceptor was the first G-protein- coupled hormone and neurotransmitter receptor whose gene was cloned .

Nerve fibers with norepinephrine in the iris

Targeted catecholamine research began with the production of a pharmacologically effective extract from adrenal glands by George Oliver and Edward Albert Schäfer in 1893 and 1894. However, there were earlier indications.

adrenaline

Early evidence of a substance in the adrenal medulla

In the most famous book of the 19th century on asthma , Henry Hyde Salter (1823–1871) included a chapter “Treatment with stimulants”. Strong coffee afterwards helped with asthma attacks. Strong psychological excitement worked even better. "The healing of asthma by violent excitation is faster and more complete than by any other means. … It happens instantly, the worst paroxysm dissolves in no time. ”Salter backed this up with medical histories. A release of adrenaline from the adrenal glands was undoubtedly the therapeutic mechanism.

Salter knew nothing of this mechanism. At the same time, the French doctor Alfred Vulpian noticed that the adrenal medulla had a unique property: it turned green on contact with ferric chloride , unlike the adrenal cortex or any other organ. The adrenal medulla thus contained “a special, previously unknown substance”. Vulpian also recognized that the substance got into the bloodstream, because the blood in the adrenal veins gave the iron (III) reaction.

Members of University College London circa 1895. Shepherd in front center, Oliver behind him on left in a light-colored coat.

In addition to the clinical and chemical evidence, there was a physiological one. In experiments by the German pharmacologist Carl Jacobj , electrical stimulation of the adrenal glands suppressed the peristalsis of the intestine. This has been called the "first indirect evidence of the function of the adrenal medulla as an endocrine gland". However, Jacobj did not think of a chemical signal from the adrenal glands, i.e. a hormone, but of a nerve connection from the adrenal glands to the intestine, "inhibition pathways for intestinal movement".

Oliver and Schäfer 1893/94

The story of the discovery was told by Henry Hallett Dale in 1938 and 1948 . The practicing doctor Oliver then injected his son subcutaneously with extracts from various organs and measured the diameter of the radial artery with an apparatus he had designed himself . An adrenal extract narrowed the artery. Oliver then asked the physiologist Schäfer at University College London to test the effects of blood pressure in animal experiments. Schäfer was skeptical, but then found that after an intravenous injection of an anesthetized dog, the mercury in the manometer “rose rapidly to an unexpected level. This is how the active principle of the adrenal gland was discovered, which was later recognized as an ingredient exclusively in the adrenal medulla and was later shown in pure, crystalline form and called 'epinephrine' or 'adrenaline'. "

Oliver experimented in line with the contemporary notion of “organ therapy”, according to which organs contained potent substances whose therapeutic benefits had to be found out. He immediately proceeded to the extraction of the pituitary gland , which led to the discovery - again together with Schäfer - of the blood pressure-increasing antidiuretic hormone or vasopressin. Dale knew the story of the discovery of adrenaline from tradition at University College London, where he had worked as a shepherd himself and before him. His report of Oliver's subcutaneous injections contradicts reports from Oliver and Schäfer themselves, according to which Oliver administered the extracts orally. Oral adrenaline is very unlikely to be effective. Later, Oliver's offspring didn't know anything about experiments on the son. Parts of the tradition are probably legend.

Experiment by Oliver and Schäfer: An adrenal extract increases blood pressure and causes the spleen to contract.

In any case, Oliver and Schäfers reports in the Journal of Physiology in 1894 caused a sensation. Oliver tried his extracts therapeutically, and quite arbitrarily, from Addison's disease ("Addison's disease") to arterial hypotension ("loss of vasomotor tone"), diabetes mellitus and diabetes insipidus to endocrine exophthalmos ("exophthalmic goitre") . In 1903 the use of the - now purified - adrenaline began for asthma. The New York doctors tried not because of the bronchospasmolytic effect, which was only discovered later, but because of the vasoconstriction , from which it was hoped that the bronchial mucous membrane would swell. In the same year, the addition to solutions of local anesthetics began . In 1905, the Leipzig surgeon Heinrich Braun showed that adrenaline prolonged its effect at the injection site, while at the same time weakening the "systemic" effects, i.e. effects outside the injection site (see history of local dental anesthesia ).

Independent further explorers

A year after Oliver and Schäfer, Władysław Szymonowicz (1869–1939) and Napoleon Cybulski from the Jagiellonian University in Kraków reported on similar animal experiments. The blood of the adrenal veins also contained the blood pressure-increasing substance. This entered the cycle, as Vulpian had already concluded from the iron (III) reaction.

Another year later, in 1896, the American doctor William Bates gave a lecture on two years of experience with instilling adrenal extracts into the conjunctival sac of the eye. The conjunctiva became white within a few minutes, "whitened in a few minutes", by vasoconstriction , as he correctly noted. In contrast to Oliver and Schäfer as well as Szymonowicz and Cybulski, it has hardly found its way into the research literature. Even an ophthalmological review article from 1905 mentions him only in passing.

Isolation, structure elucidation and synthesis

John Jacob Abel in Baltimore cleaned adrenal gland extracts incompletely in 1899 as "Epinephrine", Otto von Fürth in Strasbourg in 1900 as "Suprarenin". The pure representation succeeded in 1901 by the Japanese Jokochi Takamine , who had set up his own laboratory in New York. He had his product, which he called "Adrenalin", patented and marketed as "Adrenalin" by Parke, Davis & Co., which is now part of Pfizer Inc. In 1903, adrenaline was recognized as optically active and left-turning. In 1905 Friedrich Stolz synthesized the racemate at Farbwerke Hoechst AG and Henry Drysdale Dakin at the University of Leeds . In 1906 Ernst Joseph Friedmann (1877–1957) clarified the structure in Strasbourg. In 1908 Arthur Robertson Cushney (1866–1926) at the University of Michigan recognized that dextrorotatory adrenaline was pharmacologically almost ineffective, and drew the remarkable conclusion that the "receptive substance affected by adrenaline" differentiates between the optical isomers and is therefore optically active itself. In total, adrenaline has been given 32 names over time, of which science uses "adrenaline" - preferably in the United Kingdom - and "epinephrine" - preferably in the United States.

Discovery of the neurotransmitter function

A new chapter began with Max Lewandowsky's finding in Berlin in 1899 that adrenal extract acted on the smooth muscles of the eyes of cats - including the nictitating membrane and the dilator pupillae muscle - as well as irritating the sympathetic nerves. John Newport Langley and under his leadership, Thomas Renton Elliott in Cambridge more parallels added. In a lecture to the Physiological Society in London on May 21, 1904, Elliott expressed the visionary hypothesis that adrenaline acts on a component of the muscle cells at their contact point with the sympathetic nerve fibers . The task of this component is to receive the nerve impulse and translate it into a response from the muscle cells. "Adrenaline might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery - Adrenaline could be the chemical stimulant that is released every time a nerve impulse arrives in the periphery." The publication was the "birth certificate" of the chemical neurotransmission, the chemical synaptic transmission of information. Elliott has never been so clear-cut again. He was probably disappointed with the lack of response from leading physiologists, including Langley, and in 1906 he retired from physiological research.

  • The "birth certificate" of chemical neurotransmission
  • Elliott 1904 xx.jpg
  • Elliott 1904 xxi.jpg

The breakthrough in chemical synaptic transmission came in 1921 with Otto Loewi's experiments on frog and toad hearts in Graz and his essay “On humoral transmission of the cardiac nerve effect”. Vagus substance transmitted the effect of the vagus nerve , accelerator substance the effect of the sympathetic nerve on the heart. In 1926 Loewi identified the vagus substance with acetylcholine, and in 1936 he wrote: "So I no longer stand in line to consider the sympathetic substance to be identical to adrenaline."

He got lucky. In amphibians , adrenaline is indeed the main transmitter of the ( postganglionic ) sympathetic nervous system. The question of the transmitter in mammals, however, led to difficulties. In a detailed structure-effect analysis in 1910, Dale and the chemist George Barger pointed out that, according to Elliott's hypothesis, the effects of adrenaline and sympathetic nerve stimulation must coincide more closely than they do. "Amino-ethanol-catechol", that is norepinephrine, imitates the sympathetic system more closely. In the 1930s the physiologists Walter Bradford Cannon and Arturo Rosenblueth at Harvard Medical School came up with the idea of ​​two transmitters, Sympathin E and Sympathin I. Norepinephrine was repeatedly considered. The question remained unanswered until after World War II. In the meantime, Dale created a terminology that has shaped the thinking of neuroscientists ever since: Nerve cells should be named after their transmitter, so "adrenergic" if the transmitter is "some substance like adrenaline", and "cholinergic" if it is " a substance like acetylcholine - some substance like acetylcholine “. In the meantime, the biosynthesis and breakdown of catecholamines began to clear.

In 1936, the year in which Loewi opted for adrenaline as a sympathetic transmitter (in amphibians), he and Dale received the Nobel Prize in Physiology or Medicine "for their discoveries in the chemical transmission of nerve impulses".

Norepinephrine

Thanks to Holtz and Blaschko, it was known that animals synthesized noradrenaline. As a transmitter, however, it had to be stored in sympathetically innervated tissues and not just a short-lived intermediate product. Evidence succeeded Ulf von Euler , who had already discovered the prostaglandins and substance P (with John Henry Gaddum had co-discovered), at the Karolinska Institute in Stockholm. His first communication was received by Nature on April 16, 1946 . After many other bioassays and chemical tests, he concluded that sympathetically innervated tissue, in smaller quantities also the brain, but not the nerve-free placenta , contained noradrenaline and this was the "sympathetic" of Cannon and Rosenblueth, "the physiological transmitter of the effect of adrenergic nerves Mammals ". The release of noradrenaline into the venous blood of the spleen of cats when the sympathetic nervous system was stimulated - proven at Gaddum's Pharmacological Institute in Edinburgh - supported the conclusion two years later. Von Euler confirmed the transmitter function of adrenaline in amphibians.

The war prevented Holtz and his colleagues in Rostock from going down in the history of catecholamine research as co-discoverers of noradrenaline as a neurotransmitter. They looked for catecholamines in human urine and found substances that increase blood pressure, "urosympathetic", which they identified as a mixture of dopamine, noradrenaline and adrenaline. Dopamine is only a precursor to norepinephrine and adrenaline. On the other hand: "Arterenol [noradrenaline] and adrenaline are released in the area of ​​sympathetic nerve endings when they get excited." The manuscript was received by Springer Verlag in Leipzig on October 8, 1944 . On October 15, the publishing house's printing plant in Braunschweig was bombed. Publication was delayed until Volume 204, 1947, of Naunyn-Schmiedeberg's Archives for Experimental Pathology and Pharmacology . Holz later used the article as “Holtz et al. 1944/47 ”or“ Holtz, Credner and Kroneberg 1944/47 ”.

Looking back, Dale wrote in 1953 that in 1910 he and Barger actually had to see that noradrenaline was the main transmitter, and that Elliott's theory was correct in principle and only incorrect in this detail. It is no fame to come so close to the truth and then stop.

Nerve cell bodies with noradrenaline and (small picture) serotonin in the brain stem

Marthe Vogt , who had left Germany in 1935, took the step from the peripheral sympathetic to the central nervous system in Gaddum's institute in 1954 . It mainly contained noradrenaline, with some adrenaline as well; Vogt summarized the two as a "sympathizer". Were they only transmitters of the sympathetic nerves of the blood vessels of the CNS or did they play a role in the nerve cells themselves? The different areas of the CNS contained very different concentrations of "sympathetic", and the distribution could not be explained by a different density of blood vessels. In addition, the concentrations remained the same after the sympathetic nerves were destroyed. “So it makes sense to ascribe a transmitter function to the sympathetic in the brain similar to the sympathetic in the postganglionic sympathetic nerves.” She was right. With the 1962 by Nils-Åke Hillarp (1916-1965) and Bengt Falck (1927 *) developed in Sweden formaldehyde - fluorescence method and immunohistochemistry methods have been made later noradrenaline, adrenaline and dopamine pathways in the central nervous system directly visible microscopically .

Dopamine

The noradrenaline story repeated itself. Like noradrenaline on the biosynthetic pathway to adrenaline, dopamine is on the path to noradrenaline (and thus adrenaline). Was it, contrary to what Peter Holtz had suspected, a messenger substance in its own right? Arvid Carlsson at the Pharmacological Institute of Lund University and his student assistants Åke Bertler and Evald Rosengren found dopamine in the brain unevenly distributed in 1958/59, following the pattern of Marthe Vogt, unlike noradrenaline. That spoke in favor of a function beyond that of an intermediate product. The corpus striatum contained the highest concentration , where there were only traces of noradrenaline. Carlsson's group had previously found that the alkaloid reserpine , which caused Parkinson's syndrome in humans and laboratory animals , depleted dopamine stores (as well as norepinephrine and serotonin stores) in the brain. The group brought the corpus striatum, reserpine parkinsonism, human Parkinson's disease and dopamine into a context for the first time. A year later, Oleh Hornykiewicz , whom Hermann Blaschko had introduced to dopamine when he carried out a color reaction with extracts from the corpus striatum in the Pharmacological Institute of the University of Vienna , saw the dopamine deficiency in human Parkinson's disease "with his own bare eyes: instead of the pink coloration caused by the relatively high dopamine concentrations in the control samples, the test tubes with the samples from Parkinson's patients barely showed a hint of pink. "

In 1970 von Euler and Axelrod were two of the three winners of the Nobel Prize in Physiology or Medicine "for their discoveries about the chemical transmitters in nerve endings and the mechanism of their storage, release and inactivation," and in 2000 Carlsson was one of three winners who won the Award "for their discoveries about signal translation in the nervous system".

Biosynthesis and degradation

The Jew Hermann Blaschko , who left Germany in 1933, wrote in Oxford in 1987: “Our current knowledge of the biosynthesis of catecholamines began in 1939 with a publication by Peter Holtz and his colleagues. They described an enzyme in the kidneys of guinea pigs that they named DOPA decarboxylase because it catalyzed the formation of dopamine and carbon dioxide from the amino acid L-DOPA . ”The publication by Holtz and colleagues came from the Pharmacological Institute of the University of Rostock . Blaschko's own research in the 1930s - he was in Cambridge at the time - was close to that of Peter Holtz. In the same year, 1939, both he and Holtz predicted the complete biosynthetic pathway tyrosine → L-DOPA → dopamine → noradrenaline → adrenaline. The last step, the methylation of noradrenaline to adrenaline, was demonstrated by Edith Bülbring , who had also fled to England from National Socialism , in Oxford in 1949, and Julius Axelrod purified the enzyme responsible for phenylethanolamine-N-methyltransferase in 1962 in Bethesda . The two missing biosynthetic enzymes, tyrosine hydroxylase and dopamine β-hydroxylase , were also characterized around 1960.

As early as 1937, before the formulation of the biosynthesis, Blaschko had recognized a potential for degradation: a “tyramine oxidase” found in 1928 also oxidized dopamine, noradrenaline and adrenaline. It was then called monoamine oxidase . But Blaschko wrote in 1956 that the oxidation seemed too slow to him, that there had to be other inactivation processes. “There is a gap in our knowledge here.” Within a year, Axelrod narrowed the gap with the discovery of catechol-O-methyltransferase . The degradation enzymes were also complete. However, to close the gap and to really understand the fate of released catecholamines, the role of membranes was needed.

The role of membranes

Membranes have a double meaning for catecholamines: They have to cross membranes and have to pass on their chemical message to membranes.

Membrane passage

The catecholamines are synthesized intracellularly and stored in intracellular membrane-covered vesicles. This was first known in 1953, thanks to Blaschko and Arnold Welch (1908–2003) in Oxford and Hillarp and his group in Lund, for the adrenal medulla and later - these are synaptic vesicles - for sympathetic nerves and the catecholamine neurons of the brain . In addition, the vesicles contained adenosine triphosphate in the sympathetic nerves of the spleen of cattle according to Hans-Joachim Schümann and Horst Grobecker (1934–2019) at the Peter Holtz Pharmacological Institute of the University of Frankfurt am Main in a molar noradrenaline: ATP ratio of 5.2: 1. Blaschko and Welch asked: “What happens in the cells when nerve impulses arrive?” They did not consider the answer “ exocytosis ”. To enter and gain their recognition, it took the analogy of the "quantal release" of acetylcholine in the neuromuscular junction , the Bernard Katz had discovered the third winner of the 1970 Nobel Prize in Physiology or Medicine; the detection of the joint release of catecholamines and other vesicle constituents such as ATP; and the clear electron microscopic images of the fusing of vesicles with the cell membrane.

Acetylcholine is broken down extracellularly after its release , because the acetylcholinesterase turns its active center to the extracellular space. The catecholamines are different. Like the synthesis enzymes, monoamine oxidase and catechol-O-methyltransferase are also found intracellularly. The primary inactivation step is not degradation but uptake into cells. From 1959 he was recognized. Axelrod and his colleagues injected cats with 3 H-adrenaline and 3 H-noradrenaline of high specific radioactivity intravenously. A portion was O-methylated to 3 H-metanephrine and 3 H-normetanephrine ; but another part was taken up in cells and stored there unmetabolized. Erich Muscholl in Mainz, who had worked for Marthe Vogt in Edinburgh, came to the same result in another way . He wanted to know how cocaine sensitized organs to catecholamines - a fundamental effect of cocaine discovered by Loewi and Alfred Fröhlich in Vienna in 1910. Rats ingested intravenously infused noradrenaline unchanged in the heart and spleen; Cocaine prevented absorption "and thus increased the amount of norepinephrine that could react with the adrenoceptors ". It was mainly sympathetic nerve cells that took up 3 H-noradrenaline, as destruction of the sympathetic system reduced the uptake. In addition , as Axelrod and Georg Hertting elegantly demonstrated, absorbed 3 H-noradrenaline was released again when the sympathetic nervous system was stimulated. However, a few years later in Cambridge, Leslie Iversen found that other cells were also taking up catecholamines. He called the uptake in noradrenergic neurons that was blocked by cocaine "uptake 1 " and uptake in other cells that was not blocked by cocaine "uptake 2 ". So, with uptake into the storage vesicle, which was blocked by reserpine, there were three membrane passage mechanisms for catecholamines. Iversen's 1967 book “The Uptake and Storage of Noradrenaline in Sympathetic Nerves” was a great success, a sign of the researchers' fascination with the membrane transporters and their rich pharmacology. In the 1980s , the Würzburg pharmacologist Ullrich Trendelenburg called “metabolizing systems” biological constructions in which a membrane transporter and an intracellular enzyme work hand in hand to inactivate extracellular substances.

With the help of molecular genetics , the transporters have been traced to their genes and protein structure since 1990. They include the cell membrane transporter NAT or NET, the classic uptake 1 , and the analogous dopamine transporter DAT; the “extraneuronal monoamine transporter” EMT, also called “organic cation transporter 3”, from the group of SLC transporters , Iversens uptake 2 ; and the vesicular monoamine transporter VMAT with two isoforms, VMAT1 and VMAT2.

Receptors

Adrenaline reversal in blood pressure and uterus in a cat according to Dale (1906). Ergot extract was injected between the left and right records.

Research on the catecholamines and research on their receptors were intertwined. In 1904 Dale became head of Wellcome Physiological Research Laboratories in London and began studying ergot extracts . In 1906 he published "On some physiological actions of ergot". The essay is less important because of the effect of the extracts alone than because of their interaction with adrenaline: They turned its normal blood pressure-increasing effect into a decrease in blood pressure and the normal induction of contraction in the uterus of prematurely pregnant cats into relaxation: the famous adrenaline reversal . The blood pressure and uterine effects of pituitary extracts , however, remained unchanged, as did the cardiac effects of adrenaline and the effects of irritating parasympathetic nerves. Dale clearly saw the specificity of the “paralyzing” effect of the ergot on “the myoneural junctions of the sympathetic or thoraco-lumbar part of the autonomic nervous system ” - in today's terminology the “adrenoceptors”. He also clearly saw the specificity for those myoneural contact points that mediated contraction rather than relaxation in smooth muscles. But he didn't go any further. He saw no relationship between the smooth muscle relaxing and cardiac stimulating sites of action of catecholamines.

The catecholamine receptors remained in this mist for more than forty years. New antagonists were found, such as tolazoline in Switzerland and phenoxybenzamine in the USA , but like the ergot alkaloids they only blocked the smooth muscle stimulating receptors. The synthesis of new agonists at Boehringer Ingelheim was more important . Isoprenaline, N-propyl noradrenaline, stands out among them. It was examined together with adrenaline and other N-substituted noradrenaline derivatives by Richard Rössler and Heribert Konzett at the Pharmacological Institute of the University of Vienna , especially for bronchospasmolysis. The two pharmacologists used the so-called Konzett-Rössler test , which they developed themselves . First they injected pilocarpine into the anesthetized test animals to induce bronchial spasm , then the catecholamine. “If you compare all the amines examined from the point of view of the broncholytic potency, you get a series that leads from the most effective isopropyladrenaline <= isoprenaline> via ethyladrenaline to the roughly equally effective bodies adrenaline, propyladrenaline, butyladrenaline and finally to the only weakly effective isobutyladrenaline . “In addition, isoprenaline had a strongly positive inotropic and chronotropic effect . Boehringer introduced it as an asthma medicine in 1940. After the war, it was also used by Germany's former enemies, and over time it received around 50 brand names . In addition to its therapeutic benefits, it was one of the agonists with whose help Raymond Ahlquist solved the mystery of myoneural junctions, the “myoneural junctions”. "This spread the reputation of this substance around the world and it became a tool for much pharmacological and therapeutic research." However, cardiac overdose has resulted in numerous deaths, reportedly around three thousand in the UK alone.

Ahlquist headed the Pharmacology Department at the University of Georgia , now Georgia Health Sciences University. He saw in 1948 what Dale had missed in 1906. “A distinction has been made between two classes of adrenoceptors, those for stimulating and those for inhibiting the effector cells . The experiments described here show that although there are two types of adrenoceptors, they cannot simply be differentiated as excitatory or inhibitory, because each type of receptor can convey both excitation and inhibition, depending on where it is located. ”Ahlquist determined these Effects of six agonists, including adrenaline, noradrenaline, α-methylnoradrenaline and isoprenaline, on various organs. He found that the six had two and only two orders of potency on the organs . For example, in the sequence "adrenaline> noradrenaline> α-methylnoradrenaline> isoprenaline" they had a vasoconstrictor effect, but in the sequence "isoprenaline> adrenaline> α-methylnoradrenaline> noradrenaline" positively inotropic and chronotropic on the heart. He called the receptors with the first order of potency (for example for vasoconstriction) α-adrenoceptors (" alpha adrenotropic receptor"), the receptors with the second order of potency (for example for cardiac stimulation, but also for bronchodilation) he called β-adrenoceptors (" beta adrenotropic receptor "). “This concept of two fundamental types of receptors is in direct conflict with the concept of two mediator substances (sympathetic E and sympathetic I) that Cannon and Rosenblueth presented and which is now often referred to as the 'law' of physiology. There is only one adrenergic neuro-hormone or sympathetic, and this sympathetic is identical to adrenaline. "

The fog around the adrenoceptors was blown away. However, Ahlquist's manuscript was rejected by the responsible Journal of Pharmacology and Experimental Therapeutics and accepted by the American Journal of Physiology on the second attempt . Perhaps the harsh criticism of Cannon and Rosenblueth contributed to this.

In retrospect, it can be stated that Ahlquist was right in the postulate "one transmitter - two receptors", but wrong in identifying the transmitter with adrenaline. He also failed to turn the selectivity of the then known antagonists for α-adrenoceptors into an additional argument. Looking back, we even need to put things into perspective: we now know that the adenosine triphosphate, stored together with noradrenaline, contributes as a cotransmitter to the contraction of many smooth muscles when the sympathetic nervous system is stimulated, including neurogenic vasoconstriction . It acts on the P2X purinoceptors, very different from the adrenoceptors.

The α, β terminology initially slowly gained acceptance, and has quickly gained acceptance since two publications in 1958. In the first publication, from the laboratories of Eli Lilly and Company in Indianapolis , dichloroisoprenaline selectively blocked some of the smooth muscle relaxing effects of adrenaline and isoprenaline. In the second, it blocked the cardiac effects of the two substances. In the first, which Ahlquist does not mention, dichloroisoprenaline blocked "certain inhibitory adrenoceptors"; In the second, however, the results underpin “Ahlquist's postulate (1948) that the inhibitory adrenoceptors and the positive chronotropic and inotropic cardiac receptors are functionally identical, namely both of the beta type. ... We propose to expand this terminology, namely to name the antagonists after the receptor for which they have the highest affinity, as either α- or β- adrenergic blocking drugs (either alpha or beta adrenergic blocking drugs). "

Presynaptic α 2 -autoreceptor and postsynaptic adrenoceptors on a noradrenergic axon terminal .

Dichloroisoprenaline was the first “ beta blocker ” (with some intrinsic activity ). Pronethalol followed in 1962 and Propranolol in 1964, both invented by James Black and his colleagues at Imperial Chemical Industries Pharmaceuticals in England. In 1967 the β-adrenoceptors were subdivided into β 1 and β 2 , and in the late 1970s a third β-type appeared, mainly in fat cells.

The subdivision of the α-adrenoceptors began in 1971 with the discovery of a self-regulation of noradrenaline release via α-receptors at the noradrenergic presynaptic endings , so-called presynaptic α-autoreceptors . Their existence was initially highly controversial, but is now confirmed, for example, by the detection of their messenger RNA in noradrenergic nerve cells. They deviated from the long-known α receptors of the effector cells and became the prototype of the α 2 receptors, while the smooth muscle-stimulating receptors became α 1 .

Amine receptor branch on the family tree of G-protein-coupled receptors.

Even before dopamine was recognized as the third catecholamine transmitter, Blaschko suspected that it had its own receptors. He recalled a 1942 Rostock work by Holtz and his group: Dopamine lowered blood pressure in small doses in guinea pigs and rabbits, while adrenaline always increased it. Holtz interpreted erroneously, but Blaschko had "no doubt that his observations are of the greatest historical importance as the first indication of an effect of dopamine that was characteristically and specifically different from the effects of the other two catecholamines". A follow-up in 1964 suggested “specific vasodilation-mediating dopamine receptors”, and at the same time other evidence increased for separate dopamine receptors other than the α- and β-adrenoceptors.

In 1986, sixteen scientists, including Robert Lefkowitz and Brian Kobilka of Duke University in Durham , North Carolina , cloned the first gene for a catcholamine receptor, the β 2 -adrenoceptor, from the lungs of hamsters. Today, the genes of all mammalian catecholamine receptors are cloned, for the nine adrenoceptors α 1A , α 1B , α 1D , α 2A , α 2B , α 2C , β 1 , β 2 and β 3 as well as the five dopamine receptors D 1 , D 2 , D 3 , D 4 and D 5 . One begins to understand their fine structure in agonist-free and agonist-activated states.

The β 2 -adrenoceptor (blue) and its coupling to the G protein G s (red, yellow, green) after binding an agonist. Extracellular space above.

Earl Wilbur Sutherland received the 1971 Nobel Prize for Physiology or Medicine “for his discoveries about the mechanisms of action of hormones”, in particular the discovery of cyclic adenosine monophosphate as a second messenger of catecholamines on β-adrenoceptors and glucagon on glucagon receptors. From here, research moved on to G-protein-coupled receptors . In 1988 James Black was one of three winners of the award "for their discoveries of important principles in drug treatment", in Black for the principle of blocking β-adrenoceptors and histamine H 2 -receptors. In 2012 Robert Lefkowitz and Brian Kobilka shared the Nobel Prize in Chemistry “for their studies of G-protein-coupled receptors”.

Review article on catecholamine research

  • Paul Trendelenburg : Adrenaline and Adrenaline-Related Substances . In: A. Heffter (Hrsg.): Handbuch der experimental Pharmakologie. Second volume, second half. Berlin, Julius Springer 1924, pp. 1130-1293.
  • H. Blaschko: Catecholamines 1922-1971 . In: H. Blaschko and E. Muscholl (eds.): Catcholamines. Handbook of Experimental Pharmacology XXXIII. Berlin, Springer-Verlag, 1972, pp. 1-15. ISBN 0-387-05517-7 .
  • Herman Blaschko: A half-century of research on catecholamine biosynthesis. In: Journal of Applied Cardiology 1987; 2: 171-183.
  • Zénon M. Bacq: Chemical transmission of nerve impulses . In: MJ Parnham and J. Bruinvels (Eds.): Discoveries in Pharmacology. Volume 1: Psycho- and Neuropharmacology , Amsterdam, Elsevier, 1983, pp. 49-103. ISBN 0-444-80493-5 .
  • MR Bennett: One hundred years of adrenaline: the discovery of autoreceptors. In: Clinical Autonomic Research 9, 1999, pp. 145-159. doi: 10.1007 / BF02281628
  • Josef Donnerer and Fred Lembeck : Adrenaline, noradrenaline and dopamine: the catecholamines. In: The Chemical Languages ​​of the Nervous System. Basel, Karger, 2006, pp. 150–160.

Individual evidence

  1. ↑ John Henderson: Ernest Starling and 'Hormones': an historical commentary . In: Journal of Endocrinology . 184, 2005, pp. 5-10. doi : 10.1677 / joe.1.06000 .
  2. ^ Henry Hyde Salter: On Asthma: its pathology and therapy. Philadelphia, Blanchard 1864.
  3. ^ A. Vulpian: Note sur quelques réactions propres à la substance des capsules surrénales. In: Comptes rendus de l'Académie des Sciences. 43, 1856, pp. 663-665.
  4. ^ C. Jacobj: Contributions to the physiological and pharmacological knowledge of intestinal movements with special consideration of the relationship of the adrenal glands to them . In: Archives of Experimental Pathology and Pharmacology . 29, 1892, pp. 171-211. doi : 10.1007 / BF01966116 .
  5. ↑ Stephen W. Carmichael: The history of the adrenal medulla . In: Reviews in Neurosciences . 2, 1989, pp. 83-99. doi : 10.1515 / REVNEURO.1989.2.2.83 .
  6. ↑ H. Dale: Natural chemical stimulators . In: Edinburgh Medical Journal . 45, 1938, pp. 461-480.
  7. ^ Henry Dale: Accident and opportunism in medical research. In: British Medical Journal. 1, 1916, pp. 73-73, doi: 10.1136 / bmj.2.4574.451
  8. ↑ Merriley Borell: Organotherapy, British physiology, and discovery of the internal secretions. In: Journal of the History of Biology 9, 1976, pp. 235-286.
  9. ↑ G. Oliver and EA Schäfer: On the physiological action of extracts of pituitary body and certain other glandular organs. In: Journal of Physiology 18, 1895, pp. 277-279. PMC 1514634 (free full text)
  10. ↑ a b George Oliver: On the therapeutic employment of the suprarenal glands . In: British Medical Journal . , Pp. 653-655. doi : 10.1136 / bmj.2.1811.635 .
  11. ^ EA Schäfer: On the present condition of our knowledge of the function of the suprarenal capsules . In: British Medical Journal . , Pp. 1277-1281. doi : 10.1136 / bmj.1.2474.1277 .
  12. ↑ K. Starke: Pharmacology of noradrenergic and adrenergic systems - pharmacotherapy of bronchial asthma - doping. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Elsevier, Munich 2009, pp. 161–199. ISBN 978-3-437-42522-6 .
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