William Paton (pharmacologist)

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William Paton

William Paton , full name William Drummond Macdonald Paton , (born May 15, 1917 in the London borough of Hendon , † October 17, 1993 in Oxford ) was a British pharmacologist .

Life

He was one of six children of the Presbyterian clergyman William Paton and his wife Grace nee. Macdonald. He attended schools in St Albans and Brackley and the Repton School , a private school in Repton , Derbyshire . This was followed by a degree in medicine, first as a member of New College in Oxford , then at University College London . In 1942 he received the Oxford degree of Bachelor of Medicine, Bachelor of Surgery (MB, BCh) and married Phoebe geb. Rooker. The couple remained childless. In poor health - he had been suffering from pneumonia since a whooping cough - he could not become a soldier, did not believe that he was up to clinical work and decided to begin a research career at the National Institute for Medical Research in Hampstead (London) . Under the direction of the physiologist George Lindor Brown (1903–1971) it was a matter of war-important research: the physiology of humans under water, at high pressures, during decompression (pressure relief) and especially when leaving submarines. A pressure chamber that the respiratory physiologist John Scott Haldane had constructed a generation earlier was used for experimentation. As soon as the war was over, the institute reverted to its ancestral physiology and pharmacology in the tradition of Henry Hallett Dale , Marthe Vogt and Wilhelm Feldberg , and Paton found a taste for pharmacology (see “Research”). In 1952 he moved to the University College Hospital as a lecturer and in 1954 to the newly established Pharmacological Department of the Royal College of Surgeons of England on Lincoln's Inn Fields in London . This is where his most famous works were created, in which he used isolated, surviving organs. “In order to be able to combine his duties as head of department with experimentation by hand, he liked to carry out the experiments in his office, often with rather shaky equipment. A noisy thermostat kept the organ baths warm and caused flooding if old rubber seals failed. ”In 1959 he took over the Chair of Pharmacology at Oxford, which had become the most prestigious in the UK under his predecessor Joshua Harold Burn . Here worked Hermann Blaschko , Edith Bülbring and Edward Miles Vaughan Williams, known for his classification of antiarrhythmic drugs . Paton, together with physical chemists , was able to revisit physiology under high pressures - hyperbaric medicine . To the laboratory staff, accustomed to delicate, isolated organs, the colossal pressure chambers with their tangle of copper pipes and pressure gauges appeared "like a return to the steam engine age ." In 1983, shortly after his retirement, Paton took over the provisional management of the library of the Wellcome Trust in the Euston Road in London. When his strength waned, the library committee met in the Oxford home of the Patons instead of in London. Here he suddenly died of a stroke . His wife survived him. A. David Smith succeeded him in the Pharmacological Institute.

research

Little noticed by the scientific community, Paton wrote the official manual of hyperbaric medicine for the Navy doctors on behalf of the British Admiralty in Hampstead . But his first scientific publication also comes from research accompanying British naval warfare . He got into pharmacology when he was asked to test the toxicity of a new antibiotic, licheniformin . It caused a drop in blood pressure with some delay by releasing histamine . The observation seemed so “interesting and 'clean'” to him and his colleagues that they pursued it further. Licheniform contained a guanidine group. It turned out that “whenever the two basic groups of a dibasic substance were separated by about five or more methylene groups or equivalent structures, the substance released histamine.” “A clean effect through a specific chemical structure - that opened a new one World. ... The fish was caught. ”At the same time, Paton had found two of his main themes: the methonium compounds and the release of histamine.

The methonium compounds

The known histamine-releasing substances included the muscle relaxant tubocurarine . Paton and his colleagues, including Eleanor Zaimis (1915–1982) from Greece, therefore tested their histamine-releasing polymethylene-bis-trimethylammonium compounds (CH 3 ) 3 N + - (CH 2 ) n -N (CH 3 ) 3 + - they called them methonium compounds - also on muscle relaxation and the pharmacologically related blockade of the ganglia of the autonomic nervous system . In a first publication in 1948, they reported that the compounds with 8 or 10 methylene groups between the quaternary heads of the molecule (n = 8 or n = 10; the latter substance was named decamethonium ) did indeed paralyze skeletal muscles . Shortly afterwards they presented the decamethonium and the substance with 6 methylene groups (n = 6; it was given the name hexamethonium ) in more detail. Hexamethonium was not a muscle relaxant, but it was a powerful ganglion blocker . If decamethonium could replace tubocurarine in anesthesiology, hexamethonium is an antihypertensive agent . The following year they announced the first clinical trials and the details of the animal experiments: “The pharmacological properties of the series depend on the length of the polymethylene chain, with a sharp maximum in ganglion blockade at 5 or 6 and a sharp maximum in muscle relaxation at 10 methylene groups. “However, the decamethonium muscle relaxation was different from the tubocurarine muscle relaxation; for example, the paralysis was preceded by muscle twitching. An electrophysiological investigation showed why: like the body's own neurotransmitter acetylcholine - and unlike tubocurarine - decamethonium depolarized the motor end plate , only in contrast to acetylcholine for a long time, thus preventing nerve impulses from spreading to the muscle cells. In 1952 Paton and Zaimis summarized the area in an overview. Today (2013) decamethonium and hexamethonium are obsolete as drugs . But Paton and Zaimis have established one of the most famous structure-activity relationships in pharmacology, recognizing the dichotomy of depolarizing and non-depolarizing muscle relaxants and differentiating the nicotine receptors on muscle cells from those on nerve cells.

Histamine release

Paton's licheniformine publication also reports on the release of histamine by 63 other basic substances, including tubocurarine and strychnine , of which this was also known. Apparently, many organic bases possessed this ability, which could lead to undesirable effects when used as medicinal substances. Shortly thereafter, Paton found a particularly powerful substance in a phenylethylamine condensation product called Compound 48/80 . It has become a standard tool in histamine research. The "basic histamine liberators" - including morphine and the mast cell degranulating peptide from bee venom belong to it - put histamine via a different mechanism than the free immunoglobulin E .

The ileum of the guinea pig

Few scientific text messages have been as momentous as the summary of Patons lecture in 1954 before the British Physiological Society "The response of the ileum of guinea pigs to electrical stimulation by coaxial electrodes ." He wanted to research the regulation of the small intestine by the nervous system and was looking for a model. “I still vividly remember the first attempt in my office-with-laboratory at the Royal College of Surgeons . I attached a Trendelenburg preparation of the small intestine in an organ bath. I threaded my only piece of platinum wire into the lumen. An alligator clip immersed in the bath liquid served as the outer electrode. It worked like a bomb, contractions even with power surges of only 50 µsec. ... the model is a great gift for pharmacologists. ... I don't know anything more useful. ”The short message has been cited 225 times to date. The acetylcholine that was released during the irritation came exclusively from the nerve cells of the intestine, not from the smooth muscles .

Opioids

Two years later, Paton succeeded in making his most famous discovery, if one follows bibliometrics , on the guinea pig ileum , described in the article in Volume 11 of the British Journal of Pharmacology, which has been cited 979 times to date, “The effect of morphine and related substances on contraction and acetylcholine release coaxially stimulated guinea pig ileum. ”Morphine and other opioids such as heroin and methadone reduced both the release of acetylcholine and the contractions it induced. The effect diminished after repeated administration: an in vitro manifestation of tolerance development . Paton showed for the first time a basic effect of opioids: the inhibition of the release of neurotransmitters, in this case the postganglionic parasympathetic transmitter acetylcholine. “The isolated intestine seemed to be 'a paradigm of the brain'”. With his help, Hans Walter Kosterlitz and his colleagues later discovered endogenous opioids and subclassified the opioid receptors. The essay became a Citation Classic . After all, he had parallels and precursors.

  • The German pharmacologist Wolfgang Schaumann in Frankfurt am Main published similar findings in the next volume, Volume 12, of the British Journal of Pharmacology and in the same year 1957 using a different method.
  • Forty years earlier, in 1917, four years before the chemical transmission of nerve impulses and long before the transmitter role of acetylcholine was recognized, Paul Trendelenburg in Freiburg im Breisgau had noticed that morphine inhibited the peristalsis of excised pieces of small intestine from guinea pigs. His article was cited 285 times up to 1998 - strangely enough, not by Paton, who was familiar with the "Trendelenburg preparation" (see above).
  • Also in Volume 12 of the British Journal of Pharmacology , Paul Trendelenburg's son Ullrich , at that time in Oxford, reported that morphine inhibited the contraction of the cat's nictitating membrane when its nerves were stimulated, retrospectively inhibiting the release of the postganglionic sympathetic transmitter norepinephrine .

The special status of Paul Trendelenburg's 1917 and Paton's 1957 work emerges from another aspect of their afterlife. Paul Trendelenburg's 75-page article in the Archives for Experimental Pathology and Pharmacology was reprinted with a comment in the same journal in 2006, translated into English. Paton's paper was also reprinted in 1997 on the 50th anniversary of the British Journal of Pharmacology .

Presynaptic receptors

“Particularly gratifying,” wrote Paton in his 1986 autobiography, “was working with Sylvester Vizi on the effects of catecholamines on transmitter release; We came across a high-yielding presynaptic ore vein. ”With the Hungarian pharmacologist Szilveszter E. Vizi (* 1936) and a modification of the guinea pig ileum model, he found in 1969 that like opioids, the catecholamines noradrenaline and adrenaline release acetylcholine decreased in the guinea pig ileum. They acted on adrenoceptors of the α-adrenoceptor type. The special feature was their localization: not like the "classic" α-adrenoceptors in the history of catecholamine research on muscle cells, but on nerve cells. The location was not unambiguous because of the complexity of the intestinal nervous system , but Paton and Vizi thought of the presynaptic endings of the acetylcholine nerve cells. Her work therefore belongs to the research on presynaptic receptors that began in the late 1960s . It has a general meaning in a second respect: The sympathetic nervous system not only counteracted the parasympathetic nervous system on the muscle cells, but even before that, in that the sympathetic nervous system transmitter norepinephrine inhibited the release of the parasympathetic nervous system transmitter acetylcholine. The opposite, inhibition of the release of the sympathetic transmitter noradrenaline by the parasympathetic transmitter acetylcholine, was shown by the Mainz pharmacologist Erich Muscholl and his colleagues in 1968. "A reciprocal presynaptic antagonism complements the long-known postsynaptic antagonism between the two parts of the autonomic nervous system."

The rate theory of drug action

How did pharmaceuticals work? Most apparently via specific endogenous macromolecules, " receptors ". But how did it come about that a drug, such as histamine, often triggered an effect via its receptor, while another , an antihistamine , administered alone via the same receptor did not trigger an effect, rather only prevented the effect of histamine? How did it come about that an effect often wore off after a while? Paul Ehrlich , Walther Straub , Alfred Joseph Clark (1885–1941), John Gaddum , Heinz Otto Schild and Everhardus Ariëns had thought about it. Most of the time it was assumed that the adherence of the drug to the receptor was crucial. If the drug was an agonist like histamine, the receptor changed while it was attached, and the more receptors occupied, the stronger the result. If the drug was an antagonist , the receptor did not change during adhesion, it was only inaccessible to the agonist. This theory did not satisfy Paton. From 1955 he made notes on the subject, and in 1961 he published “A theory of drug action based on the rate of drug-receptor combination.” “Many pharmacological phenomena can be interpreted on the assumption that the action of a drug is not dependent on the The number of drug-afflicted receptors depends, but rather on the frequency or speed ('rate') of attachment. ... The effect does not result from sticking, but from the process of attachment; every attachment provides a quantum of excitation. ... I call the assumption of a proportionality of the effect to the number of drug-afflicted receptors occupation theory ; ... the assumption of a proportionality to the number of attachments to the receptor per unit of time is what I call rate theory . Both theories are based on the law of mass action ; they differ in the assumption of a proportionality of the effect to the number of drug-afflicted receptors on the one hand, to the attachment rate ('association rate') on the other hand. ”Paton compared the effect of clinging to an organ sound that lasted as long as the key was pressed; He compared the effect of the process of attachment to a piano sound that faded away after pressing a key once and required frequent key presses to continue. As evidence, he cited experiments with histamine and acetylcholine and their antagonists. “Later studies of ion channels have shown that it is the agonist that opens them, not the act of attachment. If rate theory turned out to be wrong, it has revived interest in receptor mechanisms. ... Paton himself was a little disappointed that he had not achieved the conceptual breakthrough and turned to other problems. ”It was a similar story with Walther Straub over fifty years earlier with his potential poison theory .

Hyperbaric medicine

High pressure physiology has been largely applied science . Paton contributed to the knowledge of the High Pressure Nervous Syndrome . He headed the Committee of the Medical Research Council for the study of decompression sickness , edited the decompression tables and was involved in the development of the trimix gas mixture oxygen , nitrogen and helium for deep diving. Last but not least, a question of basic research, he came across a new theory of anesthesia .

anesthesia

On top of all anesthetics theories that stood Meyer-Overton correlation of Hans Horst Meyer and Charles Ernest Overton : the lipophilic an anesthetic was, the more it seemed. That left the question of why open. Paton's group observed that anesthetized crested newts and mice regained their reflexes when exposed to high pressures - about 100 atmospheres for crested newts . This led to the hypothesis of a “critical volume”: “Anesthesia occurs as soon as the volume of a hydrophobic region of the cells has increased beyond a critical volume due to the deposition of the anesthetic molecules.” It remained open which cell region was responsible. High pressure removed the anesthesia by compressing the cell region to its normal volume. The Oxford researchers soon found that their hypothesis was oversimplifying. There were differences between different animal species, and high pressure had its own effects, regardless of the anesthetics used. Today, instead of being stored in hydrophobic cell regions, the effect of the anesthetic on receptors, especially neurotransmitter receptors and ion channels, is considered to be the decisive mechanism.

Social Commitment

Paton used his science for the British Navy and the Medical Research Council (see above). From 1954 to 1956 he was secretary of the British Physiological Society , from 1968 to 1987 trustee of the Rhodes Trust , from 1978 to 1987 trustee of the Wellcome Trust. As President of the Research Defense Society , he dealt with opponents of animal experiments. He also wrote a book "Man and Mouse - Animals in Medical Research".

recognition

1956 Paton became a member of the Royal Society . In 1959 he was awarded the Gairdner Foundation International Award .

literature

Individual evidence

  1. ↑ Rang and Perry 1996, pp. 297-298.
  2. ↑ Rang and Perry 1996, p. 300.
  3. ^ WDM Paton and A. Sand: The optimum intrapulmonary pressure in underwater respiration. In: The Journal of Physiology 106, 1947, pp. 119-138. PMC 1393750 (free full text)
  4. ^ A b F. C. Macintosh and WDM Paton: The liberation of histamine by certain organic bases. In: The Journal of Physiology 109, 1949, pp. 190-219. PMC 1392579 (free full text)
  5. ^ WDM Paton: Hexamethonium. In: British Journal of Clinical Pharmacology 13, 1982, pp. 7-14. PMC 1401766 (free full text)
  6. ↑ Paton 1986, p. 3.
  7. ↑ DMJ: Eleanor Zaimis MD, FRCP. In: British Medical Journal 285, 1982, p. 1280. PMC 1499813 (free full text)
  8. ^ WDM Paton and EJ Zaimis: Curare-like action of polymethylene bis-quarternary ammonium salts . In: Nature . 161, 1948, pp. 718-719. doi : 10.1038 / 161718b0 .
  9. ↑ WDM Paton and EJ Zaimis: Clinical potentialities of certain bis-quaternary salts causing muscular and ganglionic block . In: Nature . 162, 1948, p. 810. doi : 10.1038 / 162810a0 .
  10. ↑ Geoffrey Organe , WDM Paton and EJ Zaimis: Preliminary trials of bistrimethylammonium decane and pentane diiodide (C10 and C5) in man . In: The Lancet . 253, No. 6540, 1949, pp. 21-23. doi : 10.1016 / S0140-6736 (49) 90345-1 .
  11. ^ WDM Paton and Eleanor Z. Zaimis: The pharmacological actions of polymethylene bistrimethylammonium salts. In: British Journal of Pharmacology 4, 1949, pp. 381-400. PMC 1509928 (free full text)
  12. ↑ B. Deslisle Burns and WDM Paton: Depolarization of the motor end-plate by decamethonium and acetylcholine. In. The Journal of Physiology 115, 1951, pp. 41-73. PMC 1392009 (free full text)
  13. ^ WD M: Paton and Eleanor Z. Zaimis: The methonium compounds. In: Pharmacological Reviews 4, 1952, pp. 219-253.
  14. ↑ K. Starke: Neuromuscular blocking substances. In: K. Aktories , U. Förstermann , F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 145–152. ISBN 978-3-437-42522-6
  15. ↑ K. Starke: Amines: Acetylcholine. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 112-115. ISBN 978-3-437-42522-6
  16. ↑ WDM Paton: Compound 48/80: a potent histamine liberator. In: British Journal of Pharmacology 6, 1951, pp. 499-508. PMC 1509129 (free full text)
  17. ↑ WDM Paton: Histamine release by compounds of simple chemical structure. In: Pharmacological Reviews 9, 1957, pp. 269-328.
  18. ↑ E. Schlicker and M. Göthert : Pharmakologie des Histamin. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 211-218. ISBN 978-3-437-42522-6
  19. ^ WDM Paton: The response of the guinea-pig ileum to electrical stimulation by coaxial electrodes. In: The Journal of Physiology 127, 1955, pp. 40P-41P. PMC 1365709 (free full text)
  20. ↑ Paton 1986, p. 13.
  21. ^ A b W. DM Paton and M. Aboo Zar: The origin of acetylcholine released from guinea-pig intestine and longitudinal muscle strips. In: The Journal of Physiology 194, 1968, pp. 13-33. PMC 1365672 (free full text)
  22. ↑ WDM Paton: The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum. in: British Journal of Pharmacology 11, 1957, pp. 119-127. PMC 1509640 (free full text)
  23. ↑ a b Paton WM: The action ot morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum. (PDF; 218 kB) In: Brit. J. Pharmacol. Chemother. 12:11 9-27, 1957.
  24. ^ W. Schaumann: Inhibition by morphine of the release of acetylcholine from the intestine of the guinea-pig. In: British Journal of Pharmacology 12, 1957, 115-118. PMC 1509655 (free full text)
  25. ^ Paul Trendelenburg: Physiological and pharmacological experiments on the small intestinal peristalsis . In: Archives of Experimental Pathology and Pharmacology . 81, 1917, pp. 55-129. doi : 10.1007 / BF01862644 .
  26. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology. In: Naunyn-Schmiedeberg's Archives of Pharmacology 1998; 358: 1-109, here p. 80. PMID 9721010 . doi: 10.1007 / PL00005229
  27. ^ U. Trendelenburg: The action of morphine on the superior cervical ganglion and on the nictitating membrane of the cat . In: British Journal of Pharmacology . 12, 1957, pp. 79-85. doi : 10.1111 / j.1476-5381.1957.tb01366.x . PMID 13413156 .
  28. ^ Wim JEP Lammers, Anne Marijke Lammers-van den Berg, John FB Morrison and Georg A. Petroianu: Translating Trendelenburg; back to the future . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 373, 2006, pp. 134-138. doi : 10.1007 / s00210-006-0051-8 .
  29. ^ Paul Trendelenburg: Physiological and pharmacological investigations of small intestinal peristalsis . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 373, 2006, pp. 101-133. doi : 10.1007 / s00210-006-0052-7 .
  30. ↑ WDM Paton: The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum. In: British Journal of Pharmacology 120, Supplement 1, 1997, pp. 123-131. PMC 3224282 (free full text)
  31. ↑ Paton 1986, p. 14.
  32. ↑ WDM Paton and ES Vizi: The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip. In: British Journal of Pharmacology 35, 1969, pp. 10-28. PMC 1703074 (free full text)
  33. ↑ ES Vizi: Presynaptic modulation of neurochemical transmission . In: Progress in Neurobiology . 12, 1979, pp. 181-290. doi : 10.1016 / 0301-0082 (79) 90011-X .
  34. ↑ a b K. Starke: Presynaptic Receptors . In: Annual Review of Pharmacology and Toxicology . 21, 1981, pp. 7-30. doi : 10.1146 / annurev.pa.21.040181.000255 .
  35. ↑ R. Lindmar, K. Löffelholz and E. Muscholl: A muscarinic mechanism-inhibiting the release of noradrenaline from peripheral adrenergic nerve fibers by nicotinic agents . In: British Journal of Pharmacology . 32, 1968, pp. 280-294. PMID 5646310 .
  36. ^ WDM Paton: A theory of drug action based on the rate of drug-receptor combination . In: Proceedings of the Royal Society B seris . 154, 1961, pp. 21-69. doi : 10.1098 / rspb.1961.0020 .
  37. ↑ Rang and Perry 1996, p. 304.
  38. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology. In: Naunyn-Schmiedeberg's Archives of Pharmacology 1998; 358: 1-109, here p. 37. PMID 9721010 . doi: 10.1007 / PL00005229
  39. ↑ KW Miller, WDM Paton, WB Streett and EB Smith: Animals at very high pressures of helium and neon . In: Science . 157, 1967, pp. 97-98. doi : 10.1126 / science.157.3784.97 .
  40. ^ HB Griffiths, KW Miller, WDM Paton, EB Smith: On the role of separated gas in decompression procedures. In: Proceedings of the Royal Society Series B 178, 1971, pp. 389-406.
  41. ^ DD Koblin, HJ Little, AR Green, S. Daniels, EB Smith, WDM Paton: Brain monoamines and the high pressure neurological syndrome . In: Neuropharmacology . 19, 1980, pp. 1031-1038. doi : 10.1016 / 0028-3908 (80) 90098-2 .
  42. ↑ MJ Lever, KW Miller, WDM Paton and EB Smith: Pressure reversal of anesthesia . In: Nature . 231, 1971, pp. 368-371. doi : 10.1038 / 231368a0 .
  43. ↑ KW Miller, WDM Paton, RA Smith and EB Smith: The pressure reversal of general anesthesia and the critical volume hypothesis. In: Molecular Pharmacology 9, 1972, pp. 131-143.
  44. ↑ K. Engelhardt and C. Werner: Anesthesia - Inhalation and injection anesthetics. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 253-274. ISBN 978-3-437-42522-6
  45. ^ William Paton: Man and Mouse - Animals in Medical Research. Oxford University Press, Oxford 1984.
personal data
SURNAME Paton, William
ALTERNATIVE NAMES Paton, William Drummond Macdonald (full name)
BRIEF DESCRIPTION British pharmacologist
DATE OF BIRTH May 15, 1917
PLACE OF BIRTH Hendon
DATE OF DEATH 17th October 1993
Place of death Oxford