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Historical Perspective: Centenary Series: 3 |
1 School of Medicine and Medical Science, Health Science Centre, University College Dublin, Dublin 4, Ireland
(Received 26 September 2008;
accepted after revision 2 November 2007; first published online 15 February 2008)
Corresponding author J. F. X. Jones: School of Medicine and Medical Science, Health Science Centre, University College Dublin, Dublin 4, Ireland. Email: james.jones{at}ucd.ie.
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On the shoulders of Henry Dale
A cursory inspection of the bibliography of Alcock et al. (1935) shows a singular and powerful influence: almost one-quarter of the total was written by Henry Hallet Dale, and a pump devised by Dale is used to perfuse the preparation (Dale & Schuster, 1928). The authors are primarily interested in transmitters of the autonomic nervous system, and I suggest that histamine was thrown into the mix because it was a favoured substance of Henry Dale. Finally, the drug ergotoxine, made famous by Dale, is employed to uncover hidden actions of adrenaline. It was Henry Wellcome who suggested to the young Dale that the ergot question (or ergot morass, as Dale referred to it) was worth exploring. Ergot is produced by Claviceps purpurea, a base fungus that grows on rye parasitically and when ingested can cause ergotismus gangraenosus. The order of St Anthony treated victims of ergotism; hence the disease became known as ‘St Anthony's fire’. Ergot was popular as a treatment for quickening childbirth and arresting postpartum haemorrhage. Dale realized that the ergot alkaloids are sensitive, unstable and easily decomposed; however, he worked with talented chemists and managed to isolate an active principle called ergotoxine (which was originally thought to be a pure substance but which later proved to be a mixture of alkaloids). Whilst Dale recorded and quantified the blood pressure response of a pithed cat to ergot derivatives, his predecessors observed the dry, qualitatively assessed, gangrene of a cock's comb. Dale writes warmly about the fortuitous moment that ergot pharmacology became more than a chore that pleased his paymaster, Henry Wellcome. When given a batch of suprarenal extract to test for purity, he used a spinalized cat that had already received doses of ergotoxine. Instead of the expected pressor response, adrenaline produced a fall in blood pressure. It is this moment of fortune, when he witnessed a reversal of action, that struck a prepared mind with force. When one considers the numerous pitfalls that Dale faced and dodged in the ergot morass, it is as if he walked through a cow field and trod only on clover.
Aims
Alcock, Berry and Daly wished to elucidate the actions and minimal effective doses of the neurotransmitters adrenaline and acetylcholine upon the pulmonary circulation.
Methods
A solution to the problem of recording pulmonary inflow and outflow simultaneously is illustrated in Fig. 1 of the paper. Two interdependent reservoirs act as followers of the rate of inflow and outflow and are necessarily connected because of the circular nature of blood flow. Perfusion is conducted under conditions of constant pressure. A trigonometric delight is added by limiting measurement of angles (
) to less than 65 deg. As flow is proportional to tan and this is asymptotic to 90 deg, measurement rapidly becomes unreliable when exceeds 65 deg. The Dale–Schuster pump is a single or double pump which uses an expanding and contracting rubber fingerstall in a glass dome to draw and express blood cyclically. It is worth revisiting the original description written in 1928, to observe the draughtsmanship.
Surviving without heparin by whipping the blood
In the old whipping technique, blood is received in a basin, ‘whipped’ with an India rubber brush and filtered through muslin followed by a plug of washed cotton wool. But there is another secret. Lungs are better than the best artificial ventilators, since the potent vasoconstrictor effect of freshly defibrinated blood is removed by first passage through the pulmonary circuit and vascular tone is maintained.
Surviving without statistical analysis by tabulation
The paper contains no statistical analysis but the investigators are reliable gentlemen of science. However, the paper is handicapped by the cumbersomely tabulated results of Fig. 4. According to Galileo, all science is measurement, but here flow measurements are missing, therefore no intergroup comparisons are possible. But the paper is too old for the kind of statistical analysis that is commonplace now. According to Stigler (2002), the year 1933 was the year that mathematical statistics became a professional discipline. Perhaps the precision of that date without a confidence interval is surprising in a book on the history of statistical concepts.
Findings
The modern scientific paper is a fraud in construction. It seldom reflects the original plan of investigation. Results dictate what material must be introduced to seduce and direct the reader; the discussion sustains the narrative. In this paper, the concept of ‘minimal effective dose’ is constantly emphasized to introduce a physiologically driven investigation, rather than a pharmaco-toxicological foray. The pulmonary inflow–outflow measurements are modestly downplayed as the authors concede that it cannot be precisely known what region of the pulmonary circulation has altered when these indices change. This honest, sceptical approach has the effect of instilling confidence in the authors. However, in contrast to Aldersey-Williams (2005), who analyses the minds of investigators through the style of their writings, I cannot reliably separate the hand of author, editor or referee. Historians neglect occasionally the revisionist work of invisible editorial hands.
Envoi
In summary, the findings of this paper are clear. Small doses of acetylcholine increase pulmonary inflow but larger doses decrease it; both phenomena are atropine sensitive. Adrenaline increases pulmonary venous outflow. Relive the heroic ‘plumbing experiments’ of the past: enjoy the paper!
References
Alcock P, Berry JL & Daly I de Burgh (1935). The action of drugs on the pulmonary circulation. Q J Exp Physiol 25, 369–392.
Aldersey-Williams H (2005). Findings: Hidden Stories in First Hand Accounts of Scientific Discovery. Lulox Books, Norwich.
Dale HH (1953). Adventures in Physiology. Pergamon Press, London.
Dale HH & Schuster EHJ (1928). A double perfusion pump. J Physiol 64, 356–364.
Hill AV (1965). Trails and Trials in Physiology. A Bibliography, 1909–64; with Reviews of Certain Topics and Methods and a Reconnaissance for Further Research. E. Arnold Ltd, London.
Stigler SM (2002). Statistics on the Table: the History of Statistical Concepts and Methods. Harvard University Press, Harvard, MA, USA.
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