Cushny, Arthur Robertson
CUSHNY, ARTHUR ROBERTSON
(b. Fochabers, Morayshire, Scotland, 6 March 1866; d Edinburgh, Scotland, 25 February 1926)
pharmacology, physiology.
Cushny was the fourth son of Rev. John Cushny, of the manse of Speymouth, and his wife, Catherine Ogilvie Brown. After attending Fochabers Academy, he went to the University of Aberdeen, where he graduated M. A. in 1886. The year before he had entered Marischal College, the medical school of Aberdeen, from which he graduated Bachelor of Medicine and Master of Surgery in 1889. His interest in pharmacology and physiology was aroused by John Theodore Cash, who taught physiology at Aberdeen. Upon his medical graduation, Cushny won the university’s George Thompson fellowship, which he used to study on the Continent. He went first to Bern, where he worked in the physiological laboratory of Hugo Konecker. After about a year, during which he seems also to have studied at Würzburg, Cushny went to Stasbourg to work with pharamacolgist Oswald Schmiedeberg, He stayed there for nearly three years, during the last two of which he held an assistantship in Schmiedberg’s laboratory.
In the spring of 1893 J. J. Abel, himself a student of Schmiedberg’s, came to Strasbourg and persuaded Cushny to accept the chair of pharmacology at the University of Michigan, which Abel was giving up to go to Johns Hopkins. Cushny taught at Michigan from 1893 to 1906. In the latter year he went to University College, London, as the first occupant of a new chair pharmacology and materia medica. Hitherto the latter subject had been taught at University College by one of the physicians attached to the affiliated hospital. The regulations for the new chair, the first of its kind in England, were designed to ensure an emphasis on experimental pharmacology and to release its occupant from clinical duties, Cushny was initially housed in one small, poorly lit room, but a gift from Andrew Carnegie permitted the construction of a new and well-equipped institute of pharmacology, which was opened in 1912. He remained at University College until 1918, when he succeeded Sir Thomas Fraser in the chair of materia medica at the University of Edinburgh. Simultaneously a rearrangement was made in the duties attached to the chair. As at University College, Cushny was relieved of immediate clinical duties, these falling instead to a professor in clinical therapeutics. It was arranged, however, that the occupants of the experimental and of the clinical chairs should work in close association.
Cushny was elected to fellowship of the Royal Society of London in 1906 and of the Royal Society of Edinburgh in 1919. His death in 1926 was attributed to cerebral hemorrhage. He was survived by a daughter and by his wife, Sarah Fir-bank, an Englishwoman whom he met in Strasbourg and married in the United States in 1896.
Cushny made important contributions to three separate problems: the action and therapeutic application of digitalis, the secretion of urine by the kidney, and the action and general biological relationships of optical isomers. The study of digitalis came first, both chronologically and in terms of practical importance. Cushny began to study the effects of drugs on the heart while working under Schmiedeberg, who had attracted considerable attention for his own work on the effects of muscarine and other poisons on the frog’s heart. One of Cushny’s first major papers, published while he was at Strasbourg, concerned the same problem.1 Although he had also begun to study digitalis at Strasbourg, his first publications in this area did not appear until after he had gone to the University of Michigan.
In 1897 Cushny published a major paper on the effects of the digitalis series on the circulation in mammals. He emphasized that the usual method of studying this problem rested on estimates of the blood pressure in the systemic arteries. Rejecting this method as “entirely unsuited” to the question at hand, he used instead the myocardiograph and cardiometer recently introduced to physiology by Charles Smart Roy and J. G. Adami. The measurements permitted by these instruments gave Cushny a new insight into the effects of digitalis on the mammalian heart. He found that the effects could be divided into two main stages. In the first stage, the heartbeat slowed, the ventricular contraction became more complete, and the systolic pressure increased. The second stage was marked by an accelerated rhythm due to increased irritability in the heart muscle, and by periodic changes in the strength of the ventricular contractions.
Cushny suggested that these effects resulted from a dynamic interplay between two antagonistic powers possessed by the digitalis series. On the one hand, digitalis exerted a marked inhibitory action on the heart, probably by directly stimulating the vagus nerve as well as by stimulating the central inhibitory apparatus in the medulla oblongata. On the other hand, digitalis also exerted a direct tonic effect on the cardiac musculature. These two actions were difficult to separate, and neither seemed to be confined entirely to either of the two stages. Since, however, a slower ventricular rhythm was the first dramatic indication of digitalis action, Cushny concluded that the nervous, inhibitory action predominated at first. He believed that the tonic, muscular action developed more gradually and persisted longer, so that it predominated by the time the accelerated rhythm of the second stage appeared.
Cushny then sought to relate these experimental results to the therapeutics of digitalis. He emphasized that the beneficial effects of digitalis, both as a diuretic and in heart disease, depended mainly on its direct action on cardiac muscle, and particularly on its capacity to promote the general circulation by increasing the strength and completeness of the ventricular contractions. Thus, he argued, digitalis increases the flow of urine not by any direct effect on the kidney but, rather, by increasing the blood flow in the renal arteries and thus allowing the kidney to filter a larger quantity of urinary fluid from the blood plasma. By the same token, it was the capacity of digitalis to increase the strength of ventricular contractions that made it “practically specific” in patients with incomplete systole of the ventricle.
Cushny also emphasized how cautiously the results of animal experiments should be extended to hitman patients. In particular, his experimental animals had received their digitalis by direct intravenous injection, whereas patients took the drug orally. By the time it was absorbed from the stomach, Cushny suggested, digitalis probably affected human hearts chiefly through its tonic muscular action rather than its nervous inhibitory action. He conceded, however, that this conclusion required further demonstration.
In this paper of 1897, Cushny defined the central issues that would guide all of his later work on digitalis. He revealed throughout an unusual concern with the clinical and therapeutic aspects of heart disease and digitalis. In 1899, in an important paper on the interpretation of pulse tracings, Cushny complained that clinicians had failed to keep pace with the tremendous advance in knowledge about the physiology of the mammalian heart. In this paper he sought” to fill in one hiatus existing between clinical observation and physiological experiment“. He had already noted in his paper of 1897 that lethal doses of digitalis tended to produce irregularities in the dog’s heart during the second stage of the drug’s action. In the meantime he had conducted purely physiological experiments in an attempt to elucidate these irregularities.2 Very often, he had observed, his digitalized dogs displayed an auricle in which the fibers beat rapidly but not as a coordinated whole (auricular fibrillation). These conditions—auricular fibrillation and general cardiac irregularity—could be produced by rapid electrical stimulation of the auricle as well as by lethal doses of digitalis.
Cushny now began to suspect that the auricle had been inadequately appreciated as a possible factor in the cardiac irregularities observed clinically. He was particularly struck by the apparent similarity between auricular fibrillation in dogs and an extreme irregularity observed frequently in the diseased human heart. This condition, known clinically as delirium cordis, was attributed either to paralysis of the auricle or, more commonly, to ventricular abnormalities, but Cushny thought it possible that auricular fibrillation was responsible instead. He found that the clinical sphygmogram in cases of delirium cordis paralleled exactly that obtained from dogs with auricular fibrillation, and , he pointed out that this fibrillation, like delirium cordis, could persist for a long time without proving fatal. While cautiously resisting the conclusion that “the clinical delirium cordis is identical with the physiological delirium auriculae,” he did insist that “the resemblance is certainly striking.”
In 1906, independently of H. E. Hering (1903), Cushny and Charles W. Edmunds published a diagnosis of auricular fibrillation in the case of a diseased human heart they had been observing since late 19013 Their diagnosis was at first doubted by clinicians, who found it hard to believe that a patient could survive so long with a fibrillating auricle. By 1910, however, Thomas Lewis and others had applied the electrocardiogram to a large number of diseased human hearts and had found that auricular fibrillation; was frequently involed. Almost paradoxically, moderate doses of digitalis proved to be of special benefit in cases of auricular fibrillation, and in much of his later work on digitalis, Cushny sought to explain why this should be so. From the beginning he seemed to suspect that the muscular action of digitalis was the main reason for its therapeutic value in auricular fibrillation, despite suggestive evidence that its inhibitory action must be responsible.
Clearly the most beneficial effect of digitalis in such cases was to slow the ventricular beats so that the chamber could recuperate and generate a stronger beat each time. This reduction in ventricular rate was normally ascribed to inhibitory vagus action; but Cushny eventually concluded that it ought, rather, to be ascribed to the capacity of digitalis directly to impair the muscular libers of the atrioventricular bundle. He emphasized this view in his monograph The Action and Uses in Medicine of Digitalis unci Its Allies (London, 1925). This important work also bore witness to Cushny’s long experience in the administration and assay of the digitalis series and in the use of digitalis in cases of heart disease other than auricular fibrillation. In many of these other cases, Cushny emphasized, the drug’s inhibitory action probably played an important role.
From the outset of his work on digitalis, Cushny must have encountered and considered the problem of urinary secretion. Digitalis had originally been introduced into the materia medica not as a remedy for heart disease but chiefly because of its marked diuretic properties. In his first major paper on urinary secretion (1902), however, Cushny traced his serious study of the question to an isolated observation that did not seem to fit the prevailing theory of kidney action. According to this theory, due largely to Rudolf Heidenhain, urine was formed in two stages: water and inorganic salts, taken from the blood plasma, were secreted by the cells of the glomerular capsule into the urinary tubules, then urea and uric acid were secreted into this water by the cells of the epithelium lining the tubules. In its general features this theory represented a return to the view William Bowman had set forth in 1840, when he established the connection between the glomerular capsule and the urinary tubule. Heidenhain had, however, added impressive experimental evidence to Bowman’s histological work, and in 1883 he had gathered all the evidence in a large and cogent treatise.4
The observation that first aroused Cushny’s suspicion followed the injection of phlorhizin into rabbits. This procedure produced glycosuria, as expected, but Cushny also noticed a concomitant increase in the concentration of chloride ions in the urine. This chloride increase was hard to explain on the basis of Heidenhain’s theory, which assumed that the concentration of inorganic ions in urine must depend essentially on their concentration in the circulating blood. Cushny decided to investigate more closely the fate of inorganic salts in the body. He injected isoanionic amounts of sodium chloride and sodium sulfate into the bloodstream and found that the two salts eventually appeared in the urine in concentrations that varied independently of their concentration in the blood. He argued that these results could best be explained by a modified version of Carl Ludwig’s fil-tration-reabsorption theory. According to that theory, which had been eclipsed by Heidenhain’s. urine was formed in the following way: First, all of the constituents of urine, including urea and uric acid, were filtered out of the blood plasma in the glomerular capsule, second, the dilute fluid thus produced was concentrated into urine by a simple process of diffusion-more specifically, by the diffusion of most of the water in the filtrate through the tubular epithelium. Thus Ludwig had emphasized the physical forces involved in urinary secretion, while Heidenhain emphasized the unknown “vital” forces possessed by secretory cells.
To explain his results with sodium chloride and sodium sulfate, Cushny adopted Ludwig’s theory with one fundamental modification concerning the events taking place in the urinary tubules after filtration. Simple diffusion could not explain the differential concentration of inorganic salts in the urine. Cushny therefore proposed that the epithelial cells of the tubule possessed a capacity for differential reabsorption-or, to put it another way, that the chloride and sulfate ions possessed differential powers of permeating those cells.
Later in the same year (1902) Cushny published a paper confirming this suggestion. When the outflow from one ureter was obstructed, he found, absorption in the tubules was differential, with the water and chlorides returning to the blood much more readily than did the sulfates, phosphates, urea, and pigment. In 1904 he argued that the formation of an acid urine from an alkaline plasma, a phenomenon typical during saline diuresis, could also be explained by this modified filtration-reabsorption theory. Not until 1917 did Cushny publish another major paper on urinary secretion. This time he directly criticized one of Heidenhain’s 1874 Heidenhain had injected indigo carmine into rabbits after experimentally abolishing urinary secretion. He found that the dye subsequently accumulated in the cells of the tubular epithelium. From this he concluded that under normal circumstances, the dye would have been secreted into the urine by the epithelial cells. He argued by analogy that urea, which, like carmine, is a nitrogenous substance, must also be secreted by the epithelial cells. Without disproving Heidenhain’s conclusions about indigo carmine, Cushny destroyed the analogy. He abolished urinary filtration in a rabbit, using Heidenhain’s method. Two hours later he removed the kidney, macerated it, and subjected it to careful chemical analysis. No urea could be detected, and therefore could not have accumulated in the cells of the tubular epithelium. Its total absence indicated that it had no access to the kidney once its normal passage through the glomerular filter was abolished.
Also in 1917 Cushny published his monograph The Secretion of Urine, in which he advocated the filtration-reabsorption theory. He was now able to undermine the second major argument for Heiden-hain’s theory-that the tubular epithelium was incapable of absorbing the large quantity of water that would be required by the filtration-reabsorption theory. By quantitative determinations of the rate of absorption in the urinary tubule of a cat, Cushny showed that it was in fact adequate to meet Heidenhain’s objection. He modestly called the filtration-reabsorption theory the “modern theory,” although he had, since 1902, probably done more than anyone else to establish it. He believed that this theory, unlike Heidenhain’s, would pave the way for new research, and he hoped that his book might serve “as un advance post from which others may issue against the remaining ramparts of vitalism.” He insisted that differential absorption, while it too involved unknown and therefore “vital” forces, was an essentially automatic action, The epithelial cells of the urinary tubule did not really possess powers of discrimination. Each substance in the filtrate possessed its own constant “threshold” of permeability (urea and uric acid were “nonthreshold” substances and therefore were never absorbed), and “blind” physicoehemical forces determined the composition of the exudate returned to the circulating blood.
In 1921 Cushny and a co-worker admitted that the modern theory probably emphasized too exclusively the role of the blood supply in diuresis. Finding that the action of caffeine and certain other diuretics was independent of changes in the blood supply, they concluded that these substances might reduce the resistance to filtration by a specific action on the cells of the glomerular capsule. Cushny incorporated this and other changes into the second edition of his monograph (1926). Subsequent research has confirmed Cushny’s theory in its essentials, although many details remain in dispute.5
The pharmacological action of optical isomers was the third major area in which Cushny made fundamental contributions. The problem had attracted great interest ever since Louis Pasteur, in the 184(Vs, had dtscovered optical isomers in the tartrates. Cushny felt, however, that much of the literature on the subject was distinguished more by zeal than by sound judgment. Beginning in 1904, he published seven nuyor papers in which he carefully and quantitatively investigated the pharmacological action of several pairs of optical isomers and their optically inactive racemic forms. His first paper can be taken as illustrative. He compared the effects of inactive atropine with those of its isomer, levorotatory hyoscyamine. In frogs, he found, the two isomers were equally poisonous to many organs, such as the heart and muscle, but atropine was a more powerful stimulant for the central nervous system. In mammals, on the other hand, the two isomers acted equally on the central nervous system, but the levorotatory form acted almost exactly twice as powerfully on the terminations of the autonomic nervous system. By this work, Cushny provided the first decisive evidence that a pair of optical isomers could differ in their action on the cells of higher organisms.
In his later work Cushny demonstrated more fully just how complex the pharmacological action of optical isomers could be. In many cases neither ol a pair of isomers exerted any effect, while in many other cases, cither of the isomers would yield the same effect. Any one isomer might produce entirely different effects on different tissues in the same organism, or on the same tissues in different organisms. Just before his death Cushny collected his own work and that of others into a critical monograph, issued posthumously under the title Biological Relations of Optically Isomeric Substances (1926). In keeping with his own experience, broad generalizations are rare. He even hesitated to endorse the general belief that the isomers occurring naturally are more active than their synthetic counterparts. He applied equal caution to the fundamental question of the relation between chemical structure, physical properties, and pharmacological action. On balance, Cushny supposed that such physical properties as solubility, volatility, and divisibility played a more important pharmacological role than did chemical structure in general or alleged specific “receptor substances” in particular.6 But on this issue, too, he displayed considerable theoretical reserve. “It may be surmised,M he wrote, ’that in pharmacological activity the relation between the living cell and the drug is seldom purely chemical or purely physical and that the proportion that these forces bear to each other varies from instance to instance.” He did, however, agree with Pasteur that there was a close connection between optical activity and life. Earlier, in 1919, he had described optical activity as “the most persistent evidence” and “the most definite physical characteristic” of life.7
Cushny published papers on various topics other than digitalis, urinary secretion, and optical isomerism, including two on the pharmacology of the respiratory center and two on the hepatic cirrhosis produced in cattle by the Senecio alkaloids. Besides the monographs on each of his three major interests, he also wrote A Textbook of Pharmacology and Therapeutics (1899), which reached its thirteenth edition in 1947. Here, as elsewhere, Cushny revealed his concern for the practical applications of his own work and of pharmacology in general. Because of this concern he often worked in close cooperation with clinicians, and he deplored the general lack of communication between experimental pharmacologists and clinicians.8 But neither did he minimize the importance of animal experimentation or basic research. Indeed, convinced that therapeutics had become fundamentally and irreversibly dependent on animal experiments, he produced a pamphlet in support of vivisection. And in his book on optical isomers, after giving several examples of the practical benefits of research pursued out of mere “idle curiosity,” he wrote that “Saul was not the last who, going forth to seek his father’s asses, found a kingdom.”
NOTES
1. “Ueberdic Wirkungdes Museurins aufdas Froschheiv,” in Archiv fur experinwiuelle Pathologic und Pharmacologie, 31 (1893), 432-453.
2. “On the Effects of Electrical Stimulation on the Mammalian Hearth” inJournal of Physiology.21 (1897). 213-230. written with S. A. Matthews
3. “Paroxysmal Irregularity of the Heart and Auricular Fibrillation,” in Studies in Pathology Written … to Celebrate the Quatercetitenary of Aberdeen University, William Builoch, ed. (Aberdeen 1906), 95-110; also in American Journal of the Medical Sciences, n.s. 133 (1907), 66-77.
4. Rudolf Heidenhain, “Physiologie der Absonderungs organge,” in Ludimar Hermann, ed., Handbuch der Physiologie, V (1883), 279-373.
5. See F. R. Winton, ed., Modern Views on the Secretion of Urine (London, 1956), the Cushny memorial lectures, esp. 246.For another attempt to place Cushny’ work on urinary secretion in histórical perspective, see John F. Fulton and Leonard G. Wilson, eds., Selected Readings in the History of physiology, 2nd ed. (Springfield, III., 1966), 347-378.
6. See John Parascandola, “Arthur Cushny, optical Isomerism, and the Mechanism of Drug Action,” in Journal of the History of Biology, 8 (1975), 145-165; and “The Controversy over Structure-Activity Relationship in the Early Twentieth Century,” in Pharmacy in History, 16 (1974), 54-63.
7. See Abel, “Arthur Robertson Cushny and Phamacology,” 280.
8. See esp. “A Plea for the Study of Therapeutics,” in proceedings of the Royal Society of Medicine, 4 (1910-1911), Therapeutical and pharmacological Section, 1-12.
BIBLIOGRAPHY
I. Original Works. For the titles and dates of publication of Cushny’s three monographs and his textbook, see the text above. His most important papers on digitalis and heart action are “On the Action of Substances of the Digitalis Series on the Circulation in Mammals,” in Journal of Experimental Medicine, 2 (1897), 233-299; “On the Interpretation of pulse-Tracings,” ibid., 4 (1899), 327-347: “paroxysmal Irregularity of the Heart and Auricular Fibrillation,” in American Journal of the Medical Sciences, n.s. 133 (1907), 66-77; “The Therapeutics of Digitalis and Its Allies,” ibid., 141 (1911), 469-486; and “Irregularity of the Heart and Auricular Fibrillation,” ibid., 826-837.
His major papers on urinary secretion are “On Diuresis and the Permeability of the Renal Cells,” in Journal of physiology, 27 (1902), 429-450; “On the Secretion Diuresis,” ibid., 28 (1902), 431-457; “On the Secretion of Acid by the Kidney,“ibid., 31 (1904), 188-203;” The Excretion of Urea and sugar by the Kidney,” ibid., 51 (1917), 36-44; and “The Action of Diuretics,” ibid., 55 (1921), 276-286, written with C. G. Lambie.
His major papers on optical isomers are “Atropine and Hyoscyamines; a Study of the Action of Optical Isomers,” in Journal of Physiology, 30 (1904), 176-194; “The Action of Optical Isomers. II. Hyoscines,” ibid., 32 (1905), 501-510, written with A. R. Peeples; “The Action of Optical Isomers. III. Adrenalin,” ibid., 37 (1908), 130-138; “Further Note on Adrenalin Isomers,” ibid., 38 (1909), 259-262; “On Optical Isomers. V. The Tropeines,” in Journal of Pharmacology and Experimental Therapeutics, 13 (1919), 71-93; “On Optical Isomers. VI. The Tropenies,” ibid., 15 (1920), 105-127; and “On Oprical Isomers. VII. Hyoscines and Hyoscyamines,” ibid., 17 (1921), 41-61.
J. J. Abel (see below) gives a bibliography of eightyfive works by Cushny, with incomplete pagination and minor ambiguities in dating. Although nearly complete, it does omit “paroxysmal Irregularity of the Heart and Auricular Fibrillation” (1907).
Several bound volumes of Cushny’s research notebooks and lecture notes are in the MSS Division, Edinburg University Library.
II. Secondary Literature. The best and most complete account of Cushny’s life and work is J. J. Abel, “Arthur Robertson Cushny and Pharmocology,” in Journal of Pharmocology and Experimental Therapeutics, 27 (1926), 265-286, repr., without bibliography, in Science, 63 (1926), 507-515. Also of special interest is Helen MacGillivary, “A Personal Biography of Arthur Robertson Cushny, 1866-1926,” in Annual Review of Pharmocology, 8 (1968), 1-24. For other obituary notices, see G. B., in Proceedings of the Royal Society of Edinburgh, n.s. 46 (1926), 354-356, repr. in Edinburg Medical Journal, n.s. 33 (1926), 247-249; Henry H. Dale, in Archives internationales de pharmacodynamie et de thérapie, 32 (1926), 3-8, with bibliography identical to that given by Abel; H. H. D[ale], in Proceedings of the Royal Society, B100 (1926), xix-xxvii; John D. Comrie, in Medical Life, 33 (1926), 245-248; J. F. F[ulton], in Dictionary of American Biography, 2nd ed., III, 6-7; Hans H. Meyer, in Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmokologie, 113 (1926), i-iv (after 128); and J. A. Gunn, in Dictionary of National Biography, 1922-1930, 234-235. Also see B. Holmstedt and G. Liljestrand, Readings in Pharmacology (New York, 1963), 261-268, which includes a considerable selection from Cushny’s book on optical isomers; and Parascandola (see n. 6). who provides the best available analysis of Cushny’s work on the pharmacological action of optical isomers.
Gerald L. Geison