Biographical Memoirs: Volume 57 (1987)

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OTTO KRAYER October 22, 1899—March 1S, 1982 BY AVRAM GOLDSTEIN Sie konnen eigentlich nur Soiche brauchen, die sick brauchen lassen. Schopenhauer. Neue Paralipomena §676, HandschriftlicherNachiass, Vol. 4 (Leipzig: P. Reclam, 1930~. For the style is the man, and where a man's treasure is there his heart, and his brain, and his writing, will be also. A. Quiller-Couch, On The Art Of Writing (London: G. P. Putnam's Sons, 1916~. IN your letter of 15 tune you state that you feel the barring of Jewish scientists is an injustice, and that your feelings about this injustice prevent you from accepting a position offered to you. You are of course personally free to feel any way you like about the way the government acts. It is not acceptable, however, for you to make the practice of your teaching profession dependent upon those feel- ings. You would in that case not be able in the future to hold any chair in a German university. Pending final decision on the basis of section 4 of the Law on the Restoration of the Professional Civil Service, I herewith forbid you, effective immediately, from entering any government academic insti- tution, and from using any State libraries or scientific facilities. 151

152 BIOGRAPHICAL MEMOIRS THIS REMARKABLE LETTER, dated 20 June 1933, and here reprocluced in its entirety, was from the Prussian Minister for Science, Art, and National Education. The re- cipient, Otto Krayer, who cried IS March 1982, at the age of eighty-two, will be remembered for many things—his out- standing research contributions to cardiovascular pharma- cology, his intensely enthusiastic teaching style, his very high stanclards of scientific publication and editorship, his guid- ance ant! support of the many young scientists who came under his influence and went on to significant careers in pharmacology or physiology. Krayer's unique contribution, however, was the example he set in ethical behavior behav- ior that in his thirty-fifth year anc! in the flowering of a prom- ising career brought upon him the full retribution of the Nazi hierarchy. Robert Jungk, in his book Brighter Than A Thousand Suns, A Personal History of the Atomic Scientists, writes about those clays in early 1933 in Gottingen: "Only a single one of Got- tingen's natural scientists had the courage to protest openly against the dismissal of the Jewish savants. This was the phys- iologist Krayer. He clid not allow himself to be intimidated either by his own dismissal, which was then orclered by the new Prussian Minister of Education, Stuckart, or by the threat of being clebarrecT from employment for the rest of his life." Yet rare though it was for a non-}ewish German intellec- tual to jeopardize his own future for the sake of a moral principle, "protest openly" is certainly not accurate. That was not Krayer's style. Never a political activist nor an organizer or preacher for causes Krayer wouic] have been the last to condemn his colleagues who, with various rationalizations, ' Robert Muck, Brighter Than A Thousand Suns, A Personal History of the Atomic Scientists (New York: Harcourt, Brace and Company, 1958), p. 36. .

OTTO KRAYER 153 accepted the evil situation as beyond their control. Krayer believed, very simply, that a person tract to do what their con- science saict was right, that in such matters it was not a ques- tion of weighing consequences. His letter of 15 June 1933, which so infuriated the Nazi bureaucrat, is poignant testi- mony to this belief. He explains why he cannot accept the proffered appointment to the chair of pharmacology at Dus- seldorf the chair from which the Jewish incumbent Philipp Ellinger hack just been removed: . . . the primary reason tor my reluctance is that I feel the exclusion of Jewish scientists to be an injustice, the necessity of which I cannot under- stand, since it has been justified by reasons that lie outside the domain of science. This feeling of injustice is an ethical phenomenon. It is innate to the structure of my personality, and not something imposed from the outside. Under these circumstances, assuming such a position as the one in Dus- seldorf would impose a great mental burden on me a burden that would make it difficult to take up my duties as a teacher with joy and a sense of dedication, without which I cannot teach properly. I place a high value on the role of university teacher, and I myself would want the privilege of engaging in this activity to be given only to men who, apart from their research capabilities, also have special human qualities. Had I not expressed to you the misgivings that made me hesitate to accept your offer immediately, I would have compromised one of these essential human qualities, that of honesty. It seems to me, therefore, that the argument that in the interests of the task at hand I must defer my personal misgivings, is an empty one. I would not place even a lesser task in the hands of someone who cannot remain true to himself. Moreover, it is clear to me how great is the re- sponsibility that you have to carry a responsibility that gives you the right to expect honesty. The work to which I have heretofore dedicated all my strength, with the goal of applying my scientific knowledge and research expertise to effective university teaching, means so much to me that I could not com- promise it with the least bit of dishonesty. I therefore prefer to forego this appointment, though it is suited to my inclinations and capabilities, rather than having to betray my convic-

54 BIOGRAPHICAL MEMOIRS tions; or that by remaining silent I would encourage an opinion about me that does not correspond with the facts. A moral dilemma arises when the policies of a legitimately constitutes] authority are morally unacceptable. Resistance to a tyranny that can make no claim to a popular mandate is difficult and risky enough. But HitIer's regime had all the trappings of legitimacy, it had come to power in a constitu- tional manner, and its support went creep anc! wide among the German people, not exclucting the university faculties and students. Noncompliance, under such circumstances, re- quires the courage of one's convictions to an extraordinary clegree. One's support has to come principally from one's own conscience, while one's peers, by and large, tend to distance themselves, in order to avert unpleasant repercussions and to avoic! confronting their own consciences. The events that facet! Krayer with a moral choice were unusual, from a historical perspective, but they were not unique. Fanaticism political, religious, tribal, racial, intel- lectual, nationalistic has perioclically infected one or an- other part of the earth's population since civilization began. No country and no time is immune, and so the moral di- lemma is an ever-recurring theme. During the agony of Viet- nam, American academics could witness the same cautious neutrality on the part of most of their colleagues, at least until it became acceptable anct popular to speak one's outrage. Ap- parently the simple ability to distinguish right from wrong and to act accordingly was incompatible with the scholarly temperament. "Not to clecicle is to decide," wrote the Amer- ican theologian Harvey Cox. Most fount! it easiest "not to clecicle." The surgeon Rudolf Nissen, writing of the German uni- versity faculties in 1933, has this to say: Another example of rare, almost isolated conduct amidst the crowd of opportunists was given by the Berlin Professor Extraordinarius, Otto

OTTO KRAYER 155 Krayer. His pupil, M. Reiter, has these wonderful words for this conduct: "The world is not particularly rich with people who prefer to jeopardize their career rather than sanction it with alien injustice. Nothing is more characteristic of Krayer's personality than his repeated refusal in 1933 to take over the chair in Dusseldorf, whose former holder, Philipp Ellinger, was driven from it on account of his race. The Professor Extraordinarius in Berlin, who was 34 at the time, did something that those in power felt was an open revolt and that many of his colleagues felt was at least inop- portune and disturbing in the repercussions it had for them."2 Finally Nissen remarks: "It is unfortunate that such coura- geous and manly incliviclual actions in the universities were not collectecl ant! made available to the public by officials who occupied themselves with the history of the Nazi periocl." He concludes by quoting Shakespeare (The Winter's Tale, act I, scene 2) on the importance of publicly recognizing such ac- tions: "One good (leed, dying tongueless, slaughters a thou- sand waiting upon that." Krayer's own laconic account of this landmark event in his life is found in an autobiographical sketch he wrote after his retirement for the International Biographical Archives and Dic- tionaryofCentralEuropeanEmigres, 1933-45: In the Spring of 1933, while engaged in collaborative studies with Prof. H. Rein in the Department of Physiology, University of Gottingen, I was asked by the Department of Education of the State of Prussia to take over the Chair of Pharmacology in the Medical Academy of Dusseldorf. The vacancy had been created by the dismissal of the Jewish incumbent Prof. Philipp Ellinger. Refusal to fill the vacancy because of my stated disagree- ment with the unjust policies of the government led to my immediate suspension by the Prussian Minister of Education from my academic po- sitions. Moreover, I was forbidden to enter any university premises includ- ing University and State libraries. Returning from Gottingen to Berlin, where I could make use of private libraries, I was able to continue literary work in progress. I was especially anxious to complete and edit and to supervise the printing of Volume 2 of P. Trendelenburg: Die Hormone, a task 2 Rudolf Nissen, Helle Blatter dunkle Blatter: Erinnerungen eines Chirurgen (Stutt- gart: Deutsche Verlags-Anstalt, 1969), pp. 140-44.

56 BIOGRAPHICAL MEMOIRS which had been entrusted to me by my teacher shortly before his death in 1931. Later in 1933 Krayer's academic privileges at the Univer- sity of Berlin were restored. However, he obtained a leave of absence and accepted an invitation to join the Department of Pharmacology at University College, London, with support from the Rockefeller Foundation, anct on the last day of 1933 he departed Germany. There followed an intense ant! pro- cluctive nine months of research in collaboration with E. B. Verney, who had been Starling's pupil. The substance of the investigations with Verney is recounted in a later section of this memoir. Krayer's former Berlin associate W. Felciberg, himself a recent refugee from the Nazis, was also in Lonclon. And dominating the scene was H. H. Dale, the foremost pharmacologist of the day. In the autumn of 1934 Krayer was callect to head the De- partment of Pharmacology at the American University of Beirut. His research and teaching accomplishments there are Ascribed later. Officially representing the American Univer- sity of Beirut at the Tercentenary Celebration of Harvard University in 1936, he was asked to stay on for a few months as a lecturer in pharmacology at the Harvard Meclical School. Then in 1937 an invitation was extencled for Krayer to join the faculty as associate professor of pharmacology. He ac- ceptecl and two years later became Reid Hunt's successor as heat] of the department, a position he held until his retire- ment in ~ 966. A littIe-known event of his early days in Boston sheds fur- ther light on the idealism that was a strong motivating force in Krayer's life. The Nobel peace prize had just been awar(le(1 to the German writer and journalist Car! van Ossietzky, a pacifist of international renown, who had exposed the secret rearming of Germany ant! who had been (and was until his

OTTO KRAYER 157 death) incarcerated by the Nazi regime. Hitler's response to the award of the prize was a clecree forbidding Germans to accept any Nobel prize in the future. At the regular meeting of the German Chemical Society on May 8, 1937, the presi- clent of the Society, Professor Stock, acictressed himself to the honor bestowal upon van Ossietzky: "Every true German," he said, "must regard as a slap in the face this insulting abuse . . . an abuse dictated by political hatred. It is unclerstanclable that both the government and the people are indignant over this, and want nothing more to do with Nobel prizes . . . the crime of the Norwegian parliament's committee will be re- gretted cleeply by Science."3 Krayer's immediate reaction was the following brief note to the society's office: "The remarks of President A. Stock concerning the awarcl of the Nobel peace prize, which are printed on page 121 of the Proceedings of the German Chemical Society of 9 June 1937 oblige me to request that you strike my name from the list of members of the German Chemical Society." Professor Stock, in reply, couIct only imagine that he had been misunderstoocI. "I was only reflecting the feelings of every German scientist," he wrote, "in being upset by such a conscious provocation . . . by the honoring of a person who- even before the time of Hitler! hac] been branclect a traitor; and in cleploring that the scientific Nobel prizes had to suffer from this circumstance.... Perhaps you will be so kind as to write me a word of clarification." Krayer's response will ring a familiar note for all who, as students or colleagues, came under his influence. It recalls the curious blend of careful reasoning and objective presen- tation of facts on the one hancI, coupled with extraordinary 3 A. Stock, "Opening Remark," Berichte der Deutschen Chemischen Gesellschaft, 70(1937): 12 1.

58 BIOGRAPHICAL MEMOIRS emotional intensity on the other, that colored many of his formal lectures and informal discourses. Dear Mr. President: I am happy to communicate to you the reason for my protest against your remarks. However, it is not my intention to enter into a discussion about the political expression "traitor". That this expres- sion does not necessarily have a precise ethical value must be obvious to everyone who has experienced how easily the meaning can be changed by various political trends that appear especially strongly and clearly at times of upheaval in the structure of a State. What made me write my letter of 3 September was the urge to express the view that not every German and- as I am convinced not every Ger- man scientist shares your feelings of being upset by the award of the recent Nobel peace prize. The reason for this conviction is what I have read over the last ten years of the writings of Carl van Ossietzky and have learned from other sources about him. I have had no occasion to meet this man personally. But whoever, over the past decade in Germany, has followed the course of his career in an unprejudiced way would even if he were a political op- ponent—not be able to ignore the fact of the man's extraordinary person- ality. Here is a man who, in a hard life full of work and an abundance of general human and political experience, has developed a world outlook and has deduced from it the principles of his life philosophy, who has made the profession of political writer his mission in life, and who is ready to dedicate to this profession not only all the strength of his spirit but also his whole personality. An unyielding character who, whenever the obli- gation of sincerity necessitates, openly uses his right of free speech to ex- press his opinion. A man who is not motivated by the lust for power and fame but who is forced to speak by the persuasion of the rightness of his beliefs, and who fights unafraid for that persuasion with the force of his arguments. Carl von Ossietzky has proven the sincerity of his mind and his selflessness by again refusing (he had already been amnestied once) to evade responsibility for his convictions. To back up his words with deeds was a necessity of life for him although he must have known that he could not expect any justice from his political enemies. The reason for such a judgment as you, Mr. President, have formu- lated, must be sought in an ethical evaluation of the man. I do not find

OTTO KRAYER 159 sufficient basis for your interpretation, and I am not of the opinion that the scientific Nobel prizes have lost any of their value or significance by the honoring of Carl van Ossietzky. It is to the credit of the Nobel orga- nization that it honored the ethical qualities of this man; that is my con- viction. What can promote peace between nations if not the deeds of such men, who are motivated by a pure and deep consciousness of their re- sponsibility to a higher human order than is represented by the nation into which we [sic!] are born? A final incident is noteworthy, again for the light it sheets on the ethical stanciarcls by which Krayer consistently guiclect all his actions. In 1965 the Academic Council of the Medical Academy of Dusseldorf votect to confer honorary member- ship on Krayer. Writing about this decision, the rector of the University explainer] as follows: They would like thereby to show their appreciation of the stand you took when, on grounds of conscience, you refused the call to the chair of pharmacology and toxicology in Dusseldorf in 1933, which would have been your first opportunity to be head of your own institute. At the same time the Academic Council wishes to acknowledge the fact that even after your emigration, and despite the unpleasantness you experienced in Dus- seldorf, you nevertheless maintained and furthered your contacts with German science. Not the least, we would also like by our decision to ac- knowledge your scientific accomplishments, which relate to us in a special way through a traditional field of research at our Academy, namely, heart and circulation research. Krayer's immediate response was to accept the honorary membership with pleasure. But as time passed, he evidently became increasingly uneasy. Somehow a mutually suitable ciate for the presentation ceremony in Dusseldorf collie not be arranged. Finally, on January 26, 1966, Krayer sent what must have been a very difficult letter to write, as we can sur- mise from the three different preliminary handwritten drafts that are preserved, each full of cleletions ancT alternative

160 BIOGRAPHICAL MEMOIRS worclings. Addressing the rector of the University of Dussel- clorf, Krayer wrote: In the course of the correspondence with you concerning the time of my visit to Dusseldorf, I have thought more deeply about the honor you are planning for me. I have come to the conclusion that the right thing for me to do is not to accept the honorary membership of the Medical Academy of Dusseldorf. Despite my happiness at your first letter, which reached me during my trip to Japan, I had certain reservations from the beginning. It is now clear to me that the original ethical position I took in 1933 does not permit of any external reward. I must ask you, therefore, to nullify the decision of the Scientific Council of the Medical Academy. I regret that I took so long to express my convictions clearly. Krayer closes with the hope that his decision will not cause bact feelings to mar his personal relationships with colleagues at Dusseldorf. The reference, in the rector's original letter, to Krayer's maintaining anct furthering contacts with German science will be cryptic to those unfamiliar with an episode that fol- lowed shortly on the close of World War Il. With Central Europe literally in ashes, its universities and research insti- tutes in ruins, and its people starving, the Unitarian Service Committee organized a medical mission to Czechoslovakia with Harvard carctiologist Paul DuctIey White as director and Krayer as an active participant. During that trip Krayer be- came fully aware of the (levastation of the German universi- ties through personal visits with university colleagues. It must have been then that he formulated a plan for rendering spe- cial material and moral assistance to the German academic communities. On his return to Harvard, he foundecI, and served as secretary-treasurer of, a Committee to Help Ger- man University Scientists. By lL948 a medical mission to Ger- many had been organized by the Unitarian Service Commit- tee, with Krayer as its chairman. This effort was supported

OTTO KRAYER 161 by the Department of State and by the U.S. occupation au- thorities. The visits to the universities of Frankfurt, Berlin, Gottingen, Munchen, Tubingen, Freiburg, and Heidelberg brought a sense of concern and collegial friendship to sup- plement the material sect aIreacly being furnished by various groups in the United States. . RESEARCH CONTRIBUTIONS Krayer's first research, publishecl in 1926, the same year he received his M.D. degree at Freiburg, concerned the phar- macologic properties of apococleine, an opiate alkaloid closely related to apomorphine. In this work he first experi- enced the importance of employing only pure compounds in pharmacologic investigations a recurrent theme in his later writings. Here he shower! that apococleine obtained from one manufacturer was pure and gave reliable and reproclucible results, while impure mixtures behaves! differently in impor- tant respects. Two investigations followed dealing with the pharmacologic and pharmacokinetic aspects of thyroid hor- mone action (1928a,b), no doubt inspirer! by the endocrino- logic interests of his mentor Paul Trenclelenburg. By 1929, however, he seems to have found his metier. In that year he publisher! the first of two investigations into the cardiovas- cular toxicity of Neosalvarsan, an organic arsenical then in wide use for the treatment of syphilis. Thus was initiated a lifelong commitment to the study of the circulatory system. Over a period of four decacles, Krayer published seventy- six original research articles (not counting abstracts and text- book chapters), all but one in the field of cardiovascular phys- iology and pharmacology; the exception was a brief note concerning pumpkin seects as a chemotherapy for tapeworm infestation, a byproduct of his brief stay at the American Uni- versity of Beirut. Nearly all his research employed a single technique the clog heart-lung preparation (HEP) techni-

162 BIOGRAPHICAL MEMOIRS cally a very difficult setup of which he was the acknowledged world-class master. From the purely statistical and descriptive aspects of Kray- er's research career, there is much to be learned. By standards presently in vogue, one might judge a lifetime output of seventy-six original papers to be surprisingly scanty. Closer scrutiny, however, reveals several features decidedly no longer fashionable today. Of the total output, for example, one-third were sole-author papers; and Krayer was first au- thor on another one-third. To those who knew him, these numbers merely express what we saw every day in the "heart- lung room" a scientist with hands-on involvement in every phase of his research and a devotion to thoroughness that precluded the publication of incomplete or indecisive exper- imental results. Nor did Krayer follow the traditional German procedure (now so common elsewhere, too) of making the department or institute head a pro forma coauthor of all papers by junior colleagues. Here numbers and names are instructive. In the last decade of his career at Harvard, for example, Krayer himself was first author on three papers and coauthor on ten others. In the same period, ninety-one additional investiga- tions in the field of cardiovascular pharmacology were pub- lished by those working under his tutelage, and none of those carry his name. To Krayer, evidently, coauthorship implied direct responsibility for important aspects of the experimen- tal work. He was always generous with suggestions, technical assistance, and criticism, but he would not put his own name to research unless he had been a direct participant. ~ consider it more remarkable now than ~ realized at the time that al- though at the beginning ~ was only a medical student en- gaged in part-time research in his department, it was taken as a matter of course that ~ would coauthor work for which Krayer had prime responsibility and would be sole author

OTTO KRAYER 163 when he hac! not been involvect cTirectly. This was for me a refreshing contrast to my one previous (and more typical) experience of publication, a short cticiactic clinical article ~ conceived and wrote without assistance, which my clinical in- structor then submitted for publication with his own name aciclec] as first author! Another interesting number is the mean length of Kray- er's papers Il.2 pages and the fact that one-quarter of them exceeclecl 14 pages. This, of course, was in the spirit of the times and not only in the German literature so noto- rious for prolixity. If research was worth doing well, it was worth publishing well and fully. One's pride as a scientist simply ruled out the publication of incomplete or uncertain or fragmentary data. Modern biomedical science suffers from the "bit-by-bit" syndrome, wherein a staccato series of short papers report findings that may be raw, superficial, un- ctigestect, unconvincing, unexplorecT, anct uninterpreted. Krayer's style, the very opposite, was to make each paper a complete Arbeit, every cletai! honec! as nearly as possible to perfection. In an obituary on Otto Loewi (1962b), he wrote the following laudatory sentence, which is also an apt clescrip- tion of his own attitude: "He felt that any work worth pub- lishing deserves] as much care in the preparation of the man- uscript as in the concluct of the experimental work." Krayer held the belief that the aim of pharmacologic in- vestigation is to elucidate mechanisms of drug action, that phenomenologic observations by themselves are only step- ping stones to this ultimate goal. It follows automatically from this position that one's efforts have to be focused on a single problem and preferably on the perfection anct use of a single methoctology. The history of every fielcT of science tells us that technique is the key to progress. Given the avail- able knowledge base ancT technology, Krayer's adaptation of the Starling heart-lung preparation (HEP) to pharmacologic

64 BIOGRAPHICAL MEMOIRS . Investigations represented a major achievement. The HEP was a new and powerful tool, with which a lifetime of re- search on cardiovascular cirugs couIc] be carried out. A fundamental problem in pharmacology is the multi- plicity of the actions of most drugs. Even a drug that acted with absolute specificity on a single receptor would usually find that receptor in numerous organs throughout the bocly. And in reality most drugs have overlapping selectivities for more than a single type of receptor cleployecI in more than one organ system. Thus even the direct actions of a drug are often too complex to analyze in the whole animal. To this clifficulty must be aciclec! the confounding effects of indirect (secondary) actions, such as physiologic reflexes or other adaptive responses to a primary drug action. This problem . — Is especially serious for cardiovascular drugs since the heart and circulation are under continuous reflex regulation. Con- sicler, for example, a compounc! that increases the heart rate. Does it do so by a direct agonistic effect on receptors me- ctiating carctioacceleration at the pacemaker? By antagonist effect on receptors mediating cardiac slowing? By causing the local release of a carctioaccelerator neurotransmitter? By re- leasing a carclioaccelerator hormone from a ctistant tissue into the circulation? By stimulating chemoreceptors, leading to reflex decrease of vagal activity or increase of sympathetic tone? By causing a pharmacologic action remote from the heart (e.g., a decrease in blood pressure through relaxation of arteriolar tone) that leacis to a reflex carctioacceleration? In the HEP the heart and lungs remain in situ, but the entire output of the left ventricle (except for the coronary circulation) is router! through an external circuit. There the peripheral resistance is under the experimenter's control, and the height of the blood reservoir determines the pres- sure at which the right atrium fills. Oxygenation is provided in a quasi-normal manner by a respiration pump. The in- nervation can be left intact, or specific kinds of partial or

OTTO KRAYER 165 complete Enervation can be carried out. Effects of drugs on the heart rate (chronotropic effects), force of contraction (in- otropic effect), atrio-ventricular conduction (dromotropic ef- fect), ant] other metrics can be studied. Thus the preparation offers a means to isolate sites anc! mechanisms of action of carcliovascular or carcliotoxic drugs free of multisite and re- flex effects. Krayer's first use of the HEP was during his Berlin period in the studies of Neosalvarsan toxicity (1929, 1930a). He dis- coverect that the toxic agent was an oxidation product of the ctrug, and he showed that the effect was a direct one on the vascular beds of all the important organs. His succinct sum- mary establishes the style that was to become his hallmark. Analyzing the evidence that the oxidation product causes a dose-relatect reduction of blood flow through the heart, lungs, kidneys, and liver, he conclucles: "The increase in vas- cular resistance in these organs is to be attributed to changes in the vessels themselves. These changes are the cause of the far-reaching disturbances of hemoclynamics, they are not the result of hemoclynamic changes elsewhere." Finding confusion among clinicians concerning the phar- macotherapy of heart failure, Krayer developed precise quantitative measures in the HEP, whereby carctioactive drugs could be characterized (1930b; 193 la,b,cI; 1932b,c; 1933e). It was in his paper, "Versuche am insuffizienten Her- zen" (1931~), that Krayer developer] extending the con- . . cepts laid clown by his teacher P. Trendelenburg a stanciarcI procedure for using the HEP to stucly drug effects on the failing heart. The competent heart increases its output in response to elevation of the venous reservoir without any significant increase in right atrial pressure that is, the ad- clitional inflow reacts responsively to an increased stroke vol- ume. A large close of a barbiturate reliably produced failure of a desired degree, which could be measured quantitatively as an impaired ability of the heart to respond this way. This

166 BIOGRAPHICAL MEMOIRS ability, after impairment by barbiturates, was enhanced by digitalis glycosicles even in the denervated heart, that is, in the absence of any change in the heart rate. Later (194Sb) this phenomenon was observed with other drugs known for their central depressant effects, and it occurred at concentra- tions that would have been in the lethal range for the whole animal. The important advance in this paper was the demonstra- tion of a method for determining quantitatively the limits of cardiac sufficiency in response to specific measured changes in right atrial pressure. Later a specific "competence index" was developed to express the heart's response numerically (1948b). This method allowed a clear distinction to be made between ctrugs that primarily affected heart rate anct those (like digitalis) that truly improved the work capacity of the impaired cardiac muscle. The paper conclucles: "A cardiac clrug, in the most rigorous meaning of the term, must restore the ability of the failing heart to put out a greater volume per beat and thereby and not simply by a rate increase restore the limits of its sufficiency." Thus the study of the actions of cardioactive drugs could be pursued "uncler controlled con- clitions of heart failure." Krayer's mastery of the HEP lee} to a very fruitful colIab- oration with W. Feldberg in the Department of Physiology at Berlin. Loewi's demonstration of chemical neurotransmis- sion in 1921 tract ushered in a new era for physiology and pharmacology. By the early ~ 930s, evidence inclicated strongly that the Vagus-Stoff was acety~choline, which could be identified in the leech muscle treated with the specific cho- linesterase inhibitor physostigmine. The early experiments had been carried out with frogs. In the classical paper by Felciberg anct Krayer (1933c), intact clogs and cats were used at the outset to show that an "acety~choline-like substance" is releasect into the coronary circulation of mammals on elec- trical stimulation of the vague. But here was also the perfect

OTTO KRAYER 167 opportunity to apply the HLP. The authors explain: "In or- der to make sure that as few extracardiac influences as pos- sible modify the effect of stimulating the vague, we consict- ered it necessary also to demonstrate the Vagus-Sto~ in the HEP." The same results were obtained in the HEP as in intact animals (Figure I). Unless physostigmine was act~ecl both to the coronary circulation and to the bioassay preparation, and unless the vagus was stimu~atecT, no "acety~choline-like sub- stance" was cletectable. In a subsequent refinement of this experiment, Krayer (with Verney), soon after his emigration to Lonclon, showed that the vagus clid not have to be stimu- lated artificially but conic] be stimulated reflexly by an in- cluced increase in blood pressure (1934b). These ingenious experiments were carried out with an innervated HEP, the head (with no vascular connection to the heart) being per- fused from a clonor dog. Krayer's interest in the Veratrum alkaloids, which dome natecI his research interests from 1942 on, was stimulated, according to his own account ~ ~ 962b), by his learning through a medical stuclent's report that these substances were being used to lower blood pressure in ecIampsia at the nearby Boston Lying-in Hospital. Crude extracts of the Euro- pean Veratrum album (white false hellebore), the North American Veratrum viride (green false hellebore) (Figure 2), and the Central and South American Veratrum sabadilla . (Schoenocaulon officinale) aIreacly enjoyed] something of a rep- utation as beneficial in the management of heart clisease. All parts of these plants and also of the North American Zyg- aclenus family contain the carclioactive principles. As long ago as ISIS, Meissner and also Pelletier and Cav- endou isolatecT veratrine, a potent alkaloiclal mixture from sabactilIa seeds. While still at Berlin, and recalling his earlier experience with apococleine, Krayer had remarket on the futility of sophisticated pharmacologic studies with crucle ex- tracts. At that time he wrote: "Only when pure substances

168 BIOGRAPHICAL MEMOIRS - I / / / / / / / l IJ II III IV 1 FIGURE 1 The first demonstration of acetylcholine release in a mam- malian organism. Blood from the coronary sinus of a dog was tested on the eserinized leech muscle. Before injection of the cholinesterase inhibi- tor physostigmine, the blood had no effect on the leech muscle (I). Nor was there any effect of blood collected during electrical stimulation of the vagus (II), even though a transient cardiac arrest was produced. After the dog was injected with physostigmine and atropine, the blood was still with- out effect (III); but now vagal stimulation released an "acetylcholine-like substance" into the coronary blood (IV). [From Feldberg and Krayer, 1933b]. (Technical limitations made it necessary to reproduce this kymo- graph tracing and that in Figure 4 as black-on-white records rather than the original white-on-black.) are available will it make sense to determine, by means of a thorough pharmacologic analysis, the conditions under which a favorable effect on the heart and an improvement of the circulation can be achieved" (1933cI). Thus the initial ex- periments with a crucle "veratrine" mixture ~1942a) were im- mectiately followecl by studies on pure alkaloicls. Krayer

OTTO KRAYER 169 FIGURE 2 Veratrum viride, popularly known as Indian poke- weed. This North American wild plant and related species that grow in Central and South America and Europe contain the cardioactive steroidal alkaloids in their roots, stems, and leaves.

170 Veracevine BIOGRAPHICAL MEMOIRS ~OH l l r" OH POOH HO ~,<~J OH OH Veratramine POOH HO I FIGURE 3 Typical structures of the two families of veratrum alkaloids. Left: Veracevine, the base of the ester alkaloid veratridine, which contains one mole of veratric acid (3,4-dimethoxybenzoic acid). Other ester alka- loids such as protoveratrine are mono-, di-, or trimesters of various organic acids. Right: Veratramine, a typical secondary amine alkaloid, which occurs naturally as a glycoside with a single mole of glucose. sought and received help from chemists, beginning in 1941 ant! continuing for the next twenty-five years. At the De- partment of Chemistry at Harvard, there were R. P. Linstead and D. Todd, later S. M. Kupchan, anti then in his own cle- partment F. C. UhIe. Much help came also from W. A. Jacobs anti L. Craig at the Rockefeller Institute anct also from chem- ists at Eli Lilly anc! Company anct Winthrop Chemical Com- pany. There are two major groups of veratrum alkaloids, the tertiary amine esters and the secondary amines (Figure 3), anc! their pharmacologic actions are entirely different. The special virtues of the HOP provect wonclerfully suited to the investigation of these compounds, and Krayer studiect them for the rest of his research career. Most of our present knowI- ecige about the pharmacology of this group of naturally oc- curring carctioactive substances is clue to that sustained effort by Krayer ant! his colleagues over the years. . . . .

OTTO KRAYER 171 The tertiary amine esters, such as protoveratrine A and veratricline, each contain a polycyclic polyhy(lroxylated amine (e.g., veracevine, as in Figure 3) anc} one or more or- ganic acids. Much as with acety~choline, the ester linkage prover! to be essential to the full pharmacologic activity. The "veratrine effect" was well known in skeletal muscle a re- petitive discharge after a single stimulus, now recognized to be a consequence of the opening of sodium channels by the cirug. The hypotensive effect is a reflex action caused by stim- ulation of chemoreceptors in the heart, lungs, ant! carotid sinus (the BezoIct-]arisch effect). The hypotension is accom- panied by braclycardia, also of reflex origin, ancT is mectiatecl by a vagal mechanism, as conic! be demonstrated by compar- ison of the innervated and denervatect HEP (1943b,6; 944b,c). With the discovery of the reflex mechanism of action of the ester alkaloids, Krayer characteristically immersed him- self in a scholarly investigation of the very early work of von Bezold and the later studies of Jarisch. Eventually he pub- lished a historical review with forty-nine citations, "The His- tory of the BezoIcl-Jarisch Effect" (1961a), as a tribute to Pro- fessor Tarisch on the occasion of his seventieth birthday. One of the conclusions was that the name of this reflex, hitherto known as the Bezold effect, should more appropriately also bear the name of ~arisch. Krayer's studies with the tertiary amine polyesters, espe- cially protoveratrine A, led him to explore their therapeutic utility in human hypertension. With E. Meilman, a clinician at nearby Beth Israel Hospital, he carrier! out systematic studies on closage, toxicity, and duration of action (1950b; 1952e; 19771. Protoveratrine A was chosen from among a number of candidate compounds for its favorable therapeu- tic ratio and long duration of action when given by the oral route. In contrast to veratricline, its action was more selective

172 BIOGRAPHICAL MEMOIRS for sensory nerves than for skeletal muscle. Also favorable was a positive inotropic action in the failing heart, as clem- onstratecl by an increased work capacity in the HEP, later confirmed in patients. The positive inotropic action of vera- tridine or protoveratrine is of theoretical interest because of its similarity to the effect of the digitalis glycosicles. Inhibition of the sodium pump (soclium-potassium ATPase) by the lat- ter anc! opening of sodium channels by the former could both, through their different mechanisms, cause a net in- crease in sodium influx. The basic pharmacology of the tertiary ester veratrum alkaloicis is summarized in an exhaustive review by Krayer anct Acheson ( 1946b). Protoveratrine A hacT some usefulness for a time in the treatment of malignant hypertension, hy- pertensive encephalopathy, and ecIampsia (1949h, 195Sa). Since it effectively lowered the "set point" for reflex control of the blooct pressure without disturbing the adaptive re- flexes themselves, it did not (for example) cause postural hy- potension such as is common with the autonomic ganglionic blocking agents. Unfortunately, nausea anct vomiting were common side effects (also from stimulation of vagal affer- ents), and in time a whole armamentarium of more effective antihypertensive drugs was developect. Thus protoveratrine A was eventually supersedecl, but it undoubteclly played a seminal role by pointing the way to a practical pharmaco- therapy of hypertension. The secondary amine alkaloids and their glycosides proved to have an entirely different pharmacology from the tertiary amine esters despite the close similarity of chemical structure. These compounds, of which veratramine (Figure 3) is the best studied, are also hypotensive in their action, but their most interesting effect proved to be a cardiodecelera- tion by a direct effect on the cardiac pacemaker (1949cl,f,g). There were two main lines of evidence. First, the effect was

OTTO KRAYER 173 not blocked by atropine, which abolishes the action of ace- ty~choline released by the vague. Seconcl, in the clenervatec! HEP infused continuously with epinephrine, the steacly-state marked increase in heart rate is promptly abolishect by small doses of veratramine. At the same time the positive inotropic action of epinephrine remains unchanged. Thus this exper- iment sharply separates the cellular mechanisms that mediate the chronotropic anct inotropic ejects of the catecholamines (Figure 41. The novelty lay in the fact that although antago- nists to the presser action of epinephrine tract been dis- covered, no antagonist to the cardioaccelerator effect was known. Most of the thirty-seven papers in the series entitlect "Studies on Veratrum Alkaloicts" dealt with these secondary amines and their glycosicles. Related steroid alkaloids with similar pharmacologic effect were found among the com- pouncIs isolatecl from plants of the Zygadenus and Solanum families. The aglycones and glycosicles were found to be equi- potent. Investigations of the structure-activity relationships, which incluclecl a group of novel steroids synthesized from pregnenolone by F. C. UhIe in Krayer's department, revealed that high potency required the N atom to be in a piperidine ring. The selectivity of veratramine anct its congeners for the pacemaker tissue intrigued Krayer. Not only did veratramine lack the positive inotropic actions of epinephrine, it also lacked all the other characteristic carcliovascular effects of the catecholamines. It diet not constrict the peripheral arterioles and therefore lacked presser action. It did not dilate the cor- onary vessels. It ctict not share the depressant effects of epi- nephrine upon the functional refractory period and A-V propagation time within the heart. Krayer wrote: "When a group of substances exhibits a high degree of selectivity of action, it shouIcl attract the investigative curiosity of the phar-

174 WI 1 l I output In 100 cc. BIOGRAPHICAL MEMOIRS I 111 1 1 1 1 1 1 1 1 1 1 1 1 1,,,,,,,,,,,,,,,,, time In minutes mm Hg —120 _100 _ 80 AP hi 105 105 10597 96 92 93 I ~ 1 1 1 1 —60 1~ ~ ~ ~ ~ ,, 200 1 \- ~ ~ ~~ ~~— mm H2O 100 80 40 ..~' 20 96 98 I . 1 FIGURE 4 Dissociation, by means of veratramine, of the chronotropic and inotropic actions of epinephrine. The record is from a dog HLP in failure, treated with veratramine during the previous two hours. Epineph- rine (10 micrograms) was administered at the broad marker signal on the bottom line. Within a minute, epinephrine increases the cardiac output (top line), thus lowering the elevated right atrial pressure and pulmonary pressure; it also increases the systolic arterial pressure all without any increase of heart rate. Symbols: AP, arterial pressure; PP (lower curve on left, middle curve on right), pulmonary pressure; RAP (middle curve on left, lower curve on right), right atrial pressure; bottom horizontal row of figures, heart rate per minute. [From Krayer, 1949d]. (See parenthetic note under Figure 1 legend.) macologist. The search for selective activity and the analysis of its nature is the central theme of his scientific pursuit" (1952cI). As Krayer learner! later (19586), the direct action of the secondary amine alkaloicts on the pacemaker was not a block- ade (at the receptor level) of the accelerator action of the catecholamines. Thus, veratramine was not a true forerun-

OTTO KRAYER 175 ner of the beta-adrenergic receptor blocking agents, which have proved to be so useful therapeutically. Krayer's work, however, was the first demonstration that a carclioselective antagonism of a noracirener~ic nhv~iolo~ir~1 r~ rt ~t the sino-atrial nocle was possible. O__ ~ __J ~ ~ t~ ~ ~^ ~ ~ ~_~ ~~ ~~ Often, as plant alkaloicts of various families became avail- able in pure form, Krayer would test their effects in the HEP. Thus it was that in 1955 he began to examine the action of reserpine, a pure alkaloid from Ranwolfia. The Ranwolfia al- kaloicis had long been used in India for their tranquilizing ejects, and the early 1950s hacl seen intensive interest in their therapeutic potential in Europe and the United States. Reserpine tract been introcluced into psychiatric practice as a tranquilizer ant! also for its antihypertensive effect. Because reserpine was regarcled as primarily a psychopharmacologic agent, those interested in its mechanism of action naturally turned to the brain; even the hypotensive effect was pre- sumed to be centrally mediated. It had aIreacly been shown, first in Brodie's and then in Marthe Vogt's laboratory that reserpine clepletes the brain of its serotonin stores, and this same approach was being extended to brain catecholamines in several laboratories. The immediate stimulus for Krayer's interest was a letter In the New England fournal of Medicine reporting heart failure . - in patients treated with reserpine. Krayer seized the oppor- tunity to exploit the unique value of the HEP for distinguish- ing clirect peripheral actions of ([rugs from those requiring intact innervation, and he was soon able to sort out the com- ponents of reserpine's actions. The alkaloid produced an im- me(liate carclioacceleration that was similar in all respects to that of an infusion of norepinephrine. Matti Paasonen, a vis- iting scientist from FinIancI, measured tissue anct blooct cat- echolamine levels and found that the norepinephrine con- tent of the heart fell sharply that is, reserpine clepleted the cardiac stores. In the HEP from reserpine-pretreated dogs,

176 BIOGRAPHICAL MEMOIRS reserpine failed to produce the characteristic carctioacceler- ation. Moreover, serotonin infusions had no effect on the heart rate, showing that serotonin release (which also occurs) floes not participate in the carclioaccelerator action. An ad- ditional finding of interest, revealing an independent effect of reserpine, was that in the HEP under the rate-increasing effect of a catecholamine infusion, reserpine recluced the heart rate in an atropine-resistant manner reminiscent of veratramine. All these effects occurred! also in the clenervatec! HEP, permitting the conclusion that ". . . reserpine exerts an action upon the heart in the absence of connections with the central nervous system" (195Sb). Curiously (although it was not realizer! until later), the release of catecholamines in amounts sufficient to produce effects of their own was a pe- culiar property of the HEP, not evident in most organs or in whole animals. These important studies were published orig- inally in 1957 in three abstracts in Federation Proceedings ~ ~ 957a), Acta Physiologica Scandinavica ~ ~ 957b), and the Jour- nal of Physiology ( l 957c). In summary, Krayer had shown that reserpine clepletes biogenic amine transmitters from peripheral as well central stores by a direct action. Thus the reserpine effect was a gen- eral phenomenon, not limited to the central nervous system, and this was pointed out explicitly in one of the 1957 ab- stracts. As so often happens, however, the same discovery was made almost simultaneously in several laboratories. Caris- son's group in Sweden was studying the depletion of cate- cholamines in peripheral as well as central tissues. A short paper from this group,4 which was submitted for publication October 20, 1956, reported on the (1epletion of catechol- amines from rabbit heart by reserpine. They also showed that 4A. Bertler, A. Carisson, and E. Rosengren, "Release by Reserpine of Catecho} Amines from Rabbits Hearts," Natunvissenschaften, 43(1956):521.

OTTO KRAYER 177 reserpine-treated adrenalectomizect cats given carbacho} to stimulate sympathetic ganglia and atropine to block the mus- carinic actions of carbacho! hacl no blood pressure rise, as they wouIc! normally have done as a result of norepinephrine release at the sympathetic nerve terminals in arteriolar walls. Moreover, electrical stimulation of the splanchnic nerves was without its usual hypertensive effect in these animals. On March 22, 1957, Broctie et al. (National Institutes of Health) submitter! a paper under the title "Possible Interre- lationship Between Release of Brain Norepinephrine and Serotonin by Reserpine."5 The paper also includes] a report of the depletion of norepinephrine from rabbit heart even after high cervical section of the spinal cord, showing that the clepleting action of reserpine was direct ant! not centrally meciiatect. The British pharmacologist I. H. Burn (Oxford) visited Krayer in 1957. In a letter ciated May 7 of that year, express- ing thanks for hospitality, Burn wrote: ". . . ~ enjoyed seeing the results with reserpine in the heart-lung preparation." More than a year later, on June 3, 1958, Burn and Rand submitted for publication "The Action of Sympathomimetic Amines in Animals Treated with Reserpine."6 This major contribution establishecl very thoroughly that reserpine cle- pletes the stores of norepinephrine in arterial walls. In acl- clition, several bioassay preparations from reserpine-treated animals were used to demonstrate that some sympathomi- metic amines (e.g., tyramine and other noncatecho! phenyI- ethylamine derivatives) only act when the tissue catechol- amine stores are intact, ant] therefore presumably owe their ~ B. B. Brodie, I. S. Olin, R. G. Kuntzman, et al., "Possible Interrelationship Be- tween Release of Brain Norepinephrine and Serotonin by Reserpine," Science, 125(1957): 1293-94. 6J. H. Burn and M. J. Rand, "The Action of Sympathomimetic Amines in Animals Treated with Reserpine," Journal of Physiology (London), 144(1958):314-36.

178 BIOGRAPHICAL MEMOIRS own actions to the release of catecholamines. In addition, it was reported that tissues from reserpine-treated animals were supersensitive to catecholamines and that both the in- sensitivity to tyramine and the supersensitivity to catechol- amines could be reverser! by an infusion of norepinephrine that repletes the stores. Further significant conclusions were that a continuous slow release of norepinephrine from arter- iolar stores probably plays a role In maintaining the normal vascular tone anct also that circulating catecholamines from the adrenal gland probably participate in maintaining the stores at their proper level. This paper had an immediate and lasting impact in physiologic and pharmacologic circles; it is still regarded as a landmark contribution. The full-length ~ 958 papers from Krayer's group ~1958b,d,e,f) tract not appeared} in print when the manuscript by Burn ant! Rand was submitter! for publication. Curiously, however, none of Krayer's three 1957 abstracts is cited, nor is any "personal communication" acknowledgect. We know from his intimate associates that Krayer felt miffed; he may even have thought that Burn made improper use of what was learned during the May 1957 visit. A letter from Burn to Krayer dated October ~ I, 1958, is interesting in this respect. Eclith Bulbring, one of Burn's colleagues at Oxforc! and a longtime friend! of Krayer (they were colleagues in the Berlin clays), had just returnee} from a visit to Boston. Burn writes: "A remark of E(lith's since her return prompts me to write to you about my interest in reserpine, and how it began." There follows a detailed historical account anct then the fol- lowing passage: "l know that you showed me the action of reserpine on the rate of the heart-lung preparation in 1957, but it passed from my mind and played no part in my thoughts. ~ had forgotten what you showed me until ~ read your papers a month or two ago." In one of the papers on reserpine that was publishect

OTTO KRAYER 179 from Krayer's laboratory in 1958, Innes and Krayer (1958d) compared the negative chronotropic effects of reserpine and veratramine. Using the HEP from reserpine-treated cate- cholamine-depleted dogs, they showed that the action of ver- atramine was unchanged and therefore that it did not act by antagonizing sympathomimetic amines. Until then such an adrenergic blocking mechanism could not be ruled out. It had earlier been shown that when the heart rate was elevated to a high steady-state level by an infusion of epinephrine or norepinephrine, veratramine lowered it dramatically. In the absence of added catecholamines, it also reduced the heart rate, but the normal heart rate might have been under the tonic accelerator action of a slow release of endogenous nor- epinephrine. Only by substantially eliminating the catechol- amine stores could the direct depressant effect of veratra- mine on the atrial pacemaker be proved. In another paper Innes, Krayer, and Waud (1958e) ex- amined ten Ranwolfia alkaloids and showed that, whereas they all displayed a direct depressant effect on both the heart rate and atrio-ventricular transmission, only half of them were catecholamine depleters. Waud, Kottegoda, and Krayer (1958f) studied dosage and time-course details of the de- pleting effect of reserpine. Their method was to pretreat the dog with various doses of reserpine 24 hours prior to a chal- lenge dose on the HEP or, alternatively, to pretreat with a standard dose at different times prior to the challenge. In this clever method the attenuation of the heart-rate increase caused by the challenge dose serves as a measure of the de- gree of catecholamine depletion by reserpine. They found a very sIow onset of action of reserpine, peaking at 24 to 72 hours, and a good correlation with norepinephrine content (determined by bioassay on the cat blood pressure) through- out the time course. The threshold single dose was found to be a remarkably low 30 micrograms per kilogram.

180 BIOGRAPHICAL MEMOIRS In 1960 Wauct and Krayer published a stucly that is a mocle! of the application of sophisticated statistical methocI- ology to a complex pharmacologic problem a so-callec! "split-split-plot design." Epinephrine was compared with nor- epinephrine and shown to be equipotent. The HEP was found to become progressively less sensitive (as an experi- ment continued) to the carcliovascular effects of both cate- cholamines. Finally, reserpine pretreatment clid not influence the effects of norepinephrine or epinephrine on the heart rate. This last conclusion was contrary to the findings of Burn and RancI. Burn, in a letter to Krayer, took issue, asserting that the methocl of catecholamine infusion could not have cletectec! the reserpine-incluced supersensitivity inasmuch as the infusion itself would quickly replete the stores. Waud and Krayer themselves acknowlecige in their discussion: "The use of single doses might also contribute to the discrepancy." In- asmuch as their paper cites Burn and Rand, who showed that an infusion of norepinephrine abolishes the supersensitivity, it is surprising that Wauc! and Krayer did not compare single doses with infusions in their own experiments. Papers in ~ 962 (Krayer, Alper, and Paasonen), ~ 966 (Krayer, Mosimann, and Silver), and 1972 (Krayer, Weiner, ant! Mosimann) completed the studies on catecholamine de- pletion. Guanicline derivatives had been fount! to share this action with reserpine, guanethidine having been studied principally in this respect. Krayer compared guanethictine with reserpine in the HEP; here he found that the catechol- amine-clepleted preparation was sensitizer! to both the chron- otropic and inotropic effects of norepinephrine. Further studies employecl a very simple compound, methy~guanidine, which is 250 times less potent than guanethi(line but has the same pharmacologic effects. By now, fluorimetric methods of catecholamine assay hac! been introduced, and these macle possible precise, direct measurements in the coronary sinus

OTTO KRAYER 181 blood. Methylguanidine always produced a higher level of norepinephrine in coronary sinus blood than in arterial blood that had passed through the pulmonary circulation, showing that the elevated norepinephrine was indeed de- rived primarily from cardiac stores. Krayer's studies on reserpine never had the historical scientific impact they deserved. The reasons are evident in retrospect. His focus on the HEP tended to limit his "audi- ence." Moreover, his steadfast refusal to draw a conclusion that went beyond his own data meant that the broad signifi- cance of the reserpine findings did not "leap off the page." It is true that the field quickly became competitive, whereas Krayer's discovery of catecholamine depletion was probably unique in 1955. Painstaking thoroughness about every aspect of experimentation and the preparation of manuscripts accounted for the passage of two years until the first brief meeting abstracts appeared, and three years until the first full-length papers were published. More than sixty HEP preparations were used for Krayer and Fuentes (195Sb), about thirty-seven for Paasonen and Krayer (1958c), twenty- five for Innes and Krayer (1958d), and forty-four for Wand, Kottegoda, and Krayer (1958f). Finally, it was not Krayer's style to promote his own work by aggressive public pronouncements, nor to engage in "priority battles." Certainly, he would never have voiced his concern in public over matters of scientific priority, and he disdained secrecy in the laboratory, always welcoming visitors and freely discussing work in progress with them. Not only the intensely competitive environment that developed around reserpine but also the passionate disputes over the relative importance of norepinephrine depletion and sero- tonin depletion disgusted him, and probably accounted for his withdrawal from further research on the reserpine prob- lem. In retrospect there is no doubt that his studies, limited

182 BIOGRAPHICAL MEMOIRS as they were, nevertheless represented an important contri- bution to the biochemical pharmacology of the catechol- amines, with implications for physiology and pharmacology that reached far beyond the cardiovascular system. Krayer's mastery of the HEP as an experimental tool placed him virtually in a class by himself. His department, at the peak of its activity from the late ~ 950s until his retirement in 1966, was certainly one of the world's leading centers for the training of cardiovascular physiologists and pharmacol- ogists of the traditional kind. Yet it was the end of an era. Young physiologists and pharmacologists were turning in- creasingly to the methods of biophysics, biochemistry, and molecular biology to solve fundamental questions about physiologic mechanisms and their alteration by drugs. Krayer has to be seen, in historical context, as one of the last and one of the greatest in the long tradition of physiologic pharmacologists. He was not only a master of the HEP, he was also a master of kymography. In an obituary memoir, P. B. Dews, long a member of Krayer's department, wrote: "Krayer brought ky- mography to its highest level as an art." We who experienced the transition from crude mechanical recording devices to electronic ones (polygraphs) can perhaps understand better than our younger colleagues the significance of kymography practiced as an art. To produce experimental records of the quality evident already in Krayer's Berlin publications of 1929-1933 implied an attention to detail affecting all aspects of an experiment. Thus kymography was a kind of window on the experimenter's methodology through which one could form some judgment of the overall quality of the work. The published experimental records let us appreciate the fastid- ious attention to detail that was his credo. Close inspection of any figure from his publications (e.g., Figure 4) must elicit admiration even from users of modern electronic recording

OTTO KRAYER 183 crevices. He hacl a stubborn pride in his ability to tame a ctif- ficult preparation anc! make it serve sophisticated purposes. He enjoyed the directness and truthfulness of the kymo- graph, and he was ever suspicious of the "black boxes" be- tween input and output in modern experimental procedures. Above all, he took pleasure in squeezing the maximum of quantitative tiara out of so gross and intrinsically crude a bioassay system (cf. Waud ant! Krayer, 19601. His perfectionism about scientific publication inclucled a strong insistence on the correct use of words. His philosophy about this is expressed, in part, in a publication summarizing many of his studies on drugs affecting the heart rate (1963a). He allucles to Engelmann, a turn-of-the-century physiologist who coined the term "chronotropic," and he discusses a wicle- spread confusion between direct and indirect chronotropic effects. He writes as follows: The creation of new words for new or old concepts is a continuous process in the biological as in other—sciences. Men like T. W. Engel- mann, and in our own time for example, H. H. Dale, who combine this creative ability with a deep biological knowledge and clarity of thought, are rare. As I have sought to demonstrate, the progress of science makes old concepts inadequate. It is therefore not surprising that scientific vo- cabulary should lose its precision through misuse of old terms and through poor choice of either old or new terms for new concepts. The time is ripe now for a systematic attempt, in physiology and pharmacology, to preserve the significance and beauty of our scientific language. The academic scien- tist has a dual obligation-not only to make advances in our understanding but also to create the appropriate new language to describe those advances. PERSONAL HISTORY Otto (Hermann) Krayer was born October 22, IS99, the seconc! child ant! first son of Hermann ancT Friecia Berta (Wolfsperger) Krayer, in the village of Kondringen (Baden), Germany. The Krayers, like most of the villagers, were churchgoing Protestants. They were relatively well off, at

184 BIOGRAPHICAL MEMOIRS least by the stanciarcis of this farming community of about one thousand inhabitants. They ran an inn (the Zum Reb- stock) and a butcher shop, and they farmed. The father served as treasurer of the village. Before and after school there were chores for the chilciren to do in the fields, vine- yards, barnyard, and home. The boy developed a feeling of closeness to the lane] and to nature a feeling he often ex- pressed in later years. And though he lived most of his life in Boston and then in Tucson, Krayer always consiclered the little village at the edge of the Black Forest as home. The local dialect—Alemannic, virtually incomprehensible outside southern Germany ant] Switzerland—rolled easily off his tongue, and tales are toIc! of his experimental dogs being castigated in that language at moments of exasperation. His attachment to Konciringen was lifelong. His mother livecl to a very oIc} age, and Krayer visited her in the oIc! homestead on many occasions. He often said that among all the honors accorded him, the one that meant most was that of honorary citizenship of Kondringen, bestowed in 1957. Young Krayer's intellectual gifts attracted the attention of the local schoolmaster and of the minister, who persuaclec! the parents to continue the boy's education. Thus he at- tendec} the six-year micIdle school in the nearby town of Em- mendingen. This was follower! by another three years of schooling in order to qualify for university matriculation, anct he began these in the nearby city of Freiburg. However, WorIct War ~ was in progress, and his education was inter- ruptec! when he turned eighteen: He was conscripted on June 19, 1917, and after half a year of infantry training was sent to the Western Front. A combat wound shortly before the armistice sent him to hospital and then, while still con- valescing, he completed the educational requirements for university entrance. Finally, in the autumn of 1919, he en- rolled as a medical student at the University of Freiburg.

OTTO KRAYER 185 The course that mainly captured Krayer's interest at the outset was gross anatomy. He discovered real joy in the use of manual skills for dissection—no doubt a foretaste of the pleasure he would experience in setting up hundreds of heart-lung preparations during his career. Years later he wrote about these early dissection experiences: "The beauty of the forms and the relation between form and function became a source of great satisfaction." In the autumn of 1920, following the German student tradition of moving from university to university, Krayer transferred to the University of Munchen. Here the profes- sor of histology, Siegfried Mollier, made a lasting impression. "Every one of his lectures," Krayer recalled, "was a feast for the mind and the eye. His joy, uttered in a word of approval when he recognized in the drawing of a microscopic structure that the student had caught its beauty, made the course in microscopic anatomy a memorable, intellectually and spiri- tually enriching experience." For his clinical studies Krayer returned, in 1922, to Frei- burg. His love of the outdoors took him on long walks through the countryside, in the foothills of the Black Forest and along the little river EIz. Here was rooted his lifelong love of botany; he always made a point of knowing all the native plants and flowers of whatever region he was living in. In the winters he was fond of skiing, and he was expert enough to win a student ski competition. The prize, donated by the pharmacologist Walther Straub, is said to have been a single U.S. dollar—a princely sum in those days of rampant inflation in Germany. And here on the ski slopes near Frei- burg he enjoyed the companionship of a classmate, Erna Ruth Philipp, who was (much later) to become his wife. He found the didactic courses in medicine and surgery uninspiring, the more so as there was hardly any contact with patients. Seeking more intellectual stimulation, he undertook

186 BIOGRAPHICAL MEMOIRS his first experimental research at this time a project in the comparative morphology of amphibian kidneys, under the direction of Wilhelm von Mollendorf. Krayer would collect the specimens himself in the fielcl often near his native vil- lage ant! make microscopic measurements on gIomeruli ant! proximal tubules after vital staining with trypan blue. Enthusiasm for research lee! Krayer next to pharmacology professor Paul Trendelenburg, whose personality and lec- tures had made a strong impact on him. After completing his formal course-work and passing the university and state examinations at the end of 1924, Krayer spent the first half of 1925 full time in Trenclelenburg's department. In the sec- onct half of 1925 he fulfi~lecT internship requirements in in- ternal medicine. Finally, in 1926, he received the M.D. degree for his dissertation research on apocodeine, and he formally began his career in pharmacology as Assistent uncler Tren- delenburg. Krayer's creep commitment to teaching must have tract its roots in this Freiburg period. His task was to prepare the lecture demonstrations. These were the students' only op- portunities to observe the effects of cirugs on animals; there were no facilities for routine laboratory teaching of medical students. It is interesting, in the light of Krayer's later strong belief in the importance of practical laboratory work in phar- macology for medical students, that in 1927 he embarked on what was then a raclical innovation—a small, elective exper- imental laboratory course. Seven years later, in a letter re- questing a leave of absence to study laboratory teaching, American style, at the American University of Beirut, he wrote as follows: "This form of instruction has outstanding advantages, proviclec! it is carried out with the necessary ear- nestness and the number of students is not too great . . . as compared with a method that is based almost entirely on the

OTTO KRAYER 187 textbook and spoken word, i.e., on knowlecige divorcecT from experience." Tren(lelenburg's interests lay in endocrinology, and at that time he was completing the first volume of a major treatise, Die Hormone. shoe Physiologie und Pharmakologte. Krayer natu- rally began investigations in that fielcI. He undertook a stucly of the relation between thyroid function and the autonomic nervous system and published some results (192~3a). How- ever, the aspect of endocrinology that clealt with the adrenal medulIary hormone epinephrine turned Krayer's interests to the circulatory system. Soon he began to assemble equipment for the heart-lung preparation, which hacT been introducect by E. H. Starling. Attendance at the International Physiology Congress at Stockholm in 1926 gave Krayer the opportunity to meet some of the leading cardiovascular physiologists and pharmacologists of the clay Starling himself, J. H. Burn, and G. Li~jestrancl. Among the many visitors to the Freiburg department was H. B. van Dyke, who later became professor of pharmacology at Peiping Union Meclical College and then at Columbia University, and who became a lifelong friend. When Trendelenburg assumed the chair of pharmacol- ogy at Berlin in 1927, Krayer went with him. There he acl- vancecl rapidly through the academic ranks, from Assistent to Oberassistent to Privatdozent. He had by now turned his re- search interests fully to the circulatory system; the two man- datory lectures to qualify for the appointment as Privatdozent were on coronary Hood flow (for the faculty) and on the analysis of the circulatory actions of drugs (for the public). Trenclelenburg became seriously ill in 1930, and Krayer had to assume full academic responsibility for the clepart- ment. Then, with his chief's death in 193 I, Krayer was made acting hea(l; the following year at the age of thirty-two- he was promoted to Professor ExtraorcTinarius of Pharma-

188 BIOGRAPHICAL MEMOIRS cology and Toxicology. Now research had to be put aside while he dealt with the heavy teaching load: the required course in pharmacotherapy, an elective laboratory course, and special elective courses on cardiovascular pharmacology and industrial toxicology. The system of oral examinations for all medical students required his personal participation in more than 500 of these per year. He was also required to assist the courts with forensic toxicologic analyses and even ad hoc experimental studies. In addition, it was necessary to supervise the planning for a new building for the Denart- ment of Pharmacology. <A - 1- Trendelenburg had left two literary legacies—his uncom- pleted second volume on the hormones and a textbook on the principles of therapeutics, the second edition of which had appeared in 1929. Krayer inherited both. The third edi- tion of the textbook was brought to publication in 1931, but the more demanding task of completing the second volume of Die Hormone had to be deferred until the spring of 1932, when W. Heubner was appointed head of the department. Research could then also be resumed, and it was at this time that the important collaborative study with W. Feldberg was initiated. A leave of absence in April 1933 allowed Krayer to join H. Rein, the new professor of physiology at Gottingen, to pursue collaborative experiments with the HEP. But these plans were abruptly terminated in June by the events de- scribed at the opening of this memoir. Returning to Berlin, Krayer found ways (despite the ban on his use of state libraries) to obtain the necessary books and journals needed to complete Die Hormone. One of those who assisted him at this difficult time was Dr. Erna Ruth Philipp, who had been a fellow medical student at Freiburg and even- tually was to become Krayer's wife. In August Krayer received Verney's invitation to University College and in November an offer from van Dyke at Peiping. The Nazi authorities rein-

OTTO KRAYER 189 stated him in September, whereupon he requested and was grantee! a one-year leave of absence for study abroad. On December 3l, 1933, with a fellowship from the Rockefeller Foundation, he left Berlin for London. In Verney's laboratory Krayer plungecl into research with the clog heart-lung-kiciney preparation as his tool. The aim was to obtain quantitative information about the effects of anti(liuretic hormone on kidney function. Using intact dogs equipped with in(lwelling ureteral catheters, he (levelopecl a method of standardizing the hormone. But Krayer's most significant work in the first half of 1934 was the clemonstra- tion with Verney (1934b, 1935b) that a physiologic indirect stimulus a vagal reflex would release acety~choline into the coronary circulation. This asides! considerably to the force of the earlier proof (with Feldberg) that direct stimu- lation of the vagus released acety~choline. Within a few months Krayer was approached about the possibility of assuming direction of the Department of Phar- macology at the American University of Beirut. At the same time he was a leacling cancti(late for the chair of pharmacol- ogy at Zurich. By the end of the summer he had accepted the Beirut position, technically a visiting professorship, and here his former associate in Freiburg and Berlin, Dr. Erna Ruth Philipp, joined him as his literary assistant. Because the class was small anc! newly built facilities were available, he was able to realize his dream of teaching pharmacology primarily as a laboratory course. Among the students who were at- tractec! to his department for research experiences, at least two were inspired to pursue careers in pharmacology. These were Alfred Farah, who later joiner! Krayer at Harvard and then became department head at Syracuse; and George Fa- waz, who eventually became professor of pharmacology and heat] of the department at Beirut. Glimpses into Krayer's per- sonal life in Beirut are afforclec! by Fawaz, who describes a

190 BIOGRAPHICAL MEMOIRS vigorous outdoor regimen of hiking and climbing and trips on horse-back experiences that lecI to a deep attachment to the scenery of the region. Mount Sannin near Beirut espe- cially captures! Krayer's imagination, as slid the alpine beauty of Mount Lebanon and its famous cedars. Anct in winter there was skiing. "Krayer on skis," according to Fawaz, "was an entirely different person: iollY. ant! uninhibited as a child." ~ . . . . . , ~xp~a~n~ng wny Grayer gainer! the respect anct love of all members of the University community, Fawaz writes: The explanation is simple: he was considerate and modest and de- manded very little for himself and his own comfort. His ego never played a role in his decisions. His main concern was his work, which he performed conscientiously; he then sought to serve his students and friends.... How- ever, his natural docility abandoned him when he was lecturing or dem- onstrating an experiment. Then he was transformer] into an ev~n~f~lict full of zeal. ~~ ~ , Although he carried on some research during the three- . · ~ · . · . . . ~ _ _ ...;, 0.._ add. _ _ year stay in Beirut, 1nc~uct1ng a study on pumpkin seeds as anthelmintics (1937), his chief preoccupation was teaching anct revising the fourth edition of the Trenclelenburg text- book of pharmacotherapy (19381. His sojourn in Lebanon left creep and lasting impressions of the natural beauty of that semiarid region remarkable for its mixture of populations and cultures. "The country is, to my taste, of an exceptional beauty," he wrote to his successor J. O. Pinkston. The circum- stances of Krayer's seemingly impulsive clecision, thirty-five years later, to spenc] the latter part of his life in Tucson- much to the surprise of former students and associates who hac! tried to attract him, after his retirement, to their own geographic areas suggest that the clesert beauty, the stark mountains, the climate with its rainy and ciry seasons, and the ethnic diversity of Arizona evokocl again all his strong positive feelings about the Beirut experience.

OTTO KRAYER 191 In 1936 Krayer was sent to Harvarcl's tercentenary cele- brations as the official representative of the American Uni- versity. Whether this was part of a granct design to move him to Harvarcl, or whether it was just a fortunate turn of events, is unclear. We do know that Krayer had made the acquaint- ance of Walter B. Cannon at the International Physiology Congress in the summer of 1935 in Moscow. Cannon was professor of physiology at Harvarc! Medical School and one of the worIcl's foremost physiologists. And Cannon was the . . . . . ~ moving spirit In arranging a t. aree-mont n appointment tor Krayer as a lecturer in pharmacology for September, Octo- ber, and November 1936. In 1937, shortly after his return to Beirut, the invitation was proffered to become, in effect, the successor to Reic] Hunt, who hac] retired a year earlier as head of the Department of Pharmacology. We shall probably never know the details of the internal academic politics be- hind this curiously ambivalent appointment as associate pro- fessor without tenure and acting head of the department. Perhaps it was only shrewd Yankee trading practice to offer as little as possible; this is the interpretation put forward by Peter Dews in his obituary article. ~ think it was probably more than that, in view of Krayer's difficulties with the med- ical school administration over the next fourteen years. We can only speculate. Those were the clays now happily gone- when ethnic and national and cultural diversity were counted as liabilities rather than as assets to an institution. The faculty and stu- clent bocly of Harvard Medical School were overwhelmingly white Anglo-Saxon Protestant males (indeed, women were excludecl as a matter of explicit formal policy). Anct here was this rather intense foreigner, not exactly fitting the "old Har- vard" moIcI. Acceptance was probably made no easier by Krayer's European mannerisms, an excessive formality (by American standards), and a stern—even measly tempera-

192 BIOGRAPHICAL MEMOIRS meet. No easygoing, back-slapping, "old boy" camaraderie here; one could not imagine him cheering at a football game, playing a rubber of bridge or a round of golf, telling (or laughing at) a dirty joke. With close friends, however, the stern demeanor vanished, and he engaged readily in relaxed anct good-natured banter or even teasing. His absolute rec- titude must have repelled some, even while it attracted oth- ers. We know, furthermore, that prominent American phar- macologists communicated to the Harvard administration their displeasure that no qualified American had been found to fill the prestigious post. When Krayer arrived, the department was a shambles. The only other faculty member was occupied nearly full time with administrative chores in the dean's office, equipment and facilities were primitive, and the school provided only a miniscule budget. Krayer became increasingly disillusioned with the situation and especially with the lack of support from the medical school administration. Six months after his arrival he was offered the chair of pharmacology at Peiping, which had been vacated when van Dyke moved to Columbia. Krayer was strongly inclined to accept, and on June 23, 193S, he actually informed Dean C. S. Burwel1 that he planned to accept the Peiping offer effective September ~ 939. What hap- pened next may well be unique in the history of Harvard Medical School. In January 1939 the entire medical school class of 1941, who were in the midst of their pharmacology course, and many of the class of 1940, who had been taught pharmacology the previous year, petitioned Krayer to stay and delivered a copy of their petition to the dean. The doc- ument, with 152 signatures appended, reads as follows: We, the undersigned, have heard with regret of your plans to leave the Harvard Medical School. Students naturally form opinions of their teach- ers. As your students we wish to express our admiration for your teaching, our gratitude for all your efforts on our behalf, and our hope that, should

OTTO KRAYER 193 future developments make it possible, you might stay here to give coming classes something of what you have given us. Forty-five years later, this episode was recalled vivictly by one of its participants, Curtis Prout, as follows: "All of us signed it with great enthusiasm.... The morning following this action, when we hac! clelivered one copy to Dean Burwell ant} put the other uncler his (i.e., Krayer's) floor in Vanclerbilt Hall, he gave his lecture as usual; it was technical, almost dry but precise and a gem. At the conclusion of the lecture, he started to walk out of the amphitheatre but just before he got to the door, he stopped, turned around, looked up, and he said, 'I have received your petition. Thank you very much.' and quickly made his exit. We gave him a round of applause." For all who knew ancT admired Krayer, this description of his restrained and clignifiec! reaction to so extraordinary an event wild ring absolutely true. At all events, the move to China was cancellecI, and Krayer was given tenure (as asso- ciate professor) anc! made head of the department. At this time, too, he married Erna Ruth Philipp anct moved into the comfortable house in West Newton in which so many stu- dents and young colleagues anct their families were to be entertained. Another vignette, from the spring of 1939, epitomizes Krayer's readiness to clo instantly and without weighing consequences—whatever was needed when a worthy person or cause requirec! help. The government of the Spanish Re- public, led by the physiologist Juan Negrin, had been over- thrown in a bloody civil war. Military support of the insur- gents under Franco by Nazi Germany ant! Fascist Italy, and of the leftist government of the Republic by the Soviet Union, had made Spain a controversial political cause celebre in the Unitecl States. The safe course, in university life as elsewhere, was to distance oneself from political controversy and to keep quiet.

94 BIOGRAPHICAL MEMOIRS Rafael Mendez (later a distinguished scientist at the Na- tional Institute of Cardiology in Mexico and recently ap- pointed general coordinator of the National Institutes of Health there) arrived in the United States as a political ref- ugee in April 1939. A young pharmacologist still early in his career, Mendez had been drawn into government service by Negrin, first as financial attache in Paris and Washington re- sponsible for procuring military hardware, later as undersec- retary of the interior in charge of information and internal security, and finally as the Spanish consul at Perpignan in southern France with the sad task of directing the mass em- igration of the defeated loyalists from Spain to France. Men- dez had met Krayer only twice: once while a visitor in Tren- delenburg's department in 1929 and once for a few hours in London in 1934. Mendez tells how, after arriving in the United States, he wrote to several universities and pharmaceutical companies asking for a job, and received "many kind replies but no of- ferings." Then Walter B. Cannon (who was an ardent sup- porter of the Spanish Republic) learned that Mendez was in New York. "The next day," Mendez writes, "Krayer showed up at the modest hose] in which ~ was staying with my wife and four-month-old son, and two weeks later he received me hospitably in Boston appointing me Instructor and Research Associate.... Krayer took care of me as a loving father...." From December 7, 1941, Krayer found himself in the awkward position of "enemy alien." Among the inconve- niences he had to endure was a restriction of his travel to a 25-mile radius of Boston, so he could not attend the annual meetings of pharmacologists and physiologists at the "Fed- eration" in Atlantic City every spring. Nevertheless, the war years saw increasing productivity of his own research and the foundations laid for the very strong department that was ul- timately to develop. Krayer's first Ph.D. student, Albert Wol- lenberger (now a professor at the Academy of Sciences of the

OTTO KRAYER 195 German Democratic Republic in Berlin), received his degree in 1946. Junior faculty in this early period (1941-1944) in- clucled George H. Acheson, Ec~win B. Astwood, H. Stanley Bennett, Ralph W. Brauer, Sydney Ellis, Dale G. Friencl, Ber- tranc! E. Lowenstein, Harriet M. Maling, Rafael Mendez, Gordon K. Moe, Richard TysIowitz, WilIarct P. Vander Laan, Jr., and Ear] H. Wood. With the help of these colleagues- anc! later of Alfred E. Farah, Arthur I. Linenthal, Douglas S. Riggs, and the author Krayer was able to implement a full- flecigec] laboratory course in pharmacology for all the medi- cal students, on a larger scale than he tract clone in Beirut. With a class of 125 each year, this was a major logistic under- taking, carried out by the capable and loyal Diener Mr. George, with Mary Root as the first of a succession of gract- uate students assigned to this important task. The clay began with a pharmacology lecture to the whole class. And what Harvard graduate of those early years cloes not recall with nostalgic delight the quaint Germanisms like "Make ciark, Mr. Chorge!" or "If you administer alcohol to a typewriter...."? Following the lecture, one-quarter of the students, in rotation on successive days, trooped upstairs to the old barn-like student laboratory on the top floor of BuilcI- ing E. It may not be fully realized the extent to which the concepts ant! even the specific experiments carried out in this laboratory course at Harvard spread to other medical schools by word of mouth, by dissemination of the laboratory prep- aration manual, and by Krayer's people leaving to join (or establish) other departments. Thus by the middle 1960s the Krayer influence had made itself felt in pharmacology courses throughout the Unitecl States. Subsequently, to Kray- er's dismay, laboratory teaching was abandoned in school after school, as faculty members succumbed to pressure from student activists, who saw this and the rest of basic science as largely "irrelevant." The immediate postwar years saw Krayer in the role of

196 BIOGRAPHICAL MEMOIRS organizer of relief efforts for the German university stu- clents and professors, and later as a member of the Unitarian Service Committee Mectical Mission to Czechoslovakia (cti- rected by Harvard carcliologist Paul DuctIey White). In 1948 Krayer served as chairman of the medical mission to Ger- many uncler the same auspices. His precisely craftecl, thoughtful, 21-page typewritten report makes interesting reading even today. The question was what should and couIct be (lone most effectively to help the reconstruction (intellec- tual, moral, anct physical) of the German universities and of German biomeclical science. Krayer's faith in young people was a constant theme of his life, and here it dominated his response to the catastrophe that had befallen his homeland. He wrote: Of the "lost" generation, grown up under Hitler and supposedly poi- soned beyond hope by the Nazi teaching, not much if anything can be seen. This generation is not lost. On the contrary, many of these young people now in the first years of their university education became skeptical of the Nazi doctrine long before its fallacies and disastrous features began to dawn upon the older generations. If they find response and encourage- ment at home and abroad as well as appropriate and wise guidance, these young men and women will be the best guarantee for a "better" Germany. The report made a series of concrete recommendations: study tours abroad for professors who hacI not been active Nazis, fellowships for younger scientists, reconstruction of libraries, provision of equipment and supplies to selectecl in- stitutions, establishment of bloocl banks ant! plasma fraction- ation laboratories, and production facilities for antibiotics. But most important, in Krayer's view, was the maintenance and extension of the personal contacts that couch help bring the German intellectuals back into the civilized worIc! system. The greatest accomplishment of the Mission seems to me to be that for the first time since cultural and political ties between Germany and the

OTTO KRAYER 197 rest of the democratic western world were ruptured ten to fifteen years ago a large group of university members not connected with government and not having political motives have met with their counterparts in Ger- man universities on a basis of equality in the scientific field and with the aim and good will to establish friendly relations.... have shown the Ger- man colleagues that the possibility exists of ending their isolation from the rest of the world.... An interesting sicle event of these years was the formation of the ill-fated Pharmacotherapy Committee at Harvard. President lames B. Conant himself was a prime mover in this program for integrating research anct teaching in pharma- cology and therapy, with the hope of attracting major cor- porate and inctiviclual donors. Krayer saw in it an opportu- nity to develop an adequately large single department of pharmacology and pharmacotherapy. In this he anticipated later developments elsewhere, when clinical pharmacology programs with strong roots in basic science became popular. Krayer's memoranda concerning this committee reflect his long-stancling interest in the clinical applications of phar- macology and his view that goof! therapists require a very solic! training in basic pharmacology. Internal disagreements frustrated the committee's work under the chairmanship of Professor of Medicine W. B. Castle. Krayer's failure to concur with plans that struck him as opportunistically clonor oriented but scientifically un- souncl must have irked powerful committee members; his lack of suitability for the role of "team player" surely also made trouble. Abruptly, without consulting Krayer or the other members, Conant dissolved the committee. Not sur- prisingly, by ~ 947 we find Krayer again considering a move- this time to Base] ant] with both Burwell and Conant actu- ally urging him to leave. As matters cleveloped, however, the Base] chair was given to an internal candiclate, and Krayer remained.

198 BIOGRAPHICAL MEMOIRS The turn in his political fortunes at Harvard came ctra- matically with the retirement of Burwell, and a few years later, of Conant. George Packer Berry, who was to bring clis- tinction to the Harvard Medical School in many ways, became (lean in 1949. He immecliately recognized what had been obvious to so many as a rank injustice unworthy of Harvard, and he moved to correct it. So in 1951, after fourteen years as associate professor, Krayer was finally promoted to full professorship. The years of the Berry deanship were flour- ishing ones for the Department of Pharmacology. Buclgets at last grew, plans for reconstruction anc} expander! space took shape, anti a swelling stream of students, trainees, junior fac- ulty, anct visiting scientists filled the department. Krayer's re- lationship with Berry became exceeclingly close, and Krayer playoc! an increasingly important part in the affairs of the school, to be recognized before long as one of the wise senior statesmen in the Longwood Avenue basic sciences "quaciran- gle." His public vindication (if it may be called that) came with his election to the National Academy of Sciences in 1964. Krayer's style in discourse with his peers couIcT be bluntly honest. An excerpt from his remarks at a meeting of the Preclinical Council shecis light on this tendency to speak the unvarnished truth: The task is to build a strong faculty around the HMS quadrangle. We are not, in my opinion, an exceptional group. There are probably half a dozen medical schools in the country who measure up to us or are stronger.... We cannot allow to let the reputation of HMS rest with past glory.... Let us not be concerned overly much with the problem of per- sonality.... Certainly we are not assembled here to form a group of con- genial people who have the foremost task of getting along superbly with each other. Krayer's view of pharmacology was a broad one. Although his own research was wholly devotect to unclerstanding drug action at the physiologic level on the functions of organs

OTTO KRAYER 199 and organ systems—he nonetheless recognized and fully supported the most modern developments. He encouraged the new lines of experimentation by the young people in his department. ~ was one of the early beneficiaries of this en- thusiasm for the newly developing fields of biochemical and molecular pharmacology. S. Ellis, F. L. Plachte, O. H. Straus, and ~ were able to apply enzymologic methods to studying the pharmacokinetics of cholinesterase inhibitors in dogs and in patients with myasthenia gravis (1943e; 1944a; 1949b), and in the course of those studies to discover some new prin- ciples about enzyme-substrate-inhibitor interactions. Krayer's interest was in learning how to quantitate the concept of "es- erinization" the blockade of the destruction of acety~cho- line by inhibition of cholinesterases in order to lay a basis for more rational treatment of myasthenic patients. In like manner he foresaw the importance of behavioral pharmacology very early. He brought P. B. Dews into the department to establish a laboratory of behavioral pharma- cology at a time when the pioneering techniques being de- veloped across the river by B. F. Skinner had not yet been applied anywhere to studying the behavioral effects of drugs. His plan and outlines for the ideal department he hoped to build reveal his belief that the strength of pharmacology lies in its cross-disciplinary breadth. To understand fully the action of a drug usually through the joint efforts of several investigators requires that the effects on whole organisms and their organ systems be related to the relevant biochemical and biophysical actions on cells and subcellular elements. He often ridiculed the reductionism that sometimes led to pro- posed mechanisms of drug action based on some test tube phenomenon at a concentration vastly higher than could ever be attained in viva. By 1960 the department had moved into new quarters, financed in part with funds provided by the National Insti-

200 BIOGRAPHICAL MEMOIRS totes of Health in recognition of the national importance of this center for research ant! training in pharmacology. AncI in ~ 966, just before his retirement, Krayer's department was ranked first among all pharmacology departments in the na- tion by the American Council on Education. Seeing the great future of neurobiology on the horizon, ant! recognizing quality wherever he saw it, Krayer had playect the key role in bringing S. W. Kuffler and his col- leagues from Johns Hopkins to Harvard. Putting the inter- ests of the meclical school ahead of the long-term needs of his own department, Krayer tract set aside space for a labo- ratory of neurophysiology "temporarily," as such arrange- ments are often planned to be at the outset. This statesman- like action certainly brought glory to the Harvard Mectical School (including, as it turner! out, a Nobel prize), but there are those who argue (anc} Krayer ctiscovered) that altruism can be a losing proposition amidst the intramural competi- tions of modern university life. In the subsequent few years until his retirement, Krayer hac] to watch, painfully ant] helplessly, as the stage was set for the dismantling of the strong department he had built. The search for his successor was delayed repeatedly by fruitless philosophical debates about the role of pharmacology; mean- while, other (lepartment heads made plans for possible uses to which one or another part of the pharmacology space could be put. Berry's retirement (in 1965) anct Robert H. Ebert's accession to the deanship left pharmacology without an effective advocate. In January 1966, only seven months before his mandatory retirement, Krayer framed a letter of resignation, as a gesture of protest, and was only restrained from sending it by the insistence of his close colleagues that nothing couIcl be accomplished that way. It is ironic, after his unquestioned research and teaching achievements and his

OTTO KRAYER 201 worIdwicle recognition for having built what was probably, on balance, the most important department of pharmacology in the worIcl, that Krayer felt compeller! to say to a group of his younger associates at this time: "Frankly, T am impressed more by what ~ missect or bunglecl than by what ~ recognized ant] resolved." On August 3l, 1966, having reached the mandatory age, Krayer retiree] to the rec! brick house in West Newton, and for the next five years he never once returned to Harvard Medical School. Here, uncler the great apple tree, ancT in the carefully tencled garden with its medicinal plants (especially Digitalis ant! Veratrum), was where so many generations of medical students and young scientists had gathered for tea or to ctrink Rhine wine, and to experience Krayer's sincere interest in their welfare and their educational anct scientific progress. Whenever small children were brought to these gatherings, Krayer's stern exterior dissolvect. TocIdiers would climb onto his lap, and older children took him by the hand. UlIrich Trendelenburg, the son of Krayer's chief at Freiburg and Berlin a longtime Krayer associate and now professor of pharmacology at Wurzburg recalls this remarkable affin- ity for children, which he himself experienced as a small child. Trendelenburg writes: "Onkel Krayer" was very popular with us. He invariably wore a dark suit, and he was very quiet. Nothing of his considerable temper ever showed when he was with children. It was in 1948 when he visited.... he mentioned that lightning had struck his plane, my little nephew wanted to know why being struck by lightning was less dangerous for a plane than for a human being on the ground. Otto promptly turned his full attention to the child, and he gave a full (though slightly simplified) explanation; there was no attempt to "palm off" the inquisitive child. At that moment I realized that Otto had always been willing to give complete answers to our questions, quite in contrast to all those innumerable adults who were convinced that the child was unable to understand it in any case.

202 · 1 1 ~ BIOGRAPHICAL MEMOIRS For the first six months after his retirement Krayer held the title of Special Consultant to the Dean, but Dean Ebert did not seek advice and by June the post was abruptly abol- ~shed. Continued proximity to events at Harvard clepressed Krayer deeply. He and his wife began to travel, and in Sep- tember 1971 they settled in Tucson. The Krayers founct this part of the Southwest much to their liking especially the mountains, where they enjoyed long walks and strenuous hikes. Krayer worked sporadically on a biographic ant! scien- tific history of the schools of Rudolf Buchheim ~ ~ 820-T 879) and Rudolf Boehm (~844-1926), pioneers of German phar- macology, but this work was never completed. Making the best of both climates, the Krayers spent winters in Tucson ant! summers in Munchen. He held a visiting professorship at the University of Arizona School of Medicine anc! a similar appointment at the Technical University of Munchen, where his former associate Melchior Reiter was professor of phar- macology. Krayer's abiding devotion to young people (as though they were all surrogates for the chilciren he himself never had) was expressed well in a letter written toward the end of his life. In it, Krayer thanks the faculty and staff at the Tech- nical University of Munchen for their good wishes on the occasion of his eightieth birthday: My dear young friends: Your good wishes, at the end of my SOth year, were a welcome present. You gave me the possibility while I was living amongst you for some time to get to know your academic work and, more than that, to share some part of your personal thoughts, joys, and sorrows. Contact and exchange of ideas with teachers, coworkers and stu- dents were especially close to my heart during the half century of my academic activity. Thanks to your confidence and your friendly inclina- tions towards me, I am allowed once more, so near to the end of my time, to experience some of the joy which is the source of a fruitful contact between the generations. I thank you for it.

OTTO KRAYER 203 In anticipation of Krayer's eightieth birthday, a celebra- tion and two-day symposium were organized by Thomas F. Burks and his colleagues and held at Tucson in March 1978. There many of his younger associates gathered in a moving display of affection and admiration. The papers presented were later published in Life Sciences (22:~13-1372, 19781. At Harvard Medical School an Otto Krayer Lectureship had been established, and the Krayers journeyed to Boston to attend the first lecture, which was delivered on March 13, 1974, by the noted British physiologist Sir Bernard Katz. Subsequent Otto Krayer lecturers (through 1984) have been S. Ebashi, G. Burnstock, H. W. Kosterlitz, E. G. Krebs, I. R. Vane, H. Umezawa, I. W. Black, T. LindahI, and Y. Nishizuka. In ~ 982 (posthumously), Harvard established the Otto Krayer Professorship of Pharmacology, the first incumbent of which was Krayer's successor as head of the department, Irving H. Goldberg. No account of Krayer's life would be complete without noting his services to the American Society for Pharmacology and Experimental Therapeutics. His first major contribu- tion, appropriately, was to serve for five years as associate editor of one of the Society's journals, Pharmacological Re- v~ews. This was followed by another five years as editor-in- chief. The year 1957-1958 saw him in the role of president of the Society. He organized and conducted, with great dig- nity, the centennial celebration, at Johns Hopkins University, commemorating John Jacob Abel, the father of American pharmacology. Krayer worked tirelessly and successfully to acquire a physical home for the Society at Beaumont House in Bethesda, near the National Institutes of Health. He con- ceived and brought to fruition the Corporate Associates pro- gram, which brings financial support to pharmacology from the pharmaceutical and chemical industries. Posthumously,

204 BIOGRAPHICAL MEMOIRS in 1984, the Society that Krayer tract server! so well instituted the Otto Krayer Award in Pharmacology. In 1980, after nine years of shuttling between Tucson and Munchen, a macrogIobulinemia of Tong standing progressed and became complicated by other conditions, so that the reg- imen of twice-yearly travel proved too taxing. Toward the enct of 1981 Krayer's health deteriorated rapidly, a prostatic cancer being superimposed on the blood dyscrasia. Repeated hemoctialyses and hospitalizations became necessary, he grew progressively weaker and more uncomfortable, and finally, at his own request, he was discharged from hospital to die at home in the care of his wife on March I8, 1982. With Otto Krayer's passing the world lost one of the great pharmacologists of his time. But to those fortunate enough to have come uncler his influence he was much more than that. He will be remembered for the uncompromising stan- ciards he set in research, in teaching, in ethical behavior. "Throughout the years," wrote U. Trendelenburg, "he has been the favourite of my younger coworkers. He set them something that is very rare nowadays an example." Over the course of his thirty years at Harvard, Krayer trained, colIaboratec! with, and set an example for an extraordinary number of scientists, a great many of whom became leaclers in pharmacology throughout the worIcl themselves. The names of these people are just as much Krayer's "bibliogra- phy" as the compendium of his own publications, and there- fore it is appropriate that they be listed here. Represented are scientists from 26 foreign countries on 5 continents, as well as students, staff, anct visiting scientists from the United States. M. Abe G. H. Acheson R. Aiman M. A. Aliapoulios A. A. Alousi M. H. Alper E. Amundsen R. T. Anselmi L. Aronow

OTTO KRAYER R. B. Arora E. B. Astwood D. Atanackovic V. Atanackovic M. L. Bade B. W. Baker D. L. Bassett T. Bayer J. M. Benforado H. S. Bennett F. G. Bergmann J. R. Blinks J. L. Borowitz R. W. Brauer P. Braveny F. N. Briggs L. H. Briggs W. S. Brimijoin H. Buch F. J. Bullock W. R. Burack E. A. Carr, Jr. J. Chamberlain A. Clark J. S. Cohen V. H. Cohn, Jr. C. W. Cooper G. L. Coppoc P. J. Costa J. R. Crout H. Croxatto P. C. Dandiya G. S. Dawes C. V. Deliwala P. B. Dews R. Di Nirjana J. Dorner B. Douglas P. R. Draskoczy A. J. Dunipace S. Ellis H. L. Ennis V. Eybl J. D. Falk A. E. Farah J. J. Fischer W. E. Flacke J. H. Fleisch W. W. Fleming J. M. Flynn G. N. French S. Friedman D. G. Friend M. E. Fuday J. Fuentes M.-P. I. Gabathuler R. R. Garcia J. M. Garfield R. A. Gillis A. Goldstein B. Gomez (Alonso de la Sierra) J. S. Gravenstein P. K. Gujral J. M. Hagen P. B. Hagen R. Hancock L. S. Harris K. Hashimoto D. F. Hawkins M. L. Heideman, Jr. P. F. Hirsch F. Hoffmann B. Hofheinz F. Honerjager F. A. Howard A. M. Hughes H. Ibayashi 205 A. Illanes I. R. Innes S. D. Iversen 0. Jardetzky J. A.Jehl B. R. Jewell H. Jick N. S. Johary J. A. Johnson G. R. Julian R. Kadatz A. J. Kaumann R. T. Kelleher A. D. Kenny C. J. Kensler D. Kessel R. Kilpatrick J. Koch-Weser H. W. Kosterlitz S. R. Kottegoda K. Kramer J. E. Krueger S. M. Kupchan S. Z. Langer D. Lavie F.-L. Lee M. V. Leeding T. H. Li J. Liebman A. J. Linenthal W. K. Long A. V. Lorenzo B. E. Lowenstein M. Lubin U. C. Luft G. K. MacLeod W. A. Mahon H. M. Maling J. J. Mandoki

206 I. F. Marchand G. Maresh E. Marley I. M. Marshall M. L. Mashford A. Matallana H. M. Mazzone R. J. McKay, Jr. I. W. McKearney D. E. McMillan E. Meilman C. Mendez R. Mendez M. D. Miller B. A. Mitman G. K. Moe E. Moisset de Espanes G. Montes W. H. Morse P. L. Munson A. I. Muskus (Arevalo) A. Nakamura M. F. Narrod P. Ofner C. B. Olson P. B. Ourisson M. K. Paasonen P. Pappas A. F. Parlow A. Pekkarinen T.-C. Peng S. A. Pereira F. L. Plachte R. Pluchino S. B. Pluchino BIOGRAPHICAL MEMOIRS L. T. Potter M. Rabadija S. Ramachandran H. A. Ravin H. W. Reas M. Reiter U. I. Richardson D. S. Riggs S. H. Robinson B. H. Rogers A. Roos M. A. Root C. O. Rutledge H. J.-P. Ryser I. K. Saelens M. M. Saint-Paul F. Sallmann H. Schaer I. Scheuling I. Schmier G. L. Schmir H. R. Schroter B. W. Searle J. C. Seed E. E. Seifen G. W. G. Sharp C. B. Smith L. H. Smith E. Sodi-Pallares M. Speckert J. B. Stanbury J. D. Stoeckle O. H. Straus V. S. Subbu C. R. Swaine N. Taira ~ rim . I. mamas K. Tanaka A. H. Tashjian, Jr. E. W. Thomas P. J. Thomas E. Thorogood C. D. Thron U. G. Trendelenburg T.-H. Tsai R. Tyslowitz F. C. Uhle W. Ulbricht G. E. Vaillant W. P. Vander Laan, Jr. C. G. Van Dongen M. van Leeuwen E. F. Van Maanen A. Vere T. K. Wadhwani M. B. Waller A. B. Wasthed }. M. Wattenberg (Sanpere) D. R. Wand N. Weiner H. Wells P. N. Witt D. E. Wolfe D. Wolff A. Wollenberger E. H. Wood E. A. Wright M. M. Wright S. J. Yaffe T. S. Yeoh C. Yuan B. Zimmermann

OTTO KRAYER 207 A few selected assessments by Krayer's trainees, cowork- ers, and academic colleagues may serve, collectively, as an appropriate epitaph with which to end this memoir. P. B. Dews: "One of Krayer's great strengths was his absolute honesty and trustworthiness. When he advised a course of action, one could be quite sure that it represented his judgment of what was best for the indi- viduals involved, untinged by what was best for Krayer. The complete loy- alty to his colleagues and helpers engendered a reciprocal loyalty to him- self. He was dedicated to the pursuit of excellence but did not believe this pursuit required a lack of consideration of others or ruthlessness. He con- fidently expected people to rise to excellence." P. R. Draskoczy: "His integrity and high ethical standards combined with a special place in his heart for those who were suffering or deprived made him both strong and compassionate." D. S. Riggs: ". . . a man of unflinching conscience and shining integrity, he set his associates—young and old—an example which none of us will ever forget." A. C. Barger: "He was one of the few teachers in the medical school that I worshipped—for his superb pedagogic skills, his warm human qual- ities, and his willingness to fight for principles." B. D. Davis: "Otto was for me the personification of academic integrity and dignity, and I often thought of his high standards of behavior as I watched the deterioration of standards that has been creeping into medi- cal research in recent years." if. R. Blinks: "He was, without doubt, the finest human being I have ever known." ~ AM GRATEFUL to Mrs. Otto Krayer for making numerous source materials available to me and for helpful discussions about past events. Mr. Richard I. Wolfe, archivist at the Countway Library of Harvard Medical School, facilitated my access to Krayer's Harvard files. All original documents upon which this memoir was based can now be found at the Countway Library. Ullrich Trendelenburg, Melchior Reiter, and Peter B. Dews fur- nished much useful information both in personal communications

208 BIOGRAPHICAL MEMOIRS and in their published obituary notices, which are listed at the end of these acknowledgments. Many colleagues in the United States and abroad were helpful to me in large ways and small. Wilhelm Feldberg, G. Kuschinsky, and Marthe Vogt provided information and reminiscences about the Berlin years; and George Fawaz contributed material about the Lebanon period. For recollections of the early Harvard years, A. Baird Hastings and Eugene M. Landis graciously allowed me to impose on their time. My own memories were supplemented by those of Rafael Mendez and Douglas S. Riggs. Others who were helpful included George H. Acheson, John R. Blinks, Alfred E. Farah, Werner E. Flacke, William W. Fleming, Louis S. Harris, Werner F. Mosimann, Paul L. Munson, Matti K. Paasonen, Douglas R. Wand, and Norman Weiner. Some of those mentioned above commented on a draft of the manuscript and pointed out errors, but of course they have no responsibility for the final product. I am grateful to all my colleagues who helped so generously. German texts of letters or articles have been translated freely here; the reader should consult the original documents for exact wordings. I had help with some of the translations, for which I thank Malcolm Brown, Louisa Laube, and {ean-Pierre von Wart- burg. Finally, for her invaluable and expert assistance at all stages of this project, I am indebted to my secretary, Sharon Fields.

OTTO KRAYER TESTIMONIAL AND OBITUARY ARTICLES 209 Otto Krayer zum 65. Geburtstag. 1965. Gewidmete Arbeiten er- schienen, in Naunyn-Schmiedebergs Archiv fur experimentelle Patho- logie and Pharmakologie, Berlin, Heidelberg, and New York: Springer-Verlag. (Reprinted from 248: 1-560; 249: 1-528; 250:59-71.) M. Reiter. 1964. "Otto Krayer zum 65. Geburtstag," Die Medizinische Welt, 48:2604-5. U. Trendelenburg. 1964. "Zum 65. Geburtstag von Professor Dr. Dr.h.c. Otto Krayer," Arzneimittelforschung, 14: 1171 - 72. U. Trendelenburg. 1978. "Remembrances. Otto Krayer," Life Scien- ces, 22:1113 - 14. M. Reiter and U. Trendelenburg. 1982. "In memoriam. Otto Krayer," Naunyn-Schmiedebergs Archives of Pharmacology, 320: 1-2. H. Raskova. 1982. "Otto Krayer 1899-1982," Physiologia Bohemo- slovaca, 32:468 - 69. P. B. Dews. 1983. "Otto Krayer: 1899 - 1982," Trends in Pharmacolo- gical Sciences, 4: 143 - 46. U. Trendelenburg. 1983. "Otto Krayer: 1899-1982," The Pharma- cologast, 25:31 - 32. P. B. Dews. 1983. "Otto Krayer 1899 - 1982," Harvard Medical Alumni Bulletin, 571:60 - 61.

210 BIOGRAPHICAL MEMOIRS HONORS AND DISTINCTIONS DEGREES AND HONORARY DEGREES 1926 1942 1957 1962 M.D. (Honorary), University of Gottingen 1973 M.D. (Honorary), Technical University of Munchen M.D., University of Freiburg M.A. (Honorary), Harvard University M.D. (Honorary), University of Freiburg PROFESSIONAL APPOINTMENTS 1926 Assistant in Pharmacology, University of Freiburg (with P. Trendelenburg) 1928 Senior Assistant in Pharmacology, University of Berlin (with P. Trendelenburg) 1929 Pr~valdozent for Pharmacology and Toxicology, University of Berlin 1930 Acting Head, Department of Pharmacology and Toxicology, University of Berlin 1932 Professor Extraordinarius of Pharmacology and Toxicology (with W. Heubner), University of Berlin 1934 Rockefeller Fellow, University College, London (with E. B. Verney) 1934 Visiting Professor and Head, Department of Pharmacology, American University of Beirut 1936 1937 Lecturer in Pharmacology, Harvard Medical School Associate Professor of Pharmacology, Harvard Medical School 1939 Associate Professor of Comparative Pharmacology and Head, Department of Pharmacology, Harvard Medical School 1951 Professor of Pharmacology, Harvard Medical School 1954 Charles Wilder Professor of Pharmacology, Harvard Medi- cal School 1964 Gustavus Adolphus Pfeiffer Professor of Pharmacology, Harvard Medical School 1966 Gustavus Adolphus Pfeiffer Professor of Pharmacology, Emeritus, Harvard Medical School

OTTO KRAYER MEMBERSHIPS 211 Deutsche Pharmakologische Gesellschaft (1927) Deutsche Chemische Gesellschaft (1933, resigned 1937) American Society for Pharmacology and Experimental Therapeu- tics (1938~; President (1957-1958~; Chairman, Board of Publi- cations Trustees ~ 1960 - 1962) New York Academy of Sciences (1943~; Fellow (1951~; Life Member (1975) American Association for the Advancement of Science (1944) Society for Experimental Biology and Medicine (1944) American Academy of Arts and Sciences (1949) Pharmacological Society of Canada ~ 1957) National Academy of Sciences (1964) HONORARY MEMBERSHIPS Alpha Omega Alpha, Harvard Medical School (1943) Society for Pharmacology and Therapeutics of the Argentinian Medical Association ~ 1947) Czechoslovakian Medical Society of I. E. Purkinje (1948) Deutsche Pharmakologische Gesellschaft (1952) British Pharmacological Society (1956) Finnish Pharmacological Society ~ 1961 ~ Deutsche Akademie der Naturforscher Leopoldina (1962) Swiss Academy of Medical Sciences (1964) Japanese Pharmacological Society (1972) PROFESSIONAL AND PUBLIC SERVICE Associate Editor, Ergebnisse der Physiologie, biologaschen Chemie And experimentellen Pharmakologie ( 1933-1935, 1939-1976) Treasurer, Boston Committee to Help German Scientists (1946- 1948) Member, Unitarian Medical Mission to Czechoslovakia (1946) Chairman, Unitarian Medical Mission to Germany (1948) Associate Editor, Pharmacological Reviews ( 1948-1953) Member, Pharmacology Study Section, U.S. Public Health Service (1950-1954) Consultant, Eli Lilly & Co. (1950-1956) Editor-in-chief, Pharmacological Reviews ~ 1953 -1959)

212 BIOGRAPHICAL MEMOIRS Member, Scientific Advisory Committee, Massachusetts General Hospital (1959-1961) Member, U.S. National Committee for the International Union of Physiological Sciences ~ 1959-1965) Special Consultant to the Dean, Harvard Medical School (1967) Member, Editorial Board, Annual Review of Pharmacology (1967- 1972) AWARDS AND HONORS Order of the White Lion, Class IV, Republic of Czechoslovakia (1946) Medal for Service to the University, Charles University, Prague (1946) Commemorative Plaque, Czechoslovakian Medical Society (1946) Honorary Citizen of Kondringen (1957) Torald Sollmann Award of the American Society for Pharmacology and Experimental Therapeutics ~ 1961 ~ Schmiedeberg Plakette of the German Pharmacological Society (1964) Festschrift (65th Birthday), Naunyn-Schmiedebergs Archiv fur expert mentelle Patholo`gae und Pharmakolo`~e, volumes 248-250 (1964) Otto Krayer Lectureship at Harvard Medical School (established, 1966) Research Achievement Award, American Heart Association (1969) Otto Krayer Professorship of Pharmacology, Harvard Medical School (established posthumously, 1982) LECTURESHIPS Mayo Foundation Lecturer, Rochester, Minnesota (1947, 1952) University Lecturer, Aberdeen, Scotland (1955) Litchfield Lecturer, University of Oxford, England (1955) Special Lecturer, University College, London, England (1955) Fahr Lecturer, University of Minnesota (1956) University Lecturer, Helsinki, Finland (1961) A. N. Richards Lecturer, Physiological Society of Philadelphia (1962) Visiting Lecturer, Tohoku Medical Society, Sendai, Japan (1965)

OTTO KRAYER 213 Visiting Centennial Professor of Pharmacology, Howard University Medical School (1966) Visiting Professor of Pharmacology, Stanford University (1968) Visiting Professor, Department of Pharmacology, Technical Un versity of Munchen ~ 1972-1980) Visiting Professor, Department of Pharmacology, College of Med- icine, University of Arizona (1972-1980)

214 BIOGRAPHICAL MEMOIRS B I B LI OGRAPHY 1926 O. Krayer. Die pharmakologischen Eigerschaften des reinen Apo- kodeins. Arch. Exp. Pathol. Pharmakol., 111 :60-67. 1928 a. O. Krayer and G. Sato. Schilddrusenwirkung und autonomes Nervensystem. Arch. Exp. Pathol. Pharmakol., 128:67-81. b. O. Krayer. Uber Verteilung und Ausscheidung des Jodes nach Zufuhr von Schilddrusenstoffen. Arch. Exp. Pathol. Pharma- kol., 128: 116-25. 1929 O. Krayer. Die akute Kreislaufwirkung des Neosalvarsans. I. Mit- teilung: Die Analyse der Kreislaufwirkung. Arch. Exp. Pathol. Pharmakol., 146:20-43. 1930 a. O. Krayer. Die akute Kreislaufwirkung des Neosalvarsans. II. Mitteilung: Uber die Ursache der Kreislaufwirkung. Arch. Exp. Pathol. Pharmakol., 153:50 - 66. b. O. Krayer. Uber die Beziehung zwischen Pulsfrequenz, Minu- tenvolumen und Venendruck am isolierten Saugetierherzen. Verh. Dtsch. Pharmakol. Ges., 157:90-91. 1931 a. O. Krayer. Die Theorie der Digitaliswirkung. Verh. Dtsch. Ges. Kreislaufforsch., IV. Tagung, 163-90. b. O. Krayer. Die Physiologie der Coronardurchblutung. Verh. Dtsch. Ges. Inn. Med., XLIII. Kongress Wiesbaden, 237-47. c. O. Krayer. Paul Trendelenburg. Arch. Exp. Pathol. Pharma- kol., 162:III-IX. (Obituary.) d. O. Krayer. Versuche am insuffizienten Herzen. Arch. Exp. Pa- thol. Pharmakol., 162: 1-28. .. e. O. Krayer and A. Ruhl. Uber die Wirkung einer reinen Gefas- serweiterung auf den Gesamtkreislauf. Arch. Exp. Pathol. Pharmakol., 162: 70-85.

OTTO KRAYER 215 f. O. Krayer. Der toxikologische Nachweis des Coniins. Arch. Exp. Pathol. Pharmakol., 162:342-72. g. O. Krayer and W. Koll. Coniinahnliche Eigenschaften einiger Aminbasen. Arch. Exp. Pathol. Pharmakol., 162:373-84. h. ~ Trendelenburg's Grundlagen der allgemeinen und speziellen Arznei- verordnung, 3d ed. rev. O. Krayer. Berlin: Springer. 1932 a. O. Krayer. Uber die Behandlung von Kreislaufstorungen mit Organ- und Muskelextrakten. Bemerkungen zur Pharmakolo- gie. Dtsch. Med. Wochenschr., 58:123-24. O. Krayer and E. Schutz. Mechanische Leistung und Aktions- strom des Warmbluterherzens. Verh. Dtsch. Pharmakol. Ges., XI. Tagung, 99 - 100. c. O. Krayer and E. Schutz. Mechanische Leistung und einphasi- sches Elektrogramm am Herz-Lungen-Praparat des Hundes. Z. Biol., 92:453-61. 1933 a. O. Krayer. Ist die Integritat der sympathischen Schilddrusenin- nervation notwendig fur die thyreotrope Wirkung des Hypo- physenvorderlappens? Arch. Exp. Pathol. Pharmakol., 171 :473-79. b. W. Feldberg and O. Krayer. Nachweis einer bei Vagusreiz frei- werdenden azetylcholinah nlich en Subs tan z am Warmbl u ter- herzen. Verh. Dtsch. Ges. Kreislaufforsch, VI. Tagung, 81-83. c. W. Feldberg and O. Krayer. Das Auftreten eines azetylcholinar- tigen Stoffes im Herzvenenblut von Warmblutern bei Reizung der Nervi vagi. Arch. Exp. Pathol. Pharmakol., 172: 170-93. d. O. Krayer. Zur Kreislaufwirkung der Leberpraparate des Han- dels. Dtsch. Med. Wochenschr., 59:576-78. e. O. Krayer. Zur Pharmakotherapie der Herzinsuffizienz. Er- krankungen des Herzmuskels und der Herzklappen, pp. 84- 94. Dresden and Leipzig: Steinkopff. 1934 a. F. Grabe, O. Krayer, and K. Seelkopf. Beitrag zur Aufklarung der kreislaufwirksamen (adrenalinahnlichen) Stoffe in Lebe- rextrakten. Klin. Wochenschr., 13: 1381-83.

216 BIOGRAPHICAL MEMOIRS 1934 b. O. Krayer and E. B. Verney. Veranderung des Acetylcholinge- haltes im Blute der Coronarvenen unter dem Einfluss einer Blutdrucksteigerung durch Adrenalin. Klin. Wochenschr., 13: 1250-51. c. Die Hormone. Ihre Physiologte und Pharmakolog~e, by Paul Tren- delenburg, vol. 2, ed. O. Krayer. Berlin: Springer. 1935 a. O. Krayer. Beitrag zur Aufklarung der Natur der kreislauf- wirksamen Stoffe in als Heilmittel verwandten Leberextrakten. Institut de Recherches Physiologiques de Moscou. Problemes de Biologie et de Medecine Volume {ubilaire dedie au Prof. Lina Stern, pp. 179 - 83. b. O. Krayer and E. B. Verney. Reflektorische Beeinflussung des Gehaltes an Acetylcholin im Blute der Coronarvenen. Arch. Exp. Pathol. Pharmakol., 180:75-92. 1937 O. Krayer. Kurbissamen als Bandwurmmittel. Klin. Wochenschr., 16: 1651-52. 1938 Trendelenb?~rg's Grundlagen der allgemeinen und speziellen Arznei- verordnung, 4th ed. rev. O. Krayer. Berlin: Springer. 1941 a. D. G. Friend and O. Krayer. The estimation by a manometric method of the activity of cholinesterase in lymph. }. Pharmacol. Exp. Ther., 71:246-52. b. D. G. Friend and O. Krayer. The elimination of prostigmine. J. Pharmacol. Exp. Ther., 72:15. 1942 a. O. Krayer and R. Mendez. Studies on veratrum alkaloids. I. The action of veratrine upon the isolated mammalian heart. T. Pharmacol. Exp. Ther., 74:350-64. b. R. P. Linstead and O. Krayer. Effect of l-ascorbic acid on the isolated frog heart. Science, 95:332-33.

OTTO KRAYER 217 c. O. Krayer, R. Mendez, E. Moisset de Espanes, and R. P. Lin- stead. Pharmacology and chemistry of substances with cardiac activity. I. Effect of unsaturated lactones on the isolated frog heart. I. Pharmacol. Exp. Ther., 74:372-80. d. O. H. Lowry, O. Krayer, A. B. Hastings, and R. P. Tucker. Effect of anoxemia on myocardium of the isolated heart of the dog. Proc. Soc. Exp. Biol. N.Y., 49:670-74. e. E. B. Astwood, l. M. Flynn, and O. Krayer. Effect of continuous intravenous infusion of glucose in normal dogs. }. Clin. Invest., 21:621. f. O. Krayer. The effect of veratrum alkaloids on circulatory reflexes. Fed. Proc. Fed. Am. Soc. Exp. Biol., 1:156. 1943 a. O. Krayer, R. P. Linstead, and D. Todd. Pharmacology and che- mistry of substances with cardiac activity. II. Effect of l-ascorbic acid and some related compounds and of hydrogen peroxide on the isolated frog heart. I. Pharmacol. Exp. Ther., 77:113- 22. b. G. K. Moe and O. Krayer. Studies on veratrum alkaloids. II. The action of veratridine and cevine upon the isolated mam- malian heart. I. Pharmacol. Exp. Ther., 77:220-28. c. O. Krayer. Action of l-ascorbic acid upon the isolated frog heart. Proc. Soc. Exp. Biol. N.Y., 53:51-52. d. O. Krayer, E. H. Wood, and G. Montes. Studies on veratrum alkaloids. IV. The sites of the heart rate lowering action of ver- atridine. J. Pharmacol. Exp. Ther., 79:215-24. e. S. Ellis, O. Krayer, and F. L. Plachte. Studies on physostigmine and related substances. III. Breakdown products of physostig- mine; their inhibitory effect on cholinesterase and their phar- macological action. J. Pharmacol. Exp. Ther., 79:309-19. 1944 a. O. Krayer, A. Goldstein, and F. L. Plachte. Studies on physo- stigmine and related substances. I. Quantitative relation be- tween dosage of physostigmine and inhibition of cholinesterase activity in the blood serum of dogs. J. Pharmacol. Exp. Ther., 80:8-30. b. G. K. Moe, D. L. Bassett, and O. Krayer. Studies on veratrum

218 BIOGRAPHICAL MEMOIRS alkaloids. V. The effect of veratridine and cevine upon the cir- culation in anesthetized dogs, with particular reference to femoral arterial flow. i. Pharmacol. Exp. Ther., 80:272-84. c. O. Krayer, G. K. Moe, and R. Mendez. Studies on veratrum alkaloids. VI. Protoveratrine: Its comparative toxicity and its circulatory action. i. Pharmacol. Exp. Ther., 82: 167-86. d. O. Krayer. A difference in cardiodecelerator action between di- gitoxin and digitoxigenin. Proc. Soc. Exp. Biol. N.Y., 57:167- 69. 1946 a. H. M. Mating and O. Krayer. The action of erythrophleum al- kaloids upon the isolated mammalian heart. I. Pharmacol. Exp. Ther., 86:66 - 78. b. O. Krayer and G. H. Acheson. The pharmacology of the ver- atrum alkaloids. Physiol. Rev., 26:383-446. c. A. Farah and O. Krayer. The action of dimethylaminoethanol upon the heart-lung preparation of the dog. Fed. Proc. Fed. Am. Soc. Exp. Biol., 5:177-78. O. Krayer, A. Farah, and F. C. Uhle. Pharmacology and chem- istry of substances with cardiac activity. IV. Effect of methyl- aminoethanol, dimethylaminoethanol, and related substances on the isolated mammalian heart. I. Pharmacol. Exp. Ther., 88:277-86. d. 1947 O. Krayer, }. C. Aub, I. T. Nathanson, and P. C. Zamecnik. The influence of antitoxin upon the action of Clostr~dium oedematiens toxin in the heart-lung preparation of the dog. }. Clin. Invest., 26:411-15. 1948 a. O. Krayer and A. Farah. Action of cysteine and of dimercap- topropanol in heart failure caused by sodium bismuth tartrate. Fed. Proc. Fed. Am. Soc. Exp. Biol., 7:235. b. A. Wollenberger and O. Krayer. Experimental heart failure caused by central nervous system depressants and local anes- thetics. I. Pharmacol. Exp. Ther., 94:439-43.

OTTO KRAYER 1949 219 a. O. Krayer, S. B. Wolbach, I. H. Mueller, and G. B. Wislocki. Reid Hunt. Harv. Med. Alumni Bull., 23:39 - 42. (Obituary.) b. A. Goldstein, O. Krayer, M. A. Root, G. H. Acheson, and M. E. Doherty. Plasma neostigmine levels and cholinesterase inhibi tion in dogs and myasthenic patients. I. Pharmacol. Exp. Ther. 96:56-85. c. O. Krayer. Veratramine, an antagonist to the cardioaccelerator action of epinephrine. Proc. Soc. Exp. Biol. N.Y., 70:631-32. d. O. Krayer. Studies on veratrum alkaloids. VIII. Veratramine, an antagonist to the cardioaccelerator action of epinephrine. {. Pharmacol. Exp. Ther., 96:422-37. e. E. Meilman and O. Krayer. Clinical studies on the pure ver- atrum alkaloids: Protoveratrine and veratridine. Forty-first An- nual Meeting, American Society for Clinical Investigation, At- lantic City, May 2. I. Clin. Invest., 28:798. f. O. Krayer. Studies on veratrum alkaloids. IX. The inhibition by veratrosine of the cardioaccelerator action of epinephrine and of norepinephrine. I. Pharmacol. Exp. Ther., 97:256-65. g. O. Krayer and E. F. Van Maanen. Studies on veratrum alka- loids. X. The inhibition by veratramine of the positive chrono- tropic effect of accelerans stimulation and of norepinephrine. I. Pharmacol. Exp. Ther., 97:301-7. h. O. Krayer. The pharmacological basis for the use of veratrum alkaloids in the treatment of hypertension. Proc. Rudolf Vir- chow Med. Soc. City N.Y., 8:126-27. 1950 a. Lectures Unitarian Service Committee Medical Mission to Germany, July2—September3, 1948, ed. O. Krayer. Berlin: Springer. b. E. Meilman and O. Krayer. Clinical studies on veratrum alka- loids. I. The action of protoveratrine and veratridine in hyper- tension. Circulation, 1 :204-13. c. O. Krayer. A quantitative comparison of the antiaccelerator ac- tion of veratramine and jervine. I. Pharmacol. Exp. Ther., 98:19. d. K. Kramer, U. Luft, and O. Krayer. Action of epinephrine and veratramine upon heart rate and oxygen consumption in the

220 BIOGRAPHICAL MEMOIRS heart-lung preparation of the dog. Fed. Proc. Fed. Am. Soc. Exp. Biol., 9:292. e. M. Reiter and O. Krayer. tervine and pseudojervine, antago- nists to the cardioaccelerator action of epinephrine and of ac- celerans stimulation. I. Pharmacol. Exp. Ther., 98:27. f. O. Krayer and M. Reiter. Studies on veratrum alkaloids. XI. Heroine and pseudojervine, antagonists to the cardioaccelerator action of epinephrine and of accelerans stimulation. Arch. Int. Pharmacodyn. Ther., 81:409-26. g. O. Krayer. Studies on veratrum alkaloids. XII. A quantitative comparison of the antiaccelerator cardiac action of veratra- mine, veratrosine, jervine and pseudojervine. I. Pharmacol. Exp. Ther. 98 :427-36. h. O. Krayer. Solanum alkaloids with antiaccelerator cardiac acti- vity. Fed. Proc. Fed. Am. Soc. Exp. Biol., 9:292. i. O. Krayer and L. H. Briggs. Studies on solanum alkaloids. I. The antiaccelerator cardiac action of ,13-dihydrosolasodine and tetrahydrosolasodine. Br. i. Pharmacol., 5:118-24. j. O. Krayer and L. H. Briggs. Studies on solanum alkaloids. II. The antiaccelerator cardiac action of solasodine and some of its derivatives. Br. J. Pharmacol., 5:517-25. k. O. Krayer. The antiaccelerator cardiac action of quinine and quinidine. I. Pharmacol. Exp. Ther., 100:146-50. O. Krayer. Untersuchungen uber die Kreislaufwirkung der Veratrumalkaloide. Arch. Exp. Pathol. Pharmakol., 209:405- 20. 1951 a. J. I. Mandoki, C. Mendez, R. R. Garcia, and O. Krayer. The action of veratramine and epinephrine on the functional re- fractory period of A-V conduction. I. Pharmacol. Exp. Ther., 101:25. b. O. Krayer. Quinine-like action of veratramine upon the single twitch and upon the "veratrine response" of the sartorius muscle of the frog. Fed. Proc. Fed. Am. Soc. Exp. Biol., 10:316. c. O. Krayer, F. C. Uhle, and P. Ourisson. Studies on veratrum alkaloids. XIV. The antiaccelerator cardiac action of derivatives of veratramine and jervine and of synthetic steroid secondary

OTTO KRAYER 221 alkamines obtained from pregnenolone and from sapogenins. I. Pharmacol. Exp. Ther., 102:261 - 68. d. O. Krayer and H. W. George. Studies on veratrum alkaloids. XV. The quinine-like effect of veratramine upon the single twitch and upon the "veratrine response" of the sartorius muscle of the frog. I. Pharmacol. Exp. Ther., 103:249-58. e. O. Krayer, I. I. Mandoki, and C. Mendez. Studies on veratrum alkaloids. XVI. The action of epinephrine and of veratramine on the functional refractory period of the auriculo-ventricular transmission in the heart-lung preparation of the dog. J. Phar- macol. Exp. Ther., 103:412-19. 1952 a. O. Krayer, B. H. Rogers, S. M. Kupchan, and C. V. Deliwala. Pharmacological and chemical relation between the veratrum alkaloids and the zygadenus alkaloids. Fed. Proc. Fed. Am. Soc. Exp. Biol., 11:364. b. R. B. Arora, E. Meilman, and O. Krayer. Action of veratramine and of sympathomimetic amines upon the automaticity of the atrio-ventricular node. Fed. Proc. Fed. Am. Soc. Exp. Biol., 11:318. c. P. Ourisson and O. Krayer. Antagonistic action to the cardio- accelerator effect of ephedrine, synephrine? isuprel, tuamine and oenethyl. Fed. Proc. Fed. Am. Soc. Exp. Biol., 11:381. d. O. Krayer. Antiaccelerator cardiac agents. I. M. Sinai Hosp. N.Y., 19:53-69. e. E. Meilman and O. Krayer. Clinical studies on veratrum alka- loids. II. The dose-response relations of protoveratrine in hy- pertension. Circulation, 6:2 12 - 2 1 . f. R. B. Arora and O. Krayer. The antiveratrinic action of the cardiac glycosides and of bufotoxin. I. Pharmacol. Exp. Ther., 106:371-72. g. ~ Trendelenburg's Grundlagen der allgemeinen and speziellen Arznei- verordnung, 7th ea., rev. O. Krayer and M. Kiese. Berlin, Got- tingen, and Heidelberg: Springer. 1953 a. O. Krayer, S. M. Kupchan, C. V. Deliwala, and B. H. Rogers. Untersuchungen uber die Veratrumalkaloide. XVIII; Die

222 BIOGRAPHICAL MEMOIRS chemischen und pharmakologischen Beziehungen zwischen den Zygadenusalkaloiden und den Veratrumalkaloiden. Arch. Exp. Pathol. Pharmakol., 219:371-85. b. O. Krayer. The history of the Bezold-tarisch effect. Presented at a symposium, Reflexes from the Cardiac and Pulmonary Areas. Nineteenth International Physiology Congress, Mon- treal. 1954 a. H. W. Kosterlitz, O. Krayer, and A. Matallana. The eject of moderately large doses of veratramine and veratrosine on the rhythm of the acutely denervated heart of the cat. }. Physiol. (London), 124:40P. b. O. Krayer and P. Ourisson. Studies on veratrum alkaloids. XIX. The action of veratramine upon cardioacceleration caused by ephedrine, tyramine, phenylephrine and isopropylarterenol. J. Pharmacol. Exp. Ther., 112:341 - 55. c. O. Krayer. Veratrum alkaloids. In: Pharmacology in Medicine, ed. V. A. Drill, pp. 1-10. New York: McGraw-Hill. 1955 c. a. O. Krayer and t. M. Benforado. Die Schlagfrequenz des akut denervierten Herzens im Herz-Lungen-Praparat des Hundes mit einem Hinweis auf die frequenzbeschleunigende Wirkung des Adrenalins. Pflug. Arch. Ges. Physiol., 260:177-87. b. O. Krayer, R. B. Arora, and E. Meilman. Studies on veratrum alkaloids. XXI. The action of veratramine upon impulse gene- ration in the dog heart. J. Pharmacol. Exp. Ther., 113:446-59. H. W. Kosterlitz, O. Krayer, and A. Matallana. Studies on ver- atrum alkaloids. XXII. Periodic activity of the sino-auricular node of the denervated cat heart caused by veratramine. i. Pharmacol. Exp. Ther., 113 :460-69. d. S. Ellis and O. Krayer. Properties of a toxin from the salivary gland of the shrew, Blarina brevicauda. ]. Pharmacol. Exp. Ther.,114:127 - 37. 1956 a. O. Krayer and }. Fuentes. Chronotropic cardiac action of reser- pine. Fed. Proc. Fed. Am. Soc. Exp. Biol., 15:1462.

OTTO KRAYER 223 b. F. C. Uhle, B. A. Mitman, and O. Krayer. Synthetic esters of dimethylaminoethanol exhibiting positive inotropic cardiac ac- tivity. J. Pharmacol. Exp. Ther., 116:444 - 49. I. R. Innes, H. W. Kosterlitz, and O. Krayer. Studies on ver- atrum alkaloids. XXIV. The inhibition by veratramine and ver- atrosine of the cardioaccelerator effect of electrical stimulation of the accelerator nerves. l. Pharmacol. Exp. Ther., 117:317- 21. c. 1957 a. M. K. Paasonen and O. Krayer. Effect of reserpine upon the mammalian heart. Fed. Proc. Fed. Am. Soc. Exp. Biol., 16:326-27. b. O. Krayer and M. K. Paasonen. Direct cardiac action of reser- pine. Acta Physiol. Scand., 42:88-89. c. I. R. Innes and O. Krayer. Depletion of the cardiac catechol- amines by reserpine. I. Physiol. (London), 139: 18P. 1958 a. O. Krayer. Veratrum alkaloids. In: Pharmacology in Medicine, 2d ea., ed. V. A. Drill, pp. 515-24. New York: McGraw-Hill. b. O. Krayer and I. Fuentes. Changes in heart rate caused by di- rect cardiac action of reserpine. I. Pharmacol. Exp. Ther., 123: 145-52. M. K. Paasonen and O. Krayer. The release of norepinephrine from the mammalian heart by reserpine. I. Pharmacol. Exp. Ther., 123:153-60. d. I. R. Innes and O. Krayer. Studies on veratrum alkaloids. XXVII. The negative chronotropic action of veratramine and reserpine in the heart depleted of catecholamines. J. Pharma- col. Exp. Ther., 124:245-51. e. I. R. Innes, O. Krayer, and D. R. Waud. The action of Ranwolfia alkaloids on the heart rate and on the functional refractory pe- riod of atrio-ventricular transmission in the heart-lung prepa- ration of the dog. i. Pharmacol. Exp. Ther., 124:324-32. f. D. R. Wand, S. R. Kottegoda, and O. Krayer. Threshold dose and time course of norepinephrine depletion of the mamma- lian heart by reserpine. I. Pharmacol. Exp. Ther., 124:340-46. c.

224 BIOGRAPHICAL MEMOIRS 1959 M. K. Paasonen and O. Krayer. The content of noradrenaline and adrenaline in the rat heart after administration of Ranwolfia alka- loids. Experientia, 15:75 -76. 1960 D. R. Wand and O. Krayer. The rate-increasing effect of epineph- rine and norepinephrine and its modification by experimental time in the isolated heart of normal and reserpine-pretreated dogs. J. Pharmacol. Exp. Ther., 128:352-57. 1961 a. O. Krayer. The history of the Bezold-larisch effect. Arch. Exp. Pathol. Pharmakol., 240:361-68. b. O. Krayer, E. B. Astwood, D. R. Wand, and M. H. Alper. Rate- increasing action of corticotropin and of a-intermedin in the isolated mammalian heart. Proc. Natl. Acad. Sci. USA, 47: 1227-36. 1962 a. O. Krayer, M. H. Alper, and M. K. Paasonen. Action of gua- nethidine and reserpine upon the isolated mammalian heart. }. Pharmacol. Exp. Ther., 135: 164-73. b. O. Krayer, B. D. Davis, and S. W. Kuffler. Obituary Otto Loewi. Pharmacologist, 4:47-49. c. O. Krayer. Accidents in the pursuit of knowledge. (Sollmann- Award oration.) Pharmacologist, 4:68-76. a. O. Krayer. 1963 Uber chronotrope Herzwirkung. Klin. Wo- chenschr., 41:272-76. b. M. H. Alper, W. Flacke, and O. Krayer. Pharmacology of reser- pine and its implications for anesthesia. Anesthesiology, 24:524-42. 1964 D. F. Hawkins, F. C. Uhle, and O. Krayer. Studies on veratrum alkaloids. XXXVII. Chronotropic cardiac action and toxicity of

OTTO KRAYER 225 N-alkyl derivatives of veratramine. I. Pharmacol. Exp. Ther., 145:275-85. 1965 O. Krayer, W. Mosimann, and G. Schroder. Positive chronotropic cardiac effect of methyl guanidine. Fed. Proc. Fed. Am. Soc. Exp. Biol., 24:487. 1966 O. Krayer, W. Mosimann, and G. Silver. Rate-increasing action of methylguanidine upon the isolated mammalian heart. l. Phar- macol. Exp. Ther., 154:73-82. 1972 O. Krayer, N. Weiner, and W. Mosimann. Blood norepinephrine levels during responses of the heart-lung preparation to me- thylguanidine. J. Pharmacol. Exp. Ther., 181: 108-15. 1977 O. Krayer and E. Meilman. Veratrum alkaloids with antihyperten- sive activity. In: Handbook of Experimental Pharmacology, Hef~ter- Heubner, new ser., ed. G. V. R. Born, O. Eichler, A. Farah, H. Herken, and A. D. Welch, pp. 547-70. Berlin, Heidelberg, and New York: Springer-Verlag.