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IRVINE HEINLY PAGE January 7, 1901-June 10, 1991 BY HARRIET P. DUSTAN FOR OVER FIFTY W^S, from his first scientific paper on hypertension (high blooc! pressure) in 1935 to the pub- lication of a massive text (1,102 pages), Hypertension Mecha- nisms, in 1987, Irvine Page was a dominant figure in the field of hypertension research. In a(ldition to his scientific contributions, which were many and seminal, his unflag- ging advocacy of hypertension as a major public health prob- lem diet much to focus the attention of patients, physicians, investigators, ant! politicians on the neecl for its control. Largely forgotten is the fact that Page initiated the negotia- tions that eventually led to the establishment of the Insti- tute of Medicine of the National Academy of Sciences. Irvine Heinly Page was born on January 7, 1901, in Inclia- napolis, Tncliana. His father was Lafayette Page, a physician of considerable local repute. Irvine Page was one of three chilciren; his brother was a lawyer, and his sister, Ruth Page, became a famous ciancer. She died in 1991 en cl was eulo- gizecl by the Chicago Tribune as "a worIc! renowned choreog- rapher who reigned as the grand dame of ciance of Chi- cago." Page's early schooling was in Indianapolis, and his summers were spent on Cape Coc! at Hyannis Port. He at- tencled Cornell University, majored in chemistry, and di- 237

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238 BIOGRAPHICAL MEMOIRS rected a dance band that nicely supplemented! his family's financial support. Page liked chemistry, so after graduating in 1921 he worked for a year on the recently cliscoverect insulin with George Clowes en c! Elliott Muslin. Then he en- rollec! in Cornell Meclical College, attracted by biochemist James Sumner who won a Nobel Prize for crystallizing ure- ase. Page found he likes! medicine also but not to the ex- clusion of chemistry, because after a two-year internship at Presbyterian Hospital he was recruiter! by Geheimrat Rich- arct Wilstatter to establish a department of brain chemistry at the Kaiser Wilhelm Institute of Psychiatry in Munich, Germany. Page in his memoir, Hypertension Research, recounts that in the three years he spent there his accomplishments were to set up a laboratory of neurochemistry and conduct research that gave "fats and sterols a better name." During that time he also accomplished a marriage to Beatrice Allen, a ciancer with the Denishawn Company. Page returned to the United States in lL93l, having been warned by a Ger- man army officer of the likelihood of war. When he macle the decision to return he hacI no position to go to; nobody wan test or needled a brain chemist Then good fortune struck. Donald Van Slyke of the Rockefeller Institute happened to be in Munich with his family and neeclecI a cloctor for his daughter who hac! an infected finger. Page was the only American physician there, so he was consulted. Not only was Van Slyke one of Page's heroes but, as it turned out, he held the key to Page's immediate future. The results were that the finger infection was treated successfully and Page was offerer! a position at the Rockefeller Institute. Before leaving Europe, Page went to Frankfurt for two months of study with Fran s VoTharcI, a professor of mecli- cine particularly interested! in hypertension who was respon- sible for some of the early descriptions of its effect on the kidney. There Page met two of VoTharcl's assistants, who

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IRVINE HEINLY PAGE 239 played important roles in his future. One of them, Bohn, claimed that he coulc! extract a blood pressure raising (pres- sor) substance from the blood of malignant hypertensives. (Malignant hypertension is a type of elevated blood pres- sure that is uniformly fatal if untreated. The term "malig- nant" refers to its clinical course and not to any specific causation.) The other Volharcl associate was Hessel, who was working on renin, a presser substance fount! in saline extracts of kidney that had been describecl forty years ear- lier by Tigerstedt and Bergman. Page spent six years at the Rockefeller Institute as an associate member, en cl it was there that he began his work in hypertension. First, he tried to reproduce Bohn's f~nd- ing of circulating pressor substances in malignant hyper- tension but to no avail; none was found. He also tried to purify renin and isolate it from blood; that was not success- ful either. He die! make an important observation, however, when he lowerec! blood pressure with colloidal sulfur injec- tions and fount! that kidney function was well maintained. Prior to that observation, conventional wisdom held that elevated blood pressure was essential for blood to circulate through narrowed renal arteries. Toward the end of Page's stay at the Rockefeller Insti- tute, Arthur Corcoran joined him, anti in 1937 the two men moved their research activity to the Laboratory for Clinical Research at the Inclianapolis City Hospital, which was supported in part by the Eli Lilly Company. Alreacly there were Kenneth Kohlstaecit en cl Oscar Helmer. This team had great success, and in a 1940 publication they clescribec3 renin as an enzyme that produces a presser compound they called angiotonin. Braun-Menendez and his colleagues in Buenos Aires had similar success, and the two discoveries were published almost simultaneously. The Argentineans,

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240 BIOGRAPHICAL MEMOIRS however, had a different name for the presser compound; they called it hypertensin. In another first, Page, in collaboration with a young cTi- nician, Robert Taylor, was able to reduce blood pressure by kidney extracts and later by pyrogen therapy. Those were the only nonsurgical treatments available in the early 1940s; low-sodium diets were under study but at that time were not widely used. In 1945 Page was invited to set up a hypertension re- search program at Cleveland Clinic. Corcoran and Taylor went with him. Page was director of the Research Division at Cleveland Clinic from 1945 until his retirement in 1966. Much was accomplished by him and his co-workers: seroto- nin was isolated and its pharmacology carefully detailed, the mosaic theory of hypertension was introduced and re- fined, the importance of the autonomic nervous system as the controlling mechanism in hypertension was firmly es- tablished, angiotensin was crystallized, treatment of hyper- tension was a constant and successful focus, the National Foundation for High Blood Pressure was begun, and the Institute of Medicine had its origins there. Retirement for Irvine Page did not mean a retirement from hypertension activities; he only changed his venue by moving to Hyannis Port. Separated from a laboratory and research administration he did the next best thing; he wrote. From that period came four important scientific texts: Re- nal Hypertension in 196S, edited with J. W. McCubbin; Seroto- nin in 1968; Ang~otensin in 1973, edited with F. M. Bumpus; and Hypertension Mechanisms in 1987. Equally informative but in a different vein was his last book, Hypertension Re- search, A Memoir, ~ 920-1960, published in ~ 988. For almost three decades Page was associated with Mod- ern Medicine, and for at least half that time he was the edi- tor. The journal was published biweekly, and this meant

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IRVINE HEINLY PAGE 24 writing two editorials a month for practicing physicians, a task in which Page was aided immeasurably by his wife, who is herself a writer ant! was his justifiably trusted critic and copy editor. Although Page was not a practitioner in the usual sense, nor had he ever been, he user] his editorial position to inform, cajole, teach, and exhort the country's practitioners, who were the reaclers of that journal. In the 1992 presiclential campaign lexicon, it was a bully pulpit for him ant! it worked; thousands of physicians came to know more science, politics, and sociology through those editori- als than they wouIcl have otherwise. In 1972 a selection of them was published under the title of "Speaking to the Doctor." Page was injured in an auto accident in March 1990 and was in poor health from then until his sudden ant! unex- pected death on June 10, 1991. He is survived by his wife and two sons, Christopher and Nicholas, and their wives ant] chilciren. The honor of election to the National Academy of Sci- ences came to Page in 1971, some time after his major scientific contributions. Having known him as T clid through an association of forty-three years ~ can hear him say "about time." Of course, he was immensely pleased but being a bit of a curmudgeon was a necessary part of his public per- sona. This brief biographical sketch in no way details the qual- ity of Page's contributions anal their impact on biology and medicine as we unclerstan(1 them tociay. One of Page's ma- jor scientific contributions was his description of the enzy- matic nature of renin and its production of a potent pres- sor compound, angiotonin, from a plasma protein substrate. Although his first efforts at isolating renin while at the Rockefeller Institute were unsuccessful, he hit pay dirt when he resumed his studies upon moving to Indianapolis. There

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242 BIOGRAPHICAL MEMOIRS he hac! the manpower neecled for the task. Oscar Helmer prepared protein fractions of kidneys, which were tested for their ability to raise blooc! pressure in the clog by Page; to cause vasoconstriction in isolated vascular beds by KohIstaecit; anti to decrease blooc! flow to the dog kidney by Corcoran. They found that, as purification proceedecI, activity clecreasec3 but couict be returnee! if plasma was adcled to the injectate. They called that plasma substance renin activator and the presser compound that it proclucec! ang~otonin. A little later they realized the nature of the acti- vator and called it renin substrate. At about the same time, a group in Argentina heaclec! by Ecluardo Braun-Menendez also found a pressor substance of kidney origin. It too was the product of the enzymatic action of renin, but they called the presser substance so producer! hypertensin an cl the substrate hypertensinogen. Some years later Page ant! Braun-Menenclez agreed on the names angiotensin en c! angiotensinogen. That was onIv the beginning of the story Pane we At on . . ~ - ~ <~ _ _ _ ~ _ ~ ~ crystallizing rennin, and after moving to Cleveland he en- listect the collaboration of Arcia Green, a protein chemist, but years of effort, many kilos of kidneys, and tons of am- monium sulfate produced nothing. However, work on the renin-angiotensin system was proceeding. First, it was learned that angiotensin was more complex than first thought when Skeggs en c! colleagues (1954) shower! that the product of repin's action on its substrate is a pepticle that is without effect on blood vessels and must be converted to an active form by what they called converting enzyme. These angio- tensins came to be known as angiotensin T and TI. Very soon ( 1956) Peart clescribed the amino acid composition of angiotensin I, and within a year Bumpus, Schwarz, and Page reporter] the synthesis of angiotensin IT, the active com- pound, anc! conf~rmec! that it is an octapeptide. Almost

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IRVINE HEINLY PAGE 243 simultaneously Schwyzer and colleagues reported the syn- thesis of L-arginine angiotensin IT. Some years later renin was finally isolated and characterized in the laboratories of Corval and Menard, of Tnagami, and of Haber. The renin-angiotensin system is widely distributed and has been identified in blood vessels, brain, salivary glands, uterus, placenta, adrenal, and, of course, the kidney, where it was originally found. It is one of the most important systems of the body: it regulates blood pressure by directly affecting the smooth muscle of arteries, it is the primary factor in aldosterone release, it has an independent effect on salt excretion by the kidney, and it influences brain func- tion. It plays a major role in hypertension and heart fail- ure, as witnessed by the beneficial effects of angiotensin- converting enzyme inhibitors. Page's description of the renin-angiotensin system was a major contribution. Another major contribution was the isolation and charac- terization of serotonin. lit had been known for eighty years that when blood clots, the serum contains a vasoconstrictor that, as later work showed, is absent when sodium citrate is used to prevent clotting. Also, the appearance of this vaso- constrictor was found to have a quantitative relationship to the platelet count, and other work found a vasoconstrictor in platelet extracts. The isolation of this substance Page assigned in 1946 to a young postdoctoral research fellow, Maurice Rapport. This Page considered a necessary step before undertaking a search for substances in the blood of hypertensives that could be responsible for raised arterial pressure. Success came shortly, and in 1948 Rapport, Green, and Page reported the isolation, identification, and crystal- lization of that vasoconstrictor. It is 5-hydroxytryptamine that they called serotonin because it was isolated from se- rum and had a tonic effect on arteries. In 1953 Twarog and Page showed that the brain contains serotonin, and now it

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244 BIOGRAPHICAL MEMOIRS is recognized as a neurotransmitter. Subsequently, Page and his colleague McCubbin carried out an extensive investiga- tion of the carcliovascular pharmacology of serotonin, and they showed, among many other effects, that the bloocl pres- sure response is strongly influencer! by the activity of the sympathetic nervous system. Now, almost fifty years later, we still do not know the true scope of serotonin's activity in human biology. Page influenced the conceptualization of hypertension in a unique fashion. In the 1940s and early 1950s the cause of essential hypertension was searcher! for. By 1950 Page hac3 concluclecI, however, that hypertension results from an interaction of many mechanisms. This he called the mosaic theory. It was first suggested as a combination of five mecha- nisms ancI subsequently refined, so that by 1960 it was macle up of eight factors, all interrelated. Because this theory (as he called it, although it was actually a schema) presaged a large volume of evidence for the interlocking of multiple mechanisms of hypertension control, the mosaic "theory" is now the dominant concept and no longer are investiga- tors looking for a single cause of hypertension. Although Page was not a practicing physician, he hac! a keen appreciation of the public health importance of hy- pertension and what could be achiever! by bloocl pressure control. From 1951, when antihypertensive drugs of Tong- term effectiveness were first introclucecI, until his retire- ment in 1966, Page was actively concerned! with the treat- ment of hypertension: he tested every new cirug in clogs, so that he ant! those of us involved in the care of patients knew the pharmacology anc! what we were dealing with. He was insistent on the importance of treating hypertension, and we were among the first to demonstrate a causal rela- tionship between high blooct pressure ant! the lethal conse-

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IRVINE HEINLY PAGE 245 quences of malignant hypertension by showing the life-sav- ing effects of antihypertensive drug therapy. In addition to his advocacy for the treatment of hyper- tension, Page was a strong, fervent, and vocal supporter of research and specifically research on hypertension. Early on he maintainer! that industry and business should con- tribute directly to that support because hypertension en cl other cardiovascular diseases ravaged micIdIe-agecI men, caus- ing businesses to suffer accordingly. Thus, in 1945 he orga- nizec] the National Foundation for High Blood Pressure, whose members were businessmen from Cleveland and hy- pertension researchers from across the country. The busi- nessmen raisecl money for research support, which was com- peted for by all scientists involved in hypertension research, not just those who were members of the foundation. Page hoper! that other cities would follow the lead of these Cleve- lanct businessmen, so that a network of support for hyper- tension research could be established in this country. But other events overtook these aspirations; the network never materialized, the National Institutes of Health became the major funding source of biomedical research in this coun- try, en cl the foundation gave up its inclepenclent status and joiner! the American Heart Association as the Council for High Blood Pressure Research. The annual meetings of the council represent the best of contemporary hypertension research and are a continuing tribute to Page's advocacy of research. In the early 1960s Page became convincer! that establish- ment of a National Academy of Medicine would benefit by bridging "the wide gaps among government, the American Medical Association, specialty societies, academia and in- clustry an ecumenical movement." He used his Modern Medicine editorials to test the waters. Finding considerable support for this iclea he approached the president of the

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246 BIOGRAPHICAL MEMOIRS National Academy of Sciences, who also was interested. Page then obtainer! a planning grant from the Cleveland Foun- dation, and in January 1967 the first organizational meet- ing was held at Cleveland Clinic. The deliberations took a long time, and in the end a National Academy of Medicine was not establishecI. In its place was the Institute of MecTi- cine, which came into being in 1971. This then is a brief look at the life of a man who macle significant scientific contributions; altered the course of the investigation and treatment of high bloocl pressure; and, in a more general sense, influencer! medicine in the United States. MATERIALS USED IN WRITING this memoir came from my forty-three- year friendship with Irvine Page, twenty-four years of which I worked closely with him; from his book Hypertension Research, A Memoir, 1920-1960, and from a rereading of his major scientific papers.

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IRVINE HEINLY PAGE HONORS 247 In addition to his election to the National Academy of Sciences, Page received many other honors. He was president of the Ameri- can Heart Association (1956-57~; he received ten honorary degrees and a number of prestigious awards the Ida B. Gould Memorial Award of the American Association for the Advancement of Science ~ 1957~; Albert Lasker Award ~ 1958~; Gairdner Foundation Award (1963~; Distinguished Award of the American Medical Association (1964~; Oscar B. Hunter Award (1966~; Passano Foundation Award (1967~; and the Stouffer Prize for Hypertension Research (1970~.

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248 BIOGRAPHICAL MEMOIRS SELECTED BIBLIOGRAPHY 1934 The effect on renal efficiency of lowering arterial blood pressure in cases of essential hypertension and nephritis. {. Clin. Invest. 13:909- 15. 1940 With K. G. Kohlstaedt and O. M. Helmer. The activation of renin by blood. Am. Heart I. 19:92-99. With O. M. Helmer. A crystalline presser substance (angiotonin) resulting from the reaction between renin and renin activator. {. Exp. Med. 71:29-42. With O. M. Helmer. Angiotonin-activator, repin-and angiotonin-in- hibitor and the mechanism of angiotonin tachyphylaxis in nor- mal, hypertensive and nephrectomized animals. J. Exp. Med. 71:495- 505. 1941 With O. M. Helmer, K. J. Kohlstaedt, P. J. Fouts, and J. F. Kempf. Reduction of arterial blood pressure of hypertensive patients and animals with extracts of kidneys. [. Exp. Med. 73:7-41. 1948 With M. M. Rapport and A. A. Green. Partial purification of the vasoconstrictor in beef serum. [. Biol. Chem. 174:735-41. With M. M. Rapport and A. A. Green. Crystalline serotonin. Science 108:329-33. 1951 The renin-angiotonin presser system. In Hypertension: A Symposium, ed. E. T. Bell, B. I. Clausen, and G. E. Fahr, pp. 48-67. Minneapo- lis: University of Minnesota Press. 1952 - With R. D. Taylor, H. P. Dustan, and A. C. Corcoran. Evaluation of 1-hydrazinophthalazine ("Apresoline") in treatment of hypertensive disease. Arch. Intern. Med. 90:734-49.

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IRVINE HEINLY PAGE 1953 249 With B. M. Twarog. Serotonin content of some mammalian tissues and urine and a method for its determination. Am. J. Physiol. 175:157-61. 1954 With F. M. Bumpus and A. A. Green. Purification of angiotonin. /. Biol. Chem. 210: 287-94. 1957 With F. M. Bumpus and H. Schwarz. Synthesis and pharmacology of the octapeptide angiotonin. Science 125:886-87. 1958 With H. P. Dustan, R. E. Schneckloth, and A. C. Corcoran. The effectiveness of long-term treatment of malignant hypertension. Circulation 28:644-51. 1960 The mosaic theory of hypertension. In Essential Hypertension: An International Symposium, ed. K. D. Bock and P. T. Cottier, pp. 1- 29. Berlin: Springer-Verlag. 1963 With B. M. Baker, I. D. Frantz, A. Keys, L. W. Kinsell, J. Stamler, and F. l. Stare. The national diet heart study. An initial report. [AMA 185:105-6. 1965 With A. C. Corcoran, H. P. Dustan, and T. Koppani. Cardiovascular actions of sodium nitroprusside in animals and hypertensive pa- tients. Circulation 1 1:188-98. 1968 With H. P. Dustan, R. C. Tarazi, and E. D. Frohlich. Arterial pres- sure responses to discontinuing antihypertensive drugs. Circula- tion 37:370-79. With I. W. McCubbin (ed.~. Renal Hypertension, ed. Chicago: Year- book Medical Publishers. Serotonin. Chicago: Yearbook Medical Publishers.

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250 BIOGRAPHICAL MEMOIRS 1971 institute of Medicine. Science 172:635. 1974 Angiotensin, ed. with F. M. Bumpus. Heidelberg: Springer-Verlag. 1987 Mechanisms of Hypertension, Orlando, Fla.: Grune & Stratton. 1988 Hypertension Research, A Memoir, 1920-1960. New York: Pergamon Press. .

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