The History of the Renin–Angiotensin System

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Introduction

The history of the renin–angiotensin system begins with the studies of Tigerstedt and Bergman. The number of publications related to this system was relatively few until the mid-20th century. However, as shown in Fig. 29.1 , the number of references listed in PubMed increased exponentially between 1966 and 2006, making any formal review cumbersome. Instead, this overview will take a hypothetical voyage around the world, stopping at various cities where, throughout the years, momentous contributions have been made. The reader can readily find references to supplement this approach in two previous reviews.

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The 20th Century

Our journey begins in Buenos Aires, home of Houssay, Braun-Menendès, Fasciolo, Taquini, and Leloir, where many bright and well-educated Argentinean scientists left their imprint on the physiology and pathophysiology of the renin–angiotensin system by their detailed in vitro and in vivo studies before spreading out around the globe. The next stop is Sao Paulo, to look at the history of Feireira and his discovery of bradykinin. From there, we fly to Cleveland, where Skeggs, Gould, Goldblatt, and Haas worked throughout their careers and where Page, Corcoran, Masson, MacCubbin, Dustan, Bumpus, Khairallah, Tarazi, and others made seminal observations of this system over several decades in the middle of the last century. Goldblatt and Page had little contact, until Page became the second investigator in the world (the first was working in Belgium) to write to Goldblatt inquiring about the material used to clip dog renal arteries. Concurrently, in the United States, Page made seminal contributions to the study of the renin–angiotensin system. He was a leader for the field, as were Pickering in the UK, Milliez and Hatt in France, Bartorelli and Zanchetti in Italy, Genest in Canada, Gross in Germany, Brod in Czechoslovakia, Smirk and Simpson in New Zealand, and Strasser in Switzerland. In 1958, Page laid out the roadmap for the study of the renin–angiotensin system for the next 50 years. He theorized: “The possibility of operating on renin, i.e., to prevent or control the rate at which angiotensin I is formed, or on the converting enzyme to prevent or control angiotensin II formation, is worth considering. A small molecule antagonist of angiotensin (not a peptide) might be found if we had some angiotensin for the pharmacologists to use in a screening test.” In the 1960s, however, nothing was evident, as outlined by the discussions at the first two consecutive international meetings organized in 1965, in Sienna by Bartorelli and Zanchetti and in Paris by Milliez, Meyer, and Tcherdakoff. Verniory and Potlieve (Brussels) said that: “their observations suggest that renin is not a mandatory participant of the mechanisms by which a stenosis of renal artery increases blood pressure. The importance of the juxta-glomerular apparatus in hypertension development no longer seems to be predominant as suggested by Goldblatt and Goorgmaghtig. In many circumstances, high blood pressure occurs without the juxta-glomerular’s or the adrenal gland’s participation.” According to Genest (Montreal), “research results of our laboratory demonstrate that the renin–angiotensin system does not seem to play an important role in the occurrence or maintenance of arterial hypertension” and also “our studies demonstrate a close link between sodium regulation and renin in humans, and contribute to a better understanding of the renin–angiotensin system pathophysiology.” From Glasgow, Brown, Lever, and Robertson declared: “Plasma renin is inversely correlated to plasma sodium, independently on aetiology and severity of hypertension, its complications and its treatments.” And from New York, Laragh started developing his concepts on the renin–angiotensin system: “Our studies demonstrate a homogeneous relationship between angiotensin, aldosterone and sodium balance. In this relationship, the blood level of angiotensin finally interacts with available sodium ions to maintain vascular tone regulation.”

For decades, many brilliant investigators were privileged to study in Boston. They were educated in endocrinology with Thorn, renal physiology with Barger, cardiology with Braunwald, and immunology with Haber. They had immediate access to both basic research and clinical research—the specific element that has boosted many scientific and medical contributions in the field—an approach now known as “translational medicine.” Fascinating, elegant studies of the adrenal glands and kidneys were performed by Williams and Hollenberg, uncovering the identity of the modulator and the nonmodulator in hypertensives. The Pfeffers moved from studies on coronary artery ligature in rats to the management of large-scale randomized controlled trials that established angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists as the major treatments for postmyocardial infarction and congestive heart failure. Brenner started out analyzing glomerular filtration rate in Wistar-Munich rats and subsequently shared his key discoveries with nephrologists worldwide, triggering major efforts to reduce proteinuria and microalbuminuria and to slow the decrease in glomerular filtration rate in most renal diseases. The desired results were accomplished using a converting enzyme inhibitor, an angiotensin II receptor antagonist, or the combination in tandem. Dzau uncovered the components of tissue renin–angiotensin systems and their function in vascular and cardiac tissue, while Ingelfinger was studying kidney angiotensinogen. Investigators associated with the Framingham Heart Study began to use this same cohort to increase our understanding of the role of the renin–angiotensin system as a cardiovascular risk factor.

Substantial contributions were being made by the Laragh and Sealey group in New York, some of whom made critical independent observations regarding the regulation of the renin–angiotensin system and the role of interrupting it in treating cardiovascular disease. The contributions made by Brunner, Buhler, Weber, Case, Atlas, Maack, Catanzaro, and others have provided the underpinnings of a rational approach to hypertension treatment, based on a solid methodology established both in the clinic and in the laboratory. At the same time, blood pressure measurements were being refined by Pickering Jr, the cardiac mass was being explored by Devereux, and observational epidemiologic approaches and their limitations were being confronted by Alderman.

At several laboratories in the southern United States, Guyton, Hall, Young, and Cowley were refining their integrated view of the physiology of system regulation and analyzing the close fit between modeling and experimentation—with one focus being the renin–angiotensin system, the kidney, and volume homeostasis. Carey was refining the role of renin and several of its active peptides in regulating renal function as O. Smithies was developing the technology required to prepare precisely modified genes in mice as tools to understand the molecular mechanisms underlying the renin–angiotensin system’s physiologic effects. Inagami was increasing our understanding of the biochemical structure of this system. In Canada, Genest and his many collaborators were expanding our knowledge of how this system is modified in disease states and had a major role in the training of many young European investigators, from Germany to France and from Spain to Czechoslovakia.

At the National Institutes of Health, Catt and his colleagues were teasing out the action of various angiotensins on adrenal and vascular function and the effects of the level of salt intake on this activity. He has assumed the same responsibilities in the training of young and motivated investigators such as Mendelssohn, Capponi, and the author, as those assumed at Cleveland, Boston, New York, Montreal, or San Francisco. Halfway across the world in Japan, Yamamoto, his research group, and many other skillful Japanese investigators were using rat models of disease to further our understanding of the renin–angiotensin system and other vasoactive factors in causing cardiovascular diseases. In Australia, beginning in the 1960s and extending for four decades, Coghlan, Denton, Funder, Johnston, Morgan, Mendelsohn, Whitworth, Campbell, Chalmers, MacMahon, and colleagues have contributed substantially to our knowledge of the renin–angiotensin system. They used their easy access to sheep in the most appropriate way to analyze sodium balance and aldosterone and contributed to major observational and interventional studies. To mention just one of the prolific numbers of insights provided by Australian investigators, Skinner established the link between the perfusion pressure of the kidney, as described by Selkurt, and renin release, as investigated by the aforementioned Cleveland Clinic group.

A number of groups in Europe also contributed to our knowledge of the renin–angiotensin system during the latter third of the 20th century. In Edinburgh, Mullins was developing elegant models of knockout mice. The team composed of Brown, Lever, and Robertson and colleagues set up a Blood Pressure Unit—not a Hypertension Unit—in Glasgow. Even now, Fraser is linking the generations, with Connell and Dominiczak, whereas the clinical pharmacology developed by Sir Colin Dollery in London has been finely applied to the renin–angiotensin system by Reid and his colleagues. MacGregor, Edwards, and Stewart further expanded our knowledge particularly related to RAS interactions with mineralocorticoids and inhibitors of the renin–angiotensin system. In Rotterdam, the complex metabolism of angiotensins was being analyzed by Schalekampf, Derkx, Deinum, and Danser. In Lausanne, other groups were expanding our knowledge base in several related areas. Brunner, Nussberger, and Burnier were evaluating the regulation of angiotensins in conjunction with the regulation of sodium in the proximal tubule, whereas Rossier and his colleagues were doing the same in the distal tubule. The connection they established between animal models and clinical pharmacology has been an extremely effective legacy, thanks to the methodological and conceptual efforts of Nussberger, Burnier, Weber, Pedrazini, and Biollaz, who worked with Brunner. In Basel, at the top of the Ciba-Geigy building, in 1986, there was a splendid library. Some pages of the journals in that library were well worn, as the books automatically opened at certain pages. It was here that the author, working with Hofbauer, Wood, and de Gasparo, found the spirit and work of Gross that helped them develop new therapeutic agents that modified the activity of the renin–angiotensin system, such as benazepril, valsartan, and aliskiren.

In Paris, the Broussais Hospital has closed but, fortunately, at Georges Pompidou European Hospital a new generation of researchers—Jeunemaitre, Azizi, Plouin, and Alhenc-Gelas—has carried forth the undertakings of Corvol and Menard. Laurent and Simon have extended the work of Safar on arterial functions. In parallel Geneviève Nguyen, at the College of France, is assessing the relevance of the prorenin/renin receptor.

We arrive in Berlin. Before Ganten and Unger is the shadow of Gross and the Heidelberg trio Taugner, Hackenthal, and Ritz. Close to Ganten, as a star among American and European clinical investigators, Luft reminds us that dedicated researchers should take their research, but not themselves, seriously. This journey ends in Berlin because Ganten has imbued all of us with his political vision and scientific dreams. The large contribution of many Italian scientists, around Zanchetti, Bianchi, and Mantero, Spanish investigators with Ruilope and of a small country such as Denmark that has generated Bing, Poulsen, Leyssac, and many others are not forgotten.

This abbreviated reminiscence has omitted many worthy names and countries; yet it is hoped that the message of this approach is clear: when a wide variety of techniques, access to large numbers of patients and a strong commitment to research freedom and education are found at the same place and when there is an effective link between experimental, clinical, and/or epidemiological research, the city and the institution become as renowned for their contribution to renin–angiotensin–aldosterone system research as the scientists themselves.

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