Key words : Hypertension, Renin-angiotensin-aldosterone system

Introduction

The kidneys produce several substances affecting the intrarenal blood flow. The renin-angiotensin-aldosterone system (RAAS) is critical for regulating general and local blood circulation. The synthesis of the individual elements of the RAAS takes place in distinctive tissues and is driven by specific local factors. The functioning of the system, consisting of 3 essential chemicals (renin, angiotensin, and aldosterone), is based on mutual feedback among the elements.¹ The clinical use of angiotensin-converting enzyme inhibitors, part of the RAAS, in the treatment of hypertension and heart or renal failure is considered to be one of the breakthroughs of modern medicine.² The 125th anniversary of the discovery of renin (1897), the first link of the RAAS, is an excellent occasion to depict its chief author, Robert Tigerstedt,^3,4 whose 170th birthday and 100th anniversary of death we will celebrate next year.

Robert Tigerstedt

Robert Tigerstedt was born on February 28, 1853, in Helsinki, Finland. His family came from Falun in Sweden and emigrated to Finland in the 17th century to settle in the small university town of Åbo. The members of the family occupied high academic positions and were distinctive figures of the civil service. Tigerstedt’s father, Karl, was a renowned historian and a teacher in the Åbo secondary school, which Tigerstedt completed at the age of 16. Unrestricted access to his father’s vast library offered him a chance to gain a broad knowledge and aroused his interest in history (Figure 1).

Tigerstedt continued his education until 1876 when he obtained a Bachelor of Science degree. Afterward, he studied medicine at the University of Helsinki and became deeply interested in natural sciences, notably chemistry. He graduated from the Medical Faculty in 1878 and, until 1880, worked as a secretary in the “Finnish Newspaper,” writing articles about medicine, humanities, and social topics. Then, at age of 25, he presented a doctoral dissertation, On the Mechanical Stimulation of the Nervous System, performed with the sciatic nerve on a nerve-muscle preparation from frogs. This work, along with 10 other original publications on neurophysiology, earned him the position of associate professor and recognition in the world of neurophysiology. However, his superior at the Physiology Institute, a 45-year-old professor K. Hällsten, did not find the doctoral dissertation adequate. As a result of this controversy, and for personal reasons, Tigerstedt accepted a job offer from the professor of physiology Carl Lovén from Stockholm, who was impressed with Tigerstedt’s doctoral dissertation presented during the Scandinavian Congress of Physiology in Stockholm in 1880.

In 1881, Tigerstedt moved to the Physiology Department at Karolinska Institute Stockholm, Sweden, to take on the position of an assistant and, finally, an associate professor. There, he created Scandinavia’s best laboratory, where he had a leading and stimulating role in all the experiments. He was known for helping his coworkers prepare their publications, yet his name rarely appeared on the list of authors.⁵ After Professor Lovén’s retirement, Tigerstedt became a full professor at 33 years of age. After he established contact with Carl Ludwig in Leipzig, Tigerstedt visited his laboratory in 1881 and developed an interest in central blood circulation. In 1883 and 1884, Tigerstedt visited and experimented in many other laboratories of famous European physiologists in Germany, France, Switzerland, Belgium, and Austria.⁴ In those days, endocrinology was at the center of interest of many researchers in physiology. Tigerstedt’s contacts with Carl Ludwig proved essential as they led to the construction of the famous blood flow meter, called stromuhr, used to measure blood flow in different parts and organs of the body. Tigerstedt observed that the kidney blood flow was at least 10 times the mean blood flow of animals.⁶

The interest in the possible presence of pressor substances in the kidneys resulted from the earlier work of eminent doctors and researchers like Britain’s Richard Bright (1789-1858) and France’s Charles Brown-Séquard (1817-1894). However, the level of knowledge in this subject was still limited, making Tigerstedt’s achievements in the discovery of renin even more significant. These experiments were undertaken at the prospect of participation as an honorary President at the 12th International Congress of Medicine in Moscow in 1897.

Between November 1896 and May 1897, helped by his assistant and medical student Per Bergman, Tigerstedt started a series of 50 meticulously performed experiments with cold water or saline extract of the rabbit kidney cortex, which when injected intravenously resulted in increased blood pressure in rabbits^7,8 (Figure 2). The experiment involved only young rabbits weighing 1500 to 2000 g. Identical experiments using the extract of kidney cortex heated to over 54 to 56 °C and 50% alcohol extract failed to result in higher blood pressure. The extract of the kidney medulla brought about only a limited blood pressure increase in selected experiments. Tigerstedt called the newly discovered, hypothetical blood pressure-raising substance renin. It turned out to be not dialysable and present in defibrinated renal venous blood, and it did not show any activity in nerves or effects on the heart. The point of action was probably peripheral vascular centers⁹ (Figure 3). Tigerstedt presented his research at the Congress in Moscow and was the only author to publish a summary of his lecture. Despite these efforts, the findings did not incite much interest in the topic. In the autumn of 1897, complementary experiments were performed whose results were published together with Per Bergman in the German language Skandinavisches Archiv für Physiologie under the title “Niere und Kreislauf” (kidney and circulation)7 (Figure 4). Their results were not confirmed by other researchers, probably because of an unsatisfactory level of accuracy applied in the experiments that proved too advanced for the time. This, combined with the researchers’ engagement in administrative work for the creation of a new Institute of Physiology in Helsinki, was the reason why Tigerstedt and Bergman’s line of renin research was interrupted for almost 40 years until 1934, when Harry Goldblatt confirmed Tigerstedt’s theory that “the substance which comes from kidneys increases blood pressure.”

Goldblatt created the first reliable model of hypertension based on the observation that abnormalities in the intrarenal arteries could be found in those who died from arterial hypertension. In his model, he employed stenosis of both renal arteries. He found that hypertension caused by the narrowing of the renal arteries develops even with normal renal function. The compression of other arteries did not cause hypertension.¹⁰

Further discoveries regarding RAAS were made in the following years. In 1940, angiotonin was discovered, later named angiotensin II by Page and Helmer, and, in 1954, Skeggs discovered angiotensin I and predicted the presence of an angiotensin-converting enzyme.

In 1901, being an already renowned physiologist and driven by patriotic feelings, Tigerstedt returned to Finland, which was struggling for its independence from Russia. Professor Hällsten had retired and Tigerstedt became the head of the Physiology Institute in Helsinki. He created a new physiology laboratory containing, among other things, a respiratory chamber for 1 or 2 people for the measurement of CO₂ production under different activity conditions. It was the best-equipped laboratory in Europe at the time. He continued studies in 3 basic directions: physiology of nerves and muscles; heart, respiratory, and blood pressure systems; and metabolism and nutritional questions.

Tigerstedt is the author of several important books, with the leading Textbook of Human Physiology having numerous editions in 5 languages (10 editions in German) over 26 years (1897-1923). This book was described as the greatest textbook in physiology ever written. The Russian edition was printed with the foreword by his friend I. Pavlov. Tigerstedt also wrote The Textbook of Physiological Methodology in 3 volumes (1911-1914) and The Physiology of Circulation in 4 volumes (1921-1923).¹¹

He published over 200 scientific papers, mostly in experimental physiology (at least 12 000 printed pages) and managed 30 PhD students. Many of his publications were concerned with popular medical and personal hygiene issues. Despite remarkable scientific achievements in the field, he only published 2 works on kidney function.

Tigerstedt was also interested in history and published several papers on the history of medicine from antiquity up to his days (Documents From the History of Medicine), which is only available in Swedish (Figure 5). He translated parts of works by such physicians as Paracelsus, Andreas Vesalius, William Harvey, Giuseppe Malpighi, and Thomas Sydenham. Tigerstedt presented the history of his secondary school in Åbo in the book Åbo Secondary School 1828-1872.

His further activities, besides medical studies and teaching medical staff, were concerned with socially oriented issues. Alcohol abuse was widespread in Scandinavia, leading to medical and social troubles. Since 1893, Tigerstedt was involved in alcohol temperance activity as the vice chairman of the Swedish Temperance Society. His pertinent books and brochures warning against alcohol (as a part of the antiliquor activity) were circulated in over 200 000 copies. He was against alcohol prohibition, introduced in Finland in 1919 and abandoned in 1932 after it became a complete fiasco.

Tigerstedt became a member of the Swedish Academy of Sciences in 1890. Three years later, he was a patron and lecturer of the Finnish Society in Stockholm. He was also chief of the editorial staff at “Skandinavisches Archiv für Physiologie,” a highly respected scientific journal established in 1889 in Leipzig. He founded the International Union of Physiological Sciences in 1889 and in 1901 became a member of the Society of Science in Uppsala. He was Dean of the Faculty of Medicine in Helsinki from 1916 to 1919. Tigerstedt was also an active member of other medical and social organizations during his stays in Sweden and Finland. His outstanding achievements earned him the title of doctor honoris causa at 5 universities.

When Albert Nobel died in 1896, Tigerstedt was asked by the Karolinska Institute to become a member of the Nobel Committee and to execute Nobel’s will, that is, to establish and promote the Nobel Prize. He nominated I. Pavlov for the Nobel Prize and supported the Nobel Prize in physiology and medicine for Alexis Carel, who had remarkable achievements in the development of organ transplants. Tigerstedt himself was a Nobel Prize nominee twice: in 1919 for the construction of a respirator and in 1923 for the textbook Physiology of Blood Circulation.

Tigerstedt made extensive efforts to improve the nutrition and quality of food for Finnish workers of different professions. In the early 20th century, the Finnish population suffered from famine because of crop failure, World War I, and the revolution in Russia, resulting in disrupted food imports. With people forced to use substitutes for properly nutritious food, the rate of scurvy was high. In his publications, Tigerstedt specified the daily caloric and nutritional requirements and the importance of adequate food quality. In addition, he recommended a simple treatment of scurvy with potatoes and cloudberries included in the diet.

Robert Tigerstedt was known for his strong personality, critical judgment, idealism, humor, and warm heart. In addition to Swedish and Finnish, he was fluent in German, French, and Russian but not English. As a medical student, at the age of 25, he married a Ukrainian, Ljuba Martinau, in 1878. The couple had 3 children, including a daughter (1879), a son, Carl (1882), and another daughter (1891). Carl Tigerstedt, a known physiologist, followed in his father’s footsteps and became professor and chief of the Physiology Institute in Helsinki. Per Bergman worked for several years at the Karolinska Institute but then moved to the University of Lund and later became a practicing doctor in Malmo in southern Sweden, where he died in 1957.¹¹

After his retirement in 1919, following the civil war of the previous year, Robert Tigerstedt accepted the position of a chief physician for a prison camp, where he struggled to improve the nutritional and sanitary conditions. He was also involved in fighting for prisoner rights, an effort that was later accompanied by his son Carl. Many reports (partially confidential) about the hard conditions of these people were sent to the camp authorities and the ruling political party. Being a devoted bibliophile and remembering his father’s vast book collection in Åbo, Tigerstedt created an impressive library in the Physiology Institute in Helsinki, which, to his despair, was lost in fire in 1923. Tigerstedt continued giving lectures on the physiology of the nervous system, with the last one on December 12, 1923. The great researcher died suddenly on that very same day and was buried at the cemetery in Helsinki. His life finds its best reflection in the words, “the truth will be revealed only to those who doubt.”⁹

Conclusions

The achievements of Robert Tigerstedt and his assistant Per Bergman paved the way for medical progress made in the next century, especially in cardiology, nephrology, and endocrinology. Although initially underestimated, Tigerstedt finally gained universal recognition equal to the Nobel Prize, which he never received. The development of his ideas made it possible to discover the entire RAAS and invent common drugs for hypertension, heart failure, and kidney failure, without which modern medicine is hard to imagine.

References:

1. Hedner T, Hansson L, Himmelmann A. The renin-angiotensin system--a century of progress. Blood Press. 1998;7(2):68-70. doi:10.1080/080370598437411
   CrossRef - PubMed
   
2. Postel-Vinay N. Stulecie nadciśnienia tętniczego 1896-1996. Gdañsk: Wydawnictwo ViaMedica; 1998.
   CrossRef - PubMed
   
3. Aurell M. Robert Tigerstedt: scientist, teacher and critic: a review by Mattias Aurell for the Renin-Angiotensin Centenary Symposium Stockholm, September 1997. Sven Med Tidskr. 2001(5):1:75-89.
   CrossRef - PubMed
   
4. Tarkiainen K. Robert Tigerstedt (1853-1923). Lexikon för Finland. https://www.blf.fi/artikel.php?id=3665
   CrossRef - PubMed
   
5. von Bonsdorff B. The History of the Medicine in Finland 1828-1918. Societas Scientarum Fennica. Helsinki: OY TIL-SET AB; 1975.
   CrossRef - PubMed
   
6. Aurell M. The renin-angiotensin system: the centenary jubilee. Blood Press. 1998;7(2):71-75. doi:10.1080/08037059843742
   CrossRef - PubMed
   
7. Tigerstedt R, Bergman PG. Niere und Kreislauf. Skand Arch Physiol. 1898;8:223-271.
   CrossRef - PubMed
   
8. Phillips MI, Schmidt-Ott KM. The discovery of renin 100 years ago. News Physiol Sci. 1999;14:271-274. doi:10.1152/physiologyonline.1999.14.6.271
   CrossRef - PubMed
   
9. Silverman BD. Robert Tigerstedt--scientist, educator, social activist, humanitarian. Clin Cardiol. 2002 Aug;25(8):399-400. doi:10.1002/clc.4950250810
   CrossRef - PubMed
   
10. Van Epps HL. Harry Goldblatt and the discovery of renin. J Exp Med. 2005;201(9):1351. doi:10.1084/jem.2019fta
    CrossRef - PubMed
    
11. Marks LS, Maxwell MH. Tigerstedt and the discovery of renin. An historical note. Hypertension. 1979;1(4):384-388. doi:10.1161/01.hyp.1.4.384
    CrossRef - PubMed