Bjorn Folkow
folkow

Björn Folkow

Björn Folkow (1921-2012)[1]
Ove Lundgren and Holger Nilsson

Björn Folkow, MD, PhD, professor of physiology at the University of Gothenburg, died on July 23, 2012 at an age of 90. He was a member of the Royal Swedish Academy of Sciences and a foreign member of the Danish Academy of Sciences, the Russian Academy of Natural Sciences, and an honorary member of the American Physiological Society.

Björn Folkow was born in Halmstad, a city on the west coast of Sweden halfway between Gothenburg and Lund. He received his medical education at the University of Lund during the years between 1940 and 1948, when he became an MD. Lund University was then one of only three proper universities in Sweden. Börje Uvnäs (eventually the first professor of pharmacology at Karolinska institute in Stockholm), one of Folkow´s collaborators and a supervisor of his thesis work, has described academic life in Lund at the end of the Second World War in the following way: “Lund was a provincial little university town, and so was the university with, as a whole, a sleeping medical faculty with conservative professors more occupied with academic intrigues than research problems” (Uvnäs 1988).

However, things were going to change quickly at least at the department of physiology in the forties and fifties, when the department became a breeding place for young scientists not seldom ending up as professors of physiology, pharmacology or clinical physiology. The enthusiastic and charismatic driving force behind this explosion of professors was Georg Kahlson, professor of physiology and one of the founders of the Swedish medical research council. He was also Björn Folkow´s scientific “father”. Two other persons were also important for Folkow´s thesis: the aforementioned Börje Uvnäs and Fritz Buchtal, a Dane of Jewish descent, who like most Danish Jews had fled to Sweden one night in October 1943. Buchtal introduced Folkow into the physiology of smooth muscle. Folkow´s thesis, defended in 1949, dealt with myogenic characteristics of vascular smooth muscle and its nervous control (see below).

Folkow´s intention was to become a psychiatrist after his thesis work in physiology. However, Georg Kahlson persuaded Folkow to apply for an associate professorship in physiology at the newly founded medical school in Gothenburg. Sweden had not been devastated by the Second World War, and after the war the Swedish government greatly expanded research and education at Swedish universities. This included the establishment of a medical school in Gothenburg. In 1948 a full medical school with preclinical and clinical departments started up. In 1950, Björn Folkow became  one of the two first professors in physiology at the age of 29. Hence, Folkow started his work at this physiological department more or less from scratch. There existed no local tradition regarding teaching or research in physiology in Gothenburg. However, Folkow was going to establish one of the world´s leading groups in cardiovascular physiology in the new department and, as a charismatic teacher and lecturer, he made the course in physiology one of the most appreciated courses at the medical faculty.

Folkow published nearly 400 papers covering most aspects of vascular physiology from rheology, via biophysical analyses of the effects and importance of vascular hypertrophy in the development of arterial hypertension to the central nervous vascular control. His broad knowledge in cardiovascular physiology is also reflected in the book called Circulation that he wrote together with the English physiologist Eric Neil (Folkow & Neil 1971). Folkow supervised about 40 graduate students. He wrote three review articles in Physiological Reviews covering such disparate subjects as nervous vascular control (Folkow 1955), the pathophysiology of arterial hypertension (Folkow 1982) and the physiology of ageing (Folkow & Svanborg 1993). For obvious reasons only the most important aspects of Folkow´s work will be covered here.

Some of Folkow´s major research interests were initiated already in his thesis work. One of these themes, the myogenic characteristics of vascular smooth muscles, was based on the original work performed by the British physiologist Bayliss published in 1902 (Bayliss 1902). He showed that stretching precapillary resistance vessels evoked a muscular contraction whereas a lowering of muscular tension evoked a vascular relaxation. In his thesis work Folkow confirmed these observations. Based on his own work and the work of other researchers, Folkow eventually inferred that the vascular smooth muscle effectors function as “stretch” (“tension”) receptors. Being stimulated by vascular distension the smooth muscle/pacemaker cells evoke contractions of a large number of smooth muscle cells via low-resistant gap junctions between cells (so called single-unit smooth muscles).

Physiologically, the myogenic characteristics of arterial vessels are of importance in explaining “resting” vascular tone, i.e. the tone in vascular smooth muscle in the absence of any extrinsic neuro-hormonal influence. The pressure wave evoked by the cardiac contraction and the travelling of the cardiac stroke volume through the arterial tree stimulates the vascular smooth muscle to contract. Another phenomenon, which is explained by myogenic characteristics together with chemical changes of the local environment, is autoregulation of blood flow, i.e. the maintenance of a rather constant blood flow in an organ in the face of changes of arterial pressure. In an experimental animal it is rather simple to illustrate the importance of vascular myogenic mechanisms by lowering arterio-venous perfusion pressure either by decreasing arterial inflow pressure or increasing venous outflow pressure. In the first experimental situation the arterial smooth muscles will relax due to decreased vascular stretch. When increasing venous pressure, the veins and particularly the precapillary resistance vessels will contract in response to increased vascular tension. Hence, decrease of arterial pressure leads to a decrease of flow resistance, whereas increased venous pressure leads to an increased flow resistance, although perfusion pressure in the two experimental situations is identical.

Since the start of his scientific career one of Folkow´s major scientific interests was the nervous control of the cardiovascular system and, in particular, of the blood vessels. As mentioned this was the subject of a review article in Physiological Reviews (Folkow 1955). The early nervous studies were facilitated by the availability of new pharmacological receptor agonists and antagonists. These studies were performed together with Uvnäs and led to the publications of ground-breaking work on the pharmacology of nervous vascular control as well as on the central nervous control of skeletal muscle blood vessels. The studies were the starting point of a large number of publications by Folkow on the central and reflex nervous control of circulation, often being parts of the theses of Folkow´s pupils. Repeatedly it was shown that the autonomic nervous control of the cardiovascular system can be very differentiated and not the all-or-none response described in textbooks. One study (Eliasson et al. 1951) became particularly important for Folkow´s hypothesis regarding the development of arterial hypertension in man. Folkow, Uvnäs and collaborators showed in cats that electrical stimulation of the so called defense area in the anterior part of the hypothalamus led to an increased blood pressure as will be described in more detail below.

Folkow´s interest in nervous vascular control led him to study it also at the cellular level. Around 1960, histochemical techniques had been developed that made it possible to investigate, among other things, the distribution of adrenergic nerves in tissue sections (Corrodi & Jonsson 1967) These detailed studies of the nerves to blood vessels revealed the rather surprising finding that the adrenergic nerves to vascular smooth muscles were only located between the media and the adventitia of the vascular wall. Via low-resistance bridges (gap junctions) it was possible to control all vascular smooth muscles by influencing only the outer smooth muscle layer. Moreover, pharmacologists had developed compounds that could inhibit the breakdown of noradrenaline released into the synaptic cleft as well as block the reuptake of the transmitter to the presynaptic neuron from the synaptic cleft. This made it possible to investigate the release and elimination of noradrenaline in a quantitative fashion at the vascular nerve terminals of skeletal muscles in cats. Folkow et al. (1967) took advantage of this in an extensive study that demonstrated that only about 5% of the total noradrenaline contents in a vesicle were released per action potential. It is still not certain whether neuronal vesicles release their total neurotransmitter amount or if only a small portion is released from many vesicles under physiological circumstances.

During the last decades of his life Folkow´s main research interest was the pathophysiology of arterial hypertension, but his interest in this common disease had started much earlier. In 1958 Folkow, Grimby and Thulesius published a study on normal control subjects and on patients with newly developed arterial hypertension (Folkow et al. 1958). The design of the study was very simple, yet its results were very interesting. To evoke a complete relaxation of the forearm blood vessels, the subjects were forced to perform maximal muscular work during intense local heating and increasingly prolonged ischemia. The flow resistance observed during maximal vasodilatation was related to the resistance recorded during resting blood flow to obtain a measure of vascular tone. To the authors´ surprise it was revealed that maximal rate of blood flow recorded in the hypertensive patients at maximal vasodilatation was more or less the same as in control subjects, implying that flow resistance was significantly higher in the hypertensive group with their high blood pressures, even in the absence of any known external neuro-hormonal influence. The results clearly indicated that persistent hypertension in some way was accompanied by a structural narrowing of the resistance vessels, i.e. a thickening of the vascular media secondary to hypertrophy/hyperplasia of the smooth muscle cells. Such structural changes, in turn, imply that the increased flow resistance does not necessarily need any additional contribution from smooth muscle contractions. Furthermore, Folkow pointed out that an increased tissue mass inside the line of force for a vascular smooth muscle contraction will by its very existence always create a higher resistance to flow at any given activity level of the smooth muscle cells (Folkow et al. 1958).

An obvious question in this context is of course which mechanism(s) produce the structural changes of the vascular wall. Folkow has argued in several reviews that repeated psychosocial stimuli via neuro-hormonal mechanisms cause increases of arterial pressure, which, in turn, establish the structural increase of media thickness (Folkow 1987). The proposed mechanism is in principle similar to the increased skeletal musculature seen after heavy training. Experimental evidence for these proposals was obtained on hypertensive rat strains, in particular the spontaneously hypertensive rat (Okamoto), by Folkow and his coworkers (for review, see Folkow 1978, 1982). They also showed that growth hormone and thyroxin contributed to the structural increase of the vascular media.

Folkow was particularly interested in the possible involvement of the defense reaction, the development of arterial hypertension. The defense area in the hypothalamus constitutes a nervous and hormonal control center. Its name suggests that it is only activated in situations of intense and negative emotional situations. However, it seems to be active also whenever individuals are mentally aroused by various challenging environmental influences. In the cardiovascular system a vasoconstriction is observed in all vascular beds except heart, brain and skeletal muscle, leading to a blood pressure rise. Vasodilatation in skeletal muscles is mediated via a nervous release of acetylcholine in cats whereas in man the increased blood flow is secondary to the release of adrenaline from the adrenal glands and/or to an inhibition of the sympathetic vasoconstrictor influence. Furthermore, Folkow suggested that activation of the defense area may be of importance in explaining the importance of salt intake in the development of arterial hypertension (for discussion, see Folkow 1987).

Hence, the development of arterial hypertension, briefly described above, is based on an integration of events taking place not only in the vascular wall but also in organs such as the brain. In one review Folkow points out that in the present reductionistic era of molecular and cell biology “it is more important than ever to deal with all levels of biological organization in an integrated manner to understand completely what is happening.”  “This calls for an increasingly rare talent among today´s scientists, namely to be able to deal experimentally with intact organisms in an integrative fashion” (Folkow 1995).

Björn Folkow was an outstanding scientist with an unusually great scientific intuition. In the scientific world, which is being invaded by scientists with big egos, Björn Folkow was brilliant and very successful, yet humble and modest with great integrity. He fostered many physiologists and often maintained long-lasting friendship with the pupils. His influence on Swedish medical science was therefore greater than the direct influence of his own writing since Folkow´s pupils often became professors in clinical or preclinical departments continuing their cardiovascular research.

The fact that the medical school in Gothenburg was newly started when Björn Folkow became professor implied that it was not burdened by academic traditions existing at other Swedish universities. This together with Folkow´s open minded personality was apparent in his dealings with students. Examinations with Björn often took place with the professor´s feet on his desk and the student called by their first name. Björn´s openness was reflected also in the ease with which one could get hold of him. The door to his room was almost always open.

In the nineties one of Björn´s trusted former lab technicians attempted to teach Björn how to work with a word processor. We felt that it would be perfect for him, knowing how he used to work with manuscripts constantly changing wordings and moving around paragraphs from one page to another. It turned out to be impossible. Until the last day at the department, about one month before his death, he was typing on an old electrical typewriter letters that after typing mostly were edited by hand and often were sent to his American friends by “snail mail”. Since he was continuously present in this department for 62 years, his absence is strongly and sadly noted.

Authors: Ove Lundgren (ove.lundgren@fysiologi.gu.se) and Holger Nilsson (holger.nilsson@gu.se), Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, P.O.Box 432, S-405 30 Gothenburg, Sweden. 

References

Bayliss W.M. 1902. On the local reactions of the arterial wall to changes of internal pressure. J Physiol (London) 28, 220-231.

Corrodi H & Jonsson G. 1967. The formaldehyde fluorescence method for the hisochemical demonstration of biogenic monoamines: A review on the methodology. J Histochem Cytochem 15, 65-78.

Eliasson S., Folkow B. & Lindgren P., Uvnäs B. 1951 Activation of sympathetic vasodilator nerves to the skeletal muscles in the cat by hypothalamic stimulation. Acta Physiol Scand 23, 333-351.

Folkow B. 1955. Nervous control of the blood vessels. Physiol Rev 35, 629-663.

Folkow B. 1978. The Fourth Volhard lecture: cardiovascular structural adaptation; its role in the initiation and maintenance of primary hypertension. Clin Sci Mol Med 55, 3s-22s.

Folkow B. 1982. Physiological aspects of primary hypertension. Physiol Rev 62, 347-504.

Folkow B. 1987. Psychosocial and central nervous influences in primary hypertension. Circulation 76 (Suppl 1), 110-119.

Folkow B. 1995. Integration of hypertension research in the era of molecular biology: G.W.

Pickering Memorial Lecture (Dublin 1994). J Hypertension 13, 5-18.

Folkow B., Grimby G. & Thulesius O. 1958. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Acta Physiol Scand 44, 255-272.

Folkow B., Häggendal J. & Lisander B. 1967. Extent of release and elimination of noradrenaline at peripheral adrenergic nerve terminals. Acta Physiol Scand Suppl. 307, 1-38.

Folkow, B. & Neil E. 1971. Circulation. Oxford University Press, New York, London, Toronto

Folkow, B. & Svanborg, A. 1993. Physiology of cardiovascular aging. Physiol Rev 73, 725- 764.

Uvnäs, B. 1988. Björn Folkow. In B. Johansson, O. Lundgren & M. Nordlander (eds) The Folkow Symposium: Circulatory regulation – physiology and patho-physiology. Acta Physiol Scand Suppl 571, pp 8-13.


[1] Reprinted with permission of John Wiley and Sons, Acta Physiologica 206(4): 251-254, 2012 (December issue)


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