Klin. Wochenschr. 56, (Suppl. I), 3-4 (1978)
Klinische Wochenschrift
© Springer-Verlag 1978
An Appreciation of Professor Franz Gross on the Twentieth Anniversary of the Publication of his Concept of the Interrelationships between Aldosterone and Renin G.W. Liddle Department of Medicine, Nashville, Tennessee, U.S.A.
Wiirdigung yon Professor Franz Gross anl~iBlich des zwanzigsten Jahrestages der Publikation seines Konzeptes der Zusammenh~inge zwischen Aldosteron und Renin In American medical circles there is a "standing j o k e " that, regardless of what one might discover in biomedical science, it is always possible to go back in time and find that the " n e w discovery" had been described previously in " t h e old German literature." The current issue of Klinische Woehenschrift is dedicated to one such publication, a publication that has proven prophetic of one of the most important developments in physiology and medicine during the past 20 years. On 1 August 1958, Klinische Wochenschrift published a review article by F. Gross, entitled, "Renin und Hypertensin, Physiologische oder Pathologische Wirkstoffe?" which accurately reviewed what was then known about renin and angiotensint and proposed that the renin-angiotensin system stimulated aldosterone secretion and was, in turn, suppressed by the sodium-retaining action of aldosterone. Since that time, these concepts have become standard doctrine in physiology and medicine, and literally thousands of articles have been published confirming and extending them. According to Gross, writing in 1958 and utilizing experimental data derived in his own laboratory, treatment of animals with aldosteroneZ plus sodium led to hypertension and a decrease in renal content of renin. In contrast, steroids given without sodium failed to cause hypertension and failed to suppress renal renin content. These relationships were quantitative in nature; the degree of decrease in renal renin Since publication of the 1958 article by Gross, the term "hypertensin" has, by general assent, been changed to "angiotensin" z In his experiments, Gross found aldosterone to be similar in action to "cortexon" and used the two steroids interchangeably
was a function both of the amount of sodium in the diet and the dose of aldosterone. The two factors worked together in e!evating the blood pressure and in suppressing renal renin content. Bodily sodium was considered to be the more proximate regulator of blood pressure and renal renin, whilst aldosterone was considered to be effective because it caused sodium retention. It was pointed out that hypertension and renin suppression were parallel effects of treatment with sodium and steroids and that one could design experiments in such a way as to achieve one effect without the other. For example, concomitant treatment with antihypertensive drugs would prevent the hypertensive effect but not prevent the renin-suppressing effect of sodium and steroids. The converse was also described. Removal of the adrenal glands, thus making animals deficient in aldosterone-like steroids, led to increases in renal renin content; the more severe and prolonged the adrenal insufficiency, the more pronounced was the increase in renal renin content. To illustrate his concept of the interrelationships between aldosterone and renin, Gross provided a figure, reproduced below, showing that sodium loss stimulates both the secretion of renin and the secretion of aldosterone and suggesting that renin is responsible for stimulating aldosterone secretion. On the other hand, sodium retention suppresses renin secretion and aldosterone secretion, and once again the figure suggests that the decrease in renin is responsible for the decrease in aldosterone. Furthermore, the figure illustrates the thcts that aldosterone deficiency leads to sodium loss, which, in turn, leads to increased renin production, and that hypersecretion of aldosterone should lead to sodium retention with resultant suppression of renin production. Thus in bold strokes and with firm supporting evidence, Gross clearly painted a picture of what has since become universally accepted as the major
4
G.W. Liddle: Appreciation of Concept of Interrelationships between Aldosterone and Renin Natriumentzug Adrenalektomie
Drosselung der Nierenarterie
!
Einkapselung der Niero
/
[
[,
\
+
. . . . .
+
Sekrotion ? Sekretion yon von ................ ~ Aldosteron oder
Ilenin
iihnl. Corticoiden
",,
/ t
ZMuhr y o n NaCI I Cortexon ~ ~berdosierung yon [AldosteronJ ~ NaCI
Fig. 1. (Aus: Klin. Wschr. 36, 693-706 (1958). Springer-Verlag: Berlin-Heidelberg-NewYork)
mechanism through which renin and aldosterone secretion are controlled. Meanwhile, an eminent colleague of Gross, R. Schwyzer, had synthesized angiotensin in quantities sufficient for clinical investigation. A number of other eminent colleagues working in the Western Hemisphere were busily engaged in clinical and physiological studies to ascertain how changes in bodily sodium and fluids effected changes in aldosterone secretion. Gross provided these investigators with Schwyzer's angiotensin and suggested that they "might wish to see what effect it had on aldosterone secretion." The
remainder of the story is well-known. Angiotensin was administered to human subjects in a variety of experimental settings and was consistently found to stimulate aldosterone secretion. The investigators who discovered, circa 1960, that angiotensin stimulates the secretion of aldosterone have since received much well-deserved credit, but it is still true that the concept of angiotensin as a major regulator of aldosterone secretion had appeared earlier ... in " t h e old German l i t e r a t u r e " . . , under the name of F. Gross. Anyone who has been aware of advances in blood pressure research during the past 25 years has been aware of the leading role Professor Franz Gross has p l a y e d . . , in performing illuminating experiments of elegant design, in developing powerful new concepts, in performing the basic pharmacological studies that have provided the foundation for the therapeutic use of new antihypertensive drugs, in organizing conferences and congresses for the dissemination of valuable new ideas among scientists of many disciplines, and in stimulating and guiding the research of untold numbers of investigators who have been fortunate enough to know him. Professor Gross has already received many honors. He will probably receive many more. But no matter how many honors the world of science bestows on him, it can never fully repay him for the wealth of solid facts and seminal concepts he has contributed to modern physiology, pathophysiology and pharmacology.
Received September 18, 1978 G.W. Liddle, M.D. Dept. of Medicine Nashville, TN U.S.A.
Klinische Wochenschrift
© Springer-Verlag 1978
An Appreciation of Professor Franz Gross on the Twentieth Anniversary of the Publication of his Concept of the Interrelationships between Aldosterone and Renin G.W. Liddle Department of Medicine, Nashville, Tennessee, U.S.A.
Wiirdigung yon Professor Franz Gross anl~iBlich des zwanzigsten Jahrestages der Publikation seines Konzeptes der Zusammenh~inge zwischen Aldosteron und Renin In American medical circles there is a "standing j o k e " that, regardless of what one might discover in biomedical science, it is always possible to go back in time and find that the " n e w discovery" had been described previously in " t h e old German literature." The current issue of Klinische Woehenschrift is dedicated to one such publication, a publication that has proven prophetic of one of the most important developments in physiology and medicine during the past 20 years. On 1 August 1958, Klinische Wochenschrift published a review article by F. Gross, entitled, "Renin und Hypertensin, Physiologische oder Pathologische Wirkstoffe?" which accurately reviewed what was then known about renin and angiotensint and proposed that the renin-angiotensin system stimulated aldosterone secretion and was, in turn, suppressed by the sodium-retaining action of aldosterone. Since that time, these concepts have become standard doctrine in physiology and medicine, and literally thousands of articles have been published confirming and extending them. According to Gross, writing in 1958 and utilizing experimental data derived in his own laboratory, treatment of animals with aldosteroneZ plus sodium led to hypertension and a decrease in renal content of renin. In contrast, steroids given without sodium failed to cause hypertension and failed to suppress renal renin content. These relationships were quantitative in nature; the degree of decrease in renal renin Since publication of the 1958 article by Gross, the term "hypertensin" has, by general assent, been changed to "angiotensin" z In his experiments, Gross found aldosterone to be similar in action to "cortexon" and used the two steroids interchangeably
was a function both of the amount of sodium in the diet and the dose of aldosterone. The two factors worked together in e!evating the blood pressure and in suppressing renal renin content. Bodily sodium was considered to be the more proximate regulator of blood pressure and renal renin, whilst aldosterone was considered to be effective because it caused sodium retention. It was pointed out that hypertension and renin suppression were parallel effects of treatment with sodium and steroids and that one could design experiments in such a way as to achieve one effect without the other. For example, concomitant treatment with antihypertensive drugs would prevent the hypertensive effect but not prevent the renin-suppressing effect of sodium and steroids. The converse was also described. Removal of the adrenal glands, thus making animals deficient in aldosterone-like steroids, led to increases in renal renin content; the more severe and prolonged the adrenal insufficiency, the more pronounced was the increase in renal renin content. To illustrate his concept of the interrelationships between aldosterone and renin, Gross provided a figure, reproduced below, showing that sodium loss stimulates both the secretion of renin and the secretion of aldosterone and suggesting that renin is responsible for stimulating aldosterone secretion. On the other hand, sodium retention suppresses renin secretion and aldosterone secretion, and once again the figure suggests that the decrease in renin is responsible for the decrease in aldosterone. Furthermore, the figure illustrates the thcts that aldosterone deficiency leads to sodium loss, which, in turn, leads to increased renin production, and that hypersecretion of aldosterone should lead to sodium retention with resultant suppression of renin production. Thus in bold strokes and with firm supporting evidence, Gross clearly painted a picture of what has since become universally accepted as the major
4
G.W. Liddle: Appreciation of Concept of Interrelationships between Aldosterone and Renin Natriumentzug Adrenalektomie
Drosselung der Nierenarterie
!
Einkapselung der Niero
/
[
[,
\
+
. . . . .
+
Sekrotion ? Sekretion yon von ................ ~ Aldosteron oder
Ilenin
iihnl. Corticoiden
",,
/ t
ZMuhr y o n NaCI I Cortexon ~ ~berdosierung yon [AldosteronJ ~ NaCI
Fig. 1. (Aus: Klin. Wschr. 36, 693-706 (1958). Springer-Verlag: Berlin-Heidelberg-NewYork)
mechanism through which renin and aldosterone secretion are controlled. Meanwhile, an eminent colleague of Gross, R. Schwyzer, had synthesized angiotensin in quantities sufficient for clinical investigation. A number of other eminent colleagues working in the Western Hemisphere were busily engaged in clinical and physiological studies to ascertain how changes in bodily sodium and fluids effected changes in aldosterone secretion. Gross provided these investigators with Schwyzer's angiotensin and suggested that they "might wish to see what effect it had on aldosterone secretion." The
remainder of the story is well-known. Angiotensin was administered to human subjects in a variety of experimental settings and was consistently found to stimulate aldosterone secretion. The investigators who discovered, circa 1960, that angiotensin stimulates the secretion of aldosterone have since received much well-deserved credit, but it is still true that the concept of angiotensin as a major regulator of aldosterone secretion had appeared earlier ... in " t h e old German l i t e r a t u r e " . . , under the name of F. Gross. Anyone who has been aware of advances in blood pressure research during the past 25 years has been aware of the leading role Professor Franz Gross has p l a y e d . . , in performing illuminating experiments of elegant design, in developing powerful new concepts, in performing the basic pharmacological studies that have provided the foundation for the therapeutic use of new antihypertensive drugs, in organizing conferences and congresses for the dissemination of valuable new ideas among scientists of many disciplines, and in stimulating and guiding the research of untold numbers of investigators who have been fortunate enough to know him. Professor Gross has already received many honors. He will probably receive many more. But no matter how many honors the world of science bestows on him, it can never fully repay him for the wealth of solid facts and seminal concepts he has contributed to modern physiology, pathophysiology and pharmacology.
Received September 18, 1978 G.W. Liddle, M.D. Dept. of Medicine Nashville, TN U.S.A.
