R. Beckerhoff

SHORT‐TERM FLUCTUATIONS IN PLASMA CORTISOL IN CUSHING'S SYNDROME

Short‐term fluctuations in plasma cortisol were determined overnight in twelve patients with Cushings syndrome: eight patients with bilateral adrenal hyperplasia of hypothalamic‐pituitary origin, three patients with a cortisol producing adenoma and one patient with a carcinoma of the adrenal cortex. While either secretory episodes in plasma cortisol or a fixed pattern of cortisol secretion were observed both in patients with pituitary dependent and in those with pituitary independent hypercorticism, a typical night‐day variation in plasma cortisol was only found in one of the eight patients with Cushings syndrome of hypothalamic‐pituitary origin. The patient with a cortisol producing carcinoma showed only minor fluctuations in plasma cortisol throughout the test period.

The effect of saralasin (1-Sar-8-Ala-Angiotensin II) on blood pressure in patients with cushing's syndrome

ZusammenfassungUm die Bedeutung des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom zu untersuchen, wurden bei 2 Patienten mit Hyperkortizismus 20 mg Saralasin (1-Sar-8-Ala-Angiotensin II) über einen Zeitraum von 30 min unter ständiger Blutdruckkontrolle infundiert. Zusätzlich diente ein Patient mit primärem Aldosteronismus, einer etablierten Form von Mineralokortikoidhochdruck, als Kontrolle.Weder bei den 2 Patienten mit Cushing-Syndrom noch bei dem Patienten mit primärem Aldosteronismus ließ sich ein blutdrucksenkender Effekt des Saralasins nachweisen.Die beiden Patienten mit Hyperkortizismus zeigten unter Saralasin sowohl einen Anstieg der Renin-Aktivität als auch des Plasmaaldosterons. Bei dem Patienten mit primärem Aldosteronismus ließ sich nur ein geringgradiger Anstieg der Plasmaaldosteronkonzentration nachweisen.Diese Ergebnisse sprechen gegen eine wichtige Rolle des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom. Die Unbeeinflußbarkeit des Hochdrucks durch Saralasin bei den beiden Patienten mit Hyperkortizismus und dem Patienten mit primärem Aldosteronismus stützen indirekt die Annahme, daß bei Patienten mit Cushing-Syndrom eine erhöhte Mineralokortikoidaktivität der Hauptfaktor in der Pathogenese der Hypertonie ist.SummaryTo investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushings syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-alaangiotensin II) over a period of 30 minutes under constant blood pressure control. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control.Neither in the two patients with Cushings syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed.In the two patients with hypercorticism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldosterone concentration.These results seem to exclude an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushings syndrome. The unresponsiveness of elevated blood pressure to saralasin in the two patients with hypercorticism and in the patient with primary aldosteronism indirectly supports the assumption that in patients with Cushings syndrome increased mineralocorticoid activity may be the main factor in the pathogenesis of hypertension.

CONTROL OF PLASMA ALDOSTERONE IN SUPINE ANEPHRIC MAN

Plasma aldosterone, plasma cortisol, plasma renin activity and the serum concentrations of sodium and potassium were determined at short time‐intervals in four supine anephric patients. Two patients were studied the night before and the night following haemodialysis. In both patients increases in plasma aldosterone occurred without concomitant alterations in serum sodium and serum potassium while plasma renin activity was uniformly undetectable. However, the observed fluctuations in plasma aldosterone were markedly more pronounced the night following haemodialysis. Under the latter conditions, typical secretory episodes of aldosterone occurred. The onset of these secretory episodes was not associated with simultaneous increases in plasma cortisol, whereas before haemodialysis changes in plasma aldosterone were paralleled by those in plasma cortisol. Except for the peak values of the secretory episodes of aldosterone, plasma aldosterone was markedly higher the night before than the night following haemodialysis. These differences between pre‐ and post‐haemodialysis aldosterone values correlated well with serum potassium, which was approximately 1 mEq/1 lower the night following haemodialysis. Two patients were studied the night following haemodialysis under normal conditions and with suppression of ACTH secretion by dexamethasone. Under both conditions, a typical episodic secretion of aldosterone was observed. In both patients plasma ACTH was below the lower limit of detectability (<20 pg/ml) under dexamethasone medication. It was concluded from our experiments that: (1) the differences between pre‐ and post‐haemodialysis aldosterone values reflect a direct influence of potassium on the secretion of aldosterone; (2) the fluctuations in plasma aldosterone which were observed the night before haemodialysis were mostly probably mediated through ACTH; and (3) an unknown factor had caused episodic secretion of aldosterone the night following haemodialysis.

Primäre und sekundäre Hypertonie in einem poliklinischen Patientengut

Die Annahme, das der Anteil der sekundaren Hypertonieformen am Gesamtkollektiv aller Hypertonien etwa 15–20% ausmacht, ist weit verbreitet. Erst in jungster Zeit weisen epidemiologische Studien darauf hin, das der Anteil der sekundaren Hypertonien unter 10% liegt [1, 2].

Control of plasma aldosterone in normal man during upright posture.

ZusammenfassungPlasma-Aldosteron, Plasma-Renin-Aktivität (PRA), Plasmacortisol (als Parameter der ACTH-Aktivität) und die Serumkonzentrationen von Natrium und Kalium wurden bei 10 gesunden Studenten nach Bettruhe und in kurzen Zeitabständen während drei Stunden nach dem Aufstehen gemessen. Während die PRA innerhalb von 15 min nach dem Aufstehen bei allen Studenten signifikant anstieg, wurde ein ähnlich schneller Anstieg des Plasmaaldosterons nur bei einigen der Probanden beobachtet. Nur bei diesen wurde ein gleichzeitiger Anstieg des Serumkaliums oder des Plasmacortisols beobachtet. Bei den Studenten, bei denen weder das Plasmacortisol noch das Serumkalium anstiegen, stieg das Plasmaaldosteron frühestens nach 30–60 min nach dem Aufstehen an. Aus den Ergebnissen wird geschlossen, daß der sofortige Anstieg des Plasmaaldosterons nach dem Aufstehen von einer Stimulation durch ACTH oder Kalium abzuhängen scheint. Der Hauptstimulus für das Aldosteron scheint während der Orthostase jedoch das Renin-Angiotensin-System zu sein. Wird Aldosteron nur über dieses System stimuliert, erfolgt der Aldosteronanstieg mit einer Verzögerung von 30–60 min.SummaryPlasma aldosterone, plasma renin activity (PRA), plasma cortisol as parameter of ACTH activity and the serum concentrations of sodium and potassium were determined at short time intervals in 10 healthy students after an overnight bedrest and during three hours of ambulation. While PRA rose significantly within 15 minutes of orthostasis in all students, plasma aldosterone showed a similar rapid increase in some of the subjects only. These persons demonstrated also a simultaneous increase of serum potassium or of plasma cortisol. Plasma aldosterone rose not before 30 to 60 minutes after change to the upright position in subjects who showed neigher plasma cortisol nor serum potassium increases. It is concluded that the immediate rise of plasma aldosterone during orthostasis seems to depend on a stimulation by ACTH of by potassium. The main stimulus of plasma aldosterone during orthostasis appears to be the renin angiotensin system. If the aldosterone response to posture is mediated only through this system a delay of 30 to 60 minutes is observed.

Control of Plasma Aldosterone during Hemodialysis in Patients with Terminal Renal Failure

The control of plasma aldosterone during hemodialysis was investigated in 31 patients with terminal renal failure. While before hemodialysis renin predominantly influenced aldosterone, this effect dissipated during hemodialysis. In addition, no relationship was observed between changes in aldosterone and those in sodium, potassium and plasma cortisol. In a group of 10 patients isokalemic and isonatremic hemodialysis failed to document an effect sodium or potassium on hemodialysis induced changes in aldosterone. Our data suggest that none of the four factors - renin, ACTH, sodium and potassium - had constantly caused the observed changes in aldosterone during hemodialysis.

Effect of propranolol and prindolol on renin secretion in normal supine man

ZusammenfassungUm den Effekt von Propranolol und Prindolol auf die Reninsekretion zu untersuchen, wurde unter natriumarmer Ernährung bei 10 liegenden Normalpersonen in kurzen Zeitabständen über Nacht die Plasma-Renin-Aktivität (PRA) bestimmt. 4 Personen standen unter einer 4tägigen Behandlung mit Propranolol, 3 wurden über denselben Zeitraum mit Prindolol behandelt und 3 Personen dienten als Kontrollgruppe.Bei Normalpersonen zeigte Renin sowohl eine episodische Sekretion als auch einen typischen Nacht-Tag-Rhythmus. Unter Propranolol und Prindolol wurden Sekretionsepisoden des Renins entweder nicht beobachtet oder traten seltener auf. Eine Nacht-TagSchwankung der Reninsekretion war mit einer Ausnahme nicht zu beobachten. Unter beiden Betablockern war die mittlere PRA signifikant niedriger als bei Kontrollpersonen (p<0.001).Unsere Ergebnisse zeigen, daß Propranolol und Prindolol die Renin-Aktivität senken und entweder die episodische Reninsekretion aufheben oder zu einer Frequenzabnahme der Sekretionsepisoden führen. Unsere Resultate erlauben die Schlußfolgerung, daß das sympathische Nervensystem eine bedeutende Rolle in der Steuerung der Nacht-Tag-Rhythmik und in der Regulation der Kurz-ZeitSchwankungen der Reninsekretion spielt.SummaryTo investigate the effect of propranolol and prindolol on renin secretion plasma renin activity (PRA) was determined overnight at short-time intervals in 10 sodium-restricted normal supine subjects. 4 of them were on a 4-days medication with propranolol, 3 were treated with prindolol and 3 were used as control group.In normal controls renin was secreted episodically and showed characteristic night-day variations. Both in propranolol and in prindolol-treated subjects secretory episodes in renin secretion either did not occur or were less frequent than in normal controls. With one exception night-day variations in renin secretion were not observed. Mean PRA values were significantly lower than in the control group (p<0.001).Our results show that both propranolol and prindolol lower PRA and eliminate or reduce the frequency of secretory episodes. It is concluded that the sympathetic nervous system plays an important role in regulating night-day variations and short-time fluctuations of renin secretion in normal supine man.

In vivo effects of angiotensin antagonists on plasma aldosterone in the dog.

The effects of infusions of equimolar doses of Sar1-Ile8-angiotensin II and of Sar1-Ala8-angiotensin II on plasma aldosterone, plasma renin activity and arterial blood pressure were compared in normal dogs. Plasma aldosterone increased significantly after Sar1-Ile8-angiotensin II whereas it was unaffected by Sar1-Ala8-angiotensin II. Changes in blood pressure and renin activity were small without marked differences between both groups of animals. The experiments demonstrate a clear steroidogenic potency of Sar1-Ile8-angiotensin II. Therefore, Sar1-Ala8-angiotensin II should be preferred as antagonist of the action of angiotensin II in the adrenal gland.

Characteristics of aldosterone antisera related to the duration of immunization.

Three antisera specific to aldosterone and elicited with different aldosterone protein conjugates (aldosterone-3-oxine rabbit serum albumin and aldosterone-3-oxime bovine gamma-globulin) were studied by radioimmunological methods at various times subsequent to first-immunization. A considerable variability of the parameters important in radioimmunoassay was observed over the whole experimental period. Titer, sensitivity and specificity of two antisera tended to increase as long as the animals were boosted. In the third they did not change in a uniform way.

Einfluß der Hämodialyse auf die Plasmaaldosteronkonzentration bei nierenlosen Patienten

Plasma aldosterone, plasma cortisol and the serum concentrations of sodium and potassium were determined in 5 anephric patients before and at short time intervals up to 180 minutes after hemodialysis. Plasma aldosterone increased in 4 of 5 patients during hemodialysis while in all patients plasma cortisol, sodium and potassium decreased. Only one patient showed a fall in aldosterone during hemodialysis. After hemodialysis plasma aldosterone gradually decreased over a period of 3 hours in 3 of 5 patients, whereas the remaining two patients showed typical secretory episodes of aldosterone. In each patient serum potassium rapidly increased while serum sodium showed only minor variations. Plasma cortisol followed the normal circadian rhythm. We suggest that a still unkown factor had caused the observed increases in plasma aldosterone during hemodialysis. There are reasons to believe that over the period observed after hemodialysis the intracellular potassium concentration and not serum potassium levels has influenced adrenal aldosterone release. This would explain the paradoxical decrease in plasma aldosterone in 3 of the 5 patients while serum potassium increased.SummaryPlasma aldosterone, plasma cortisol and the serum concentrations of sodium and potassium were determined in 5 anephric patients before and at short time intervals up to 180 minutes after hemodialysis. Plasma aldosterone increased in 4 of 5 patients during hemodialysis while in all patients plasma cortisol, sodium and potassium decreased. Only one patient showed a fall in aldosterone during hemodialysis. After hemodialysis plasma aldosterone gradually decreased over a period of 3 hours in 3 of 5 patients, whereas the remaining two patients showed typical secretory episodes of aldosterone. In each patient serum potassium rapidly increased while serum sodium showed only minor variations. Plasma cortisol followed the normal circadian rhythm. We suggest that a still unknown factor had caused the observed increases in plasma aldosterone during hemodialysis. There are reasons to believe that over the period observed after hemodialysis the intracellular potassium concentration and not serum potassium levels has influenced adrenal aldosterone release. This would explain the paradoxical decrease in plasma aldosterone in 3 of the 5 patients while serum potassium increased.ZusammenfassungPlasmaaldosteron, Plasmacortisol und die Serumkonzentrationen von Kalium und Natrium wurden bei 5 nierenlosen Patienten vor und in kurzen Zeitabständen bis zu 180 min nach Beendigung der Hämodialyse gemessen. Unter Hämodialyse stieg das Plasmaaldosteron bei 4 der 5 Patienten an, während bei allen Patienten Cortisol, Kalium und Natrium abfielen. Nur bei einem Patienten ließ sich unter Hämodialyse ein Abfall des Aldosterons nachweisen. Nach Beendigung der Hämodialyse kam es über den untersuchten Zeitraum bei 3 der 5 Patienten zu cinem fast kontinuierlichen Abfall des Plasmaaldosterons, während die beiden anderen Patienten Sekretionsepisoden des Aldosterons mit spontanen Anstiegen und anschließendem Abfall der Hormonkonzentration zeigten. Bei allen Patienten stieg nach Hämodialyse das Serumkalium rasch wieder an, während nur geringgradige Veränderungen des Serumnatriums nachweisbar waren. Plasmacortisol zeigte während der Beobachtungsperiode typische tageszeitliche Schwankungen. Wir nehmen an, daß ein noch unbekannter Faktor für den Anstieg des Plasmaaldosterons unter Hämodialyse verantwortlich ist. Einiges spricht dafür, daß über den nach Hämodialyse beobachteten Zeitraum die intracelluläre Kaliumkonzentration und nicht das Serumkalium die Aldosteronsekretion beeinflußt. Dies würde den bei 3 der 5 Patienten scheinbar paradoxen Abfall des Aldosterons bei steigendem Serumkalium erklären.