H. Armbruster

EPISODIC SECRETION OF ALDOSTERONE IN PRIMARY ALDOSTERONISM: RELATIONSHIP TO CORTISOL

Plasma aldosterone, plasma cortisol and plasma renin activity were determined at short time intervals in three supine patients suffering from primary aldosteronism. The patients were studied both under normal conditions and during suppression of ACTH secretion by dexamethasone. Though abnormally high levels were found, aldosterone was secreted episodically in each patient while plasma renin activity was uniformly undetectable. In each patient the secretory episodes of aldosterone were paralleled by those of cortisol indicating that physiological variations in ACTH secretion markedly altered the secretion of aldosterone. The assumption that ACTH played an important role in the regulation of aldosterone secretion in primary aldosteronism was strengthened by the observation that, contrary to normal controls, dexamethasone produced a significant decrease in plasma aldosterone concentrations and that during suppression of ACTH secretion no secretory episodes of aldosterone were observed.

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.

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.

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.

Production of antisera specific to aldosterone: Effect of hapten density and of carrier proteins

Abstract In order to investigate the influence of hapten density and of carrier proteins on the immunological characteristics of antisera, 4 groups of rabbits were injected with different aldosterone-carboxymethoxime protein conjugates. Six animals immunized with an aldosterone rabbit serum albumin (RSA) conjugate carrying 15 steroid molecules (RSA-2 conjugate) showed markedly higher antibody titers than rabbits injected with a RSA conjugate carrying 8 aldosterone molecules (RSA-1 conjugate). Low antibody titers were found in 8 animals immunized with an aldosterone bovine gamma globulin (BGG) conjugate showing a molar incorporation of 15. In a group of rabbits which was first injected with the RSA-1 conjugate and re-immunized with the RSA-2 conjugate the magnitude of antibody production was not enhanced. No differences in antibody sensitivity or specificity were observed between the 4 groups. It was concluded from these experiments a) that the density of haptenic groups depending on the molar incorporation of haptens and on the molecular weight of the carrier protein had influenced the magnitude of antibody production, b) that hapten density or carrier proteins had no effect on antibody sensitivity or specificity, c) that the magnitude of antibody production cannot be altered by re-immunizing with a more potent antigen.

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.

Plasmarenin und Plasmaaldosteron nach Nierenallotransplantation

Nach Nierentransplantation werden haufig erhohte Plasmareninwerte beobachtet [7, 10, 13]. In einer Studie wurde versucht, Einblicke in die Mechanismen zu gewinnen, die die Hohe der Plasma-Reninaktivitat und des Plasmaaldosterons nach Nierentransplantation bestimmen.

[Episodic secretion of cortisol in Cushing's syndrome (author's transl)].

SummaryIn a patient with typical features of Cushings disease, repeated ambulant determinations of plasma cortisol showed normal values with 16 to 24 µg/100 ml.The entire analysis of the circadian variations of plasma cortisol under standardized conditions led to the diagnosis of hypercorticism.Compared with 2 healthy subjects the patients curve is set at a higher level. Physiological, quiet periods of cortisol secretion in late day-time do not occur. In accord to the normal, we find great variations of plasma cortisol in this case of Cushings syndrome due to bilateral adrenal hyperplasia. The diagnostic value of plasma cortisol determinations at short term intervals in differentiating the various forms of hypercorticism is discussed.ZusammenfassungWiederholte ambulante Plasmacortisolbestimmungen bei einer Patientin mit deutlichen klinischen Zeichen des Hyperkortizismus ergaben mit 16–24 µg/100 ml normale Werte. Erst ein unter standardisierten Bedingungen erstelltes Plasmacortisol-Tagesprofil erbrachte den eindeutigen Nachweis der Hypercortisolämie. Im Vergleich zu gesunden Normalpersonen liegen die Plasmacortisolspiegel der Cushing-Patientin auf einer höheren Ebene. Die physiologischen Phasen ruhender Cortisolsekretion in den Abend- und Nachtstunden fehlen. Wie bei Gesunden können wir bei diesem Fall von Hypercortic ismus, beruhend auf bilateraler Nebennierenrinden-Hyperplasie, große Schwankungen des Plasmacortisolspiegels beobachten. Der Wert wiederholter Plasmacortisolbestimmungen in der Abklärung des Cushing-Syndroms wird diskutiert.

Untersuchungen zum Wirkungsmechanismus des Antihypertensivums Guancydin

SummaryIn rats, which were treated, with furosemide and mefruside, the effect of intraperitoneally injected guancydine (25 mg/kg) on the mean arterial blood pressure and the heart rate was studied over a period of 2 hrs. In comparison with, normal animals, a significant potentiation of the depressant effect of guancydine on heart rate and blood pressure was observed. This effect was dose dependent, since the animals, which were pretreated with 25 mg/kg furosemide or 50 mg/kg mefruside, showed a significantly lower blood pressure than rats, which received 12,5 mg/kg furosemide or 25 mg/kg mefruside (p<0.01).It is suggested, that the causes of these effects were not the saluretic-induced alterations of the water and electrolyte balance but the fact, that furosemide, mefruside and guancydine are excreted by the same renal transport system.These findings were strongly supported by the fact, that in other experiments pretreatment with guancydine significantly lowered the diuretic and natriuretic action of furosemide (p<0.01). This effect was also dose dependent.ZusammenfassungBei Ratten, die mit Furosemid oder Mefrusid vorbehandelt worden waren, wurde über einen Zeitraum von 2 Std die Wirkung von intraperitoneal injiziertem Guancydin (25 mg/kg) auf den mittleren arteriellen Blutdruck und die Herzfrequenz beobachtet. Im Vergleich zu nichtvorbehandelten Tieren konnte eine deutliche Potenzierung der blutdruck- und herzfrequenzreduzierenden Guancydinwirkung nachgewiesen werden. Der Effekt war dosisabhängig, da 2 Std nach der Guancydingabe die mit 25 mg/kg Furosemid oder 50 mg/kg Mefrusid vorbehandelten Tiere einen signifikant niedrigeren Blutdruck aufwiesen als diejenigen, die vorher 12,5 mg/kg Furosemid oder 25 mg/kg Mefrusid erhalten hatten (p<0,01).Es konnte wahrscheinlich gemacht werden, daß die Ursache für diesen Effekt weniger in einer diuretikumbedingten Veränderung des Wasser- und Elektrolythaushalts als darin liegt, daß Furosemid, Mefrusid und Guancydin über dasselbe renale Transportsystem ausgeschieden werden. Als Ausdruck einer Konkurrenz der Substanzen um dieses Transportsystem kam es möglicherweise zu einer Verzögerung der Guancydinausscheidung und somit zu einer verstärkten Wirkung des Antihypertensivums auf den Blutdruck und die Herzfrequenz.Diese Auslegung der Ergebnisse wird außerdem dadurch bestätigt, daß in weiteren Versuchen der diuretische und natriuretische Furosemideffekt durch Vorbehandlung mit Guancydin signifikant herabgesetzt werden konnte (p<0,01). Dieser Effekt war gleichfalls dosisabhängig.