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.

Control of plasma aldosterone in terminal renal failure before and after nephrectomy and after renal transplantation.

In two patients with terminal renal failure the night-day rhythm of plasma aldosterone (PA) renin activity (PRA) and plasma cortisol (PC) were examined before and after bilateral nephrectomy and after renal transplantation. Before nephrectomy changes in abnormally high PA coincided with PC whereas no significant correlation was observed between PA and PRA. In the anephric state secretory episodes of PA occurred independent from those of PC while PRA was undetectable. After renal transplantation a lack of night-day variation in renin secretion was observed in both patients; only one of the two patients showed episodic secretion of PA while PC was suppressed in both patients probably due to the chronic administration of prednisone. Our results indicate, that before nephrectomy under the conditions described in this study plasma aldosterone was predominantly controlled by ACTH. In the anephric state and after renal transplantation other (yet unidentified) factors might have caused episodic secretion of aldosterone. Finally, the lack of night-day variation and secretory episodes in renin secretion after transplantation points to an important role of the sympathetic nervous system in the control of circadian and episodic renal renin release.

[The value of renin determination in the diagnosis of hypertension]. / Die Bedeutung der Reninbestimmung bei der Hypertonie-Abklärung

Primary aldosteronism and renovascular hypertension are two different diseases in which renin determinations are necessary for establishment of diagnosis or therapeutic procedure. Low renin values which are not stimulated by acute stimuli combined with elevated plasma aldosterone concentrations confirm the diagnosis of primary aldosteronism. When in a patient with proven renal artery stenosis a significant difference in renal venous renin activity is observed between the two kidneys, a connection between hypertension and renal artery stenosis is likely when in addition the renin secretion of the unaffected kidney is suppressed. A favourable outcome for surgery can be predicted when the individual clinical picture in such a case is also considered. A similar view also holds for the connection between hypertension and unilateral small kidney not due to renal artery stenosis. In essential hypertension the plasma renin level makes it possible to a certain extent to predict whether a patient will benefit from diuretics or from beta-blocking agents. Despite this experience, however, renin determinations are not indicated in every case of essential hypertension. It has not been proven that the prognosis of this disease is improved by renin oriented monotherapy rather than by effective treatment with other antihypertensive agents.

Problems connected with plasma renin activity measurements by angiotensin I radioimmunoassay.

The main application of the radioimmunoassay for angiotensin I is the measurement of plasma renin activity (PRA). Methods published for the measurement of PRA differ in many details and make the comparison of results difficult. This paper deals with some of the problems. 1. The radioactive labelling of angiotensin I using chloramine-T requires the purification of the labelled peptide. A method applying both anion exchange chromatography and gel filtration is described. It resulted in tracer angiotensins of very reproducible characteristics. 2. For the measurement of PRA, the pH of the plasma has to be adjusted prior to the incubation. The adjustment to the physiologic pH of 7.4 is recommended. 0.1 volume of a concentrated buffer controlled the pH during a three hours incubation without diluting the plasma too much. 3. At pH 7.4, EDTA, dimercaprol, and 8-hydroxyquinoline were found to inhibit converting enzyme and angiotensinases better than EDTA and DFP and should therefore be used as inhibiting agents. 4. Nonspecific cross reaction of antisera are the cause of the blank values when angiotensin I is measured in unextracted plasma. The problem of subtraction of a blank may be minimized by the selection of an antiserum of high specificity which shows no or only little nonspecific cross reaction. Lor or unmeasurable blank values will result.

Studies on the effect of angiotensin II and of Des -angiotensin II on blood pressure, plasma renin activity and plasma aldosterone in the dog.

1. The effect of infusions of equimolar doses of angiotensin II (AII) and of Des -angiotensin II (heptapeptide) on plasma renin activity, blood pressure and plasma aldosterone were compared in normal anaesthetized dexamethasone-suppressed dogs. 2. Plasma renin activity was equally suppressed by both compounds. The increase in blood pressure induced by the heptapeptide averaged 43-62% of the increase during AII infusions. No significant differences in aldosterone increase were observed between AII and the heptapeptide. Plasma aldosterone, however, dropped significantly faster in heptapeptide-treated dogs after the end of the infusions. 3. Sar -Ala -angiotensin II (saralasin, 400 pmol min-1 kg-1) suppressed plasma aldosterone that was stimulated by heptapeptide (20 pmol min-1 kg-1) completely. The same angiotensin antagonist had only a moderate effect on plasma aldosterone stimulated by AII. After stopping the antagonist infusion, plasma aldosterone rose significantly higher in dogs infused with AII than in those receiving the heptapeptide. 4. The results demonstrate differences between the effects of AII and the heptapeptide both on blood pressure and on plasma aldosterone. They do not support the hypothesis that the heptapeptide may be the main mediator of aldosterone secretion.

The effect of saralasin (1sar-8-ala-angiotensin II) on blood pressure in patients with Cushing's syndrome.

To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-ala-angiotensin II) over a period of 30 minutes under constant blood pressue control. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control. Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed. In the two patients with hypercoritcism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldosterone concentration.

Control of plasma aldosterone in normal man during upright posture.

Plasma 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.

Diurnal variations of plasma aldosterone in supine man: relationship to plasma renin activity and plasma cortisol.

In order to investigate the role of renin secretion and of ACTH on the circadian rhythm of plasma aldosterone (PA), plasma renin activity (PRA), plasma cortisol (PC) and PA were determined at short-time intervals in 10 normal supine men. Six subjects were studied under a normal sodium intake and 4 under sodium restriction. In 4 subjects the secretion of ACTH was suppressed by dexamethasone. Under normal sodium intake changes in PA seemed to be more in parallel with changes in PC than by those in PRA as indicated by a higher significant correlation between PA and PC than between PA and PRA in 3 of the 4 subjects. In 1 subject no correlation was observed between PA and PC despite visual synchronism between the plasma concentrations of both hormones. Under dexamethasone medication fluctuations in PA were followed by those in PRA while PC was less than 2 mug/100 ml. In the sodium restricted state, changes in PA were closely paralleled and significantly correlated to PRA while no correlation was seen between PA and PC. Under dexamethasone medication the significant correlation between PA and PRA persisted. Our results indicate that in normal supine man the influence of ACTH and renin on PA may vary with different sodium intakes. Under normal sodium intake ACTH seems to be the dominant factor controlling PA, whereas under sodium restriction changes in PA are mediated through the renin angiotensin system. When the secretion of ACTH is suppressed by dexamethasone, renin controls PA both under normal and low sodium intake.

Effect of immunization against angiotensin II on blood pressure and on plasma aldosterone in the rabbit.

1. Rabbits were actively immunized aganist angiotensin II (AII). 2. Basal plasma aldosterone concentration was 0-058 plus or minus 0-027 pmol/ml (20-7 plus or minus 9-6 pg/ml) (mean plus or minus SD) in immunized and 0-056 plus or minus 0-021 pmol/ml (20-2 plus or minus 7-5 pe. When the endogenous formation of AII was stimulated by frusemide, by haemorrhage or by feeding with low sodium diet, a significant increase of plasma aldosterone was observed with no difference between immunized and non-immunized animals. 3. In non-immune rabbits, the average mean arterial blood pressure rose 13 mmgHg during the infusion of AII (5 pmol min--1 kg-1) and 27 mmHg during the infusion of 50 pmol min-1 kg-1. In contrast, there was no clear increase in blood pressure in the immunized animals. The blood pressure rose in immune animals (15 mmHg) and in non-immune animals (36 mmHg) during the infusion of 200 pmol min-1 kg-1 ALL. Plasma aldosterone rose in all animals in response to each of the three infusions with no significant difference between the two groups. 4. It is concluded that the immunization against ALL blocked only the pressor effect of the peptide but had no clear influence on the response of plasma aldosterone to increased ALL. Differences between the affinities of the adrenal and vascular AII receptors may explain these findings.

[Effect of hemodialysis on plasma aldosterone in anephric patients (author's transl)]. / 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.

[Primary aldosteronism: diagnosis, laterality and regulation of hormone secretion]. / Primärer Aldosteronismus: Diagnose, Seitenlokalisation und Regulation der Hormonsekretion

In 16 patients with hypokalemic hypertension the combination of abnormally high and unsuppressible plasma aldosterone with low or undetectable renin activity led to the diagnosis of primary aldosteronism. To differentiate between aldosterone producing adenoma and idiopathic bilateral hyperplasia, determination of aldosterone concentration in both adrenal veins was performed in 12 patients. In 4 of these patients the two forms of primary aldosteronism could not be differentiated as in these cases only one of the two adrenal veins simultaneously showing an abnormally high aldosterone concentration could be canulated. Plasma aldosterone and plasma cortisol were determined overnight (20.00-8.00 h) at short time intervals in 8 patients with adenoma, 1 patient with carcinoma of the adrenal cortex and 3 patients with bilateral hyperplasis. In all patients with adenoma a significant correlation between aldosterone and cortisol was observed (p less than 0.05-0.001) whereas no correlation was seen in the patients with hyperplasia and carcinoma. The clinical importance of these findings is that in the presence of ACTH-dependent secretion of aldosterone the site of the adenoma can be predicted even when blood from only one adrenal vein is obtained.

Control of plasma aldosterone in infancy and childhood. A study of plasma renin activity, plasma cortisol and plasma aldosterone.

In order to elucidate the main factors controlling plasma aldosterone in infancy and childhood, plasma renin activity (PRA), plasma cortisol (PC, as a parameter of ACTH activity), plasma aldosterone (PA) and serum sodium and potassium were measured simultaneously in 84 healthy children (62 recumbent, 22 upright) ranging in age from 6 days to 16 years. 10 healthy male students served as adult controls. As compared to the controls, PRA levels were significantly higher in the children up to the age of 12 years. PA was also elevated in most children; the highest values for PA and for PRA were observed during the first 4 years of life. A significant positive correlation between PRA and PA (n = 84, r = 0,62, p less than 0.001) was found. There were no significant differences in serum sodium or potassium or in PC. All PC values were - with one exception - within the range found in healthy adults. Our results indicate that high PA values are freuqently observed in healthy children. They are mainly caused by elevated PRA. The physiological significance of increased activation of the renin-angiotensin-aldosterone system in infancy is not yet clear.

[Effect of saralasin on normal blood pressure and on reno-vascular hypertension (author's transl)]. / Angiotensinblockade mit Saralasin. Einfluss auf den normalen Blutdruck und auf den renovaskulären Hochdruck

The angiotensin antagonist saralasin was given intravenously to six normotensive students before and after dietary sodium restriction and to two patients with renovascular hypertension. Both patients responded to the angiotensin antagonist with a decrease of the systolic (32 and 38 mm Hg) and of the diastolic (29 and 16 mm Hg) blood pressure. The small changes in blood pressure observed in the normotensive subjects during the infusion of the angiotensin antagonist indicate that angiotensin II plays no important role in the control of normal blood pressure in recumbent men. The fall in blood pressure induced by saralasin in both patients, however, demonstrates that their hypertension was at least partly angiotensin-dependent. Renal vein renin determination led to the same conclusions. The saralasin infusion test seems to be a simple procedure to diagnose angiotensin-dependent hypertension and will probably help to identify patients with suspected renovascular hypertension.

[Effect of the angiotensin antagonist saralasin (1-sar-8-ala-angiotensin II) on the blood pressure in secondary hypertension]. / Einfluss des Angiotensin-Antagonisten Saralasin (1-Sar-8-Ala-Angiotensin II) auf den Blutdruck bei sekundärer Hypertonie

The angiotensin antagonist saralasin (1-sar-8-ala-angiotensin II) was given to 27 patients with different forms of secondary hypertension. The blood pressure fell in 6 of 7 patients with renal artery stenosis and in 4 of 10 patients with terminal renal failure on regular hemodialysis. No change or a rise in blood pressure was observed in 3 patients with Cushing's syndrome, 4 patients with primary aldosteronism, 3 patients with hypertension and a unilateral small kidney of other than renovascular origin, and 6 patients with terminal renal failure. It can be concluded from the results that angiotensin II is involved in the pathogenesis of renovascular hypertension and in some cases of hypertension accompanying chronic renal failure.

[Transitory remission of hypercorticism by means of cyproheptadine in a patient with Cushing syndrome]. / Nicht dauerhaft Remission des Hyperkortizismus durch Cyproheptadin bei einer Patientin mit Cushing-Syndrom

In patients with Cushing's syndrome of hypothalamischem Cushing-Syndrom wereden eine zentrale Störung und eine wichtige Rolle des Serotonins. Accordingly, in the present study a patient with hypothalamic-pituitary hypercorticism was treated with the seotonin antagonist cyproheptadine. Urinary free cortisol excretion was measured repeatedly before, during and after therapy. In addition, night-day rhythm of plasma cortisol was determined before and at the end of cyproheptadine medication. Within 2 months, therapy with 24 mg cyproheptadine resulted in a lowering of urinary cortisol excretion to normal values. Then, however, despite continuation of the therapy, urinary free cortisol excretion rates again rose to pathological levels. Due to the occurrence of severe psychosis, the drug had to be withdrawn. Before and under cyproheptadine no night-day rhythm of plasma cortisol could be observed.

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.