Rise In Plasma Aldosterone Concentration Research Articles

BIOCHEMICAL, HISTOPATHOLOGICAL, AND GENETIC CHARACTERIZATION OF POSTURE RESPONSIVE AND UNRESPONSIVE ALDOSTERONE-PRODUCING ADENOMAS

Objective: Aldosterone-producing adenoma (APA) accounts for ∼30% of primary aldosteronism. Based on responses of aldosterone to upright posture, APA can be divided into posture-responsive and –unresponsive forms. Somatic gene mutations in KCNJ5, CACNA1D, ATP1A1, or ATP2B3 have been reported to exist in more than 90% of APAs. We sought to compare the biochemical, histopathological, and genetic characterization between these two types of APAs. Design and method: Posture-responsive was defined as showing a rise in plasma aldosterone concentration of at least 50% 2 - 3 h after the assumption of upright posture (10 AM) above the basal level (7 AM) following overnight recumbency. Plasma levels of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) were measured by LC-MS/MS. Histologic analysis and immunohistochemistry for CYP11B2 (aldosterone synthase) and CYP17A1 (17aplha-hydroxylase) were performed on APA tissue sections collected from 24 posture-unresponsive and 17 posture-responsive APA patients. Sanger sequencing of KCNJ5 and gene targeted next-generation sequencing were performed to detect somatic gene mutations. Results: Compared to patients with posture-responsive APA (of which 48.7% were composed of zona glomerulosa (ZG)-like cells and 35.3% showed ZG-zona fasciculata (ZF) mixed appearance), posture-unresponsive APA patients displayed higher (P < 0.01) levels of hybrid steroids, recumbent aldosterone and cortisol, greater (P < 0.05) suppression of aldosterone secretion from the contralateral unaffected adrenal, and larger (P < 0.01) tumors mostly composed of ZF-like cells that had higher (P < 0.01) expression of CYP17A1 (but not of CYP11B2). Of 41 studied APAs, 37 (90.2%) harboured aldosterone-driving somatic mutations (KCNJ5 = 14, 34.1%; CACNA1D = 13, 31.7%; ATP1A1 = 8, 19.5%; and ATP2B3 = 2, 4.9%), including 5 that were previously unreported (3 in CACNA1D and 2 in ATP1A1). Interestingly, 64.7% (11/17) of posture-responsive APAs carried CACNA1D mutations, whereas 54.2% (13/24) of posture-unresponsive APAs harboured KCNJ5 mutations. Conclusions: The excessive production of hybrid steroids by posture-unresponsive APAs may relate to their ZF-like tumor cell composition, resulting in strong expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol which acts as the substrate for CYP11B2-generated hybrid steroids.

Plasma aldosterone response to the low‐dose adrenocorticotrophin (ACTH 1–24) stimulation test

Endocrine tests for adrenal insufficiency use pharmacological doses of stimulant such as ACTH. More physiological tests have often used high-dose protocols for sampling frequency. To evaluate the response of plasma aldosterone concentration to low doses (125, 250 and 500 ng/m(2) body surface area) of synthetic ACTH. A randomised trial in six normal adult males aged 18-27 years. Aldosterone concentration was measured by radioimmunoassay in serum from blood samples taken at 10 min intervals for 90 min. All three doses produced a significant rise in plasma aldosterone concentration (125 ng/m(2), P = 0.003; 250 ng/m(2), P < 0.001; 500 ng/m(2), P < 0.001) but there was no effect of dose on either the peak or incremental plasma aldosterone concentration. Mean time to peak was similar between the doses and the two higher doses were associated with a longer secretory profile (125 ng/m(2) 56 (26 SD) mins, 250 ng/m(2) 74 (19) mins, 500 ng/m(2) 77 (21) mins; F = 3.39; P = 0.04). Peaks of 100% were detected within 30 min of drug administration and peak response was associated with the prestimulation plasma aldosterone concentration (r = 0.45; P = 0.003). The between- and within-individual coefficients of variation for prestimulation concentrations were 37.0% and 32.8%, and for the peak response were 27.2% and 27.2%, respectively. The response of plasma aldosterone concentrations to low-dose ACTH administration requires a blood sampling protocol of 0, 10, 20 and 30 min to capture concentrations near the peak response. The high-dose protocol would have missed the response. Over the dose range studied no dose-response was observed so the selection of dose should be based on the dose effective to release steroids in the glucocorticoid pathway if this study is to be used in conjunction with such evaluation.

Timing and magnitude of response of plasma aldosterone concentration to bolus adrenocorticotropin: importance of sodium balance in outpatient testing.

Plasma aldosterone concentration (PAC) response to ACTH is utilized in clinical and experimental protocols. However, PAC response to ACTH in normal subjects controlled for modifiers of PAC has not been established. Our report includes two experiments. In both, subjects were studied in the morning and were in sodium (Na+) balance prior to study on 4 g Na+ for phase I, and 2 and 8 g Na+ diets for phase II. Na+ balance was established by 24-h urinary Na+ (UNa+) in phases I and II, and also by fractional excretion of Na+ (FENa+) in phase II. After being supine for 60 min, subjects received 0.25 mg of iv bolus ACTH. PAC, plasma renin activity and plasma potassium (K+) were drawn every 30 min in phase I and every 15 min in phase II. The rise in PAC (rPAC) and correlation coefficients were calculated. In phase I, peak PAC occurred at 30 min, 1130 +/- 420 pmol/L, with a rPAC of 810 +/- 310 pmol/L. Twenty-four hour UNa+ was 86 +/- 45 mmol/24 h. In phase II, time and magnitude of peak PAC and rPAC were dependent on diet. Both occurred at 30 min for 8 g Na+: peak PAC was 640 +/- 210 pmol/L and rPAC was 440 +/- 190 pmol/L; and at 60 min for 2 g Na+: peak PAC was 1040 +/- 320 pmol/L and rPAC was 690 +/- 220 pmol/L. Correlation coefficients for rPAC and 24-h UNa+ was r = -0.44, P less than 0.05 and for rPAC and FENa+ was r = -0.46, P less than 0.05. In summary, in subjects supine for 60 min prior to iv bolus ACTH, Na+ balance is the most important determinant of PAC response. Both magnitude and timing of rPAC is influenced by Na+ balance. Finally, both 24-h UNa+ and FENa+ are valid for establishing pretesting Na+ status.

Effects of arginine vasopressin on the pituitary-adrenocortical axis of intact and dexamethasone-suppressed rats

Weekly infusion with arginine vasopressin (AVP) (2 micrograms.kg-1.day-1) exerted a slight stimulatory effect on the adrenal growth of intact female rats and induced a 2-fold rise in plasma aldosterone concentration (PAC), without apparently affecting corticosterone (B) and ACTH secretions. Weekly dexamethasone (Dx) administration (125 micrograms.kg-1.day-1) caused a marked adrenal atrophy, a conspicuous suppression of B and ACTH productions, and a 5-fold increase in PAC. AVP infusion reversed the Dx-induced adrenal atrophy. It did not counteract the suppression of B and ACTH secretions, nor did it change PAC. These findings suggest that chronic AVP treatment is able to stimulate adrenal growth by a Dx-insensitive mechanism (i.e. independent of any change in ACTH secretion). Conversely, AVP may enhance the steroid secretory capacity only in adrenocortical cells in which the maintenance of the steroidogenic machinery is assured by normal levels of circulating ACTH.

The effect of selective dopamine-1 receptor stimulation on renal and adrenal function in man.

We studied the actions of iv fenoldopam, a selective dopamine-1 (DA-1) receptor agonist, in 10 normal men eating a diet containing 150 meq sodium and 60 meq potassium per day. During DA-1 receptor stimulation systemic hemodynamic function did not change. Fenoldopam resulted in an increase in urine flow rate from 13 +/- 1 (+/- SE) to a peak of 17 +/- 2 mL/min (P less than 0.05) and an increase in renal plasma flow from 344 +/- 39 to 481 +/- 44 mL/min (P less than 0.05). Urinary sodium excretion and fractional excretion of sodium both increased. Urinary sodium excretion rose to a maximum of 0.32 +/- 0.05 compared with a control value of 0.21 +/- 0.03 meq/min (P less than 0.01), while fractional excretion of sodium rose to 2.7 +/- 0.6 compared with a control value of 1.6 +/- 0.1% (P less than 0.05). The glomerular filtration rate did not change. Administration of a predominantly DA-2 antagonist during continuous DA-1 receptor stimulation did not block the fenoldopam-induced natriuresis. The rise in plasma aldosterone concentration after metoclopramide administration was blunted by DA-1 receptor activation [19.2 +/- 2.9 during control compared with 12.7 +/- 1.3 ng/dL (P less than 0.01) during fenoldopam]. No change occurred in serum potassium, plasma cortisol, or PRA. We conclude that selective DA-1 receptor stimulation in man produces sustained natriuresis and inhibition of aldosterone release by direct renal and adrenal effects.

Endotoxin-induced prostaglandin (PGF2 alpha) biosynthesis, fever and miosis in dexamethasone-treated goats.

Prostaglandin-releasing, adrenocortical, febrile and miotic responses to endotoxin (ET) (E. coli lipopolysaccharide; 0.25 microgram kg-1) were studied in goats with and without prolonged dexamethasone influence. The i.v. injection of ET induced a three-fold peak elevation in plasma 15-ketodihydro-PGF2 alpha at 1.5 h post-injection, that is, between the first and second phase of the temperature elevation. During the latter phase, the plasma concentration of this primary PGF 2 alpha metabolite gradually returned to basal level, which implies that the second phase of ET fever is not PG dependent. The PG response exhibited a similar pattern, but was less pronounced in the dexamethasone-ET experiments, where the duration of maximum temperature elevation and of the miosis became shortened by about 20 min, and the typical biphasic pattern of ET fever was no longer seen. The ET-induced rise in plasma aldosterone concentration was completely blocked by dexamethasone. The corresponding rise in plasma cortisol concentration was prevented for 2 h, but was later only partially inhibited in spite of the repeated dexamethasone treatment.

Ammonium chloride induced acidosis and aldosterone secretion in the goat.

Responses to 30-min intraduodenal infusion of NH4Cl (total amount 75 mmol) were studied in conscious goats. The infusion caused an immediate, transient rise in plasma aldosterone concentration (PA) from a mean of 78 to 221 pmo l-1. As expected, the NH4Cl administration also induced metabolic acidosis, initially subjected to partial respiratory compensation. The acidosis did not become fully developed until 1 h after cessation of the infusion, when PA had almost returned to its initial level. Renal compensation of the acidosis was shown by acidification of the urine and reduced Na excretion being most pronounced 1-2 h post-infusion. During the infusion blood haemoglobin concentration and the haematocrit increased by 25 and 13%, respectively, without simultaneous increase in plasma protein concentration and with persisting ear vasodilatation, indicating a mobilization of stored erythrocytes in the absence of a general increase in sympathetic tone. The results suggest that the reduction of blood pH is not the cause of the increase in PA occurring in association with NH4Cl-induced metabolic acidosis, but leave open the possibility that this increase may be due to some centrally mediated or direct adrenal influence of NH+4. As regards the apparent NH4Cl-induced mobilization of stored erythrocytes, it is suggested that such a response may play a role in the defence against acidosis by increasing the buffering capacity of the circulating blood.

Indomethacin blunts the orthostatic increase in plasma aldosterone in glomerulonephritis.

To determine factors mediating the aldosterone secretory response to orthostasis, we examined the effect of angiotensin-converting enzyme inhibition (CEI) on orthostasis in eight normal subjects and 10 normotensive patients with primary glomerulonephritis ingesting a normal sodium intake. On standing with CEI, the mean plasma aldosterone concentration (PAC) did not change [68.6 +/- 3.9 (+/- SE) and 63.4 +/- 6.9 pg/ml] in normal subjects, while PAC rose significantly from 72.3 +/- 7.5 to 129.5 +/- 13.2 pg/ml (P less than 0.001) in the glomerulonephritis patients without a concurrent rise in plasma angiotensin II, serum potassium, plasma ACTH, or mean blood pressure. There was a good correlation (r = -0.7064; P less than 0.03) between the changes in PAC and the changes in fractional sodium excretion in the patients. Pretreatment with indomethacin blunted the rise in PAC from 159.0 +/- 21.5 to 63.3 +/- 10.2 pg/ml upon standing with CEI, without a concurrent change in circulating 6-keto prostaglandin F1 alpha (from 57.7 +/- 9.5 to 56.0 +/- 11.1 pg/ml) in 4 patients. These results suggest that the aldosterone secretory response to orthostasis in patients with glomerulonephritis is dependent on factors blunted by pretreatment with indomethacin in addition to angiotensin II.

Factors controlling aldosterone secretion during hypoxemia in fetal lambs.

Factors modulating the fetal aldosterone response to hypoxemia were studied in three groups of chronically catheterized fetal lambs between 131 and 143 days of gestation (term, 145 days). One group (control group) received an infusion of 5% dextrose in water; the second group (captopril-treated group) was given captopril, an inhibitor of angiotensin-converting enzyme; the third group (captopril plus dexamethasone-treated group) received dexamethasone in addition to captopril. In all groups of fetuses, hypoxemia was associated with a significant increase in plasma K+ concentration (+0.7 +/- 0.1 meq/liter). In control fetuses, changes in plasma aldosterone concentration during hypoxemia correlated closely with changes in plasma K+ concentration r = 0.79; P less than 0.001) and with changes in plasma angiotensin II concentration (r = 0.77; P less than 0.001). In the captopril-treated fetuses, the rise in plasma aldosterone concentration during hypoxemia correlated closely with plasma K+ (r = 0.79; P less than 0.001) but not with plasma angiotensin II values (r = 0.17). No significant correlation was found between percent changes in maternal aldosterone and percent changes in fetal aldosterone during hypoxemia and following recovery (r = 0.36; P greater than 0.1) in captopril-treated fetuses. Administration of dexamethasone to fetuses receiving captopril completely inhibited the rise in plasma aldosterone associated with hypoxemia. Taken together, the present results suggest that the rise in plasma aldosterone during hypoxemia is not related to the level of activity of the renin-angiotensin system but depends probably on the increased secretion of adrenocorticotrophin by the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ACTH administration on urinary kallikrein excretion in man.

The effect of ACTH administration on urinary kallikrein excretion and its relationship to changes in plasma and urine electrolytes, renin concentration and steroids was examined in normotensive and mildly hypertensive subjects. ACTH administration produced hypokalaemia, initial urinary sodium retention, a fall in active plasma renin concentration, a transient rise in plasma aldosterone concentration and sustained rises in plasma deoxycorticosterone concentration and urinary kallikrein activity. Changes in patients with mild hypertension were similar in pattern to normotensives, but urinary kallikrein concentrations were lower. The effects of ACTH on urinary kallikrein excretion appeared to be independent of aldosterone and correlated most closely with deoxycorticosterone concentrations.

Effect of prolonged exercise at altitude on the renin-aldosterone system.

The combined effect of exercise and altitude on the renin-aldosterone system was studied in six male subjects on a fixed diet. After 4 control days at rest and at low altitude, subjects ascended to 3,100 m and took about 7 h exercise daily for 5 days. There followed a 4-day recovery period at low altitude. Daily blood samples were taken for estimation of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and angiotensin converting-enzyme (ACE) activity. Results showed a maximal rise in PRA and PAC with exercise at altitude maximal on the first 2 days. ACE activity fell by 23% at altitude. Compared with similar exercise at sea level, the rise in PAC was comparable but the rise in PRA was four times greater, indicating a marked decrease in PAC response to PRA. It is suggested that this loss of sensitivity of PAC to PRA is mediated by the measured reduction in ACE activity.

Differing Effects of Metoclopramide and Adrenocorticotropin on Plasma Aldosterone Levels in Glucocorticoid-Suppressible Hyperaldosteronism and Other Forms of Hyperaldosteronism*

To investigate possible dopaminergic effects on aldosterone production, we administered the dopamine antagonist metoclopramide to 11 normal subjects, 8 patients with primary aldosteronism due to adenoma or hyperplasia, and 5 other patients with the glucocorticoid-suppressible form of hyperaldosteronism (GSH). All subjects except for those with GSH responded to metoclopramide with an increase in plasma aldosterone concentration even when endogenous ACTH was suppressed by dexamethasone pretreatment. This increase occurred without apparent mediation of other recognized stimuli for aldosterone secretion. In contrast, the patients with GSH failed to show any aldosterone response while receiving dexamethasone, but demonstrated a rise in plasma aldosterone concentration when dexamethasone was withheld. The responses in the patients with both forms of primary aldosteronism were greater in magnitude than in the normal subjects or in the subjects with GSH when not receiving dexamethasone. These studies, while demonstrating differences between the subtypes of hyperaldosteronism in their responsiveness to metoclopramide, indicate that ACTH or some other factor may exert a permissive effect in GSH for the aldosterone response to metoclopramide. A graded infusion of ACTH revealed a greater aldosterone response in GSH compared to that in the other groups, further suggesting the importance of ACTH in this disorder.

Developmental aspects of the renal kallikrein-like activity in fetal and newborn lambs

The ontogeny of the renal kallikrein-like activity and the interrelationships between this enzyme and the renin-angiotensin-aldosterone and prostaglandin systems were studied in 43 chronically catheterized sheep fetuses between 104 and 142 days of gestation (term, 145 days) and in 8 chronically catheterized newborn lambs between 5 and 23 days of age. Urinary kallikrein (UKall) excretion rate expressed in absolute values (mEU/hr) or corrected for kidney weight (mEU X hr-1 X gKW-1) or glomerular filtration (mEU X hr-1 X ml GFR-1) increased significantly during fetal maturation and after birth. The rise in UKall during fetal and newborn life was not dependent on an increase in urinary flow rate (r = 0.06). The increase in fetal UKall (mEU X hr-1 X gKW-1) correlated closely with the rise in plasma aldosterone concentration for values above 35 pg/ml (r = 0.72, P less than 0.001). A significant negative correlation was found between UKall (mEU X hr-1 X gKW-1) and log of individual urinary sodium excretion values (r = -0.78, P less than 0.001). No correlation was found between UKall and urinary prostaglandins (PGE, PGF2 alpha) excretion during fetal and newborn life, but UKall correlated closely with the rise in renal blood flow during maturation (r = 0.87, P less than 0.001). The present data suggest that aldosterone is an important regulator of UKall release early during development. It is also suggested that conceptional age is an important factor which may modulate the renal sensitivity to aldosterone-stimulated UKall excretion.

Pathogenesis of salt retention in dogs with chronic bile-duct ligation.

1. The present study investigates the role of mineralocorticoids in the pathogenesis of salt retention and ascites in dogs with chronic ligation of the common bile duct (CBDL). 2. After CBDL the natriuretic response to an intravenous sodium load [0.9% sodium chloride solution (150 mmol/l): saline; 10% of body weight] was markedly depressed. Urinary sodium excretion was 285 +/- 62 vs 960 +/- 58 mumol/min in the control period before CBDL (P less than 0.001). This antinatriuresis was associated with a significant rise in plasma aldosterone concentration, from 52.5 +/- 5.5 pg/ml before CBDL to 177 +/- 50 pg/ml after CBDL (P less than 0.02). Ascites was present in all salt-retaining CBDL dogs. 3. Bilateral adrenalectomy resulted in disappearance of ascites and in a rise in the natriuretic response to extracellular volume expansion. Urinary sodium excretion was 770 +/- 124 mumol/min, a value significantly higher than in the CBDL dogs with intact adrenals (P less than 0.001). Sodium balance studies in the adrenalectomized CBDL dogs during chronic deoxycorticosterone acetate (DOCA) treatment (25 mg/day) showed that in these animals there was failure to escape from the mineralocorticoid-induced sodium retention. Glomerular filtration rate and renal plasma flow did not change during the studies. 4. The present evidence supports the thesis that sodium retention in the CBDL dog results from a dual mechanism: (a) excess of circulating aldosterone and (b) and extra-adrenal factor which prevents escape from the salt-retaining effect of mineralocorticoids, in the CBDL dogs, thereby perpetuating the antinatriuresis in these animals.

Simplified screening procedures for primary aldosteronism. Studies on the mechanism of the hyper-responsiveness to furosemide and standing.

Screening tests for primary aldosteronism were compared in 22 patients with this disorder and 140 hypertensive controls. Adequate (93-100%) sensitivity and specificity were not provided by single tests ((1) serum K, (2) furosemide-stimulated PRA, or (3) plasma aldosterone concentration (PAC) after furosemide, or (4) after 2 liters 0.9% NaCl)), but were provided by combinations: (2) + (1) or (3); (2) + (1) or (4); and by a pressor response to saralasin + (3) or (4). Mechanism of the observed excessive rise in PAC "stimulated" by furosemide and standing for 2 h was studied in the same patients. The rise in "stimulated" PAC was (a) associated with a low PRA and not reproducible by angiotensin II infusions; (b) associated with a slight but significant rise in plasma cortisol and was reproducible by ACTH infusions. It is, therefore, attributed to the effects of slight ACTH release acting on adrenal tissue with super-sensitivity of aldosterone response to ACTH.

Effect of ethinyl estradiol on renin activity and on the concentrations of renin substrate and aldosterone in plasma of ovariectomized women.

The effect of high doses of ethinyl estradiol (0.4 mg/day) on renin substrate concentration, renin activity and aldosterone concentration in plasma was studied in eight ovariectomized women. Plasma renin substrate (angiotensinogen) increased already within 24--48 h, reaching a maximum on the third to fifth day after starting estrogen treatment. Thereafter, renin substrate concentration remained relatively constant in a range which was fourfold above the baseline levels. The increase of plasma renin activity was less pronounced and showed considerable between-patient variability; this increase was statistically significant only after 48 hours of estrogen intake. A rise in plasma aldosterone concentration was observed in two of four subjects examined. In one patient treated with 5 mg estradiol benzoate intramuscularly, plasma renin activity increased without any measurable change in renin substrate concentration. Only in one subject treated with ethinyl estradiol did plasma renin activity increase before plasma renin substrate concentration; the results presented do not preclude factors other than the stimulation of renin substrate synthesis in the liver from contributing to the activation of the renin-aldosterone axis during treatment with ethinyl estradiol.

The effect of sodium deprivation and of angiotensin II infusion on the peripheral plasma concentrations of 18-hydroxycorticosterone, aldosterone and other corticosteroids in man

The effect of angiotensin II infusion on plasma cortisol, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and aldosterone concentrations was compared in 6 normal subjects before and after different degrees of sodium depletion. Cortisol, 11-deoxycorticosterone and corticosterone levels were unaffected by sodium depletion or by angiotensin II infusion in either replete or deplete states. Plasma 18-hydroxycorticosterone and aldosterone concentrations rose in parallel when sodium replete subjects were infused with angiotensin II. Sodium depletion had a proportionately greater stimulating effect on plasma 18-hydroxycorticosterone than on aldosterone, particularly in the more severely depleted subjects. The rise in plasma aldosterone concentration following angiotensin II infusion was greater in sodium deplete than in sodium replete subjects and this difference increased with the severity of sodium depletion. Basal 18-hydroxycorticosterone concentrations were much higher in the sodium deplete state than when the subjects were replete with sodium, but the subsequent effect of angiotensin II infusion, although further increasing 18-hydroxycorticosterone levels, was less consistent. The effect of angiotensin II was not secondary to a rise in ACTH since, in a seventh subject pretreated with dexamethasone, the response was not abolished It is concluded that one effect of angiotensin II must occur at or before 18-hydroxylation in the biosynthetic pathway. The availability of a larger pool of aldosterone precursor as a result of sodium depletion may be an explanation of the phenomenon of sensitization of aldosterone production to angiotensin II infusion in this condition. The possibility of a second effect of angiotensin II on the conversion of 18-hydroxycorticosterone to aldosterone is also discussed.

The Adrenocortical Response to Angiotensin II Infusion in Anephric and Non‐Nephrectomized Patients on Regular Hemodialysis

In the present study 8 anephric and 4 non-nephrectomized patients were stimulated with angiotensin II (A-II). In 5 of the anephric patients, an increased plasma aldosterone concentration (PAC) in response to ACTH stimulation had previously been demonstrated. After A-II stimulation, all 8 anephric patients responded with a significant rise in PAC although the increase was less pronounced than in 4 non-nephrectomized patients. In both groups of patients the increase in PAC was correlated to the increase in diastolic and systolic BP and to the A-II dose. Furthermore, in the non-nephrectomized patients, the plasma renin activity showed a significant decline, which was inversely correlated to the increase in PAC. When all 12 patients, regardless of the difference in remaining renin-angiotensin system, were considered as one population, the variable basal levels of PAC correlated significantly to the increase in PAC during A-II and ACTH stimulation. It is concluded that the adrenals of anephric man respond to A-II with an increase in PAC and that the reason for a lower response appears to be the lack of the renin-angiotensin system.

The role of the renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal human subjects.

To examine the role of angiotensin II in the maintenance of blood pressure and the control of aldosterone secretion in man, eight normal subjects were studied on a tilt table in sodium replete and sodium depleted states prior to and subsequent to the intravenous infusion of an angiotensin converting enzyme inhibitor (CEI). In both the sodium replete or sodium depleted state, upright tilting resulted in an increase in heart rate and a narrowing of pulse pressure. None of the sodium replete or depleted subjects fainted. Tilting was accompanied by a rise in plasma renin activity with an associated rise in plasma aldosterone concentration. When converting enzyme inhibitor was administered, which blocked the generation of angiotensin II, sodium replete subjects were able to compensate for an upright tilt, despite the absence of angiotensin II, without significant hemodynamic change when compared to control state. In sodium depleted subjects, after the administration of converting enzyme inhibitor, there was a sharp and significant decrease in systolic and diastolic blood pressure associated with a significant rise in heart rate. All but one sodium depleted subject fainted within seven minutes. Both plasma aldosterone concentration and plasma renin activity rose on tilting in both sodium replete and sodium depleted subjects. After the administration of converting enzyme inhibitor, plasma aldosterone failed to rise in association with a rise in plasma renin activity. In supine subjects, after the administration of converting enzyme inhibitor, plasma renin activity rose but plasma aldosterone concentration fell. In sodium depleted subjects, after the administration of CEI, aldosterone fell to a level significantly lower than that in supine controls and to a level no different from the supine sodium replete subject. These results indicate that angiotensin II is essential for blood pressure maintenance in sodium depleted individuals, that angiotensin II exerts a direct feedback control on renin secretion, and that angiotensin II is the primary stimulus to aldosterone secretion in response to both sodium depletion and to posture.