Aldosterone Secretory Response Research Articles

Role of calcium fluxes in the sustained phase of angiotensin II-mediated aldosterone secretion from adrenal glomerulosa cells.

When angiotensin II stimulates aldosterone secretion, it causes a rapid but transient mobilization of calcium from an intracellular pool and a sustained increase in the influx of calcium in adrenal glomerulosa cells. The present studies were undertaken to determine the respective roles of the two angiotensin II-induced changes in cellular calcium metabolism in modulating events during the sustained phase of cellular response which is thought to be mediated by the C-kinase branch of the calcium messenger system. The sustained response to angiotensin II is only 50% of maximal in cells pretreated with dantrolene in a concentration sufficient to inhibit the angiotensin II-induced mobilization of intracellular calcium. Also, if A23187 is added to cells simultaneously with 1-oleoyl-2-acetylglycerol (OAG), the aldosterone secretory response is similar to that seen after angiotensin II. However, if A23187 is added first and the transient aldosterone secretory response allowed to decay, and OAG then added, the sustained aldosterone secretory response is only 45-50% of maximal. Addition of the calcium channel agonist, BAY K 8644, with OAG leads to an aldosterone secretory response which is only 50% of maximal, but if upon addition of OAG and BAY K 8644 the cells are also exposed for 5 min to media containing 8 mM K+, then the sustained secretory response is maximal. These data imply that the initial transient rise in the [Ca2+] of the cell cytosol plays a role in determining the extent to which C-kinase is shifted from its calcium-insensitive to its calcium-sensitive form. The second group of experiments examined the relationship between the sustained angiotensin II-induced increase in plasma membrane calcium influx and the sustained aldosterone secretory response. The results show that in the presence of 1 microM nitrendipine or 2 mM extracellular K+, angiotensin II causes no increase in calcium influx and only a transient rather than a sustained increase in the rate of aldosterone secretion indicating that the sustained phase of the response is dependent upon a continued high rate of Ca2+ influx which regulates the rate of turnover of the activated C-kinase.

The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways.

Angiotensin II (AII) regulates the secretion of aldosterone from adrenal glomerulosa cells by a calcium-dependent mechanism which involves both the uptake of calcium from the extracellular pool, and the release of calcium from a dantrolene-sensitive intracellular pool. In the present study, it was shown that AII induces the rapid (10 s) hydrolysis of phosphatidylinositol 4-phosphate and -4,5-bisphosphate, leading to the sustained production of inositol bis- and trisphosphate (Ins-P3), and diacylglycerol rich in arachidonic acid. Saponin-permeabilized glomerulosa cells accumulate calcium into a nonmitochondrial pool by an ATP-dependent manner. Ins-P3 (0.5-5 microM) induces a release of Ca2+ from this pool. This release was blocked by dantrolene (10 microM). Adrenal glomerulosa cells were shown to contain the calcium-activated, phospholipid-dependent protein kinase (C-kinase). Perfusion of glomerulosa cells with combined 12-O-tetradecanoyl phorbol 13-acetate and A23187 induced an immediately developing, sustained, maximal secretory response similar to that induced by AII. These data are interpreted in terms of a model in which, after AII addition, there is a flow of information through two separate branches of the calcium messenger system, each with its unique temporal role: a calmodulin branch activated by the transient rise in the [Ca2+] in the cell cytosol, which is largely responsible for the initial transient cellular response; and a C-kinase branch activated by the increase in both cytosolic [Ca2+] and the diacylglycerol content of the plasma membrane, which is largely responsible for the sustained phase of the cellular response. The temporal integration of these two phases underlies the observed pattern of cellular response.

Potassium regulates angiotensin II-induced aldosterone biosynthesis in acutely nephrectomized rats.

The studies described herein were designed to determine whether serum potassium modulates the aldosterone secretory response to angiotensin II (Ang II) after nephrectomy. We used isolated adrenal glomerulosa cells harvested from rats maintained with either normal (5.2 meq/liter) or high (6.8 meq/liter) serum potassium for 48 h after bilateral nephrectomy for determining Ang II-aldosterone dose-response relationships. Kayexalate, which exchanges sodium for potassium in the gastrointestinal tract, was used to achieve the desired level of serum potassium. Both groups of cells were responsive to low concentrations of Ang II (10-100 pM). Cells from rats with lower serum potassium levels had lower basal and maximum Ang II-stimulated aldosterone and ED50 values. The importance of variables as contributors to differences between the groups were ranked from most to least important by two group discriminant function analysis and revealed: serum potassium greater than maximum Ang II-stimulated aldosterone greater than ED50 greater than basal aldosterone greater than serum sodium. Stepwise multivariate discriminant analysis demonstrated that all variables except the level of serum sodium contributed to the groups being significantly different at P less than 0.05. These studies demonstrate that adrenal glomerulosa cells obtained from nephrectomized rats maintain sensitive secretory responses to Ang II. Additionally, the level of serum potassium of rats before death directly regulates both the sensitivity and magnitude of the aldosterone secretory response to Ang II in vitro.

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.

The effect of captopril treatment on potassium-induced stimulation of aldosterone production in vitro.

Potassium and angiotensin (AII) show interdependence as stimuli of aldosterone production. However, potassium stimulates in vitro in the absence of AII. In the present study we examined for a contribution by AII to the in vitro stimulatory potential of potassium, an AII effect mediated on the adrenal before killing of the animal. Captopril, an angiotensin converting-enzyme inhibitor, was administered orally and by sc injection for 3 days so as to decrease levels of AII. Aldosterone secretory responses by adrenal capsules to graded increments in potassium were measured subsequently using a perifusion system. It was found that captopril pretreatment significantly reduced the magnitude of aldosterone secretory response to increments in potassium of 0.5 to 6.0 mM, from a baseline potassium concentration of 3.5 mM. Responses to the lowest increment in potassium, 0.5 and 1.0 mM, were virtually abolished by captopril treatment. The results suggest that AII sensitizes the adrenal glomerulosa such that very small changes in potassium concentration can affect aldosterone production.

Serum aldosterone following dexamethasone in depressed patients.

Serum aldosterone and cortisol responses to dexamethasone were studied in 17 patients with major depressive disorder, 16 nondepressed hospitalized patients and seven healthy controls. Serum aldosterone was neither blunted nor stimulated following dexamethasone in any of these three groups. Cortisol nonsuppression following dexamethasone, based on a criterion greater than 5 micrograms/dl, was noted in five depressed patients and two nondepressed patients. None of the seven patients with cortisol nonsuppression revealed any apparent abnormalities in their serum aldosterone secretory responses following dexamethasone. Thus, the incorporation of aldosterone measurements was not a useful extension of the dexamethasone test under the clinical conditions of this study.

Studies of impaired aldosterone response to spironolactone-induced renin and potassium elevations in adenomatous but not hyperplastic primary aldosteronism.

Spironolactone (SPL) corrects hypertension, hypokalemia, and hyporeninemia in patients with primary hyperaldosteronism (PHA) by blocking mineralocorticoid (MCH) receptors. We evaluated the effect of continuous SPL treatment (100 to 300 mg/day for 7 days to 9 years) on plasma renin (PRC), potassium, aldosterone (PA), 18-hydroxycorticosterone (18-OHB), deoxycorticosterone (DOC), and corticosterone (B) concentrations and 24-hour urinary excretion of aldosterone (UA) in 24 patients with PHA (15 with an aldosterone-producing adenoma [APA] and nine with idiopathic PHA [IHA]). Despite the normalization of PRC and K in both APA and IHA patients by SPL, UA and PA failed to increase in APA (55.8 +/- 8.8 to 51.4 +/- 7.3 micrograms/24 hr and 54.0 +/- 9.4 to 44.6 +/- 6.2 ng/dl, respectively) in contrast to rises in IHA patients (22.3 +/- 2.5 to 69.3 +/- 10.3 micrograms/24 hr and 16.0 +/- 1.0 to 49.9 +/- 9.9 ng/dl). Similar corrections with amiloride (20-40 mg/day for 2 months) in one patient with APA produced a three- to fourfold increase in UA and PA. In addition, while on SPL the characteristic fall or no change in PA and 18-OHB during upright posture persisted in all APA patients despite further increases in PRC (4.48 +/- 1.15 to 7.86 +/- 1.89) and K (4.0 +/- 0.1 to 4.3 +/- 0.1). The patterns of the aldosterone precursors, DOC, B, and 18-OHB, and their ratios to acute stimulation with cosyntropin were not altered by SPL. Thus, SPL treatment causes a sustained impairment of the aldosterone secretory response to normalized PRC and K, but not to ACTH stimulation, only in patients with APA.

Parallel adrenal and renal abnormalities in young patients with essential hypertension

To determine whether the previously described abnormalities in adrenal secretion and renal blood flow in essential hypertension are associated, we examined the responses to the relevant systems in 18 patients with essential hypertension. Young patients, under 30 years of age, were studied to minimize the likelihood that the phenomena were secondary to long-standing hypertension. To achieve a wide span of sodium balance, studies were performed during a high (200 mEq) sodium intake, a restricted (10 mEq) sodium intake and a restricted sodium intake supplemented by a further short-term diuretic-induced volume deficit (furosemide, 180 to 300 mg, to reduce body weight by 1 to 1.5 kg). The indexes measured included cardiac output (indocyanine green indicator dilution), plasma volume ( 125I albumin space), renal blood flow (radioxenon transit), plasma renin activity and aldosterone levels and aldosterone secretory rate. All of these variables, with the exception of Mood pressure and total peripheral resistance, were within the normal range during the two diets. However, the aldosterone secretory response to diureticinduced volume depletion on a low-sodium diet was clearly blunted in nine subjects. These nine subjects (abnormal responders) had a virtually absent aldosterone increment (23 ± 34 μg per 24 hours) compared with the normal responders (502 ± 70 μg per 24 hours). In addition, renal blood flow was significantly higher in these same nine subjects during both a high sodium intake (434 ± 19 versus 342 ± 26 ml/100 g per minute) and a restricted sodium intake (446 ± 11 versus 285 ± 39 ml/100 g per minute). Yet, there were no significant differences between these two groups in sodium or potassium balance, blood pressure, plasma volume, cardiac index or plasma renin activity during a high or low sodium intake. Normally, control of both aldosterone release by the adrenal and renal perfusion is dominated by angiotensin; an apparently blunted response of both systems suggests that there may be a generalized abnormality in the way angiotensin interacts with its target tissues in many young patients with essential hypertension.

Relative roles of sodium and calcium ions in the steroidogenic response of isolated rate adrenal glomerulosa cells.

To study the relative roles of sodium (Na+) and calcium ions (Ca2+) in the response of adrenal glomerulosa cells, we investigated the effects of different Na+ concentrations in the incubation media and the actions of substances that interfere with Ca2+ fluxes. Basal aldosterone secretion and response to angiotensin II (AII), adrenocorticotropic hormone (ACTH), or potassium (K+) were dependent on extracellular Na+ concentration. Veratridine, a Na+ channel opener that dissipates Na+ gradients, blocked the stimulated steroidogenic response. Mersalyl acid and tetracaine, which are potent Ca2+ antagonists, blocked the effects of aldosterone secretagogues. Divalent cations with Ca2+ antagonistic action such as manganese M(n2+), nickel (Ni2+), and cobalt (Co2+) blocked the aldosterone secretory response to AII, ACTH, and K+. Barium (Ba2+) and strontium (Sr2+), known to mimick Ca2+ effects, increased or did not affect responses of the glomerulosa cells. Sodium vanadate, an inhibitor of ATP-dependent Ca2+ translocation, did not alter the stimulated aldosterone responses. Trifluoperazine (10(-6) M), an inhibitor of calmodulin, blocked AII and K+-induced aldosterone secretion, but was partially effective on ACTH-stimulated aldosterone output only at a concentration of 10(-5) M. The actions of ouabain on aldosterone biosynthesis were similarly affected by all these drugs. Thus, both extracellular Na+ and Ca2+ appear to play a role in the steroidogenic response of isolated glomerulosa cells. The intracellular action of Ca2+ may involve a calmodulin-like protein. The effects of ACTH are only partially dependent on Ca2+ as a second intracellular messenger.

Adrenal secretion of aldosterone in response to anaphylactic shock in hypophysectomized-nephrectomized dogs.

The adrenal secretion of aldosterone in response to anaphylactic shock was examined in intact and hypophysectomized-nephrectomized dogs which had been sensitized by horse serum injections (s.c. and i.v.) 24-30 days before the experiment. On the day of the experiment, dogs were injected intravenously with horse serum under pentobarbital anesthesia. During anaphylactic shock induced by horse serum, the adrenal secretion of aldosterone in intact and hypophysectomized-nephrectomized dogs increased from 1.32 +/- 0.55 (mean +/- S.E.M.) to 8.43 +/- 1.99 ng/(kg.min) and from 0.23 +/- 0.10 to 2.38 +/- 0.63 ng/(kg.min), respectively. Plasma potassium concentration increased slightly and plasma sodium concentration did not change after the injection of horse serum in hypophysectomized-nephrectomized dogs. The results suggest the possibility that the adrenal secretion of aldosterone in response to anaphylactic shock in hypophysectomized-nephrectomized dogs is due mainly to a direct effect of histamine on the adrenal cortex or occurs via some unknown factors, and only in a small part to an increase in plasma potassium concentration. The adrenal secretion of corticosterone and cortisol during anaphylactic shock increased slightly but significantly in hypophysectomized-nephrectomized dogs, whereas it increased markedly in intact dogs.

Effects of high potassium diet on angiotensin II receptors and angiotensin-induced aldosterone production in rat adrenal glomerulosa cells.

Alterations in potassium (K+) balance modulate the sensitivity of the aldosterone secretory response to angiotensin II, but the mechanism of this change has not been elucidated. The present study was undertaken to evaluate the role of angiotensin II receptor alterations in this phenomenon. The effects of high K+ diet, on receptor binding of [l25I]angiotensin II and angiotensin-stimulated aldosterone production have been compared using isolated rat adrenal glomerulosa cells. A decrease in the equilibrium association constant occurred from the control value of 0.8 ± 0.2 to 0.4 ± 0.09 nM−1 (n = 8; P< 0.025). All values are the mean ± SEM. The change in equilibrium association constant was associated with a decrease in sensitivity of aldosterone responses to angiotensin II, as evidenced by increases in the angiotensin II concentration at half-maximum aldosterone production. The half-maximum aldosterone production was 1.0 ± 0.25 nM (n = 6) in control cells, 1.5 ± 0.03 nM (n = 3) at 3 days on a high potassium d...

The substitutive role of ACTH in supporting aldosterone response to head-up tilt during acute renin suppression in patients with essential hypertension.

The relative contribution of the renin-angiotensin system, adenocorticotrophic hormone (ACTH) and plasma electrolytes in the response of plasma aldosterone to 30 minutes of 65 degrees head-up tilt was assessed in 10 essential hypertensive patients. Studies were carried out before and during acute blockade of renin release by propranolol, ACTH suppression by dexamethasone and combined renin and ACTH blockade. In control studies orthostasis induced significant increases only in plasma renin activity and aldosterone. In contrast, when the renin response to tilt was acutely suppressed by propranolol administration, the aldosterone response was nonetheless maintained but now appeared to be under ACTH control, since concurrent increases in cortisol were observed. During ACTH suppression aldosterone increased during tilt and so did renin. However, during combined ACTH and renin blockade aldosterone failed to increase during tilt. These studies suggest that the aldosterone secretory response to head-up tilt is normally mediated by the renin-angiotensin system but, when the renin response is suppressed, an ACTH response is elicited which assumes a backup role. However, when these two systems are blocked other factors appear unable to respond during tilt to support a normal aldosterone response.

A new approach to the difficult assessment of aldosterone secretion in anephric patients

A new method for the assessment of endogenous formation of aldosterone in anephric patients is described. (1, 2- 3H) aldosterone was administered i.v. to patients 1–2 days before hemodialysis, and then the specific activity (SA) of tetrahydroaldosterone glucosiduronate, the major aldosterone metabolite, was measured in the dialysate using a specific radioimmunoassay. The aldosterone secretion rate was determined from the extent of isotope dilution by endogenous metabolite. Aldosterone secretion rates measured in 10 patients were for the most part low. The secretion rate determined in blood from the aldosterone metabolic clearance rate and plasma aldosterone concentration closely approximate secretion rate values obtained by the isotope dilution method in 3 of 4 patients. In 2 patients in whom ACTH was administered chronically, radio-labeled aldosterone was administered at the start of the study and then the day to day aldosterone secretory response to ACTH was determined from the SA of tetrahydroaldosterone in blood. Aldosterone secretion continuously increased for as long as ACTH was administered

Adrenal Responses to Pharmacological Interruption of the Renin-Angiotensin System in Sodium-Restricted Normal Man*

We assessed the role of the renin-angiotensin system in the control of aldosterone secretion in response to sodium restriction in 62 normal subjects. Both saralasin, an angiotensin II antagonist, and SQ 20881, a converting enzyme inhibitor, induced a dose-related decrease in plasma aldosterone levels when the renin-angiotensin system was activated by restriction of sodium intake. Two types of experiments were performed with saralasin. In the first set, a dose-response relationship was established 20 min after beginning infusions ranging from 0.03-1.0 microgram/kg/min. The optimal dose was 0.1 microgram/kg/min, with a reduction in aldosterone levels of -10.1 +/- 3.8 ng/dl (P less than 0.025). Higher doses induced smaller reductions in aldosterone levels. In the second set, a 3-h infusion was given. The results were qualitatively similar but the magnitude was greater (-15 +/- 4 ng/dl; P less than 0.01). The aldosterone response 20 min after administration of SQ 20881 paralleled the angiotensin II response, with the first significant decrement (-6.5 +/- 1.5 ng/dl; P less than 0.01) occurring at 0.1 mg/kg and maximum (-10 +/- 3 ng/dl) occurring at 0.3 mg/kg. Thus, both agents produced qualitatively similar changes in aldosterone secretion in sodium-restricted normal subjects. However, neither reduced sodium restricted aldosterone levels to that measured in sodium-loaded subjects because of the intrinsic limitation of each agent. Saralasin is a partial agonist. SQ 20881 induces an increase in plasma renin activity via interruption of the short feedback loop, which probably limits its action. Yet, these data do support the hypothesis that angiotensin mediates the adrenal's response to sodium restriction in normal man.

Role of Angiotensin II in the Aldosterone Secretory Response to Adrenocorticotropin in Sodium-Restricted Normal Human Subjects*

A study was performed to determine the possible role of angiotensin II (AII) in mediating the increased adrenal aldosterone response to infused alpha 1-24-ACTH, induced by sodium deprivation. Nine normal subjects, aged 18-31 yr. received 8-h infusions of 1) alpha 1-24-ACTH (0.5 U given over 8 h) while on a diet with unrestricted sodium content; 2) saralasin at 0.5 micrograms/kg/min or ACTH alone (0.5 U over 8 h) on the 7th day of a 10 meq sodium diet; and 3) ACTH and saralasin together on the 8th day while still on sodium restriction. AII was administered for the last 2 h of infusion 3. Plasma cortisol and aldosterone concentrations were measured at hourly intervals during the infusions and plasma renin activity was measured at 2 hourly intervals. ACTH infusion produced an increase in the plasma aldosterone concentration which was significantly greater during sodium restriction than when sodium intake was unlimited. This increase was not associated with an ACTH-induced rise in the plasma renin activity and was not significantly altered when ACTH was administered with saralasin. The rise in plasma cortisol concentration induced by ACTH was not significantly different when the normal subjects were on liberal and restricted sodium intakes. It is concluded that AII plays little if any acute role in increasing the stimulatory action of ACTH on aldosterone secretion during sodium restriction.

Adrenocortical function in rats with inherited hypothalamic diabetes insipidus (Brattleboro strain)

Abstract Steroidogenic function was studied in cells isolated from the zonae glomerulosa and fasciculata/reticularis of normal and sodium deficient Brattleboro rats. Compared with those of non-DI rats, z. glomerulosa cells of rats with diabetes insipidus (DI) produced more corticosterone and were less sensitive to in vitro stimulation by angiotensin II, potassium and ACTH while their aldosterone secretory response was more sensitive to dietary sodium changes. These differences of DI and non-DI z. glomerulosa function have been analyzed with regard to quantitative and qualitative changes in enzymes responsible for cholesterol cleavage and for the conversion of corticosterone to aldosterone. Z. fasciculata/reticularis cells from DI rats were less responsive to ACTH than those of non-DI cells.

Angiotensin II regulates its receptor sites in the adrenal glomerulosa zone

DURING sodium deficiency, adrenocortical sensitivity to angiotensin II is increased in several species1–3. Following acute sodium restriction in the rat, adrenal receptor sites for angiotensin II show increased concentration and binding affinity, and aldosterone responses to angiotensin II are increased both in vivo and in vitro4. Since circulating renin and angiotensin II levels are elevated during sodium deficiency2,3, these changes in the adrenal gland could be mediated by the trophic action of angiotensin II on the zona glomerulosa. Increased levels of catecholamines and trophic peptide hormones, such as luteinising hormone, have been shown to cause receptor loss and desensitisation of specific responses in their respective target cells5–7. It is possible, however, that physiological elevations of blood angiotensin II concentration could exert the opposite effect in the adrenal zona glomerulosa, leading to enhanced receptor function and contributing to the increased adrenal sensitivity during sodium restriction. To determine whether angiotensin II modulates its own receptors as well as the aldosterone secretory response, we examined angiotensin II receptors and aldosterone production in the zona glomerulosa of rats following elevation of circulating angiotensin II levels. These studies have provided evidence that angiotensin II can regulate its own receptor sites as well as steroidogenic responsiveness in the adrenal glomerulosa cell.

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.

Primary aldosteronism: A study in contrasts

Two patients with primary aldosteronism, one with a solitary adrenal adenoma and the other with bilateral nodular hyperplasia, are described. Both patients showed the classic features of primary aldosteronism in electrolyte and hormone patterns, but there were important differences in the biochemistry of their excised adrenal tissue. In addition, the injection of plasma from the patient with bilateral adrenal hyperplasia into the sheep's transplanted adrenal gland elicited a definite aldosterone secretory response, but there was no aldosterone response to the Injection of plasma from the patient with a solitary adrenal adenoma. The findings support the hypothesis that an extra-adrenal stimulus may contribute to the pathogenesis of bilateral adrenal hyperplasia.

A proposed cybernetic system for sodium and potassium homeostasis: Coordination of aldosterone and intrarenal physical factors

Aldosterone, the most potent naturally occurring mineralocorticoid, plays a major role in regulation of the amounts of both sodium and potassium in the body. The hormone acts on the kidney tubules to increase both sodium reabsorption and the secretion of potassium ions. Because of these two simultaneous actions, there would appear to be a conflict of interest in constructing a homeostatic regulatory system for the simultaneous maintenance of the balance of the two cations, sodium and potassium, by this one hormone. Because of the two concurrent actions of aldosterone, one might expect that changes in its activity would inevitably accomplish defense in the balance of one ion at the expense of the other. One might expect, for example, that increases in aldosterone secretion in response to sodium depletion would, while defending, sodium balance, also produce potassium loss or, conversely, that after potassium ingestion the induced increase in aldosterone secretion would, in the course of promoting kaliuresis, cause unwanted sodium retention. Obviously, neither happens. In fact sodium balance remains stable in the face of wide changes in potassium intake and vice versa. This analysis is concerned then with the question of how the kidney adjusts to variations in both sodium and potassium intake to compensate for the two concurrent actions of aldosterone and to enable the appropriate excretion of both cations. In particular, the presentation considers how changes in sodium and potassium intake affect intrarenal physical factors and how, in turn, these intrarenal changes are coordinated with changes in aldosterone secretion to compose a balanced control system which works to stabilize the balance of one cation while reacting to wide fluctuations in intake of the other. First, the hormonal responses to changes in sodium and potassium intake will be characterized. Then, an analysis of the simultaneous and complementary changes in intrarenal physical factors will be presented.