Aldosterone Metabolic Clearance Research Articles

Seasonal dynamics of adrenal mineralocorticoid function in rats

Seasonal peculiarities of adrenal mineralocorticoid function and some aspects of its regulation have been studied in experiments on male Wistar rats. It has been found that changes in aldosteronemia and aldosteronurea were maximum in spring and minimum in summer--autumn period. The highest indices of aldosterone metabolic clearance from plasma were observed in winter with the following progressing decrease and a small increase in autumn. The diagram of melatonin content in the epiphysis of experimental rats was the same. Hypokinesia attenuated aldosteronurea during all the investigation periods, preserving the character of aldosterone secretion year curve. PRA level changed irrespective of aldosterone levels in plasma and urea. It has been concluded that a certain stability of mineralocorticoid adrenal function seasonal rhythms has different regulating effects.

Reduced urinary aldosterone excretion rates with normal plasma concentrations of aldosterone in the very elderly

Although aldosterone production declines with age, so does the aldosterone metabolic clearance rate (MCR), and the net effect of age on the circulating level of aldosterone may be less than can be predicted from production rates alone. The effect of age on aldosterone production and plasma levels was studied in a group of elderly individuals at a very advanced age when susceptibility to the impacts of age might be particularly pronounced. Seventeen nursing home patients, ages 75–99 (mean age 86 years), had aldosterone production assessed from the urinary excretion rate of the acid hydrolyzable 18-glucuronide conjugate of aldosterone. Aldosterone excretion was low in the elderly when compared to a group of healthy, young to middle-aged subjects: 123 ± 19 (SEM) vs. 234 ± 18 ng/h (P< 0.001). However, plasma aldosterone concentrations in the elderly were well within a range observed in much younger and fully ambulatory subjects: 14.1 ± 1.3 in the elderly vs. 15.9 ± 1.8 ng/dL in the young. The plasma aldosterone concentration was apparently maintained at a normal level by a coincident decrease in both the metabolic clearance rate and the aldosterone production rate. In conclusion, an aldosterone deficiency state resulting from an age-correlated reduction in aldosterone production is probably uncommon in the elderly.

Augmented aldosterone and insulin responses to potassium infusion in dogs with renal failure

The present study examines acute potassium-induced insulin and aldosterone responses in renal failure, and the role of chronic dietary potassium intake in modifying these acute responses. Plasma aldosterone (PA) and insulin (IRI) responses to acute KCl infusion were examined in control and remnant kidney dogs on two potassium intakes. Dogs (N = 8) received the KCl infusions after 10 days of a 60, and then 10 days of a 200, mEq daily potassium intake during control and after surgical-induced renal failure (CRF). A one hour intravenous infusion of KCl (2 mEq KCl/kg/hr) in dextrose and water was performed with blood samples for PA, IRI, creatinine and electrolytes, and urine for electrolytes and creatinine at 20 minute intervals one hour preceding, during, and after the infusion. Preinfusion PA was higher (P less than 0.05) in controls and CRF dogs on 200 mEq potassium intake compared to 60 mEq potassium intake. The peak incremental responses of PA to KCl infusion were increased (P less than 0.01) in CRF compared to controls on 60 mEq (PA 36 +/- 4.2 vs. 26 +/- 3.0 ng/dl) and 200 mEq (delta PA 49 +/- 5.6 vs. 37 +/- 2.8 ng/dl) potassium intakes. Differences in incremental PA responses in CRF were not due to altered aldosterone metabolic clearance rates, changes in renin, or ACTH activity. Pre-infusion IRI was higher (P less than 0.05) in CRF than control dogs on both potassium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging and aldosterone

We measured urinary and plasma aldosterone in normal subjects, aged 20 to 59 years, during a period of unrestricted sodium intake and after sodium depletion, using furosemide or a 20 meq sodium diet. Before and after sodium depletion, the mean and the upper limit of the range of urinary aldosterone excretion were considerably lower in subjects over 50 years compared with subjects under 30 years. Aging had no effect on plasma aldosterone concentration when the subjects were on an unrestricted sodium diet and blood was sampled while they were recumbent. In contrast, when the subjects were upright, both before and after sodium depletion, the mean and the upper limit of the range of plasma aldosterone concentration were lower in the subjects over 50 years compared with those under 30 years. The metabolic clearance of aldosterone was the same in the younger and the older subjects. Of eight patients over 40 years of age with aldosterone-producing adenoma, four had normal aldosterone excretion rates when the normal range was not age adjusted, but with age adjustment, all of the patients had clearly elevated excretion rates. Similarly, six of seven patients over 40 years of age had normal upright plasma aldosterone concentrations if the normal range of plasma aldosterone concentration was not age adjusted. We conclude that aldosterone secretion declines with advancing age. The effect of age on aldosterone secretion is an important consideration when evaluating older hypertensive patients for primary aldosteronism.

Effect of metoclopramide on the secretion and metabolism of aldosterone in man.

We performed this study to determine whether metoclopramide increases the concentration of plasma aldosterone in normal man by increasing the secretion rate of aldosterone or by decreasing aldosterone metabolic clearance. On the first day that metoclopramide was administered orally to seven normal subjects, the secretion rate of aldosterone increased significantly (P less than 0.05) from the rate during the preceding placebo period. By the fourth day of treatment, the secretion rate had returned to control values and remained there during an ensuing placebo period. The excretion rate of aldosterone followed a similar pattern. The increase in aldosterone secretion was accompanied by a transient but significant decrease in urinary sodium excretion. Metoclopramide administered iv had no effect on the metabolic clearance of aldosterone. Metoclopramide stimulated aldosterone-producing adenomas and nodular hyperplastic adrenal tissue resected from patients with primary aldosteronism to produce aldosterone in vitro. We conclude that metoclopramide increases the concentration of aldosterone in plasma by stimulating the secretion of aldosterone rather than by decreasing aldosterone metabolic clearance, and that metoclopramide probably stimulates aldosterone secretion by acting directly on adrenal tissue.

The effect of sodium on aldosterone metabolic clearance

The effect of sodium intake on the aldosterone metabolic clearance rate (MCR) was examined in 5 normal subjects. Measurements were made under conditions where dietary sodium ranged from 10 to 1500 meq/day. There were no consistent changes in MCR over these extremes of sodium intake, and the plasma level of aldosterone correlated only with the aldosterone urinary excretion rate. In an additional group of 6 normal subjects, a single dose of 100 meq sodium administered orally had no effect on the aldosterone MCR. The findings indicate that aldosterone metabolism is unaffected by sodium intake.

Increased aldosterone metabolic clearance in hypertensive patients treated with minoxidil: an effect of greater hepatic perfusion.

Since minoxidil was previously shown to raise plasma renin activity (PRA) but not the plasma aldosterone concentration (PAC), the effect of minoxidil on the rate of aldosterone metabolic clearance was studied. After the addition of minoxidil to the antihypertensive regimen of 7 hypertensive patients, the aldosterone metabolic clearance rate increased from 1,110 +/- 91 to 1,570 +/- 180 liters/day (p less than 0.01), an overall increase of 41%. Hepatic blood flow, estimated from the clearance from plasma of indocyanine green, was increased in a group of minoxidil-treated patients compared to a comparable group not treated with minoxidil (p less than 0.01). Thus, although minoxidil induces an increase in PRA, PAC does not change, since aldosterone metabolic clearance increases. Minoxidil increased hepatic blood flow, and it was probably by this mechanism that the drug accelerated the rate of aldosterone clearance.

Aldosterone metabolism in pregnant ewes and fetal and newborn lambs.

Twenty primiparous Limousine ewes whose fetuses had been chronically catheterized in utero on day 120 of gestation were used. Plasma aldosterone levels were measured by radioimmunoassay during the last 15 days of gestation both in dams and fetuses, and during the first neonatal week in lambs. Aldosterone metabolic clearance rates in dams, fetuses and newborns were determined by continuous infusion of [1, 2, 6, 7-3H]-aldosterone. The highest plasma aldosterone levels were observed in dams on days 130 and 142 of gestation, and in fetuses on days 135 and 140. No correlation was observed between plasma aldosterone and electrolyte levels in the mother, fetus or newborn. Aldosterone metabolic clearance rate decreased between days 142 and 145 in dams and at birth in fetuses of both sexes. No aldosterone transfer could be demonstrated either from dam to fetus or vice-versa.

Minoxidil increases aldosterone metabolic clearance in hypertensive patients.

It has been shown that despite an effect of minoxidil to increase PRA, plasma levels of aldosterone do not change. We observed similar findings in seven hypertensive patients undergoing treatment with minoxidil; PRA activity increased markedly, whereas the plasma aldosterone concentration showed no consistent change. The aldosterone MCRs in these patients increased by 41% in response to minoxidil, from 1110 +/- 91 to 1570 +/- 180 (SEM) liters/day; this appeared to explain why plasma aldosterone levels did not increase in parallel with renin activity. Hepatic blood flow (estimated from the clearance of indocyanine green) in a group of patients receiving minoxidil was greater than that in an otherwise comparable group (P less than 0.02). This increase in hepatic perfusion may, at least in part, have accounted for the increase in aldosterone MCR.

The Metabolic Clearance of Aldosterone Decreases Similarly during Infusion of Angiotensin II in Patients with Essential Hypertension and in Normal Subjects*

To determine if the abnormally large increases in levels of plasma aldosterone which occur during infusion of angiotensin II in some patients with essential hypertension are due to abnormal decreases in the metabolic clearance of aldosterone, we measured clearances of aldosterone before and during infusion of angiotensin II in 12 patients with essential hypertension and in 10 normal subjects. The metabolic clearance of aldosterone in the patients and that in the normal subjects were the same before angiotensin II was infused and the clearances decreased similarly during infusion of angiotensin II. In agreement with our previous observations, the plasma aldosterone responses to angiotensin II were greater than normal in most of the patients with low renin essential hypertension. Thus, the brisk increases in levels of plasma aldosterone during infusion of angiotensin II in patients with essential hypertension reflect abnormally large increases in the secretion of aldosterone. These results add further support to the idea that adrenal sensitivity to angiotensin II is increased in some patients with essential hypertension.

Secretion and metabolism of cortisol and aldosterone during controlled hyperthermia.

1. The rates of secretion and metabolic clearance of cortisol and aldosterone in response to passive heating have been investigated in fifteen young men by the controlled hyperthermia technique combined with continuous I.V. infusion of [14C]cortisol and [3H]aldosterone. 2. During a 1 hr period of elevation of deep body temperature to 38.0 degrees C mean hepatic blood flow measured by indocyanine green clearance decreased by more than 25% compared with normothermic condition. 3. The pattern of response in hyperthermia involved decreasing plasma specific activities indicating increased adrenal secretion of both cortisol and aldosterone. 4. Aldosterone metabolic clearance rate usually decreased in hyperthermia when there was little change in the clearance rate of cortisol, but an increased aldosterone clearance rate was observed when there were significant increases in the clearance rate of cortisol. A contributing factor to elevation of plasma aldosterone concentration in the heat is the reduction in hepatic blood flow which reduces aldosterone metabolic clearance rate. 5. Suppression of the thermally induced rise in plasma cortisol concentration by dexamethasone was associated with a decrease in aldosterone clearance rate which may reflect increased availability of aldosterone-binding plasma protein. 6. Marked rises in plasma cortisol were always accompanied by simultaneous rises in aldosterone, but rises in aldosterone sometimes occurred in the absence of a rise in cortisol. We therefore suggest that ACTH stimulation plays an important, but not exclusive, role in the stimulation of aldosterone secretion during hyperthermia.

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

Increased adrenal sensitivity to angiotensin II in low-renin essential hypertension.

Studies were undertaken to determine if the dissociation of aldosterone and plasma renin activity in low-renin essential hypertension is due to altered adrenal responsiveness to angiotensin II. The responsiveness of the adrenal glands to angiotensin II was determined by infusing graded doses of angiotensin II into normal subjects and into patients with essential hypertension and measuring changes in levels of plasma aldosterone in response to the infusion. To minimize the influence of endogenous angiotensin II and ACTH, supplemental sodium and dexamethasone were given before the infusions. Levels of plasma aldosterone and plasma renin activity were determined in normal subjects and in the same patients after the combined stimuli of furosemide and upright posture, a maneuver used to increase the level of endogenous angiotensin II. To determine if the changes in levels of plasma aldosterone during infusion of angiotensin II were due to alteration of the metabolic clearance of aldosterone, the metabolic clearance of aldosterone was measured before and during the infusion of angiotensin II. After sodium loading, dexamethasone treatment, and supine posture, levels of plasma aldosterone of normal subjects and patients with essential hypertension were suppressed equally. In response to the infusion of angiotensin II, the levels of plasma aldosterone of patients with low-renin essential hypertension were significantly higher than those of normal subjects or of patients with normal-renin essential hypertension. After furosemide and upright posture, levels of plasma aldosterone of patients with low-renin essential hypertension were significantly higher than those of patients with normal-renin essential hypertension, despite a blunted response in plasma renin activity of the patients with low-renin essential hypertension. Decreases in metabolic clearance of aldosterone during infusion of angiotensin II were similar in patients with normal-renin essential hypertension and in patients with low-renin essential hypertension and accounted for only a small fraction of the marked increase in levels of plasma aldosterone of patients with low-renin essential hypertension. It is concluded that patients with low-renin essential hypertension have increased adrenal sensitivity to angiotensin II. This increased sensitivity may explain the dissociation of aldosterone and plasma renin activity in low-renin essential hypertension.

The Effect of ACTH and Cortisol on Aldosterone and Cortisol Clearance and Distribution in Plasma and Whole Blood

The mechanisms of increased aldosterone and cortisol metabolic clearance rates (MCR) following ACTH or cortisol administration were studied in 13 subjects undergoing cardiac catheterization and in 9 healthy controls. In control subjects, the MCR (plasma) of both steroids increased by 29% (aldosterone: from 936 +/- 57 to 1204 +/- 55 l/day/m2, cortisol: from 205 +/- 12 to 264 +/- 17 l/day/m2 +/- SE) after ACTH (12 units/h) for 1 to 4 h, and by 20 and 32%, respectively, after cortisol (12 mg/h) for 1 to 2 h. In contrast, aldosterone MCR (whole blood) did not change with ACTH or cortisol administration (from 1276 +/- 57 to 1330 +/- 59 l/day/m2), indicating that the plasma MCR increase results from a redistribution of aldosterone from plasma to red cells. Aldosterone splanchnic extraction was 92 +/- 1% (n = 12) with normal morning cortisol levels, and extraction was unchanged after ACTH administration. For cortisol, however, the splanchnic extraction increased from 8 +/- 0.8% to 17.8 +/- 5.0%, and the MCR (whole blood) likewise increased by 15 to 31% (from 295 +/- 23 to 357 +/- 30 l/day/m2), after ACTH or cortisol administration. In vivo and in vitro measurements (at 37 C) of tracer aldosterone concentration in plasma and in red cells showed an increase in distribution to red cells with increasing cortisol concentrations. The results suggest that a fraction of aldosterone is bound in plasma and displaced by cortisol into red cells. There is an increased aldosterone plasma MCR, but unaltered whole blood MCR, since the liver extracts aldosterone almost completely from both plasma and red cells. The increase in cortisol MCR (plasma) results from both an increased splanchnic extraction as plasma binding sites approach saturation and a redistribution into red cells.

Aldosterone metabolic clearance is normal in low-renin essential hypertension.

The possibility that an abnormality of aldosterone metabolism plays a role in the pathogenesis of low-renin essential hypertension was investigated. Normal subjects and patients with low-renin or normal-renin essential hypertension were evaluated while in balance, ingesting a diet providing 120 mEq sodium and 70 mEq potassium. Aldosterone metabolic clearances were determined by a constant infusion technique using tritium-labeled aldosterone. Aldosterone secretion rates and plasma aldosterone concentrations were measured by radioimmunoassay. Aldosterone metabolic clearance in normal subjects was 1422 +/- 69 (mean +/- SE) liters/24 hours. In patients with low-renin essential hypertension, aldosterone metabolic clearance was 1351 +/- 61 liters/24 hours, and in patients with normal-renin essential hypertension, it was 1412 +/- 66 liters/24 hours. These values were not significantly different from those of normal subjects. Although aldosterone secretion rates in both groups of hypertensive patients were within the normal range, patients with low-renin essential hypertension, under the conditions of this study, had significantly higher secretion rates than patients with normal-renin essential hypertension. We have concluded that the maintenance of plasma aldosterone in low-renin essential hypertension reflects sustained aldosterone secretion despite suppression of plasma renin activity, rather than reduced aldosterone metabolism. The maintenance of normal aldosterone secretion in low-renin essential hypertension appears to be inappropriate and is not explained by alterations of known regulatory mechanisms.

The Effect of Administered ACTH on Aldosterone Metabolism and Secretion

To determine better the overall regulation of aldosterone by ACTH, the effect of administered ACTH on the aldosterone metabolic clearance rate (MCR), the excretion rates of tetrahydroaldosterone (THAldo), and the acid-labile conjugate (ALC) of aldosterone were studied in healthy male volunteers on a sodium intake in excess of 200 mEq/day. In 7 subjects, the aldosterone MCR increased significantly on the third day of ACTH treatment, as did the excretion of THAldo, but there was a decrease in the excretion of the ALC. One subject receiving ACTH for 6 days showed a steady increase in the aldosterone MCR on days 3 and 6 of treatment. In 2 of 3 subjects receiving ACTH treatment for 3-4 days, plasma aldosterone levels and plasma renin activity showed little change, whereas in 1 subject, both plasma aldosterone and plasma renin activity became suppressed. During ACTH administration there was a sustained increase in the excretion of THAldo, a metabolite formed in the liver, (in contrast to a decreasing excretion of the ALC which is made principally in the kidneys) which suggests that the increased aldosterone metabolism in response to ACTH occurred in the liver. Measurements made of the excretion of THAldo show that the ACTH stimulatory effect on aldosterone secretion may not be as transient as previously reported.

Studies of Renin and Aldosterone in Cirrhotic Patients with Ascites

Plasma renin activity and aldosterone metabolism were investigated in patients with cirrhosis and refractory ascites. All patients initially showed marked elevations of plasma and renin activity and plasma aldosterone. Although metabolic clearance of aldosterone was reduced, increased secretion rate was the major factor leading to elevated plasma levels. The elevated plasma renin activity and plasma aldosterone were only minimally affected by posture, dietary sodium restriction, and diuretic administration, suggesting a near-maximal degree of secondary aldosteronism. In most patients plasma renin activity and plasma aldosterone returned to normal when spontaneous natriuresis appeared. However, in 2 patients during spontaneous diuresis and in all 3 given aminoglutethimide, sodium excretion was poorly correlated with plasma renin activity and plasma aldosterone, suggesting that other tubular and/or vascular factors are important in the intense sodium reabsorption found with cirrhosis and ascites.

Control of aldosterone secretion in hyperthyroidism.

The control of aldosterone secretion was investigated in 23 hyperthyroid patients. Compared to normal subjects, chronically sodium restricted hyperthyroid patients had blunted aldosterone secretion (645 ± 73 μg/day); low plasma aldosterone (47 ±4 ng/100 ml); increased estimated aldosterone metabolic clearance rate (2230 ± 284 L/day); and increased plasma renin activity (32.7 ± 3.5 ng/ml/3 hr). Renin and aldosterone responses during ACTH and saline loading were normal, and oral potassium loading normalized aldosterone secretion and lowered renin activity. Propranolol significantly lowered renin activity but not aldosterone secretion. The elevated plasma renin activity was probably secondary to increased sympathetic stimulation and potassium depletion. It is likely that potassium depletion also contributed to the blunted aldosterone secretion during sodium deprivation.

A decreased metabolic clearance rate of aldosterone in benign essential hypertension.

Aldosterone secretion rate, metabolic clearance rate, and/or plasma concentration were determined in 16 patients with benign, uncomplicated essential hypertension and compared with those of control subjects. The mean metabolic clearance rate of aldosterone in 10 patients was significantly (P < 0.001) lower (mean 867 liters of plasma/day per m(2) +/-270 SD) than in a group of 7 healthy subjects (mean 1480 liters/day per m(2) +/-265 SD). Secretion rates in 13 patients (including the 10 already mentioned) tended to be low (83 +/-43 vs. 109 +/-54 mug/day) and plasma concentrations tended to be high (13.6 +/-4.6 vs. 7.5 +/-4.8 ng/100 ml), but neither of these differences was statistically significant. The lower metabolic clearance rate could account for elevated plasma concentrations of aldosterone even when the secretion rate is normal or low. Measurement of secretion rate or urinary excretion only is therefore insufficient to establish the presence and/or mode of evolution of hyperaldosteronism. Failure of the aldosterone secretion to adapt fully to a decreased aldosterone metabolic clearance rate (MCR) could explain the state of relative hyperaldosteronism in patients with benign essential hypertension, even when the secretion rate and the urinary excretion rate are in the normal range.

The effect of heparin on sodium conservation and on the plasma concentration, the metabolic clearance and the secretion and excretion rates of aldosterone in normal subjects.

ABSTRACT The effects of heparin administration on various aspects of the response to Na restriction have been investigated in a group of carefully studied healthy subjects. Administration of heparin following the attainment of Na balance during Na restriction resulted in a decline in the plasma aldosterone concentration and in the aldosterone excretion and secretion rates; natriuresis and an increase in salivary Na/K ratio also occurred. No change in the metabolic clearance of aldosterone was observed. Plasma renin activity was increased during heparin administration and no change in plasma renin substrate concentration occurred (one subject). Administration of heparin both before and during Na restriction almost completely inhibited the increase in aldosterone production but the decline in urinary Na excretion during the adjustment period was not greatly altered when compared to that occurring in the absence of heparin.