Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.     

Aldosterone and magnesium in essential arterial hypertension

Thirty mildly hypertensive patients and 27 patients with severe essential hypertension and high levels of aldosterone were selected for a study of the relationship between plasma aldosterone and magnesium in essential arterial hypertension; levels of calcium and potassium were also studied. Thirty-six individuals were used as a control group. Our findings indicate that as plasma aldosterone levels increase, serum magnesium levels decrease correspondingly: in mild hypertensives with low levels of plasma aldosterone p less than 0.05 and in the most severely hypertensive patients with high levels of plasma aldosterone p less than 0.001. In this latter group we also found an inverse correlation between serum magnesium and systolic arterial pressure (p less than 0.001) and diastolic pressure (p less than 0.01). In these patients a significant increase in urinary excretion of magnesium was found, with levels 3 times higher than in the control group. These findings suggest a close relationship between changes in plasma aldosterone and magnesium. Possibly the aldosterone contributes through this mechanism to maintaining the hypertensive state in essential arterial hypertension. This action is exercised directly through the kidney, leading to a small but constant urinary loss of magnesium. This in turn leads to a chronic depletion of magnesium in hypertensives who have high levels of plasma renin activity and highly elevated plasma aldosterone.     

Absent aldosterone response to metoclopramide in patients with high spinal cord transection: evidence that metoclopramide stimulates aldosterone secretion through central pathways

This study evaluates dopaminergic regulation of aldosterone secretion in 6 patients with high spinal cord transections. Administration of the dopamine antagonist metoclopramide resulted in a marked rise in plasma aldosterone and 18-hydroxycorticosterone levels in 12 normal individuals, but no change in plasma levels of these zona glomerulosa corticosteroid products in spinal cord patients. Spinal cord transected patients also did not have the rise in plasma renin activity that was observed in normals following metoclopramide administration. Basal levels of aldosterone, 18 hydroxycorticosterone, corticosterone and renin activity as well as the aldosterone responses to graded dose infusion of adrenocorticotropin were similar in the spinal cord patients and the normals. These data suggest that dopaminergic regulation of adrenal zona glomerulosa corticosteroid and renal renin secretion is absent in patients with high spinal cord transections, suggesting that intact neural pathways from the central nervous system are necessary for metoclopramide stimulation of aldosterone and renin secretion in men. Since basal plasma aldosterone levels were normal in spinal cord transected patients, it appears that the absence of dopaminergic control does not result in elevated secretion.     

Acute changes in plasma renin activity, plasma aldosterone concentration and plasma electrolyte concentrations following furosemide administration in patients with congestive heart failure--interrelationships and diuretic response

We studied the effects of furosemide on plasma renin and plasma aldosterone in 8 patients with mild to moderate congestive heart failure. In particular, we tried to correlate these effects with changes in plasma electrolyte concentrations and with the diuretic response on furosemide. We concluded that the diuretic response in patients with congestive heart failure is not dependent on the initial serum renin nor on the initial serum aldosterone concentration. The diuretic response did not correlate either with the changes in serum renin and/or serum aldosterone concentration. Serum renin and serum aldosterone correlated mutually before and after intravenous furosemide. We confirmed the inverse correlation between serum sodium and serum renin. SeNa and SeK correlated at all times with serum aldosterone; SeCl correlated with serum aldosterone only before intravenous furosemide administration. Indirect evidence could be provided that in patients with congestive heart failure a decreased renal blood flow is present, using the urinary beta 2-microglobulin concentration. Aldosterone has again, indirectly, proved to be integrated in the renal magnesium handling.     

Aldosterone responsiveness to an acute potassium load in diabetes mellitus and chronic renal insufficiency

The aldosterone response to increments in plasma potassium concentration in disease states associated with abnormal potassium tolerance remains undefined. We evaluated the plasma aldosterone response to an acute oral potassium load (0.25-0.50 mmol/kg body weight) in 30 patients (19 with chronic renal failure (CRF) and 11 with diabetes mellitus) with normal or decreased baseline plasma aldosterone levels and in 12 control subjects. In control subjects, plasma aldosterone levels increased initially and then declined below baseline, whereas in the patients the late decrease was not observed. In patients with CRF with and without hypoaldosteronism (5 undialyzed and all 9 dialyzed patients), plasma aldosterone increased significantly. Eight of the diabetic subjects had normal and 3 had low baseline aldosterone levels. In the former, plasma aldosterone levels did not increase above baseline following the KCI load. We conclude that diabetic patients and those with CRF manifest several abnormalities in aldosterone-potassium responsiveness that may contribute to the disturbed potassium homeostasis observed in these conditions.     

Regulation of aldosterone secretion in primary aldosteronism.

Plasma aldosterone, plasma renin activity and plasma cortisol were determined in patients with primary aldosteronism in response to posture and at short-time intervals overnight while the patient were supine. In the 5 patients with an aldosterone-producing adenoma postural changes in plasma aldosterone were paralleled by those in cortisol while plasma renin activity was generally undetectable indicating an ACTH-dependent secretion of aldosterone. This concept was supported by the observation that in 3 of these patients who were tested overnight 1. episodic secretion of plasma aldosterone was paralleled by those of cortisol and 2. episodic secretion of plasma aldosterone could be blunted by dexamethasone. In the patient with idiopathic adrenal hyperplasia concomittant changes in plasma aldosterone and plasma renin activity occurred. The assumption that in this patient the fluctuations in plasma aldosterone were mediated through changes in renal renin secretion was supported by the finding that episodic secretion of plasma aldosterone persisted under suppression of ACTH-secretion by dexamethasone. Our results indicate, that the described procedures may all serve as diagnostic criteria to differentiate between aldosterone-producing adenoma and idiopathic adrenal hyperplasia.     

The relationship of plasma aldosterone-binding globulin to blood pressure regulation in young adults with cystic fibrosis

Findings of increased secretion rate and decreased metabolic clearance rate (MCR) of aldosterone in patients with cystic fibrosis of the pancreas (CF) and our own evidence on the association of increased aldosterone-binding globulin (ABG)-binding and decreased MCR in essential hypertension (EH) inspired us to investigate the plasma aldosterone, with the inclusion of protein-binding variables, in CF patients. (1) The percentage of plasma aldosterone specifically bound to ABG was measured in 55 young adults with CF in addition to total plasma aldosterone, total plasma corticosteroids and for comparison of corticosteroid-binding globulin (CBG)-binding capacity. (2) The percentage of ABG-bound plasma aldosterone was found to vary with the seasonal change in temperature and the hepatic function of CF patients. Many of the CF patients, particularly during spring, summer and fall, had elevated plasma ABG-bound aldosterone which would be expected to result in low MCR. This binding was less elevated during cooler weather, suggesting that ABG-bound aldosterone is participating in the adaptation to warmer weather by probably increasing extrarenal sodium retention, thereby preventing a fall of blood pressure (BP) to pathologically low levels. A significant correlation was consequently found between the ABG capacity and the ambient temperature. (3) CF patients with low liver function had significantly lower protein binding of aldosterone and only slightly lower CGB capacity, presumably due to disturbed protein synthesis by the liver. (4) In some patients, elevated total plasma aldosterone and total corticosteroids were found, probably as a result of an adaptation to excessive sweat losses of sodium and the consequent contraction of intravascular volume. (5) Our findings also demonstrated a positive correlation between plasma ABG-bound aldosterone and both systolic and diastolic BP.     

Mechanism of the central effects of dopamine and metoclopramide on aldosterone regulation in the rat

To investigate the mechanism of the central action of dopamine and its antagonist, metoclopramide, on the regulation of aldosterone, studies were performed in 54 conscious rats with and without bilateral nephrectomy. In normal and sham-operated rats, intracerebroventricular injection of dopamine resulted in a significant suppression of plasma renin activity and plasma aldosterone at 30 min, and intracerebroventricular injection of metoclopramide resulted in a significant elevation of plasma renin activity and plasma aldosterone at 30 min without altering the plasma corticosterone and potassium levels. In bilaterally nephrectomized rats, the plasma renin activity was significantly reduced and it did not respond to dopamine or metoclopramide. In these rats, intracerebroventricular injection of metoclopramide exerted no effect on the plasma aldosterone, but intracerebroventricular injection of dopamine increased the plasma aldosterone slightly. However, this increase was not statistically significant. These findings suggest that the dopaminergic system in the brain is involved in the regulation of aldosterone secretion, mainly with changes in the peripheral renin-angiotensin axis in rats.     

ADRENAL FUNCTION IN WILD AND REHABILITATED PACIFIC HARBOR SEALS (PHOCA VITULINA RICHARDII) AND IN SEALS WITH PHOCINE HERPESVIRUS-ASSOCIATED ADRENAL NECROSIS

Adrenal function in harbor seals (Phoca vitulina richardii) was evaluated using adrenocorticotrophic hormone (ACTH) stimulation tests and fecal cortisol levels. The effect of ACTH administration on plasma cortisol and aldosterone levels in five free-living and 14 rehabilitated harbor seal pups was determined using enzyme immunoassay and radioimmunoassay, respectively. In free-living seals, injection of ACTH caused a significant increase in mean plasma cortisol but not of mean aldosterone levels 60 min postinjection. In these seals, mean initial plasma aldosterone was significantly higher than initial levels in rehabilitated seals, while initial cortisol levels were similar. Of the rehabilitated seals, eight died with adrenal cortical necrosis associated with herpesvirus inclusions, while six lived to be released. In the seals that were released, both mean initial cortisol levels and response to ACTH decreased through rehabilitation. In the seals that died, mean initial cortisol and response to ACTH increased through rehabilitation. The differences between initial cortisol levels in seals that lived and those that died were significant at weeks two and four of rehabilitation but not at the week of admission. There was considerable individual variation in initial plasma aldosterone levels and responses to ACTH, although initial aldosterone levels were significantly higher in rehabilitated seals that died than in seals that lived. Seals with adrenal necrosis associated with herpesvirus infection did not have decreased adrenal hormone responses to ACTH. Differences between initial hormone levels and responses to ACTH in different groups of seals may be associated with differing stress levels. Fecal cortisol assays were not a useful method of assessing adrenal function in these seals, as measured levels did not correlate with plasma cortisol levels.     

Response of adrenal steroids to angiotensin II in essential hypertension

The effect of angiotensin II (A II) on the plasma corticosteroid concentration and blood pressure was investigated in five normotensive subjects and 24 patients with essential hypertension (EH). Infusion of A II in normal subjects caused a significant increase in plasma aldosterone and significant decreases in plasma renin activity (PRA), plasma cortisol and dehydroepiandrosterone-sulfate (DHEA-S), while plasma levels of deoxycorticosterone (DOC) and ACTH remained unchanged. In patients with EH, A II infusion caused a significant decrease in PRA and a significant increase in plasma aldosterone. The percent increase in plasma aldosterone was greatest in patients with high PRA when compared to the low and normal PRA groups. The mean plasma levels of cortisol, DOC and DHEA-S after A II infusion were significantly increased in patients with high PRA but no significant changes were observed in patients with low or normal PRA. The mean blood pressure in patients with low PRA was sharply increased during the infusion when compared to the other two groups and did not return to the baseline level after cessation of the infusion. Hepatic blood flow as estimated by the disappearance rate constant of indocyanine green was significantly lower in patients with low PRA than in patients with high PRA. The above results suggest that different responses to A II infusion in steroid biosynthesis may exist between normal subjects and patients with EH. These observed phenomena may be due to biochemical (serum sodium) or functional (plasma A II level) differences in the A II receptor site or to the difference in the metabolic clearance of A II in patients with EH.     

Effect of nifedipine on effective renal plasma flow, plasma renin activity and serum aldosterone, noradrenaline and adrenaline levels in healthy persons and in patients with primary moderate arterial hypertension

Blood pressure, plasma renin activity, and serum aldosterone, adrenaline and noradrenaline were investigated in healthy individuals and patients with the primary moderate hypertension following a single oral dose of 10 mg nifedipine. It was found that the drug is hypotensive in both healthy individuals and hypertensive patients. It does not affect the effective plasma flow throughout the kidneys as well as serum aldosterone and adrenaline whereas serum noradrenaline and plasma renin activity are increased.     

Suppression of plasma aldosterone by chronic ACTH administration is offset by converting enzyme inhibitor

In order to elucidate the mechanism of suppression of plasma aldosterone by chronic ACTH administration, especially the role of the renin-angiotensin system and dopamine, we administered ACTH with or without MK422, a converting enzyme inhibitor, to reduce the endogenous angiotensin II in rats, and measured the plasma renin activity, plasma corticoid concentrations and urinary dopamine excretion. The plasma aldosterone concentration (PAC) was decreased after chronic ACTH administration. However, in the ACTH + MK422 administered group, aldosterone suppression was not observed. It appeared therefore that the aldosterone suppressing mechanism was independent of the weakened renin-angiotensin system following chronic ACTH administration, since PAC was not decreased in the ACTH + MK422 administered group when angiotensin II might be completely eliminated. The urinary excretion of dopamine was significantly increased in the chronic ACTH + MK422 administered group as well as in the chronic ACTH administered group. This suggested that the inhibitory effect of dopamine on aldosterone did not contribute significantly to the suppression of plasma aldosterone. The present results suggest therefore that the mechanism of suppression of plasma aldosterone following chronic ACTH administration was not dependent on the renin-angiotensin system and dopamine.     

The mechanism of aldosterone response to furosemide test in patients with Shy-Drager syndrome

We examined the renin-angiotensin-aldosterone system in seven patients with Shy-Drager syndrome by studying their response to the stimulation of 1 mg/kg furosemide injection followed by sitting for 1 hour. Six of the seven patients showed a low response of plasma renin activity to the stimulation. However, in five of the low responders, the plasma aldosterone levels after stimulation were observed to be similar to those of the control subjects; in addition, an increment in the plasma cortisol level appeared although no such increment was observed in normal subjects. Next, we studied the aldosterone response to angiotensin II. The five patients who showed a low plasma renin activity response and a normal aldosterone response to furosemide administration also showed low plasma aldosterone response to angiotensin II. Furthermore, in the patients who demonstrated a low plasma renin activity response and a normal aldosterone response to furosemide administration, the pretreatment with 2 mg dexamethasone for 2 days caused a marked inhibition of aldosterone response to the stimulation. These findings suggested that in most patients with Shy-Drager syndrome, the plasma aldosterone response to the stimulation of furosemide injection followed by sitting for 1 hour might be controlled by ACTH but not by plasma renin activity.     

A patient with a prolactinoma associated with an aldosterone producing adrenal adenoma: differences in dopaminergic regulation of PRL and aldosterone secretion.

A patient with a rare combination of prolactinoma and aldosterone producing adrenal adenoma (APA) was reported in relation to studies concerning dopaminergic regulation of PRL and aldosterone secretion. The patient is a 38-year-old female with plasma PRL and aldosterone concentrations (PAC) of 563 ng/ml and 54 ng/dl, respectively. A bolus of 10 mg of metoclopramide significantly increased plasma PRL in 6 normal subjects and in 4 patients with APA, whereas the responses were blunted in 7 patients with prolactinoma and in our patient. The response of aldosterone to metoclopramide was less than that of PRL, but similar in all studied subjects, indicating that the dopaminergic inhibition of aldosterone secretion is less than that of PRL in normal subjects and did not change in patients with APA or prolactinoma. Oral administration of 2.5 mg of bromocriptine suppressed plasma PRL significantly in all the subjects studied, but did not produce any consistent changes in PAC. Discrepancies in the response of PRL and aldosterone to metoclopramide and to bromocriptine suggest a difference in the dopaminergic regulation of PRL and aldosterone secretion in both normal subjects and patients with prolactinoma and APA. It is unlikely that reduced dopaminergic inhibition is the basis for hypersecretion of PRL and aldosterone in our patient.     

Plasma renin activity, aldosterone and cortisol secretions after acute hemorrhage and supine to vertical postural change in dogs

Acute hemorrhage and horizontal to vertical postural change are accompanied by decrease in blood volume of cardiovascular central reflexogenic areas (CRA) and by central hypoxia, followed by pressor responses. In these both circumstances important reflexogenic and humoral pressor reactions occured, as cathecolamine, renin and aldosterone hypersecretions. Aldosterone hypersecretion is considered as produced by angiotensin II, by a complex renin-angiotensin(RA)-aldosterone system. The main purpose of this work was to clarify the presence of this RA-aldosterone system after acute hemorrhage and in head-up postural change. In this aim we studied on dogs renin, aldosterone and cortisol responses. We analysed in these two circumstances the correlation of plasma renin activity(PRA) and aldosterone plasma concentration(p.c.) in intact and bilaterally nephrectomised(BN) dogs. We also studied correlations between aldosterone and cortisol p.c., having in view that both are stimulated by ACTH, searching in this way another modality for aldosterone secretion.     

Age dependence of the levels of plasma norepinephrine, aldosterone, renin activity and urinary vanillylmandelic acid in normal and essential hypertensives

In the present study the upper reference limits (URLs) for resting plasma norepinephrine, epinephrine, serum aldosterone, plasma renin activity, aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were established. There was a significant age effect on plasma norepinephrine, UVMA, serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60 yr), the average prevalence of elevation in the plasma norepinephrine, epinephrine and urinary vanillylmandelic acid above their corresponding URLs was 85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma catecholamine concentrations is more likely a common consequence than playing a possible role in the pathogenesis of hypertension, supported by insignificant correlation coefficients between the plasma catecholamine levels and resting systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age groups. Primary hyperaldosteronism was not detected among the normokalemic essential hypertensives at any age using aldosterone/plasma renin activity ratio as a primary screening method. In the present study, 7 statistically significant positive coefficient correlations are reported for SBP or DBP values with UVMA levels in hypertensive children and adolescents, serum aldosterone in old hypertensives, and PRA in adult hypertensives.     

Plasma atrial natriuretic peptide, plasma renin activity and aldosterone during treatment of hyperthyroidism due to Graves' disease

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and aldosterone were consecutively measured during methimazole treatment in patients with hyperthyroidism due to Graves' disease. ANP values of untreated hyperthyroid patients varied greatly from patient to patient, but decreased progressively with a decrease of serum thyroid hormone concentration during methimazole treatment. PRA was elevated in hyperthyroid patients but less aldosterone was secreted as evidenced by lower aldosterone/PRA ratio in these patients than in normal subjects and in hypertensive patients treated with thiazide. In addition, aldosterone/PRA ratio increased progressively with a decrease of ANP during methimazole treatment. The data indicated that ANP secretion was increased and ANP thus secreted depressed aldosterone secretion in hyperthyroid patients. Propranolol depressed pulse rate but failed to affect ANP secretion. It is suggested that thyroid hormone specifically acts on myocytes to stimulate ANP secretion but physiologic significance of such increased ANP secretion remains to be solved.     

Dopaminergic control of aldosterone secretion in hypertensive patients chronically treated with an angiotensin converting enzyme inhibitor

To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.     

Hypokalemia and sodium retention in patients with diabetes and chronic hepatitis receiving insulin and glycyrrhizin

Of 9 patients with chronic hepatitis treated with intravenous administration of 40 to 200 mg/day of glycyrrhizin, 3 diabetic patients receiving concomitant insulin developed hypokalemia, sodium retention and suppression of both plasma aldosterone concentration and plasma renin activity after the administration for 3 to 6 days. In the remaining 6 patients (5 nondiabetic and 1 diabetic) receiving no insulin, the administration over the long term (18 to 266 days) never caused these abnormalities. The development of hypokalemia and sodium retention in the patients was not associated with increased urinary excretion of potassium, indicating a different condition from pseudoaldosteronism caused by the desoxycorticosterone-like action of glycyrrhizin. These findings suggest that insulin which is known to have hypokalemic, antinatriuretic and antikaliuretic activity, as well as glycyrrhizin plays an important pathogenetic role in the observed electrolyte disturbance, and suppression of both renin and aldosterone.     

Polycystic ovary syndrome: Implications of measurement of plasma aldosterone, renin activity and progesterone

A positive correlation between aldosterone, inflammatory parameters, blood pressure and metabolic abnormalities in polycystic ovary syndrome (PCOS) has been reported in the early estrogenic phase. The aim of the study was to measure plasma aldosterone, plasma renin activity (PRA) and progesterone on the 21st day of the cycle, in women with PCOS and to consider the interrelationships between these hormones. Sixty-six consecutive normal BMI women with PCOS (median age 24 years, range 21-28 years) and 53 age- and body mass index-matched healthy controls were enrolled in the study. Aldosterone, aldosterone/PRA ratio (ARR) and Homeostasis Model Assessment (HOMA) index were significantly higher (p<0.0001) in PCOS women than controls. Positive correlations were found in PCOS but not in controls between (i) progesterone and aldosterone, (ii) aldosterone and PRA, (iii) PRA and progesterone. Mean blood pressures were within the normal range but significantly higher in PCOS than controls. The increase of plasma aldosterone, ARR and blood pressure in PCOS compared with controls is consistent with an increased mineralocorticoid effector mechanism in PCOS; prolonged therapy with spironolactone could counteract both the hyperandrogenism and reduce future cardiovascular risk.