Vasoactive intestinal peptide (VIP) stimulates aldosterone secretion by rat adrenal glands in vivo

VIP acutely enhanced the plasma concentration of aldosterone (but not that of corticosterone) both in normal rats, and in rats chronically treated with dexamethasone and ACTH or captopril and angiotensin II. VIP increased aldosterone blood concentration in chronically captopril-treated animals, but not in rats in which ACTH secretion was inhibited by dexamethasone. These findings suggest that VIP is specifically involved in the stimulation of the secretory activity of rat zona glomerulosa, and that this action of VIP requires a normal level of circulating ACTH.     

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.     

Further investigations on the atrial natriuretic factor (ANF)-induced inhibition of the growth and steroidogenic capacity of rat adrenal zona glomerulosa in vivo

A prolonged infusion with ANF (20 micrograms/kg/h for 7 days) induced atrophy of zona glomerulosa cells and lowering of basal plasma concentration of aldosterone in rats whose hypothalamo-hypophyseal-adrenal axis and renin-angiotensin system had been interrupted by the simultaneous administration of dexamethasone/captopril and maintenance doses of ACTH/angiotensin II. Chronic ANF treatment also caused comparable reductions in the aldosterone response of zona glomerulosa cells to the acute stimulation with angiotensin II, potassium and ACTH. These data are interpreted to indicate that ANF exerts an inhibitory effect on the growth and secretory activity of rat zona glomerulosa, and that the mechanism underlying this action of ANF does not involve blockade of renin release or ACTH secretion.     

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.     

Effect of bromocriptine on the control of plasma aldosterone diurnal variation in normal supine man.

In order to investigate the role of prolactin in the control of the circadian rhythm of plasma aldosterone (PA), plasma renin activity (PRA), cortisol (PC), aldosterone and prolactin (PRL) levels were determined in samples at 4-hour intervals from 5 normal supine men over a period of 24 h under basal conditions and subsequently over a period of 24 h during suppression of prolactin release by bromocriptine (CB-154). After suppression of prolactin, statistically signific1nt circadian rhythms in PC and PA have been detected with a moderate decrease of PA concentration, while the PC level remained unalterated. PRA rhythmicity persisted with a significant shift of acrophase and remarkable reduction of plasma levels. Moreover, during CB administration a significant correlation was obtained between PA and PC, while no correlation was detected between PA and PRA. These data are consistent with the following concepts: (a) the prolactin does not play a significant role in the regulation of circadian rhythm and concentration of plasma aldosterone in normal supine men, and (b) bromocriptine induces a remarkable reduction of PRA and a variable decrease in plasma aldosterone, but it does not influence the secretion of cortisol in normal subjects.     

Acute effects of alpha-MSH on the rat zona glomerulosa in vivo

alpha-MSH acutely enhanced the plasma concentration of aldosterone (but not that of corticosterone) in the rat, with a maximal response at a dose of 100 micrograms/kg. This dose of alpha-MSH increased the blood level o aldosterone and the activity of 11 beta-hydroxylase and 18-hydroxylase of capsular adrenals in rats infused for 24 h with dexamethasone, dexamethasone plus ACTH, or captopril plus angiotensin II, but not in animals treated with captopril alone. The plasma concentration of corticosterone and the activity of 11 beta-hydroxylase in the inner adrenal layers were not changed. These findings indicate that alpha-MSH is specifically involved in the acute stimulation of the late steps of the secretory activity of the rat zona glomerulosa, and that this action of alpha-MSH requires a normal level of circulating angiotensin II.     

Hormonal and renal responses to converting enzyme inhibition during maximal exercise

The role of angiotensin II in the hormonal and renal responses to maximal exercise was investigated by using the angiotensin-converting enzyme inhibitor captopril. Nine male subjects performed a standardized maximal treadmill test with and without acute captopril treatment (25 mg orally). At rest, captopril elevated plasma renin activity and lowered aldosterone levels. With maximal exercise, captopril treatment reduced the increase in mean arterial blood pressure by 8 mmHg and the increase in plasma renin activity by 3.0 ng ANG I.ml-1.h-1. The responses of adrenocorticotropin (ACTH), cortisol, and vasopressin to maximal exercise were not altered by captopril treatment. Although aldosterone levels were reduced at rest with captopril, during maximal exercise no difference was noted between treatments. Captopril treatment had no effects on the renal handling of salts or water during exercise. In conclusion, angiotensin II plays a role in the increase in mean blood pressure during maximal exercise in normal subjects but has no effect on the exercise responses of ACTH, vasopressin, and aldosterone or on the renal handling of salts and water.     

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.     

Effect of aldosterone on vascular angiotensin II receptors in the rat

The effect of aldosterone on the density and affinity of binding sites for 125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 micrograms/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for 125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng X kg-1 X min-1 for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng X kg-1 X min-1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiotensin II.     

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.     

Aldosterone regulation in anephric patients.

The response of plasma aldosterone to hemodialysis, 3 h orthostatism, K-loading and angiotensin II and ACTH infusions has been studied. Hemodialysis, orthostatism and angiotensin II infusion do not modify aldosterone levels. By the contrary ACTH and potassium originate a significant increase in plasma aldosterone. They seem to be the main aldosterone secretion regulators in the absence of renin production.     

Effect of prolonged ACTH stimulation on adrenal renin and aldosterone

Changes in adrenal renin, which have been regarded as mediator of aldosterone secretion in the adrenal gland, following prolonged ACTH treatment were investigated in male Wistar rats. After 2 days of daily sc injection of ACTH (Cortrosyn-Zinc, 50 micrograms/day), parallel increases in adrenal renin and aldosterone, and plasma aldosterone (PA) were induced. The plasma renin activity (PRA) was slightly but not significantly decreased. Prolonged treatment with ACTH for 8 days increased the adrenal renin, causing a marked reduction in the adrenal aldosterone concentration. The degree of decrease in the PRA was again not significant and similar to that after 2 days of ACTH treatment. Contrary to previout reports which have indicated participation of adrenal renin in the regulation of aldosterone secretion in the adrenal gland, the present results showed reciprocal changes in adrenal renin and aldosterone after prolonged treatment with ACTH. The present findings suggest a complicated relation between adrenal renin and aldosterone secretion in the adrenal gland.     

Mild adrenal 3 beta-hydroxysteroid dehydrogenase deficiency with hyperaldosteronism

The patient was admitted to our hospital at 19 and again at 22-yr of age for hirsutism and hypertension. Her baseline and ACTH-stimulated plasma 17-hydroxy pregnenolone, dehydroepiandrosterone and dehydroepiandrosterone sulfate were increased whereas plasma 17-hydroxy progesterone and androstenedione were normal and responded poorly to ACTH. Plasma deoxycorticosterone, corticosterone and cortisol baseline levels were normal, and they responded normally to ACTH. The plasma aldosterone concentration (PAC) was always high and responded well to ACTH, angiotensin III and furosemide-upright stimulation. However, plasma renin activity (PRA) was normal or slightly high, and responded normally to furosemide-upright stimulation and fluorohydrocortisone suppression. Dexamethasone (2 mg/day) for 1-2 weeks suppressed the androgens, cortisol and corticosterone levels. PRA and PAC were suppressed temporally, but PRA returned to normal and PAC to be a high level after 2 weeks of dexamethasone administration. Blood pressure was also reduced temporally but returned to a high level after 2 weeks of dexamethasone. These results indicate that primary aldosteronism and dexamethasone-suppressible hyperaldosteronism were not likely to be present, and unknown aldosterone stimulating factors which potentiated the action of endogenous angiotensin II or ACTH might be responsible for the hyperaldosteronism in this patient. We conclude that this patient had a mild and non-salt losing 3 beta-HSD deficiency in the zona reticularis with normal fasciculata and high glomerulosa function.     

Serotoninergic stimulation of aldosterone secretion in vivo: role of the hypothalamo-pituitary adrenal axis.

The control of aldosterone secretion in vivo by serotonin was studied in conscious rats. Serial blood samples were taken from indwelling arterial cannulae before and after i.p. administration of 1 ml (4 g/l) 5-hydroxytryptophan (5-HTP), the precursor of serotonin (5-HT), or saline, and analysed for 5-HTP, serotonin, 5-hydroxyindoleacetic acid, plasma renin activity (PRA), corticosterone, aldosterone, sodium and potassium concentration. The relative contribution of the hypothalamo-pituitary adrenal axis was investigated in animals pretreated with the synthetic glucocorticoid dexamethasone. 5-HTP caused a significant increase in all parameters within 45 min except for plasma sodium and potassium. Saline administration showed no significant effect. Dexamethasone pretreatment significantly impaired the corticosterone and aldosterone response to 5-HTP, although the aldosterone response was merely attenuated. No other parameter was affected by dexamethasone pretreatment. The results show that administration of 5-HTP, which increases serum serotonin levels, stimulates PRA, corticosterone and aldosterone secretion. Dexamethasone pretreatment inhibits the aldosterone response, though not completely, suggesting that the stimulatory action of 5-HTP involves the release of ACTH, which stimulates corticosterone and aldosterone secretion by the adrenal cortex. The failure of dexamethasone to block the aldosterone response completely, suggests the involvement of other mechanisms such as the renin-angiotensin system or a direct action of serotonin on the adrenal zona glomerulosa.     

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.     

Hormone and haemodynamic effects of angiotensin II infusion during captopril treatment for heart failure

Withdrawal of captopril therapy for cardiac failure results in increments in plasma cortisol, noradrenaline and heart rate. To determine whether these changes related to the concomitant rise in circulating angiotensin II, we infused angiotensin II at 0.5, 2, 4 and 8 ng/kg/minute, each infusion lasting for 1 hour, in 4 patients during maintenance captopril therapy for heart failure. A control solution of 5% dextrose was infused over a similar time interval on a separate day. The study was performed under metabolic balance conditions, with constant body posture and continuous haemodynamic monitoring. Angiotensin II induced the expected rise in arterial pressure and in plasma aldosterone. In contrast the diurnal decline in plasma ACTH and cortisol was not altered, and no changes in noradrenaline or heart rate were observed. Plasma angiotensin II appears to have little or no effect on ACTH, cortisol, noradrenaline and heart rate under the conditions of this study.     

The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.

The effect of metabolic acidosis on the renin-aldosterone system remains unclear. In the present study anesthetized mongrel dogs (n = 19) were infused at similar rates with 0.45% NaCl (controls), HCl or NH4Cl (2.5mEq/kg) for 1--3 h. The induced metabolic acidosis in the two experimental groups was not associated with increases in plasma renin activity. Plasma cortisol (as a marker for ACTH secretion) and serum potassium concentration increased in both HCl- and NH4Cl-treated animals. Plasma aldosterone increased after 30 min in the HCl group and 60 min in the NH4Cl group and did not change in controls. These findings demonstrate that metabolic acidosis induced by HCl or NH4Cl is associated with increased aldosterone production without concomitant changes in plasma renin activity.     

Plasma renin activity and urinary aldosterone in Cushing's syndrome.

The renin-angiotensin-aldosterone system has been evaluated in 19 patients with Cushing's syndrome due to bilateral adrenal hyperplasia and in 2 patients with unilateral adenoma. In the first group urinary aldosterone was within the normal limits with a mean of 8.3 +/- 1.86 microgram/24 h. Aldosterone excretion did not change significantly after furosemide administration, ACTH infusion or dexamethasone. Upright PRA was suppressed in 9/16 patients with a mean of 4.9 +/- 1.85 ng/ml/3 h and showed only a slight response to furosemide. Dexamethasone alone did not produce any change. Both aldosterone and PRA were to some extent stimulated by an association of dexamethasone and furosemide. In the 2 patients with adenoma, aldosterone excretion was also normal, but PRA was very elevated. From our data it is concluded that in Cushing's syndrome due to bilateral hyperplasia, PRA and aldosterone excretion are partially suppressed. From our results on plasma deoxycorticosterone and corticosterone concentration it seems unlikely that these mineralocorticoids are the major cause of this phenomenon. However, it may not be excluded that other yet unidentified hormones could play some role in the pathogenesis of hypertension and renin suppression in Cushing's syndrome.     

Normoreninemic hypoaldosteronism in a case of isolated ACTH deficiency

This paper documents the rare and hitherto unreported association between isolated ACTH deficiency and normoreninemic hypoaldosteronism in a 63-year-old woman. Baseline plasma aldosterone and 18-hydroxycorticosterone were extremely low. Both steroids did not respond to exogenous angiotensin II infusion, whereas they were increased in parallel to ACTH stimulation. Thus, acquired dysfunction or congenital dysgenesis of the zona glomerulosa was suspected. The upright posture-furosemide test showed a subnormal but definite plasma aldosterone response coupled with a normal increase in plasma renin activity, indicating that there may be a yet unidentified mechanism(s) underlying the postural increase of aldosterone.     

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.