Glucocorticoid suppression enhances the 18-hydroxycorticosterone and aldosterone response to metoclopramide in man

18-Hydroxycorticosterone (18-OHB) is a precursor of aldosterone and is the only corticosteroid, other than aldosterone, that is synthesized predominantly in the zona glomerulosa. Administration of the dopamine antagonist, metoclopramide results in parallel rises in plasma 18-OHB and aldosterone levels without affecting the plasma levels of other aldosterone precursors. However, 18-OHB is a product of the zona fasciculata as well as the glomerulosa. Thus, it is possible that metoclopramide may stimulate zona fasciculata secretion of 18-OHB. In order to more selectively examine dopaminergic regulation of zona glomerulosa secretion of 18-OHB we have examined the effect of glucocorticoid suppression of the fasciculata on the 18-OHB and aldosterone responses to metoclopramide, 10 mg iv in 6 normal volunteers. Dexamethasone, 2 mg every 6 hours for 5 days, suppressed basal levels of cortisol, corticosterone, 18-OHB and aldosterone. Dexamethasone treatment had no effect on basal levels of PRA or PRA responses to metoclopramide. The 18-OHB and aldosterone responses to metoclopramide were enhanced (p less than .05) by dexamethasone suppression. The results suggest that dopaminergic mechanisms selectively suppress glomerulosa production of 18-OHB. Endogenous ACTH may inhibit zona glomerulosa production of 18-OHB and aldosterone in response to the dopamine antagonist, metoclopramide.     

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.     

Evidence for direct inhibitory effects of dopamine on zona glomerulosa secretion of 18-hydroxycorticosterone in rhesus monkeys

This study was designed to more selectively investigate the dopaminergic regulation of 18-hydroxycorticosterone (18-OHB) and aldosterone production by the adrenal zona glomerulosa. Mature rhesus monkeys received either an infusion of dopamine (2 micrograms/kg/min) or 5% dextrose (0.2 ml/min) over a 60 min period (N=6). Dopamine had no effect on plasma levels of renin activity, cortisol, corticosterone, aldosterone or blood pressure. However, dopamine suppressed (p less than 0.05) plasma 18-OHB levels from a baseline of 31.6 +/- 3.5 ng/dl to 23.6 +/- 2.1 ng/dl at 60 min after onset of infusion. This observation is in agreement with some studies in humans but differs from others in which no depression in 18-OHB was observed following dopamine infusion. Dopamine infusion markedly (p less than 0.001) suppressed plasma PRL levels by 30 min after onset of infusion. Corticosteroid responses to metoclopramide (200 micrograms/kg) after dexamethasone 1 mg im every 6 h X 5 days or placebo treatment (vehicle im every 6 h X 5 days) was then evaluated. Dexamethasone significantly suppressed basal cortisol, corticosterone, 18-OHB and aldosterone. Although dexamethasone blunted the prolactin response, it did not inhibit the aldosterone response to metoclopramide. The 18-OHB response to metoclopramide was increased (p less than 0.01) following dexamethasone treatment. Following dexamethasone suppression, 18-OHB levels were still lowered (p less than 0.05) by dopamine infusion. These results suggest that dopamine selectively inhibits zona glomerulosa production of 18-OHB and aldosterone in rhesus monkeys.     

Plasma aldosterone response to metoclopramide is unmodified by hyperprolactinemia

It has been previously demonstrated that patients with hyperprolactinemia have impaired PRL response to dopaminergic blockade and increased TSH response. Since inhibitory dopaminergic modulation of aldosterone is well established, we have examined whether prolactinoma patients have an altered aldosterone response to dopaminergic blockade. To investigate this possibility we compared the plasma PRL, TSH and aldosterone responses to the dopamine (DA) antagonist metoclopramide (MCP; 10 mg i.v.) in 10 women with prolactinomas and 7 healthy female controls. Basal PRL levels in prolactinoma patients were elevated and showed a blunted rise following MCP. Although basal TSH levels were similar in the 2 groups of subjects, they significantly increased (p = 0.017) in prolactinoma patients while in contrast they did not significantly change in control subjects. Basal supine plasma aldosterone was similar in patients with prolactinomas (0.23 +/- 0.03 nmol/l) and in healthy subjects (0.25 +/- 0.04 nmol/l) and the increased aldosterone concentrations from 15 to 120 min following MCP were not significantly different in prolactinoma patients and in control subjects. It is concluded that in patients with prolactinomas, the alteration in the dopaminergic regulation is specifically related to the lactotroph.     

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.     

Effect of L-dopa and bilateral nephrectomy on the aldosterone response to metoclopramide

The dopaminergic antagonist, metoclopramide (MCP) causes an increase in plasma aldosterone (PA) by a processnot well delineated. To investigate the mechanism of action of metoclopramide (MCP), studies were performed in rats after pre-treatment with L-dihydroxy-phenylalanine (L-dopa) and after bilateral nephrectomy. Intra-arterial MCP (200 μg/kg) resulted in a significant elevation in PA and prolactin (PRL) at 5 min and plasma renin activity (PRA) at 10 min without altering serum potassium levels. Pre-administration of L-dopa (30 mg/kg) delayed and markedly blunted PA, PRL and PRA resonses to MCP. In 7 rats, studied 30 hours after bilateral nephrectomy, the PRA was measurable (2.5 ± 0.4 ng/ml h^?1) but displayed no response to MCP. In contrast, the PA and PRL responses to MCP were not significantly affected. L-dopa induced suppression of PRA and PA was prevented by pre-administration of MCP. These results suggest that dopaminergic modulation of PA secretion occurs independently of the renin-angiotensin system.     

Dopamine control of aldosterone secretion in end-stage renal failure

The role of the tonic inhibitory effect of dopamine on aldosterone secretion has been investigated in 10 patients with chronic renal failure (CRF) on hemodialysis, in 8 normotensive renal transplant recipients (Tx) with normal renal function and in 8 normotensive volunteers (NV). The following tests were performed: the response of plasma aldosterone (PA) to metoclopramide administration; the response of plasma prolactin (PRL) to TRH administration, and the changes induced by Lisuride (a dopaminergic agonist, on the values of PA and PRL). The basal values of PA and PRL were higher in CRF than in NV and Tx. The inverse was true for plasma renin activity (PRA) values. The response of PA and PRL to metoclopramide showed blunted increases in CRF when compared to NV, in the absence of changes of PRA, cortisol and potassium. After TRH administration, PRL increase in CRF was also inferior. Lisuride induced a decrease of both PA and PRL both in CRF and NV. In Tx, basal values of PA and PRL were similar to NV. Nevertheless, the response to metoclopramide and TRH were partially blunted when compared to that of NV. These results point to the existence of a deranged dopaminergic regulation of aldosterone secretion in end-stage renal failure patients. The alterations are partially corrected by a well-functioning kidney graft.     

Metoclopramide,a dopamine antagonist,stimulates aldosterone secretion in rhesus monkeys but not in dogs or rabbits

This study was designed to investigate the role of dopamine in the control of aldosterone secretion in three frequently used laboratory animals. Five New Zealand rabbits, five mongrel dogs and five rhesus monkeys received metoclopramide (MCP) (200 μg/kg iv) and blood samples were collected at 0,5,15,30 and 45 minutes after drug administration. MCP had no effect on plasma aldosterone concentrations at any sampling time in the rabbits or dogs. However, MCP produced a rapid and marked increase in plasma aldosterone from 6.5±0.6 ng/dl to 18.1±2.8 ng/dl at 5 min. and a maximum level of 40.5±4.4 ng/dl at 10 min. after drug administration in the monkeys. MCP had no significant effect on plasma cortisol or plasma renin activity levels in the three species. Prolactin rose in the monkeys from 8.6±1.2 ng/ml to a maximum of 123.5±8.5 ng/ml at 15 min. after MCP. Administration of MCP resulted in a rise in plasma 18-hydroxycorticosterone in the monkeys from 12.5±1.4 ng/dl to a maximum concentration of 50.0±5.1 ng/dl 15 min. after drug administration. Plasma corticosterone, 11-deoxycorticosterone, and 18-hydroxydeoxycorticosterone were not altered by MCP. Although unlikely, it is possible that ketamine may have accounted for some of the changes in plasma aldosterone and 18-hydroxycorticosterone observed after metoclopramide in the monkeys. The findings suggest that dopamine modulates aldosterone biosynthesis in the monkey probably by regulating glomerulosa 18-hydroxylase activity.     

Evidence for increased endogenous dopaminergic inhibition of aldosterone secretion in prolactinoma

Aldosterone responsiveness to consecutive i.v. injections of metoclopramide 1 mg, 2.5 mg and 10 mg was studied in 8 patients with prolactinoma and normally preserved adrenal function and in 14 healthy volunteers. In the patients, aldosterone response to metoclopramide 1 mg was blunted. After metoclopramide 10 mg, aldosterone rose to the same levels in patients and volunteers. In the patients, however, percentage rise of aldosterone was enhanced, since the appropriate base line concentration of aldosterone was decreased. Thus, there is evidence for increased endogenous dopaminergic inhibition of aldosterone secretion in prolactinoma.     

Angiotensin II and aldosterone regulation

The circulating renin-angiotensin system is a major regulator of the secretion of the adrenocortical hormone, aldosterone. This renin-angiotensin aldosterone system is important in the control of salt and water balance and blood pressure. This review describes the historical background leading to the discovery of aldosterone in the 1950s and the recognition in the 1960s that angiotensin II was involved in its control. Although angiotensin II is important in the regulation of aldosterone secretion, its action is influenced by multiple other factors, especially potassium and atrial natriuretic peptide. In addition to the circulating renin-angiotensin system, a local renin-angiotensin system is present in the zona glomerulosa cell. This local system also appears to be involved in the regulation of aldosterone production. The mechanism by which angiotensin II stimulates the adrenal zona glomerulosa cell is described in some detail. Angiotensin II interacts with the angiotensin receptor (AT1) membrane receptor that is coupled to cellular second messengers. Specific AT1 receptor antagonists are now clinically used to block angiotensin II's action on various target organs, including the adrenal gland.     

Effect of metoclopramide on adrenal secretion in sheep: influence of dexamethasone and sodium intake

Metoclopramide, a competitive dopamine antagonist, stimulates aldosterone in man and monkey without affecting cortisol secretion. In sheep, metoclopramide also stimulates aldosterone but ist action on adrenocortical secretion is more controversial. To clarify the action of metoclopramide in conscious sheep, the response of plasma aldosterone, cortisol, angiotensin II and potassium were studied after 0.16 and 0.64 mg/kg metoclopramide, with and without pretreatment with dexamethasone. The effect of sodium status on the response was also studied by repeating the experiments after 7 days of dietary sodium restriction. In the absence of dexamethasone, plasma aldosterone was significantly increased by metoclopramide in both sodium-replete and restricted sheep. In sodium-replete sheep, plasma cortisol was also increased by 0.64 mg/kg, and by both doses when salt-restricted. However all cortisol responses were completely suppressed by dexamethasone pretreatment. Dexamethasone also suppressed the aldosterone response to metoclopramide in sodium-replete but not in sodium-restricted sheep where significant responses of aldosterone to both doses of metoclopramide still occurred without changes in plasma angiotensin II or potassium. While a nonspecific stress effect of metoclopramide can contribute to the aldosterone response, these results show that the sheep's adrenal glomerulosa is capable of responding to metoclopramide without change in ACTH, angiotensin or potassium.     

Angiotensin and aldosterone

The object of this review is to describe the role of the renin–angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin–angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT₁ and AT₂ receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT₁ receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.     

Dopaminergic control of aldosterone: modulation of the response of rat adrenal zona glomerulosa cells to alpha-Msh by pretreatment with bromocriptine or metoclopramide

Bromocriptine treatment in rats (3 mg/kg per day, 7 days) significantly reduced alpha-msh and aldosterone plasma levels 2 hrs after the final treatment in animals on low, normal and high sodium diets. Alpha-MSH dose response curves for corticosterone and 18-hydroxydeoxycorticosterone (18-OH-DOC) in subsequently incubated glomerulosa cells gave stimulation at lower concentrations of alpha-MSH (10(-10) moles per litre) than in cells from untreated animals (10(-9) moles per 1). Curves for aldosterone (ald) and 18-hydroxycorticosterone (18-OH-B) were also affected in cells from animals on a low sodium diet. Fasciculata-reticularis cell responses to ACTH were unaffected. Metoclopramide (4 mg/kg per day, 7 days) elevated plasma alpha-MSH, although ald was unaffected, but inhibited the glomerulosa cell response to alpha-MSH in vitro. Acute dopaminergic responses in plasma ald may be mediated through alpha-MSH in rats, but chronically alpha-MSH may down- regulate glomerulosa cell alpha-MSH receptors. It is unlikely that alpha-MSH mediates the adrenocortical response to sodium depletion.     

Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects

We investigated the role of prolactin (PRL) on modurating the secretion of aldosterone in normal male subjects. Metoclopramide (5mg) which causes a significant rise of PRL was given by intravenous injection. The peak of PRL level at 30 min. after i.v. injection of metoclopramide (20.0 ± 1.6 ng/ml, mean ± S.E.) was significantly higher than the basal level (6.4 ± 2.1 ng/ml, P < 0.01), but plasma aldosterone, serum sodium, potassium and plasma renin activity did not change significantly throughout the period of the study. Cortisol levels, however, reduced significantly after 30 min. and remained significantly low, probably because of diurnal variation. Present results suggest that PRL might at least not play a physiological role on regulating the secretion of aldosterone in man.     

Calf adrenocortical fasciculata cells secrete aldosterone when placed in primary culture

Aldosterone production occurs in the outer area of the adrenal cortex, the zona glomerulosa. The glucocortocoids cortisol and corticosterone, depending upon the species, are synthesized in the inner cortex, the zona fasciculata. Calf zona glomerulosa cells rapidly lose the ability to synthesize aldosterone when placed in primary culture unless they are incubated in the presence of the antioxidants butylated hydroxyanisol and selenous acid, the radioprotectant DMSO, and the cytochrome P-450 inhibitor metyrapone. In the presence of these additives, calf zona fasciculata cells in primary culture synthesize aldosterone at rates which can approach those from cells isolated from the zona glomerulosa. Calf zona glomerulosa and fasciculata cells both responded well to ACTH and angiotensin II, but the zona fasciculata cells respond very poorly compared to glomerulosa cells to increased potassium in the media. Rat zona fasciculata cells in primary culture under similar conditions did not synthesize aldesterone, suggesting that the regulation of the expression of the enzymes responsible for the biosynthesis of aldosterone in the two species is different. Two distinct cytochrome P-450 cDNAs which hydroxylate deoxycorticosterone at the 11β position have been described in the rat, human and mouse. Both cytochrome P-450 cDNAs have been cloned and expressed in non-steroidogenic cells, but only one is expressed in the zona glomerulosa and only this glomerulosa cytochrome P450 can further hydroxylate deoxycorticosterone to generate aldosterone. Two bovine adrenal cDNAs have been described with 11β-hydroxylase activity and their expression products in transiently transfected COS cells can convert deoxycorticosterone into aldosterone. Both enzymes are expressed in all zones of the adrenal cortex. Zonal regulation of aldosterone synthesis in the bovine adrenal gland may be due to an 11β-hydroxylase with aldosterone synthesizing capacity which has not yet been isolated. Alternatively, a single enzyme might be responsible for the several hydroxylations in the pathway between deoxycorticosterone and aldosterone and zonal synthesis might be controlled by unknown factors regulating the expression of C-18 hydroxylation. The incubation of zona fasciculata with antioxidants and metyrapone results in atypical expression of this activity by an unclear mechanism.     

Lack of effect of metoclopramide on plasma aldosterone concentrations in young calves

In five 10-day-old Holstein X Friesian male calves, the intravenous injection of the dopamine blocker metoclopramide (1 mg/kg bwt) had no significant effect on plasma aldosterone concentration. Plasma sodium, potassium, cortisol, corticosterone concentrations and plasma renin activity measured in these animals during 120 min following metoclopramide injection were never significantly different from those simultaneously measured in 5 control calves.     

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.     

Effect of the endothelins on aldosterone secretion by rat zona glomerulosa cells in vitro.

Endothelins are thought to be involved in the local regulation of blood flow and tissue function. These experiments were carried out to investigate the possible role of endothelins in the control of aldosterone secretion by the rat adrenal. Suspensions of zona glomerulosa cells were prepared by collagenase digestion of capsular tissue, and incubated in the presence of increasing concentrations of endothelin. Aldosterone was measured by RIA. All three peptides caused a dose-dependent increase in the secretion rate of aldosterone by zona glomerulosa cells. The minimum concentration of peptide required to give a significant response was 10(-14) mol/l for endothelins 2 and 3 and 10(-13) mol/l for endothelin 1. At a concentration of 10(-7) mol/l endothelin 2 elicited a 20-fold increase over basal aldosterone secretion, while both endothelins 1 and 3 elicited a 30-fold increase (P less than 0.001 in all cases). These results show that the endothelins are potent stimulators of aldosterone secretion, and suggest that these peptides may have a role in the control of zona glomerulosa function.     

Effect of metoclopramide on angiotensins, aldosterone, and atrial peptide during hypoxia

The coupling of aldosterone with renin is altered during acute hypoxemia. We measured the various components of the renin-angiotensin system and the plasma levels of immunoreactive atrial natriuretic factor (iANF) during room air and hypoxic gas-mixture breathing before and after administration of metoclopramide, a competitive antagonist of dopamine. Seven resting volunteers were studied 1 wk apart under room air and hypoxic conditions (inspired O2 fraction 0.12). During hypoxemia, the release of aldosterone induced by metoclopramide was significantly smaller. This change was associated with a slight increase in iANF and with a decrease in plasma angiotensin II levels, without any change in immunoreactive blood angiotensin I concentrations. Plasma electrolytes and blood acid-base status did not show relevant changes, nor did blood pressure and heart rate. We conclude that the decreased aldosterone concentrations seen under hypoxemia are related to decreased angiotensin II levels. Other influences, such as elevated ANF, may also mediate this effect.     

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.