Aldosterone Secretion In Man Research Articles

L-Lysine Acts as a Serotonin Type 4 Receptor Antagonist to Counteract In Vitro and In Vivo the Stimulatory Effect of Serotonergic Agents on Aldosterone Secretion in Man.

In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.

Effect of Serotonin4 (5-HT4) Receptor Agonists on Aldosterone Secretion in Idiopathic Hyperaldosteronism

Serotonin (5-HT) stimulates aldosterone secretion in man through 5-HT4 receptors positively coupled to adenylyl cyclase. In particular, it has been shown that oral administration of a single dose of the 5-HT4 receptor agonist cisapride induces a significant increase in plasma aldosterone levels (PAL) in healthy volunteers. Idiopathic hyperaldosteronism (IH) is a rare disorder characterized by hypertension, hypokalemia and bilateral adrenal hypersecretion of aldosterone. In patients with IH, administration of the 5-HT precursor 5-hydroxytryptophan (5-HTP) is followed by a significant increase in PAL. 5-HTP-induced aldosterone secretion has been attributed to the activation of central serotonergic pathways. The aim of the present study was to evaluate the effect of the oral administration of a single dose of cisapride (10 mg) on aldosterone secretion in 15 patients with IH, in a simple blind fashion versus placebo. Cisapride induced a significant increase in PAL but did not affect renin, cortisol and potassium levels. The present study demonstrates that 5-HT4 receptor agonists are able to stimulate aldosterone secretion in patients with IH. These data also indicate that hyperplastic glomerulosa tissue, like normal glomerulosa cells, expresses a functional 5-HT4 receptor. Therefore, 5-HT4 receptor antagonists may represent a new approach in the treatment of primary hyperaldosteronism.

Effect of acid-base disturbances on aldosterone secretion in man.

The present study was carried out to elucidate whether changes in blood pH induced by administration of alkalinizing and acidifying agents influence aldosterone secretion in man. Since aldosterone secretion is known to be regulated by various factors such as the renin-angiotensin system, adrenocorticotropic hormone (ACTH), and serum potassium concentration, these indices were simultaneously measured during manipulation. Oral administration of tris hydroxymethyl aminomethane (THAM) resulted in a moderate but not significant decrease in serum aldosterone together with an increase in blood pH, whereas plasma renin activity (PRA) remained unchanged and serum potassium was elevated. ACTH and cortisol decreased significantly. Following CaCO3 ingestion, blood pH, serum potassium concentration, and hormones did not change significantly compared with before ingestion. NH4Cl ingestion showed a significant fall of blood pH and serum cortisol, on the other hand, aldosterone increased significantly compared with CaCO3 ingestion. Following NaHCO3 ingestion, serum aldosterone decreased with an increase in blood pH compared with before ingestion, while serum cortisol and PRA did not change significantly. The overall results of experiments using THAM, CaCO3, NaHCO3, and NH4Cl led to the conclusion that under acid-base disturbances a change in aldosterone can not be induced by either renin-angiotensin or ACTH. We suggest that under acid-base disturbances blood pH may be related, at least, in part to changes in aldosterone in humans.

Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man.

Atrial natriuretic peptide (ANP) has been shown to suppress aldosterone secretion under certain circumstances, although the physiological significance of this is uncertain. We wondered if ANP would suppress potassium-stimulated aldosterone secretion in man and, if so, whether we might find high circulating levels of ANP in patients with the syndrome of acquired hypoaldosteronism. We studied seven healthy young subjects under two conditions: 1) infusion of KCl (0.5 mmol/kg) over 45 min, and 2) KCl infused with ANP (0.01 microgram/kg.min) for 60 min. We also evaluated ANP levels in eight elderly subjects with the syndrome of acquired hypoaldosteronism, as defined by hyperkalemia (mean serum K+, 5.3 +/- 0.1 mmol/L) associated with inappropriately low aldosterone levels (216 +/- 50 pmol/L). In the normal subjects, ANP almost completely suppressed the aldosterone response to KCl infusion (P less than 0.001, by analysis of variance) despite a similar rise in the serum potassium level with KCl alone (0.70 +/- 0.07 mmol/L) and KCl plus ANP (0.75 +/- 0.09 mmol/L). PRA fell slightly during KCl plus ANP treatment, but did not change during the infusion of KCl alone. ANP levels were approximately 800 pmol/L during the ANP infusion studies. Endogenous ANP levels in the hyperkalemic patients with hypoaldosteronism were markedly elevated at 1186 +/- 340 pmol/L (compared to 93 +/- 10 pmol/L in healthy elderly controls), a level that would be capable of suppressing the potassium-mediated aldosterone response. Exogenous infusion of ANP suppressed the aldosterone response to hyperkalemia, and ANP levels were found to be markedly elevated in a group of patients with hyperkalemia and hypoaldosteronism. We suggest that ANP may contribute to clinically significant hypoaldosteronism and hyperkalemia in the syndrome of acquired hypoaldosteronism.

Effects of enhancement and antagonism of 5-hydroxytryptamine activity on metoclopramide-induced aldosterone secretion in man

This study examines the contribution of the serotonergic system to metoclopramide-induced aldosterone secretion. Six normal male volunteers, at 13 h, 9 h, and 2 h before the i.v. bolus of 10 mg metoclopramide, received the following pre-treatments in a single-blind cross-over randomized sequence: fluoxetine 20 mg, metergoline 6 mg, pizotifen 0.5 mg, or methysergide 2 mg. One regimen consisted of metoclopramide alone. Pizotifen and fluoxetine pre-treatment increased metoclopramide-induced aldosterone secretion significantly after 15 min, for the duration in the case of fluoxetine, and up to 90 min with pizotifen. The increase with metergoline was never significant, while methysergide had a negligible influence. Serotonin is postulated to play an intermediary role in acetylcholine-facilitated aldosterone release. The mechanism of fluoxetine-mediated serotonin increase is a re-uptake inhibition and that of pizotifen is suggested to be the elimination of an auto-inhibitory mechanism.

Atrial natriuretic factor inhibits metoclopramide stimulated aldosterone release in man.

1. Atrial natriuretic factor (ANF) has an inhibitory effect on angiotensin II and ACTH stimulated aldosterone secretion in man. The selectivity of this aldosterone suppressing effect of ANF is unclear in man. The present study investigated the effect of ANF on the increase in plasma aldosterone due to metoclopramide in man. 2. Eight normal male volunteers were studied on three occasions. Metoclopramide (10 mg slow i.v.) was given on all study days and each volunteer was randomised to receive 45 min infusion of either 5% D-glucose (placebo) or ANF (99-126) 3 or 15 pmol kg-1 min-1. 3. Metoclopramide increased plasma aldosterone to approximately 170% of baseline levels (P less than 0.01). Concomitant infusion of ANF 3 pmol kg-1 min-1 and 15 pmol kg-1 min-1 significantly attenuated this rise in plasma aldosterone to approximately 130% (P less than 0.05) and 110% (P less than 0.01) of baseline values respectively. 4. It is suggested, in the light of previous findings, that the inhibitory effect of ANF represents a non-selective action of ANF on aldosterone release.

Effect of Neostigmine on Metoclopramide-Induced Aldosterone Secretion in Man

This study examines the role of a neostigmine-induced increase in acetylcholine on the aldosterone stimulating effect of metoclopramide. Six normal male volunteers received the following three treatments in a cross-over randomized sequence: neostigmine, 0.5 mg s.c.; metoclopramide 10 mg i.v.; and neostigmine 0.5 mg s.c., followed by metoclopramide 10 mg i.v. Metoclopramide increased serum aldosterone significantly to 161% of basal level at 15 min. With neostigmine aldosterone levels peaked (129%) significantly at 30 min. In the presence of neostigmine, however, the metoclopramide-induced aldosterone response was blunted significantly. These results would suggest that presynaptic autoreceptors depresses the continued output of acetylcholine, thereby blunting the aldosterone responses to metoclopramide significantly.

Evidence for Cholinergic Modulation of Aldosterone Secretion in Man

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.

Effect of repeated doses of L-5-hydroxytryptophan and carbidopa on prolactin and aldosterone secretion in man

To evaluate changes in serum prolactin and plasma and urine aldosterone after a serotonergic challenge, 8 healthy men (19 to 42 yr), taking dexamethasone (0.75 mg qid), received the serotonin precursor L-5-hydroxytryptophan (L5HTP; 100 mg qid) with the peripheral decarboxylase inhibitor carbidopa (C; 50 mq qid) or matching placebos in a randomized, crossover manner. Serum prolactin concentration increased in all subjects after L5HTP/C in comparison to placebo, mean (SD) prolactin (ng/ml) at 8 h after dosing was 19.8 +/- 6.3 after L5HTP/C and 12.0 +/- 3.1 after placebo (p less than 0.05). In contrast, in comparison to values on placebo, L5HTP/C had no apparent effect on mean plasma concentration at all observation times; mean (SD) aldosterone (ng/dl) at 8 h after dosing was 12.0 +/- 5.1 and 12.0 +/- 3.8 after placebo (NS). Mean (SD) urinary aldosterone (micrograms/24 h), Na+(mEq/24 h) and K+(mEq/24 h) excretion were 7.0 +/- 4.4, 49.3 +/- 30.6, 30.1 +/- 11.2, after L5HTP/C and 7.4 +/- 5.8, 59.7 +/- 23.9, 33.3 +/- 7.4 after placebo (NS). Under these study conditions, subacute serotonergic stimulation with oral L5HTP/C resulted in prolactin but not aldosterone release.

Aldosterone response to metoclopramide is mediated through the autonomic nervous system in man.

This study primarily examines the role of the autonomic nervous system in the aldosterone response to metoclopramide since there is conflicting evidence as to the involvement of a dopaminergic mechanism in this response. Six normal male volunteers in metabolic balance at 100 mmol sodium/day and 60 mmol potassium/day constant intake received metoclopramide, 10 mg i.v., on five different occasions. The dosing was either metoclopramide alone or combined with ganglionic, muscarinic, beta-adrenergic or calcium-channel blockade. Metoclopramide increased serum aldosterone significantly to 163.3% of basal level at 10 min. Atropine blunted this response and the 10 min level was significantly reduced to 116.03% of the basal value. The highest aldosterone levels were attained when metoclopramide was administered during a trimethaphan infusion and a peak of 292.8% of basal level occurred at 90 min. In the presence of atenolol, with or without nifedipine, the metoclopramide-induced aldosterone response was significantly greater at 15 min than with metoclopramide alone. The results of this investigation suggest that the aldosterone response to metoclopramide is mediated by acetylcholine released from post-ganglionic cholinergic nerve terminals, and that an adrenergic mechanism exerts a tonic inhibitory influence on aldosterone secretion in man.

Effect of upright posture on the aldosterone responses to dopamine, metoclopramide, angiotensin II, and adrenocorticotropin.

Aldosterone secretion in man is stimulated by potassium (K), ACTH, and angiotensin II (AII) and inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA and is not inhibited further by DA administration. Sodium depletion alters plasma aldosterone responses to secretogogues. Upright posture, another physiological stimulus to aldosterone secretion, recently was demonstrated to sensitize the adrenal cortex to inhibition of aldosterone secretion by a large quantity of DA (4.0 micrograms/kg X min). The effect of upright posture on aldosterone responses to other secretogogues is unknown. In this study, we investigated the effect of upright posture on aldosterone responses to low infusion rates of DA, to the DA antagonist metoclopramide (M) and to AII and ACTH. Fourteen normal men eating a normal sodium diet were studied. In eight, PRA, plasma aldosterone (PAC), plasma cortisol (F), and serum K concentrations were determined after 4 h of upright posture and infusion of vehicle (D5W) or DA at 0.1, 0.4, and 2.0 micrograms/kg X min. Six other normal men were kept supine for 3 h and, on separate days, upright for 3 h and given iv M (10-mg bolus dose), AII (1 and 4 pmol/kg X min for 30 min), and ACTH (20 and 120 mU/h for 30 min). PAC, PRA, F, and K were measured before and after these three secretogogues were administered. In the presence of vehicle, mean PAC increased by 15.1 +/- 4.3 (+/- SEM) ng/dL after 4 h of upright posture. In the presence of DA infused at 0.1, 0.4, and 2.0 micrograms/kg X min, the PAC response to upright posture was decreased to 9.7 +/- 2.5 (P = NS), 7.5 +/- 3.9 (P less than 0.05), and 8.1 +/- 2.0 (P less than 0.05) ng/dL, respectively. This occurred without a decrease in PRA, F, or K. The stimulation of PAC 10 and 20 min after a 10-mg bolus dose of M was 9.6 +/- 3.3 and 9.3 +/- 2.6 ng/dL, respectively, in supine subjects and 8.3 +/- 2.3 and 10.8 +/- 3.4 ng/dL 10 and 20 min after the M dose in upright subjects. The responses of PAC to ACTH and AII also were unchanged after 3 h of upright posture. We conclude that upright posture sensitizes the adrenal cortex to inhibition of aldosterone secretion by DA without affecting other modifiers of aldosterone secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibitors of aldosterone secretion

Aldosterone secretion may be inhibited by potassium depletion, inhibitors of the reninangiotensin system, dopamine and atrial natriuretic factor. The latter appears to be an important physiological regulator of aldosterone secretion. ANF inhibits basal, ACTH, Angiotensin II and potassium-stimulated aldosterone production in vitro by a direct action on the adrenal gland. In vivo data also support a direct inhibitions of aldosterone. The stimulation of aldosterone secretion by infusions of Angiotensin II and potassium is inhibited by simultaneous infusions of ANF. Infusions of ANF lower the basal aldosterone secretion in man. The mechanism by which ANF inhibits aldosterone is not known. No unifying first step has been identified to explain ANF's ability to inhibit all stimuli. In vivo, part of the lowering of aldosterone levels may be due to inhibition of renin secretion. This effect of ANF upon renin is inconsistent and appears to depend upon the experimental conditions.

Evidence for dopaminergic binding sites in the human adrenal cortex

Dopamine may be a modulator of aldosterone secretion in man. Whether this effect is extraadrenal or is exerted directly at the adrenal gland via local dopaminergic receptors remains uncertain. This study examined the possibility that dopaminergic binding sites exist in the human adrenal cortex using [ 3H]spiperone, a butyrophenone with high affinity for dopaminergic receptors of the D 2 subtype. [ 3H]Spiperone binding to membranes prepared from the outer adrenal cortex obtained from eight patients undergoing adrenalectomy was studied. Specific [ 3H]spiperone binding, defined as binding displacable by 250-fold excess of unlabeled spiperone reached equilibrium within 30 minutes at 4 °C and was readily reversible. Binding was consistent with both high affinity (Kd 1 = 0.2 to 0.8 nmol/L) and low affinity (Kd 2 = 20 to 127 nmol/L) binding states. Binding capacity was 27 to 276 fmol/mg for the high affinity and 63 to 597 fmol/mg for the low affinity binding state. The relative potency in inhibition of [ 3H]spiperone binding was as follows: antagonists, spiperone > domperidone > metoclopramide > ketanserin > (−) sulpiride > (+) sulpiride; agonists, dopamine, bromocriptine > NPA ⋙ epinephrine. Serotonin and norepinephrine did not affect [ 3H]spiperone binding. These data suggest the existence of dopaminergic binding sites possibly of the D 2 subtype in the human adrenal cortex. The precise location of these sites remains to be determined.

Dopamine inhibits the aldosterone response to upright posture.

Aldosterone secretion in man is stimulated by potassium, ACTH, and angiotensin II and is inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA. Dopaminergic control of aldosterone secretion is modified by dietary sodium depletion. To determine the physiological significance of dopaminergic inhibition of aldosterone secretion, we studied the effect of DA on the aldosterone response to upright posture. Twelve normal men were studied while eating an ad libitum sodium diet, and the effect of DA was determined in the supine and upright positions. Plasma aldosterone (PAC), plasma cortisol (F), plasma aldosterone-stimulating factor (ASF), PRA, and blood pressure were measured while the men were supine and after 4 h of upright posture during an infusion of 5% dextrose vehicle and during a DA infusion of 4.0 micrograms/kg X min. The men also were studied as a time control in the supine position while receiving vehicle or DA. PAC increased from a mean basal value of 20.4 +/- 3.2 ng/dl (+/- SE) by 25.9 +/- 5.1 ng/dl to a peak of 44.4 +/- 2.4 ng/dl in response to upright posture during vehicle infusion. The PAC response to upright posture was reduced to 7.4 +/- 1.8 ng/dl (P less than 0.05) when DA was infused. The increase in PRA with upright posture was 3.7 +/- 1.3 ng/ml X h during the vehicle infusion and 4.1 +/- 1.1 ng/ml X h (P = NS) during the DA infusion. ASF, F, and blood pressure were not altered by upright posture and DA. PAC did not change in the six men infused with DA while supine. Therefore, DA inhibits upright aldosterone responses without affecting PRA, ASF, or F.

Central serotonergic stimulation of aldosterone secretion.

Serotonin stimulates aldosterone secretion both in vitro and in vivo, and serotonin antagonism decreases plasma aldosterone levels in patients with idiopathic aldosteronism. This study was designed to assess the effects of the serotonin precursor, 5-hydroxytryptophan (5HTP), upon aldosterone secretion in man, and to determine whether stimulatory effects of 5HTP are mediated through the central nervous system. Oral 5HTP, administered as a single 200-mg dose, increased plasma aldosterone levels from 4.7 +/- 0.6 to 13.3 +/- 2.8 ng/dl in dexamethasone-pretreated, normal volunteers. Peripheral inhibition of decarboxylation of 5HTP, achieved by pretreatment with carboxydopa, 25 mg three times daily for 3 d, significantly increased the stimulatory effects of 5HTP on aldosterone levels (P less than 0.001). No change in aldosterone levels occurred in subjects who received placebo after pretreatment with dexamethasone and carboxydopa. Increased aldosterone was not accompanied by increases in plasma levels of renin activity, potassium, or ACTH. Plasma levels of 5HTP were markedly increased by carboxydopa pretreatment, but peak plasma levels of serotonin were not significantly altered. Four patients with idiopathic aldosteronism all had an increase in plasma aldosterone levels after 5HTP administration, whereas the response in four patients with aldosterone-producing adenoma was variable. Incubation of isolated human and rat adrenal glomerulosa cells with serotonin resulted in increased aldosterone secretion by both sets of cells, whereas 5HTP was ineffective in stimulating aldosterone secretion in vitro. We conclude that central serotonergic pathways are involved in the stimulation of aldosterone induced by administration of 5HTP. This mechanism may be an important etiologic factor in the hypersecretion of aldosterone that occurs in patients with idiopathic aldosteronism.

Effect of human beta-endorphin on plasma aldosterone concentrations in normal human subjects.

beta-Endorphin recently was proposed as a possible physiological stimulus of aldosterone secretion based on studies in animals. Since human beta-endorphin (beta h-endorphin) does not contain the ACTH-(4-10) homology common to other ACTH-related neuropeptides that stimulate aldosterone, its mechanism of stimulation might differ from that of the other peptides. In the present study, we infused beta h-endorphin into six normal subjects under carefully controlled conditions at dosage levels several orders of magnitude higher than endogenous levels. No increase in plasma aldosterone was found in these subjects ingesting a normal sodium intake despite the fact that other biological actions of beta h-endorphin were manifest. By contrast, an equimolar infusion of ACTH-(1-24) caused a significant increase in plasma aldosterone. These studies do not support a significant role for beta h-endorphin in control of aldosterone secretion in man and are consistent with the concept that the ACTH-(4-10) amino acid sequence, common to ACTH, beta-lipotropin, gamma-lipotropin, beta MSH, and alpha MSH, is a major determinant of their aldosterone-stimulating capacity.

The Effects of Metoclopramide and Dopamine on Aldosterone Secretion in Cultured Adrenocortical Adenoma Cells and Adjacent Non-adenoma Cells from Patients with Primary Aldosteronism

Several authors have reported that metoclopramide (MCP), a dopaminergic antagonist, stimulates aldosterone secretion and that dopamine (DA) inhibits the MCP-mediated aldosterone secretion in man. However, many controversial results have been reported relating to the direct effect of MCP and DA on the secretion of aldosterone by adrenocortical cells in in vitro experiments. The present studies were designed to determine whether or not MCP and DA exerts its effect directly on the cultured human adrenocortical adenoma cells and adjacent non-adenoma cells obtained from patients with primary aldosteronism. A bolus intravenous injection of 10 mg MCP significantly increased the plasma aldosterone concentration (PAC) from 255 +/- 57 pg/ml (mean +/- SD) to 386 +/- 98 pg/ml after 15 min in patients with primary aldosteronism. But MCP (10(10)-10(-6) M) failed to increase aldosterone secretion from both adenoma cells and non-adenoma cells in culture. DA (10(-9) and 10(-6) M) did not suppress the basal secretion and the enhanced secretion of aldosterone by A II or ACTH in cells of either culture. The analysis by HPLC showed that 57% of dopamine hydrochloride added in the medium was preserved after 60 min incubation. These results suggest that MCP and DA do not act directly on the human adrenal glomerulosa cells in the regulation of aldosterone secretion.

Dopaminergic suppression of angiotensin II-induced aldosterone secretion in man: Differential responses during sodium loading and depletion

Previous studies have shown that aldosterone secretion may be inhibited by dopaminergic mechanisms in man. Dopamine does not inhibit aldosterone responses to angiotensin II in sodium-replete normal subjects. Since sodium deficiency is associated with a reduction in renal dopamine formation, we investigated the effect of dopamine on angiotensin II-induced aldosterone secretion in the sodium-depleted state. Six normal subjects in balance at 10 mEq sodium intake (UNaV 17 ± 2 meq 24 hr ) received dopamine 4 μg/kg/min or vehicle for 210 minutes on two consecutive days. After 60 minutes of the dopamine or vehicle infusion, the subjects received successive 30-minute infusions of angiotensin II in increasing doses of 0.5, 1, 2, 4 and 6 picomol/kg/min. Control plasma aldosterone concentrations before vehicle or dopamine were 15 ± 3 (mean 1 ± SE) and 25 ± 3 ng/dL, respectively. Aldosterone responses to angiotensin II were greater with vehicle than dopamine at angiotensin II doses of 4 and 6 picomol/kg/min ( P < 0.025). The slope of angiotensin-aldosterone dose-response curve was steeper with vehicle (0.33) than with dopamine (0.16), P < 0.01. Serum prolactin concentrations were lower with dopamine (1.6 ± 0.8 ng/mL) than with vehicle (6.4 ± 1.2 ng/mL, P < 0.05) by 120 minutes of infusion and remained suppressed with dopamine for the remainder of the dopamine infusion. Diastolic blood pressure was higher ( P < 0.05) with vehicle than with dopamine at angiotensin II doses of 2, 4, and 6 picomol/kg/min. Dopamine administration was associated with an increase in plasma cortisol concentration from 90 to 150 minutes of infusion ( P < 0.05). The same six subjects in balance at 300 mEq sodium intake (UNaV 287 ± 18 meq 24 hr ) had no difference in aldosterone response or slope of the angiotensin II-aldosterone dose-response curve with dopamine or vehicle. Serum prolactin concentrations were lower with dopamine (5.4 ± 1.2 ng/mL) than with vehicle (9.3 ± 1.4 ng/mL, P < 0.05) by 90 minutes of infusion and remained suppressed for the rest of the study. Cortisol levels were significantly higher with dopamine than with vehicle from 120 to 150 minutes of infusion ( P < 0.05). In conclusion, dopamine inhibits angiotensin II-stimulated aldosterone secretion during sodium deficiency in man.

The effect of dopaminergic antagonists on plasma aldosterone in normal subjects and patients with hypopituitarism

Although angiotensin II, ACTH and potassium are generally acknowledged as major factors in regulating the influences on aldosterone secretion, it has recently been reported that dopamine is a potent inhibitor of aldosterone secretion in man and animals. In the present study, we investigated the effect of two kinds of dopaminergic receptor antagonists, metoclopramide and sulpiride, on plasma aldosterone concentration (PAC) and serum prolactin (PRL) in man. Normotensive volunteers and patients with hypopituitarism were injected with metoclopramide (10 mg i.v.) or sulpiride (10 mg i.m.). In normal volunteers, metoclopramide increased both PAC and PRL levels, and showed a maximum level at 30 minutes after injection. In patients with hypopituitarism, PAC tended to increase without change of PRL, which suggested that the increase in PAC by metoclopramide might have a direct inhibitory effect on the dopaminergic receptor in the adrenal gland. Moreover another antagonist, sulpiride also increased PRL but contrary tended to decrease PAC. These results suggested that PRL responses to both inhibitors were mediated by dopaminergic antagonist activity at the level of pituitary receptors. However dopamine-induced modulation of aldosterone secretion may be different from that of PRL at dopaminergic receptors. These results suggested that modulatory inhibition of aldosterone secretion by dopamine may be affected by difference of affinity of dopamine to receptor as organ specificity, or different affinity of metoclopramide and sulpiride to adrenal dopamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopaminergic inhibition of aldosterone secretion in man is independent of the autonomic nervous system.

To determine whether the plasma aldosterone response to metoclopramide, a dopamine antagonist, is mediated by the autonomic nervous system in man, five healthy male volunteers were injected with metoclopramide during an infusion of either 5% dextrose in water or trimethaphan, a ganglionic blocker. Despite evidence of ganglionic blockade during the trimethaphan infusion, the aldosterone response to metoclopramide remained intact. This suggests that the aldosterone response to metoclopramide is not mediated by the autonomic nervous system in man as it appears to be in the sheep, and suggests species variation in the mechanism of this this mineralocorticoid response.