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.     

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 ketanserin, an inhibitor of 5-HT2 receptors, on the aldosterone-stimulating action of metoclopramide

To estimate the possible involvement of a peripheral serotonergic pathway in the mechanism of the aldosterone-stimulating effect of metoclopramide (M) the plasma aldosterone (PA), renin activity (PRA) and prolactin (PRL) response to M was studied in 6 normal subjects before and after administration of ketanserin (K), a pure, specific, and selective blocking agent of 5-hydroxytryptamine type 2 (5-HT2) receptors. With K preadministration the M-induced increase of PRL was similar to that observed in control conditions, in accordance with the specific and peripheral antiserotonergic action of the drug. K potentiated the PA and PRA elevation in response to M. These data suggest that the PA response to M is not related to M's agonist activity at the peripheral 5-HT2 receptors level. The results further indicate that K can induce an enhancement of the activity of renin-angiotensin-aldosterone system with an higher PRA and PA response to stimulatory action of M.     

Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition

The effect of chronic converting enzyme inhibition with enalapril on the PRA, PRL and plasma aldosterone responses to metoclopramide was studied in 10 patients with mild to moderate essential hypertension. Enalapril reduced supine blood pressure and increased heart rate significantly. PRA and urinary sodium excretion rose significantly. PRA levels did not change after metoclopramide neither during placebo nor during enalapril. The aldosterone response to metoclopramide was not altered by enalapril, indicating that this response is independent of the renin-angiotensin system. The PRL response to metoclopramide was considerably enhanced after 4 weeks of treatment with enalapril. It is proposed that enalapril, by decreasing the formation of angiotensin II, increases the prolactin reserve.     

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.     

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.     

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.     

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.     

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.     

Responsiveness of plasma aldosterone to angiotensin II in patients with diabetes mellitus

Aldosterone responsiveness to angiotensin II (A II) was evaluated in 65 diabetic patients with and without various diabetic complications versus 38 age-matched non-diabetic subjects. Plasma aldosterone (PA), together with plasma renin activity (PRA), was low and responded poorly to furosemide (80 mg, orally) plus upright posture (4 hours) stimulation in diabetic patients. When the PA response to stimulation relative to PRA response was estimated from the ratio of PA increase to PRA increase after stimulation (delta PA/delta PRA), the 38 non-diabetic subjects had ratios more than 3.0. Of the 65 diabetic patients, 48 had normal delta PA/delta PRA ratios (more than 3.0) and 17 had low delta PA/delta PRA ratios (less than 2.9). Graded A II infusions (1, 2, and 4 ng/kg/min each for 30 min) were performed under a low sodium intake (sodium, 120 mEq/day) in 25 of the 65 diabetic patients, whose delta PA/delta PRA ratios were normal in 15 and low in 10, and in 16 non-diabetic subjects. The PA responses to the graded A II infusions in the normal delta PA/delta PRA diabetic patients were similar to those in the non-diabetic subjects. However, the PA responses to the graded A II infusions in the low delta PA/delta PRA diabetic patients were significantly lower. It is concluded that, although the majority of diabetic patients have normal aldosterone responsiveness to A II, some diabetic patients have blunted aldosterone responsiveness to A II probably attributable to the abnormality of the adrenal cortex in addition to the impaired renin secretion.     

Plasma renin activity and aldosterone concentration in children.

Using semi-micro methods, plasma renin activity (PRA) and plasma aldosterone concentration (PA) were measured concurrently in 79 healthy children aged 1 month to 15 years to establish a reference range. PRA and PA varied inversely with age. Eleven children with renal hypertension had higher PRA and PA than age-matched controls. In contrast, PRA was much greater in 38 saline-depleted children. PA was not uniformly increased in this group and was within the normal range in children with adrenal diseases compared with the high values seen in other salt-wasting states. The findings emphasise the need to relate data from patients to age-matched control values before attempting interpretation and suggest that sodium depletion is a more potent stimulator of renin-aldosterone release than renovascular disease or renal scarring in children. Plasma renin-aldosterone profiles were also valuable in discriminating between renal and adrenal causes of salt loss in childhood.     

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.     

Evidence of altered dopaminergic modulation of prolactin and thyrotropin secretion in patients with polycystic ovary syndrome

In order to evaluate the functional activity of the tubero-infundibular dopaminergic system in polycystic ovary syndrome (PCOS), we analysed the prolactin (PRL) and thyrotropin (TSH) responses to the dopamine antagonist sulpiride. We studied 8 euthyroid women affected by PCOS and 7 normal women. The mean baseline PRL values were normal in both groups. After sulpiride administration the incremental area under the PRL profile in PCOS was significantly lower than in normal subjects (p less than 0.01). The mean basal plasma TSH levels were significantly higher in the PCOS than in the control group (p less than 0.01). After sulpiride administration the incremental area under the TSH profile was significantly lower in PCOS patients than in normal women (p less than 0.01). The higher basal plasma levels of TSH, the blunted response of PRL and the lack of response of TSH to sulpiride in PCOS suggest a relative decrease of the dopaminergic activity in PCOS patients.     

Possible dopaminergic system involvement in LH and PRL responses to naltrexone treatment

Naltrexone (Nalt) causes a rapid increase in luteinizing hormone (LH) level. This short term increase of LH concentration declines to baseline levels in less than 1 hour. Addition of pimozide (0.1 mg) caused a blunted response to Nalt challenge, with significantly reduced LH peak values compared with Nalt treatment alone. Pimozide alone caused a delayed decrease compared with baseline LH values. By following plasma prolactin (PRL) levels it was shown that pimozide administration increased PRL levels rapidly for more than 2 hours. Addition of Nalt to pimozide-treated rats significantly decreased plasma PRL values compared with pimozide alone. Nalt injected by itself attenuated PRL baseline levels. Thus, the mechanism by which pimozide caused PRL elevated level is via the dopaminergic as well as the opioid system. It is suggested that the opioid system controls plasma PRL and LH levels through other hypothalamic neurotransmitters in addition to dopamine.     

Effects of angiotensin I-converting enzyme inhibitor, SQ 14225, in nomal men.

Effects of an orally active angiotensin I-converting enzyme inhibitor, SQ 14225, on the actions of angiotensin I (AI) infused intravenously for 120 to 390 min were studied in 5 normal men. When 20 ng/kg/min of AI infusion was started immediately after a single oral administration of 100 mg of SQ 14225, a significant rise in blood pressure (BP) was observed for the first 15 min, but BP began to fall from 17 min and returned to the pretreatment level at 45 min. This BP level continued at least to 120 min and in one subject to 180 min. In this subject BP began to rise again from 185 min and reached the level of 15 min at 390 min. Plasma AI level increased gradually from 45 min. At 15 min plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased, but then PRA began to increase and PA began to decrease. At 120 min the values of PRA and PA were similar to the pretreatment values. In one subject plasma AI and PRA began to decrease and PA began to increase after 120 or 180 min. On the other hand, in the 5 men sole AI infusion caused a continued BP rise, PRA decrease and PA increase, and sole SQ 14225 administration caused increases in plasma AI and PRA and a decrease in PA but no BP change. From these results it was concluded that complete blockade and partial inhibition of AI conversion by 100 mg of oral SQ 14225 lasted for about 2.5 and 6.5 hr, respectively and that BP rise, PRA suppression and aldosterone stimulation after AI infusion were entirely due to the actions of angiotensin II converted from AI.     

Renal Na+-K+-ATPase in weanling and adult spontaneously hypertensive rats

The interrelationships among plasma renin activity (PRA, ng AI/ml plasma/hr), aldosterone concentration (ng%), and renal Na+-K+-ATPase activity (mumole PO4/mg protein/hr) were studied in 9 weanling normotensive spontaneously hypertensive rats (SHR), 9 adult hypertensive SHR, and 9 weanling and 9 adult normotensive Wistar-Kyoto rats (WKY). All groups were placed on a normal (0.4% sodium) diet. PRA and plasma aldosterone, measured in samples drawn from the ether-anesthetized rat, were higher in weanling SHR (15.2 +/- 2.0, 37 +/- 4.2) than in WKY. PRA measured in samples collected from a separate group of unanesthetized weanling SHR was also greater than in age-matched WKY. In adult SHR, PRA (6.1 +/- 0.9) and plasma aldosterone (20.0 +/- 2.7) were decreased. During the weanling period Na+-K+-ATPase activity in SHR was not only greater than in age-matched WKY but was also increased compared to adult normotensive and hypertensive rats (137 +/- 9 weanling SHR, 89 +/- 7 weanling WKY, 73 +/- 11 adult SHR, 84 +/- 17 adult WKY). Thus, during the weanling period the renin-angiotensin-aldosterone (R-A-A) system and renal Na+-K+-ATPase activity are activated in SHR. The elevation of Na+-K+-ATPase activity may be due to increased aldosterone levels. It was noted, however, that plasma aldosterone was similar in adult WKY and weanling SHR, while Na+-K+-ATPase activity was higher in SHR. These findings involving R-A-A and renal Na+-K+-ATPase activity prior to the elevation of blood pressure suggest that the kidneys may play a role in the initiation of hypertension in SHR.     

Effects of TRH on circulating growth hormone, prolactin and triiodothyronine levels in the bovine.

The effects of administration of synthetic thyrotropin-releasing hormone (TRH) on circulating growth hormone (GH), PROLACTIN (PRL) and triiodothyronine (T3) levels of lactating dairy cows, non-lactating dairy heifers, and beef cows were studied. Intravenous administration of 0.1, 1, and 5 microgram of TRH per kg of body weight (bw) elevated plasma GH and PRL levels of lactating cows within 5 min. The plasma GH and PRL levels increased in proportion to the dose of TRH and reached a peak 10 to 30 min after TRH injection. Intravenous administration of 1 microgram of TRH per kg of bw to 7 non-lactating heifers, 14 lactating dairy cows, and 5 non-lactating beef cows elevated plasma GH level to peak values after 15 min, the increase rates being 6.9, 5.6, and 3.8 times as high as those in the pretreatment levels. The mean maximum vale was also in that order. Plasma T3 levels of non lactating dairy heifers at pre- and post-injection of TRH were significantly higher than those of lactating cows. The peak values of plasma PRL were obtained between 5 to 30 min after TRH administration. The increase rates of lactating dairy cows, heifers, and beef cows were 19.2, 13.9, and 20.9 times as high as those in the pretreatment. In contrast to GH and T3, plasma PRL levels of both pre- and post-injection with TRH in lactating cows and heifers were significantly higher in May than in October, though the increase rates were similar. Plasma PRL levels of lactating dairy cows at pre- and post-injection with TRH were significantly higher than those of non-lactating heifers. Subcutaneous administration of TRH was also effective to increase plasma TH, rl, and T3 levels in lactating cows. No significant change of GH or PRL response to TRH was observed after a short-term pretreatment of thyroid hormones.     

Dopaminergic modulation of aldosterone secretion: effect of sodium balance and postural changes

The influence of an increased endogenous production of angiotensin II and of sodium homeostasis upon the response of plasma aldosterone to metoclopramide administration has been investigated in 5 normal volunteers. Our results show that the increase of plasma aldosterone after metoclopramide administration is independent of angiotensin II, ACTH and potassium, and that it increases even further due to the endogenous production of angiotensin II induced by postural changes. The state of sodium balance seems to influence the response of plasma aldosterone to metoclopramide administration as it occurs with other stimuli of aldosterone secretion.     

Ovine corticotropin-releasing factor administration in normal men. Pituitary and adrenal responses in the morning and evening

We administered ovine corticotropin-releasing factor (CRF) as a bolus intravenous injection (1 microgram/kg) at 09.00 and at 20.00 to assess the influence of circadian changes in the hypothalamic-pituitary-adrenal axis on the response to CRF. The increase in plasma ACTH levels after CRF was only slightly lower in the morning than in the evening. The plasma cortisol response to ACTH, however, was significantly greater in the evening than in the morning (p less than 0.005). At both times of day CRF administration had no effect on plasma concentrations of GH, PRL, LH, AVP, insulin, PRA or glucose. No effects were observed on the hematopoietic system, kidneys or liver. In addition, CRF had no effect on heart rate, blood pressure or respiratory rate at the dose employed. Approximately 10% of the subjects complained of a transient upper body and facial hot flush. These observations indicate that the magnitude of the plasma cortisol rise after CRF depends on the time of administration.     

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.