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.     

Dissociation of plasma cortisol and ACTH responses to dexamethasone in healthy subjects

We examined the plasma cortisol and ACTH concentrations after graded doses of dexamethasone in a group of young, healthy adults. The decrease in cortisol was uniform in all subjects, and in 8 subjects there was a high degree of correspondence with the plasma ACTH concentration. The remaining 5 subjects had no change in plasma ACTH concentration during dexamethasone administration. All subjects had an expected diurnal change in cortisol on 2 pretreatment days and there was a corresponding diurnal change in ACTH for those subjects who had associated ACTH and cortisol responses after dexamethasone, while those with dissociated ACTH and cortisol after dexamethasone had no diurnal ACTH pattern. These findings were consistent with the 24-hour pattern of ACTH and cortisol before and after 1.0 mg of dexamethasone in 2 of the same subjects. These results are further evidence for ACTH independent regulation of adrenal function and indicate that pituitary-adrenal regulation in man is more complex than the traditional model of ACTH-cortisol feedback would predict.     

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.     

Long-term ACTH induced diminished responsiveness of prolactin secretion to morphine

The effect of morphine on plasma prolactin level and on dopamine turnover in the median eminence was studied using adult male rats chronically treated with ACTH. It was found that the ACTH pretreatment caused a decrease in the effect of morphine on prolactin secretion and prevented the inhibitory effect of morphine on dopamine turnover measured in the median eminence. The prolonged ACTH administration did not influence the prolactin content of the pituitaries and the in vitro dopamine sensitivity of lactotroph cells. Acute dexamethasone injection did not change the morphine-caused prolactin release. These results suggest that chronic ACTH treatment (possibly via corticosterone hyperproduction) elicits an opiate-tolerance like state of tuberoinfundibular dopaminergic neurons.     

Plasma LH, FSH, testosterone, prolactin and androstenedione in male white-tailed deer after ACTH and dexamethasone administration

1. In order to investigate the role of the adrenocortical system in the regulation of plasma levels of reproductive hormones, adult male white-tailed deer (five intact and one castrated) from a captive herd were sedated with xylazine and ketamine and then challenged with various doses of ACTH with and without dexamethasone (DX) pretreatment. 2. Plasma levels of LH, testosterone (T), FSH, prolactin (PRL) and androstenedione (A) were determined by RIA in serial samples taken from the jugular vein. 3. An increase of A levels detected after ACTH in both intact and castrated deer indicated stimulation of secretion of adrenal androgens by ACTH. 4. No effect on FSH and PRL levels was observed in either group. 5. A significant decline of LH and T observed in various treatments could not be attributed to ACTH or DX administration. It is speculated that the decrease may be caused by anaesthetics which alleviate the stress induced in deer by the pre-immobilization activities.     

The effects of TRH on prolactin, plasma renin activity, water and electrolyte excretion in normal males.

The effect of TRH induced secretion of TSH and prolactin (hPrl) on plasma renin activity (PRA), water and electrolyte excretion, was studied in 7 normal males before and after an intravenous injection of 2 ml normal saline or 200 microgram TRH. Plasma hPrl and TSH rose significantly (p less than 0.01) in all 7 subjects after TRH but not after saline injection. No significant differences in the hourly excretion of sodium, potassium and free water clearance were noted before and after either saline or TRH injection. Mean PRA values of the 7 subjects were similar after either the 2 ml saline of TRH injection. Our results indicate that despite a correlation between basal hPrl and sodium excretion as well as free water clearance, acute TRH induced elevation of hPrl is not associated with changes of urinary sodium and potassium excretion, free water clearance and PRA in normal males. These findings provide some evidence against a direct osmoregulatory role of hPrl in man.     

5-HT1-, but not 5-HT2-serotonergic, M1-, M2-muscarinic cholinergic or dopaminergic receptors mediate the ACTH/cortisol response to metoclopramide in man

The possible mediation of dopaminergic, muscarinic cholinergic and/or serotonergic receptors in the response of ACTH/cortisol to metoclopramide (MCP) was evaluated in 27 normal men. All subjects were tested with MCP (10 mg in an intravenous bolus plus placebo or saline, NaCl 0.9%, control test). For the other tests (experimental tests), the men were divided into three groups of 9 subjects each. One group was tested with MCP in the presence of the dopaminergic agonist bromocriptine (5 mg p.o. 3 h before MCP), another group was tested with MCP plus the M1- and M2-muscarinic-cholinergic antagonist atropine (1.2 mg in an intravenous bolus, just before MCP) or the M1-muscarinic receptor blocker pirenzepine (40 mg in an intravenous bolus 10 min before MCP). The third group was tested with MCP after treatment with the selective 5-HT1-serotonergic receptor blocker metergoline (10 mg/day p.o. in 5 divided doses for 4 days before MCP) or the 5-HT2-serotonergic receptor antagonist ketanserin (10 mg as a slow 3-min intravenous injection, 5 min before MCP). ACTH and cortisol rose by 45 and 55%, respectively, in response to MCP. The basal levels of ACTH and cortisol were not modified by bromocriptine, atropine, pirenzepine, metergoline or ketanserin treatment. Both ACTH and cortisol responses to MCP did not change significantly after bromocriptine, atropine, pirenzepine or ketanserin administration, whereas they were completely abolished by pretreatment with metergoline. Additional experiments were performed in order to evaluate whether the effect of metergoline on the ACTH/cortisol response to MCP depends on the amount of the serotonergic antagonist (dose-response study).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test

Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism.     

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.     

Inhibitton of prolactin release by stimulation of presynaptic serotonin autoreceptors

The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), a serotonin agonist with a preferential action on presynaptic autoreceptors, on prolactin release in male rats was determined. Basal serum prolactin levels were not altered after administration of 1.0, 2.0, 5.0, 10.0 or 20.0 mg/kg of 5-MeODMT.Pretreatment with 5-MeODMT reduced prolactin release by agents that depend on serotonergic neurotransmission for part of their prolactin release stimulation. Prolactin release in response to L-5-hydroxytryptophan (5-HTP) or morphine was significantly reduced by pretreatment of the rats with 5-MeODMT.The results of this experiment indicate that 5-MeODMT act as a presynaptic serotonin autoreceptor stimulant and not as a postsynaptic serotonin agonist on the neuronal systems that control prolactin release.     

The short-term effect of cortisol, dexamethasone and ACTH administration on the serum levels of hexuronic acids and monosaccharides in man

The levels of serum monosaccharides (SMO) and hexuronic acids (SHA) were measured in subjects without any metabolic or endocrine disease after a short-time administration of cortisol, dexamethasone and ACTH. The effects of the three hormones were evaluated in regard to the urinary excretion of free cortisol and cortisone at basal conditions. In thirteen subjects a significant increase of SMO during cortisol treatment was registered after 24 hours. A distinct difference in the response of SMO to cortisol treatment was observed in patients with normal or increased cortisol excretion, respectively. In the subjects with high urinary free corticoids a peak of SMO occurred soon after 4 hours after cortisol administration, in the next 48 hours no tendency of return towards basal levels was observed. In the subjects with normal urinary free cortisol excretion only a slight increment was seen after 24 hours. Soon after 4 hours in eight subjects dexamethasone administration resulted in an increase of SMO without regard to the excretion of urinary free corticoids. The highest values were obtained after 28 hours of dexamethasone treatment. Ten hours after cessation of dexamethasone the levels of SMO reached the basal values. In the study in which ACTH was administered, an increment of SMO was registered only in the first four hours. In the group of subjects treated with ACTH a slight difference between subjects with normal and increased corticoid excretion was seen. The levels of SHA successively increased after the administration of all three hormones, without regard to the basal excretion of urinary free corticoids. This increase persisted also 10 hours after cessation of cortisol and dexamethasone, and 40 hours after the last dosis of ACTH, respectively. The possibility of an altered metabolism of glucose through the glucuronate pathway under conditions of glucocorticoid excess is discussed.     

Effects of a long-acting somatostatin analogue on pituitary-adrenocortical secretion in normal human subjects

A potent and long-acting somatostatin analogue, SMS 201-995 (SMS) is currently employed for the treatment of various diseases with hypersecretion of hormones such as acromegaly and gastrinoma. The suppressive effects of SMS are also reported on the other pituitary and gastrointestinal hormones. The corticotropic-adrenocortical axis is a crucial hormonal complex in maintaining normal activity and life itself. In this study, the effects of SMS on corticotropic-adrenocortical functions were studied, since the effects of SMS on this hormonal axis are not well established. Seven normal males received a sc injection of 100 micrograms SMS or placebo at 0830 h and 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) intravenously (SMS-hCRH study). Five of the 7 subjects were given an injection of a synthetic (1-24) ACTH (250 micrograms or 63 micrograms) at 0900 h after 100 micrograms SMS or a placebo at 0830 h (SMS-ACTH study). Blood samples were drawn at -30, 0, 15, 30, 60, 90 and 120 min after the hCRH injection for the determination of ACTH and cortisol in the SMS-hCRH study, and cortisol and aldosterone in the SMS-ACTH study. Although significant rises in plasma ACTH and cortisol levels were observed regardless of the preinjection of SMS, their responses to hCRH were significantly lower with the pretreatment with SMS than without SMS. A significant increase in plasma cortisol and aldosterone was observed in response to synthetic ACTH with both ACTH alone and the combined administration of SMS and ACTH, at either dose of ACTH. However, no significant difference in cortisol and aldosterone secretion was detected with and without SMS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined administration of human corticotropin-releasing factor and lysine vasopressin induces cortisol escape from dexamethasone suppression in healthy subjects

Inadequate suppression of plasma cortisol after 1-2 mg dexamethasone is frequently observed in depressive patients. To further investigate the pathophysiology underlying cortisol nonsuppression after dexamethasone we compared cortisol and corticotropin (ACTH) response to human corticotropin-releasing factor (h-CRF), lysine vasopressin (LVP), and a concurrent administration of both peptides after pretreatment with 1.5 mg dexamethasone in six male controls. Neither h-CRF nor LVP were able to produce a marked elevation of dexamethasone suppressed plasma cortisol and ACTH. If both peptides were administered in combination, a substantial escape of plasma cortisol from dexamethasone suppression was observed. ACTH responses changed in concordance with those of cortisol indicating that the LVP-CRF interaction takes place at the pituitary level. Our finding is consistent with a multihormonal control of pituitary-adrenal activity and bears several implications for interpretation of dexamethasone suppression test results in depressive illness.     

Lysosomal enzyme activities in hypo- and hypersecretory anterior pituitary cells. A combined immunocytochemical and enzyme cytochemical study

The involvement of lysosomes in ACTH and prolactin secretion was studied. Lysosomes were visualized in the anterior pituitary by their non-specific esterase (gold thioacetic acid technique) or acid phosphatase (Gomori technique) activity. Corticotrophs and mammotrophs were identified by postembedding immunocytochemistry for their respective hormones. Corticotrophs were rendered hypersecretory by bilateral adrenalectomy (7 or 12 days prior to examination), hyposecretory by dexamethasone administration. Prolactin secretion was enhanced by 17-beta-estradiol, prolactin release was inhibited by bromoergocriptine administration. Long-term hypersecretion of ACTH was accompanied by the presence of numerous autophagic vacuoles often containing secretory granules in the corticotrophs. Lysosomal enzyme-containing tubules and small lysosomes were abundant in the cytoplasm near the cell membrane, among the mature secretory granules. Feed-back inhibition of ACTH release by dexamethasone resulted in the extension of enzyme-containing tubules, continuous with cisternae and small lysosomes anywhere in the cytoplasm and in the appearance of numerous crinophagic vacuoles. A higher frequency of tubular lysosomes was described at the periphery of mammotrophs stimulated by 17-beta-estradiol. Bromoergocriptine caused a high incidence of characteristic crinophagic vacuoles in the prolactin cells. The concept of crinophagy has been extended to the corticotrophs. Morphological phenomena were attributed to the traffic and increased turnover of membranes, ligands and cytoplasmic organelles during stimulated secretion.     

The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation

Serum thyrotropin (TSH) and prolactin levels were measured after intravenous administration of 400 μg of synthetic thyrotropin-releasing hormone (TRH) in 13 normal subjects and six hypothyroid patients before and after three days of administration of dexamethasone 2 mg per day. In the normal subjects dexamethasone suppressed baseline serum levels and secretion of TSH after TRH stimulation. On the other hand, it had no effect on the hypothyroid patients. In the control group dexamethasone also suppressed baseline serum levels but not secretion of prolactin after TRH stimulation. Dexamethasone had no effect on prolactin levels in the hypothyroid group. It is concluded that in normal patients short-term administration of dexamethasone has an inhibitory effect on TSH secretion at the pituitary level. As for prolactin, our results could indicate that TRH is a more potent stimulator of prolactin secretion than of TSH secretion, or that TSH and prolactin pituitary thresholds for TRH are different.     

Some functional aspects of canine corticotrophs

To examine the regulation and functional significance of canine pituitary pars intermedia corticotrophs, ACTH and cortisol responses to CRF were studied in healthy dogs before and after treatment with dexamethasone. In addition the effects of the dopamine agonist bromocriptine and the dopamine antagonist pimozide were investigated. In the latter two instances prolactin concentrations were also measured. Finally the pituitaries were studied immunocytochemically for ACTH and alpha-MSH. No response of ACTH or cortisol to bromocriptine was observed. Pimozide caused a slight rise in ACTH levels in some dogs. However, prolactin levels significantly decreased with bromocriptine and increased with pimozide. Injection of synthetic ovine CRF to dogs was followed by sharp increases in ACTH and cortisol values. These responses were obliterated by prior treatment with dexamethasone. In 1 of 4 dogs given dexamethasone before euthanasia, there were few pars distalis cells with ACTH(1-24) immunopositivity, although persistence of ACTH(1-24) reaction was noted within cells of the pars intermedia. The results indicate that none of the CRF-induced ACTH secretion in dogs is derived from pars intermedia corticotrophs. Dosages of bromocriptine and pimozide that clearly alter prolactin secretion do not consistently affect ACTH levels.     

Hypertension,Increased Aldosterone Secretion and Low Plasma Renin Activity Relieved by Dexamethasone

A father and son are described with a condition characterized by benign hypertension, potassium deficiency, increased aldosterone secretion rate (ASR), raised plasma volume and suppressed plasma renin activity (PRA). There were intermittent elevations of urine 17-ketosteroids and 17-hydroxycorticoids (17-OHCS) but no increase in urine THS, normal circadian rhythm of plasma 17-OHCS, and normal urine 17-OHCS response to dexamethasone and intravenous ACTH. Plasma ACTH and corticosterone secretion were not elevated. Pregnanetriol excretion was normal but urine pregnanediol was increased. At operation on the father no adrenal tumour was found; the excised left adrenal weighed 7 g. and showed nodular cortical hyperplasia; juxtaglomerular cells showed only occasional granules. Following operation hypertension persisted and ASR was half the preoperative value. All abnormalities in father and son were relieved by dexamethasone (DM) 2 mg. daily. The condition recurred following cessation of DM but was relieved by a second course of treatment. No such response to DM was seen in a normal subject or in a patient with Conn''s syndrome. For a number of reasons it is suggested that patients with hypertension, increased ASR and low PRA be given a trial of dexamethasone treatment before undergoing adrenal surgery.     

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.     

Role of pineal gland in kidney-adrenal homeostasis

The effects of pineal gland on kidney-adrenal axis have been studied in male rats. Rats were pinealectomized and exposed to a photoperiod of 12 h light: 12 h dark. Plasma renin activity (PRA), corticosterone and corticotropin (ACTH) levels were measured at 10, 20 and 35 days postpinealectomy. Pinealectomy increased corticosterone and ACTH levels and decreased PRA in all age groups. A significant negative correlation was found between corticosterone and PRA, which suggest that changes in PRA were due to changes in circulating corticosterone, via feedback mechanism on renin secretion. On the other hand, melatonin administration prevents these effects of pinealectomy. It is suggested that the lack of this pineal indol is responsible for the pinealectomy-induced alterations in male rats.     

Lysosomal enzyme activities in hypo- and hypersecretory anterior pituitary cells

Summary The involvement of lysosomes in ACTH and prolactin secretion was studied. Lysosomes were visualized in the anterior pituitary by their non-specific esterase (gold thioacetic acid technique) or acid phosphatase (Gomori technique) activity. Corticotrophs and mammotrophs were identified by postembedding immunocytochemistry for their respective hormones. Corticotrophs were rendered hypersecretory by bilateral adrenalectomy (7 or 12 days prior to examination), hyposecretory by dexamethasone administration. Prolactin secretion was enhanced by 17-beta-estradiol, prolactin release was inhibited by bromoergocriptine administration. Long-term hypersecretion of ACTH was accompanied by the presence of numerous autophagic vacuoles often containing secretory granules in the corticotrophs. Lysosomal enzyme-containing tubules and small lysosomes were abundant in the cytoplasm near the cell membrane, among the mature secretory granules. Feed-back inhibition of ACTH release by dexamethasone resulted in the extension of enzyme-containing tubules, continuous with cisternae and small lysosomes anywhere in the cytoplasm and in the appearance of numerous crinophagic vacuoles. A higher frequency of tubular lysosomes was described at the periphery of mammotrophs stimulated by 17-beta-estradiol. Bromoergocriptine caused a high incidence of characteristic crinophagic vacuoles in the prolactin cells. The concept of crinophagy has been extended to the corticotrophs. Morphological phenomena were attributed to the traffic and increased turnover of membranes, ligands and cytoplasmic organelles during stimulated secretion.