The effect of ACTH and cortisol on aldosterone and cortisol clearance and distribution in plasma and whole blood.

The mechanisms of increased aldosterone and cortisol metabolic clearance rates (MCR) following ACTH or cortisol administration were studied in 13 subjects undergoing cardiac catheterization and in 9 healthy controls. In control subjects, the MCR (plasma) of both steroids increased by 29% (aldosterone: from 936 +/- 57 to 1204 +/- 55 l/day/m2, cortisol: from 205 +/- 12 to 264 +/- 17 l/day/m2 +/- SE) after ACTH (12 units/h) for 1 to 4 h, and by 20 and 32%, respectively, after cortisol (12 mg/h) for 1 to 2 h. In contrast, aldosterone MCR (whole blood) did not change with ACTH or cortisol administration (from 1276 +/- 57 to 1330 +/- 59 l/day/m2), indicating that the plasma MCR increase results from a redistribution of aldosterone from plasma to red cells. Aldosterone splanchnic extraction was 92 +/- 1% (n = 12) with normal morning cortisol levels, and extraction was unchanged after ACTH administration. For cortisol, however, the splanchnic extraction increased from 8 +/- 0.8% to 17.8 +/- 5.0%, and the MCR (whole blood) likewise increased by 15 to 31% (from 295 +/- 23 to 357 +/- 30 l/day/m2), after ACTH or cortisol administration. In vivo and in vitro measurements (at 37 C) of tracer aldosterone concentration in plasma and in red cells showed an increase in distribution to red cells with increasing cortisol concentrations. The results suggest that a fraction of aldosterone is bound in plasma and displaced by cortisol into red cells. There is an increased aldosterone plasma MCR, but unaltered whole blood MCR, since the liver extracts aldosterone almost completely from both plasma and red cells. The increase in cortisol MCR (plasma) results from both an increased splanchnic extraction as plasma binding sites approach saturation and a redistribution into red cells.     

Circadian pattern of circulating plasma ACTH, cortisol, and aldosterone in patients with beta-thalassemia

Plasma levels of ACTH, cortisol, and aldosterone were measured for an entire day every 2 h, starting from midnight, in 4 healthy subjects, and in 4 patients with beta-thalassemia, without evidence for any endocrine disease. The subjects, after synchronized standard life conditions for 10 days, were held in constant supine position during the study. The data were analysed by the "cosinor" method. The results show significant circadian rhythms for the three biological variables in healthy subjects. In the thalassemic patients a significant circadian rhythm was detected only for cortisol and aldosterone. No rhythm was demonstrated for ACTH in the patient group. While no differences were found in mesors and acrophases for the three hormones between the two groups, a significant difference was observed regarding amplitudes. These data suggest that in beta-thalassemia, the secretion rhythmicity of ACTH is modified, whereas the adrenal cortex maintains its own physiologic rhythmicity in hormone secretion.     

Adrenocorticotropin-mediated effect of metoclopramide on plasma aldosterone in man

Five healthy adult men were given metoclopramide (10 and 20 mg) iv and the effects of L-dopa and dexamethasone on metoclopramide-induced increases in plasma aldosterone concentration were determined. Plasma PRL, ACTH, and cortisol levels were also measured and the results reported in a previous study. After an injection of 10 mg metoclopramide, aldosterone levels increased significantly. The aldosterone rise was inhibited by L-dopa, but not by dexamethasone. After injecting 20 mg metoclopramide, aldosterone levels increased significantly vs. both the control and the basal level. The aldosterone increase was not inhibited by L-dopa pretreatment, whereas pretreatment with dexamethasone did suppress it. The data suggest that metoclopramide increased aldosterone secretion through an ACTH-dependent (stress mediated) effect in addition to its antidopaminergic adrenal action, simultaneously. There were no significant differences between the ACTH-dependent and dopamine antagonist-mediated aldosterone increases in either the 10- or 20-mg tests. However, the ACTH-dependent aldosterone increase was statistically greater in the 20-mg test than in the 10-mg test, whereas there was only a slight and not statistically significant difference in the dopamine antagonist-mediated aldosterone increase between the tests. This means that the ACTH-dependent component of the aldosterone secretion is affected by the doubling of the metoclopramide dose, whereas the dopamine antagonist-mediated component is not.     

Alprazolam,a benzodiazepine,does not modify the ACTH and cortisol response to hCRH and AVP,but blunts the cortisol response to ACTH in humans

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GABA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pituitary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodiazepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodiazepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22 kg/m2) on: 1) the ACTH and cortisol responses to hCRH (2.0 microg/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1-24 (0.06 and 250 microg iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean+/-SE: 29.8+/-4.4 pg/ml and 199.3+/-19.6 microg/l) were similar to those recorded after AVP (31.7+/-6.5 pg/ml and 164.8+/-18.0 microg/l); the cortisol response to 0.06 microg ACTH (190.4+/-11.8 microg/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 microg ACTH (260.6+/-17.4 microg/l). AL did not modify the ACTH response to both hCRH (42.5+/-7.1 pg/ml) and AVP (33.3+/-2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3+/-12.7 microg/l) and AVP (119.4+/-14.5 microg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 microg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0+/-7.7 microg/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7+/-16.6 microg/l). The DHEA and aldosterone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.     

Effect of clonidine on plasma ACTH, cortisol and melatonin in children

An interaction between melatonin and adrenocorticotropin (ACTH) seems to occur in humans and both hormones respond to beta-adrenergic stimulation. As in lower animal species, human pineal gland also contains alpha2-adrenergic receptors as does the hypothalamus-pituitary axis. In this study the response of the pineal gland and of the hypothalamus-pituitary-adrenal axis to alpha2-adrenergic stimulation was assessed. Twenty-nine children (21 males, mean age 11.2 +/- 0.6 yr and eight females, mean age 9.1 +/- 1.1 yr) from the University of Granada Hospital were studied. The children were diagnosed as having growth problems but with a normal response of growth hormone (GH) to clonidine test. Changes in plasma levels of ACTH, cortisol and melatonin were evaluated in these children after oral administration of the alpha2-adrenoceptor agonist clonidine (100 microg/m2) or a placebo. Plasma ACTH, cortisol and melatonin were measured before (basal) and at 30, 60 and 90 min after oral clonidine or placebo administration. Hormonal determinations were carried out by commercial radioimmunoassay kits, previously standardised in our laboratory. The results show a significant decrease in plasma ACTH, cortisol and melatonin 30 min after clonidine administration (P < 0.001), reaching lowest values at 90 min after the drug was administered. The reduction in the levels of these hormones is independent of their normal circadian decay since the control group showed a significantly different pattern of behaviour. These data support the existence of an inhibitory alpha2-adrenergic influence on both the pineal gland and the hypothalamus-pituitary-adrenal in children and further support the presence of alpha2-adrenoceptors in the human pineal gland.     

The effect of chlorpromazine on plasma renin activity and aldosterone in man.

The response of plasma renin activity (PRA) and aldosterone to the intravenous administration of chlorpromazine was determined in schizophrenic patients while they were supine and on a normal sodium diet. In all subjects PRA and aldosterone increased during chlorpromazine administration with little or no change in blood pressure. The maximum PRA and aldosterone levels occurred 60 min after the higher dose of chlorpromazine. These data suggest that chlorpromazine affects the renin-angiotensin-aldosterone system and it may interfere with the evaluation of this system in patients receiving this drug.     

Effect of two prostaglandin synthesis inhibitors, indomethacin and acetylsalicylic acid, on plasma ACTH and cortisol levels in man.

The aim of this study was to investigate the possible role of prostaglandins (PG) in the control of the hypohtalamic-pituitary-adrenocortical axis in normal volunteers. Acute oral administration of 100 mg indomethacin (ID) or 1.5 g acetylsalicylic acid (ASA) did not alter ACTH and cortisol plasma levels. Administration of 300 mg daily ID for 4 days delayed the onset, but increased the magnitude, of the response of ACTH to insulin hypoglycaemia, while it blunted the cortisol response. Administration of 3.2 g ASA daily depressed ACTH response to hypoglycaemia leaving the cortisol response unchanged, except for a 15 min delay in onset. These results are interpreted assuming that ID and ASA chiefly acted at the pituitary and hypothalamic level, respectively, and that ID, but not ASA, interfered with adrenocortical cortisol production. Our findings support the concept, based on animal studies, that PG enhance hypothalamic CRF release and adrenocortical steroidogenesis and may restrain ACTH secretion in the pituitary.     

Oxytocin reduces exercise-induced ACTH and cortisol rise in man

The effect of oxytocin on the ACTH, cortisol, GH and PRL response to physical exercise was investigated in 6 normal men. In addition, the possible involvement of endogenous opioids in the mediation of oxytocin action was evaluated. After fasting overnight, each subject was tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3-min intervals until exhaustion and lasted about 20 min in all subjects. Tests were carried out under administration of oxytocin (2000 mIU as an iv bolus injection plus 32 mIU/min per 30 min) or naloxone (10 mg as an iv bolus injection) alone; furthermore, the effect of oxytocin together with naloxone (10 mg as an iv bolus injection) was evaluated. In the remaining test, normal saline was given instead of drugs. Plasma ACTH, cortisol, PRL and GH concentrations were significantly increased by physical exercise. Administration of oxytocin, naloxone or their combination was without effect on the PRL and GH rise elicited by exercise. In contrast, the exercise-induced ACTH and cortisol response was significantly raised by naloxone and reduced by oxytocin. When oxytocin was preceded by administration of naloxone, the ACTH and cortisol response to exercise was not reduced by oxytocin. These data show that oxytocin is capable of inhibiting the rise in ACTH and cortisol, but not in GH and PRL induced by physical exercise. Since naloxone abolished the inhibitory effect of oxytocin, oxytocin action on ACTH and cortisol secretion might be supposed to be mediated by an opioid pathway.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1-39) or human corticotropin-releasing hormone in man

The effects of sc injections (at 1500 h) of increasing amounts of synthetic human ACTH-(1-39) (1.25-30 micrograms) on plasma ACTH, cortisol, aldosterone, and 18-hydroxycorticosterone were compared with those of iv injections of 30 and 100 micrograms synthetic human CRH in nine normal men. Five micrograms of ACTH, sc, was the lowest dose that significantly increased plasma levels of the three steroids. CRH (30 micrograms, iv) increased plasma cortisol and 18-hydroxycorticosterone, but not aldosterone, while 100 micrograms CRH also raised aldosterone secretion. The dose-response curve (peak plasma ACTH level vs. maximum increment of plasma cortisol within the first hour) was initially very steep. Plasma ACTH levels between 50 and 60 ng/L (11-13 pmol/L) stimulated cortisol to almost 80% of the maximal increment obtained with plasma ACTH levels above 300 ng/L (greater than 66 pmol/L). This dose-response relationship is similar to that found in clinical tests of the pituitary-adrenal axis (insulin test, metyrapone test). The effects of plasma ACTH released by CRH on cortisol secretion were not significantly different from those of injected ACTH. Our results argue against the hypothesis that the effect of CRH on steroid secretion is mediated or modulated by POMC-derived peptides other than ACTH.     

Urinary aldosterone excretion rate and plasma aldosterone concentration in the rat: effect of ACTH, DOC, furosemide and of changes in sodium balance.

In rats kept under standard conditions urinary aldosterone exretion rate (UAER) and plasma aldosterone concentration (PAC) showed a circadian rhythm with peak values at the beginning of the dark perioith a single dose of DOC (2 mg/kg sc) or given saline as drinking water UAER and PAC decreased to very low levels. Restriction of dietary sodium for 5 weeks increased UAER and PAC 60-fold and 100-fold, respectively. Treatment with ACTH (250 or 500 microng/kg iv) stimulated UAER 8 h following injection and PAC 1 h after injection. In rats treated with a single dose of furosemide (25 mg/kg sc) PAC increased to maximal values within 90 min and reached control values within 24 h. Twenty-four hours-UAER also increased after furosemide treatment. UAER paralleled PAC under all experimental conditions tested. Therefore, our results suggest that UAER is a reliable index of the activity of the renin-angiotensin-aldosterone system in rats under conditions of low and high aldosterone secretion. Measurement of UAER is a useful tool for studies on aldosterone levels in rats over a long period of time.     

Metoclopramide increases plasma aldosterone concentration in man

Plasma Aldosterone (PA) response to metoclopramide (10 mg i.v.) was studied in 11 normal, 2 hypophysectomized subjects and in one patient with bilateral adrenal hyperplasia. All the subjects were kept on a normal sodium and potassium intake. Four normal subjects were pretreated with 1 mg of dexamethasone in order to inhibit endogenous ACTH. In all subjects metoclopramide elicited a prompt rise of PA comparable to that obtained with angiotensions or ACTH. No significant change of blood pressure, serum electrolytes, plasma renin activity, Plasma Cortisol (PC) was detected. The lack of PC response to metoclopramide and the PA increase in dexamethasone pretreated subjects rule out an ACTH mediated effect. The increase of PA in hypophysectomized subjects, in whom metoclopramide did not stimulate any prolactin release, rules out a prolactin mediated effect. Metoclopramide increases plasma aldosterone concentration probably via a direct action on the adrenal glomerular zone or throught another unknown mechanism.     

Prolonged infusions of Ile5-angiotensin-II in sodium replete and deplete man: effects on aldosterone, ACTH, cortisol, blood pressure, and electrolyte balance.

Angiotensin II (Ile5) was infused for 72 h into 4 sodium replete (3 ng/kg/min) and 8 sodium deplete (3 or 6 ng/kg/min) healthy young men after appropriate control periods, and the effects on aldosterone secretion, plasma cortisol, ACTH, renin activity, plasma and urinary electrolytes, and blood pressure were assessed. Sustained contrived elevation of plasma angiotensin II levels in sodium replete subjects to the range of moderate sodium depletion led to a sustained increase in plasma and urinary aldosterone levels, which further and significantly increased between the 1st and 2nd days of angiotensin II infusion, when gross sodium retention during infusion was prevented. This additional increase may be explained as the expression of a "trophic" effect of angiotension II on the zona glomerulosa. In the sodium deplete state, the absolute increment of aldosterone secretion for a given elevation of angiotensin II levels diring infusion was larger than in sodium replete subjects. This confirms the conclusions from previous short-term angiotensin II infusion experiments that sodium deficiency sensitizes the zona glomerulosa against angiotensin II. The "trophic" effect of angiotensin II on the adrenal gland seems to be one mechanism by which the sensitization is brought about, but insufficient for its full explanation. Since plasma ACTH and cortisol, plasma sodium and potassium concentrations, and potassium blance did not change significantly across sodium depletion or angiotensin II infusion, the mechanism of sensitization awaits its full elucidation. The effect of angiotensin II on blood pressure was blunted by soidum depletion. The opposite shifts in sensitivity against angiotensin II of the zona glomerulosa and of resistance blood vessels with changes in the sodium state seem to be an effective and important means in the regulation of body sodium.     

Acute effects of digoxin on plasma aldosterone and cortisol in monkeys

Digoxin, a cardiac glycoside, is used to increase cardiac contractility via inhibition of Na⁺/K⁺-adenosinetriphosphatase (ATPase) and increase intracellular calcium in congestive heart failure. Inhibitory effects of digoxin have been demonstrated on the biosynthesis of gonadal hormones and adrenal glucocorticoids in rats. However, acute effects of digoxin on levels of adrenal corticosteroid hormones in the primates in vivo are uncertain. Therefore, we test the hypothesis that a single injection of digoxin decreases the secretion of aldosterone and cortisol in monkeys. An intravenous injection of digoxin (1 μg/kg) inhibited basal and adrenocorticotropin (ACTH)- or KCl-stimulated aldosterone release in monkeys. Furthermore, digoxin induced a decrease in ACTH- and KCl-stimulated cortisol release. Administration of digoxin did not alter plasma concentrations of Na⁺ and K⁺. Ouabain, a selective inhibitor of Na⁺/K⁺-ATPase, did not affect ACTH- or KCl-stimulated aldosterone and cortisol release. These results revealed that injection of digoxin induced an inhibitory effect on aldosterone and cortisol secretion in monkeys. Because ouabain did not affect levels of plasma aldosterone or cortisol, we suggest that (1) the Na⁺/K⁺-ATPase pathway may not be involved in the mechanism of action of digoxin on aldosterone or cortisol secretion in monkeys and/or (2) the Na⁺/K⁺-ATPase is more sensitive to digoxin than to ouabain in monkeys.     

Increased response of cortisol and ACTH to corticotrophin releasing hormone in centrally obese men, but not in post-menopausal women

There is evidence for enhanced hypothalamo-pituitary-adrenal axis (HPAA) activity in centrally obese premenopausal women. This has led to the hypothesis that increased cortisol production rates may be an aetiological factor in the genesis of central obesity. However, the relationship of obesity and body fat distribution to HPAA activity in men and postmenopausal women has not been established. We carried out CRH tests in 13 men and 8 post-menopausal women. We measured 24 h urine cortisol metabolites prior to the CRH test in each subject, as an indication of cortisol production rate. There was a significant direct relationship between central obesity as measured by the ratio of subscapular:triceps skinfold thickness (STR)--and the ACTH/cortisol response to CRH in men, but not in postmenopausal women. There was no relationship between obesity or body fat distribution and 24h urine cortisol metabolites. This study provides evidence for hyperactivity of the HPAA in centrally obese men, but not in postmenopausal women.     

Responses of plasma renin activity, aldosterone, adrenocorticotropin, and cortisol to dermorphin, a new synthetic potent opiate-like peptide, in man

This study was designed to investigate the effect of dermorphin (D), a new synthetic potent opiate-like peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on PRA, plasma aldosterone (PA), plasma cortisol (PC), and plasma ACTH levels in normal men. D infusion (5.5 micrograms/kg X min for 30 min) significantly increased PRA (P less than 0.01) and decreased PC levels (P less than 0.02). D produced a small decrease in ACTH and a small increase in PA. Pretreatment with the opioid receptor antagonist naloxone (N) blunted the D-induced PRA increase and completely prevented the D-induced PC decrease, but enhanced PC and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that 1) D, a new opioid peptide, increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; and 2) D suppresses PC levels, perhaps by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.