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beta-Adrenergic stimulation of the release of ACTH- and LPH-related peptides from the pars intermedia of the rat pituitary gland.

The intermediate lobe of the rat pituitary gland produces a series of peptides related to ACTH and LPH. The spontaneous and isoproterenol-stimulated release of such peptides was studied during in vitro superfusion of rat neurointermediate lobes with Krebs-Ringer medium. Products released into the superfusion medium were quantified by direct measurement or after chromatography on Sephadex G-50. ACTH bioactivity was determined by use of adrenal cortical cell suspension assay. In addition, NH2-terminal ACTH, CO2H-terminal ACTH, alpha-MSH and beta-endorphin radioimmunoassays were used. The results show that 1. neurointermediate lobes of rats secret spontaneously various ACTH- and LPH-related peptides in amounts proportional to the amounts in which these peptides are found in extracts of the neurointermediate lobe; 2. the beta-adrenergic agonist, isoproterenol, stimulated the spontaneous release of various peptides, including alpha-MSH, ACTH, CLIP, glycosylated CLIP, and beta-endorphin-like peptides; 3. isoproterenol induced a dose-dependent (10(-9)-10(-7) M), parallel increase in the release of alpha-MSH and ACTH following similar time courses and showing identical EC50 values (about 10(-8)M). Although the spontaneous release of alpha-MSH and ACTH from rat neurointermediate lobes is not strictly coupled under the conditions used in this study, isoproterenol seems to affect the spontaneous release of these peptides to the same relative extent.

Adrenergic beta-Agonists↗

Studies on the mechanism by which ACTH stimulates renin activity and angiotensin II formation in man.

Ten IU of ACTH (1-24) per day was infused for 34 h (starting at 7 a.m.) into 8 normal men on a constant diet containing 135 mM Na+ per day. All subjects retained between 152 and 181 mM of sodium. Potassium balance was negative. Plasma renin activity (PRA) and plasmaangiotensin II (P-A-II) started to rise in most subjects after 6 to 8 h of infusion, reached a maximum after 24 h and then tended to decline. As shown previously, the rise in PRA is not due to a rise in plasma renin substrate concentration. Systolic, but not diastolic blood pressure increased significantly on the second day of ACTH-infusion. Plasma cortisol (P-F) was continuously stimulated by ACTH. Plasma aldosterone (P-aldo) increased rapidly 1 h after ACTH administration, then tended to fall, and increased again in most subjects, roughly in parallel with PRA. No significant changes in electrolyte balance, PRA, P-A II, P-F, and P-aldo occurred in 3 subjects receiving 'sham' infusions. Additional experiments in subjects treated with propranolol or indomethacin allowed the conclusion that the effect of ACTH on PRA and P-A II is not mediated by renal beta-adrenergic receptors, but perhaps (partially?) by prostaglandins. Since the infusion rate of ACTH was not much higher than the secretion rate of ACTH in the early morning hours, it is possible that ACTH is physiologically involved in the regulation of renin secretion.

Adrenocorticotropic Hormone↗

Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity.

Five normal young males on a low sodium diet received iv ACTH (1-24) infusions (10 IU/24 h) for 100 h in addition to diuretics. The aim of the study was to find out whether the biphasic effect of ACTH on aldosterone (initial stimulation followed by 'escape') could be prevented by keeping plasma renin activity (PRA) at a fairly constant high level. PRA was around 20 ng/kg/min before and towards the end of the ACTH infusion. Plasma aldosterone and aldosterone excretion rates were, nevertheless, only transiently stimulated, but the first was relatively more suppressed than the latter at the end of the ACTH infusion. Plasma 18-OH-corticosterone followed the same pattern. Even on the last infusion day, aldosterone and 18-OH-corticosterone levels were still higher than in normal ambulatory sodium-replete men. The fasciculata steroids cortisol, 11-deoxycorticosterone and corticosterone were continuously stimulated by ACTH. It is concluded that the biphasic response of zona glomerulosa steroids to ACTH is basically independent of renin and angiotensin II. However, the marked suppression of aldosterone secretion observed in sodium-replete individuals during prolonged ACTH treatment was not seen in this study. Angiotensin II or a different factor associated with sodium depletion may, therefore, partly protect the zona glomerulosa from adverse effects of ACTH observed in the sodium-replete state.

18-Hydroxycorticosterone↗

Effect of ovine corticotrophin releasing factor, bromocriptine, and dopamine on release of ACTH and beta-endorphin in a patient with Cushing's disease.

Release of immunoreactive ACTH and beta-endorphin (beta-EP) in response to corticotrophin-releasing factor (CRF) and dopaminergic agents was studied in vivo and in vitro in a patient with Cushing's disease. Iv administration of synthetic ovine (o) CRF significantly stimulated plasma ACTH release, accompanied by increase of plasma cortisol levels. Oral administration of bromocriptine significantly suppressed plasma cortisol levels. Although reduced responses of plasma ACTH and cortisol to o-CRF was observed 1 month after removal of the pituitary adenoma, these normalized 6 months after operation. In vitro perifusion of the pituitary adenoma obtained by surgery revealed that o-CRF also stimulated ACTH and beta-EP release in a dose-responsive manner (10(-9)M 10(-5)M) and that dopamine suppressed their basal secretion. Gel exclusion chromatography of the perfusates showed that the predominant component of ACTH and beta-EP before and after o-CRF stimulation coeluted with standard ACTH and beta-EP, respectively. The present data suggest that o-CRF is a potent secretagogue for ACTH and beta-EP release from the human pituitary adenoma causing Cushing's disease and that ACTH secretion from certain adenomas, possibly originating from the intermediate lobe of the pituitary gland, is partly regulated by a dopaminergic mechanism.

Adenoma↗

The effect of nifedipine on CRF-41 and AVP-induced ACTH release in vitro.

The effect of nifedipine on CRF-41- and AVP-induced ACTH release was examined using monolayer cultured rat anterior pituitary cells and pituitary halves. Nifedipine inhibited ACTH release induced by synthetic rat CRF-41 in two systems. In pituitary halves, CRF-41 significantly stimulated both ACTH release and cyclic AMP accumulation. Nifedipine inhibited CRF-41-induced ACTH release and the inhibitory effect of nifedipine on CRF-41-induced ACTH release was accompanied by parallel decrease of cyclic AMP levels in pituitary halves. Nifedipine did not inhibit AVP-induced ACTH release in pituitary halves, and AVP did not significantly affect cyclic AMP accumulation in pituitary halves. These results suggest that CRF-41 stimulates ACTH release through the intracellular cyclic AMP system and calcium-calmodulin system which are accelerated by the influx of extracellular calcium ions. Moreover, it is suggested that the calcium required for AVP-induced ACTH release is derived primarily from intracellular rather than extracellular sources.

Adrenocorticotropic Hormone↗

Probable ACTH-secreting pituitary tumour in association with Addison's disease.

A 61 year old Japanese man with a diagnosis of Addison's disease was admitted to Kyushu University Hospital for further investigation of high ACTH levels and hyperpigmentation which 37.5 mg of cortisone acetate failed to alleviate. The basal level of plasma ACTH was 700-1000 pg/ml, and following 25-37.5 mg cortisone acetate or 1 mg dexamethasone the levels were 300-600 pg/ml. The general pigmentation showed little improvement with such medication. Radiographic studies revealed a double floor of the sella turcica and cisternal herniation. These observations suggested the existence of a pituitary ACTH-secreting tumour. Plasma ACTH showed a circadian rhythm ranging from 440 to 1570 pg/ml and it was not suppressed to a normal range by oral administration of dexamethasone, 8 mg/day or by continuous infusion of dexamethasone, 1.25 mg/h for 2 h. Plasma ACTH responses of 80% above basal level to lysine-vasopressin (LVP), and 12% above basal to synthetic ovine corticotrophin releasing factor (CRF) were observed. FK 33-824, a methionine-enkephalin analogue, suppressed plasma ACTH to 85% of basal level, while bromocriptine (CB-154) caused no significant change. These findings led to a diagnosis of pituitary ACTH-secreting adenoma (corticotropinoma) in association with Addison's disease. The persistent circadian rhythm of plasma ACTH suggested that this adenoma may not be completely free from regulation by the central nervous system. This case may be clinically significant for investigation of the pathogenesis of pituitary adenoma, particularly in Nelson's syndrome.

Addison Disease↗

Effects of fludrocortisone withdrawal on plasma angiotensin II, ACTH, vasopressin, and potassium in patients with Addison's disease.

UNLABELLED: We attempted to answer to the question whether excessive rises in endogenous plasma angiotensin II (AII) stimulate ACTH secretion by measuring PRA, AII, AVP, ACTH, and cortisol in 8 patients with Addison's disease before and after withdrawal of fludrocortisone substitution. Blood was drawn at 14.30 h, exactly 6 1/2 h after the morning dose of hydrocortisone had been taken. PRA and AII were initially higher than normal in 4 patients. After withdrawal of fludrocortisone for 1 or 2 weeks, PRA and AII rose markedly in 4 patients (up to 260 ng/l) without concomitant changes in plasma ACTH levels (r = -0.081, AII vs ACTH). Changes in plasma cortisol could not have obscured a stimulatory effect of AII on ACTH by variable feedback inhibition of ACTH release. The increase in plasma AII levels in the 4 patients was larger than that observed in a previous study in normal subjects after rigorous dietary sodium restriction. In all patients, hyperkalaemia developed after fludrocortisone withdrawal, independent of changes in PRA and AII. Rises in PRA, AII, and plasma potassium were partially reversed by increased sodium intake and further suppressed by resumption of fludrocortisone therapy. Plasma AVP remained in the normal range after fludrocortisone withdrawal, but was slightly elevated after increasing salt intake without fludrocortisone administration. CONCLUSIONS: Rises of endogenous plasma AII to levels tenfold higher than normal do not stimulate ACTH release. AII is probably not a physiological modulator of ACTH secretion. Mineralocorticoid substitution in Addison's disease should be monitored by plasma potassium measurement. Hyperkalaemia may coexist with normal PRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Addison Disease↗

Steroid hydroxylase gene expression in the ovine fetal adrenal gland following ACTH infusion.

Between 90 and 120 days of gestation (term = 147 +/- 5), when plasma cortisol concentrations in the fetus are at a minimum, levels of mRNA encoding the steroidogenic enzymes 17 alpha-hydroxylase (P-450(17 alpha] and cholesterol side-chain cleavage (P-450scc) are also very low. Over the following 30 days, P-450(17 alpha) and P-450scc gene expression increases concurrent with increasing fetal cortisol concentration. The hypothesis tested in this study was that cortisol biosynthesis is minimal in the period 90-120 days because of insufficient ACTH. Fetuses were cannulated between 98-102 days of gestation. Following recovery, 7 fetuses received 24-h ACTH infusions (12 micrograms/24 h) and 5 fetuses received 24-h vehicle infusions; 4 ACTH-infused and 4-vehicle-infused fetuses were then sacrificed immediately after cessation of the infusion. The other fetuses were left in utero for 3 days prior to sacrifice. Fetal blood samples were analysed for ACTH and cortisol and the adrenals processed for hybridization histochemistry and Northern blot analysis. ACTH, but not vehicle, induced significant increases in the width of the adrenal cortex and in the levels of P-450(17 alpha) and P-450scc mRNA. Concurrently, fetal plasma ACTH and cortisol concentrations also increased significantly. In adrenals from fetuses left in utero for 3 days after cessation of the ACTH infusion, P-450(17 alpha) and P-450scc mRNA levels returned to control levels. Plasma ACTH and cortisol levels also approximated basal values. P-450c21 mRNA levels did not vary significantly at any time with the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

Interaction between glucagon and human corticotropin-releasing hormone or vasopressin on ACTH and cortisol secretion in humans.

OBJECTIVE: It is known that glucagon administration elicits ACTH and cortisol responses in humans, although this effect takes place after intramuscular or subcutaneous but not after the intravenous route of administration. The mechanisms underlying this stimulatory effect on corticotroph secretion are unknown but they are unrelated to glucose variations and stress-mediated actions. DESIGN AND METHODS: To throw further light on the stimulatory effect of i.m. glucagon on the pituitary-adrenal axis, using six normal young female volunteers (26-32 years, body mass index 19.7-22.5 kg/m(2)) we studied the interaction between glucagon (GLU; 0.017 mg/kg i.m.) and human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) or vasopressin (AVP; 0.17 U/kg i.m.). The interactions between hCRH and AVP on the hypothalamo-pituitary-adrenal (HPA) axis and the GH response to GLU alone or combined with hCRH or AVP were also studied. RESULTS: GLU i.m. administration elicited a clear increase in ACTH (peak vs baseline, means+/-s.e.m.: 11.6+/-3.3 vs 4.2+/-0.3 pmol/l, P<0.05), cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) and GH levels (11.6+/-3.4 vs 3.3+/-0.7 microg/l, P<0.05). The ACTH response to GLU (area under the curve: 426.4+/-80.9 pmol/l per 120 min) was higher than that to AVP (206.3+/-38.8 pmol/l per 120 min, P<0.02) and that to hCRH (299.8+/-39.8 pmol/l per 120 min) although this latter difference did not attain statistical significance. The GLU-induced cortisol response (28336.9+/-2430.7 nmol/l per 120 min) was similar to those after hCRH (24099.2+/-2075.2 nmol/l per 120 min) and AVP (21808.7+/-1948.2 nmol/l per 120 min). GLU and hCRH had an additive effect on ACTH (964.9+/-106.6 pmol/l per 120 min, P<0.02) and a less than additive effect on cortisol levels (35542.5+/-2720. 2 nmol/l per 120 min). Similarly, GLU and AVP had an additive effect on ACTH (825.6+/-139.6 pmol/l per 120 min, P<0.02) and an effect less than additive on cortisol levels (33059.2+/-1965.3 nmol/l per 120 min). The effects of GLU co-administered with hCRH or AVP were similar to those of the combined administration of hCRH and AVP on ACTH (906. 0+/-152.7 pmol/l per 120 min) and cortisol (34383.5+/-1669.2 nmol/l per 120min) levels. The GH response to GLU was not modified by hCRH or AVP. CONCLUSIONS: These results show that i.m. glucagon administration is a provocative stimulus of ACTH and cortisol secretion, at least as potent as hCRH and AVP. The ACTH-releasing effect of i.m. glucagon is not mediated by selective CRH or AVP stimulation but the possibility that both neurohormones play a role could be hypothesized.

Adrenocorticotropic Hormone↗

ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo.

OBJECTIVES: Although several lines of evidence suggest that the overall effects of the ACTH receptor, melanocortin 2 receptor (MC2-R), mediated signal transduction on adrenocortical growth and tumorigenesis are anti-proliferative, activation of MC2-R induces mitogens like jun, fos, and myc and activates the MAPK pathway. In vivo, potential effects of endogenous ACTH on adrenal tumori-genesis can not be separated from effects of other POMC derived peptides. METHODS: Murine adrenocortical tumor cells that lack MC2-R expression (Y6(pcDNA)) and Y6 cells stablely transfected with MC2-R (Y6(MC2-R)) were generated. Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB. As a syngenic tumor model, LaHeF1/J mice simultaneously received 10(7) Y6(MC2-R) and Y6(pcDNA) subcutaneously, giving rise to MC2-R positive and negative tumors within the same animal. Animals were treated for 3 weeks in groups of 12 according to the following schedule: group A, control animals receiving saline injection; group B, animals receiving 5.7 ng/injection of a slow release formula of ACTH 1-24 administered i.p. three times a week (aiming at a low physiologic dose); and group C, animals receiving 57 ng/injection of ACTH 1-24 (high physiological dose). RESULTS: Twenty days of ACTH 1-24 treatment did not significantly affect corticosterone levels, endogenous ACTH levels or adrenal and thymus weight compared with saline injection. However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors. PCNA and TUNEL staining, together with morphological characterization, demonstrated that these in vivo effects were due to reduced proliferation, while apoptosis and cellular hypertrophy within the tumor remained unchanged. CONCLUSION: MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH.

Adrenal Cortex Neoplasms↗

Effects of free fatty acids on ACTH and cortisol secretion in anorexia nervosa.

OBJECTIVE: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects. DESIGN: Eight women with anorexia nervosa (ANW; means +/- s.e.m.: 23.9 +/- 2.3 years of age; body mass index (BMI): 14.9 +/- 0.6 kg/m2) and seven normal women (NW; 25.6 +/- 2.3 years of age; BMI: 22.8 +/- 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion. RESULTS: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P < 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P < 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P < 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P < 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P < 0.05). CONCLUSIONS: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity.

Adrenocortical Hyperfunction↗

[Octreotide + bilateral adrenalectomy in the management of ACTH-producing carcinoid tumors].

Cushing's syndrome (CS) due to ectopic ACTH secretion has a high morbidity and mortality. Thus, rapid treatment of ectopic CS is mandatory. Carcinoid tumors associated with ectopic ACTH (CTu-ACTH) syndrome represent a more severe clinical picture, due to the carcinoid symptoms that worsen the hypercortisolism state. Management of patients with CTu-ACTH should include the control of hypercortisolism, as well as the carcinoid disturbance. We report 3 patients (2F, 1M) with CTu-ACTH (2 pancreatic, 1 occult) who presented with clinical manifestations of CS (n= 3) and carcinoid syndrome (2): 2 were initially investigated for CS and 1 carcinoid syndrome. In all hypokalemia, hypertension and diabetes mellitus were associated with severe hypercortisolism and high ACTH levels. Administration of octreotide-LAR reduced ACTH levels from 230,000 to 30,000 pg/ml in patient 1, and controlled symptoms of carcinoid syndrome and neoplasic lesions in patient 2; treatment with subcutaneous octreotide in patient 3 controlled carcinoid syndrome and partially reduced symptoms of hypercortisolism. All 3 patients were submitted to bilateral adrenalectomy to control CS. Our data show that combined anti-neoplastic therapy may contribute to the stabilization and/or definitive control of CTu-ACTH.

Adrenalectomy↗

ACTH content in the anterior pituitary after the infusion of various doses of corticosterone and dexamethasone in normal and adrenalectomized rats.

It is well known that the administration of glucocorticoids inhibits the activities of hypothalamus-pituitary-adrenal axis. The present studies were undertaken to define the site of inhibition of both corticosterone and dexamethasone on this axis in rats. Infusion of 20 or 202 micrograms corticosterone over 6 hr did not change the ACTH content in the anterior pituitary and plasma ACTH levels even through the infusion markedly inhibited the hypothalamic CRF content in normal rats. The constant infusion of a relatively small dose of 20 micrograms dexamethasone inhibited the plasma ACTH level, but not the ACTH content in the anterior pituitary and the hypothalamic CRF content. In contrast to the above results, the infusion of 202 and 504 micrograms dexamethasone over 6 hr increased the ACTH contents in the anterior pituitary, but significantly reduced the hypothalamic CRF content and plasma ACTH levels. These results suggest that the mechanism of dexamethasone inhibition in the hypothalamus-pituitary-adrenal axis is the reduction of ACTH release rather than that of ACTH production in the anterior pituitary.

Adrenocorticotropic Hormone↗

Effect of immobilization and concurrent exposure to a pulse-modulated microwave field on core body temperature, plasma ACTH and corticosteroid, and brain ornithine decarboxylase, Fos and Jun mRNA.

Exposure of humans and rodents to radiofrequency (RF) cell phone fields has been reported to alter a number of stress- related parameters. To study this potential relationship in more detail, tube-restrained immobilized Fischer 344 rats were exposed in the near field in a dose-dependent manner to pulse-modulated (11 packets/s) digital cell phone microwave fields at 1.6 GHz in accordance with the Iridium protocol. Core body temperatures, plasma levels of the stress-induced hormones adrenocorticotrophic hormone (ACTH) and corticosterone, and brain levels of ornithine decarboxylase (Odc), Fos and Jun mRNAs were measured as potential markers of stress responses mediated by RF radiation. We tested the effects of the loose-tube immobilization with and without prior conditioning throughout a 2-h period (required for near-field head exposure to RF fields), on core body temperature, plasma ACTH and corticosteroids. Core body temperature increased transiently (+/-0.3 degrees C) during the initial 30 min of loose-tube restraint in conditioned animals. When conditioned/tube-trained animals were followed as a function of time after immobilization, both the ACTH and corticosterone levels were increased by nearly 10-fold. For example, within 2-3 min, ACTH increased to 83.2 +/- 31.0 pg/dl, compared to 28.1 +/- 7.7 pg/dl for cage controls, reaching a maximum at 15-30 min (254.6 +/- 46.8 pg/dl) before returning to near resting levels by 120 min (31.2 +/- 10.2 pg/dl). However, when non-tube-trained animals were submitted to loose-tube immobilization, these animals demonstrated significantly higher (3-10-fold greater) hormone levels at 120 min than their tube-trained counterparts (313.5 +/- 54.8 compared to 31.2 +/- 10.2 pg/dl; corticosterone, 12.2 +/- 6.2 microg/dl compared to 37.1 +/- 6.4 microg/dl). Hormone levels in exposed animals were also compared to those in swim-stressed animals. Swimming stress also resulted in marked elevation in both ACTH and corticosterone levels, which were 10-20 fold higher (541.8 compared to 27.2-59.1 pg/dl for ACTH) and 2-5 fold higher (45.7 compared to 8.4- 20.0 microg/dl for corticosteroids) than the cage control animals. Three time-averaged brain SAR levels of 0.16, 1.6 and 5 W/ kg were tested in a single 2-h RF-field exposure to the Iridium cell phone field. When RF-exposed and sham-exposed (immobilized) animals were compared, no differences were seen in core body temperature, corticosterone or ACTH that could be attributed to near-field RF radiation. Levels of Odc, Fos and Jun mRNA were also monitored in brains of animals exposed to the RF field for 2 h, and they showed no differences from sham-exposed (loose-tube immobilized) animals that were due to RF-field exposure. These data suggest that a significant stress response, indicated by a transient increase in core body temperature, ACTH and corticosterone, occurred in animals placed in even the mild loose-tube immobilization required for near-field RF exposure employed here and in our other studies. Failure to adequately characterize and control this immobilization response with appropriate cage control animals, as described previously, could significantly mask any potential effects mediated by the RF field on these and other stress-related parameters. We conclude that the pulse-modulated digital Iridium RF field at SARs up to 5 W/kg is incapable of altering these stress-related responses. This conclusion is further supported by our use of an RF-field exposure apparatus that minimized immobilization stress; the use of conditioned/tube-trained animals and the measurement of hormonal and molecular markers after 2 h RF-field exposure when the stress-mediated effects were complete further support our conclusion.

Adrenocorticotropic Hormone↗

Short-term effects of ACTH on the low-density lipoprotein receptor mRNA level in rat and hamster adrenals.

Low-density lipoprotein (LDL) receptor mRNA was found in both rat and hamster adrenals. Within 30 min after ACTH administration a significant increase in the levels of both LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) mRNAs was observed in rat adrenals; these levels remained increased for up to 240 min. The increase in the levels of LDL receptor and HMG-CoA reductase mRNAs produced by ACTH was reduced by co-administration of aminoglutethimide while, at the same time, the adrenal cholesterol content of rats treated with both aminoglutethimide and ACTH was significantly increased compared with that in groups treated with ACTH alone. Cycloheximide also induced increased levels of rat adrenal mRNAs for LDL receptor and HMG-CoA reductase, but this effect was not additive with that of ACTH. These results suggest that, in the rat, the short-term effect of ACTH on the levels of mRNAs for the LDL receptor and HMG-CoA reductase is similarly controlled and might be mediated through changes in the adrenal cholesterol content. In the hamster adrenal, however, no significant fluctuations were found in the level of LDL receptor mRNA, although a marked increase was found in the level of HMG-CoA reductase mRNA, 2 h after ACTH administration. This indicates that an important effect of ACTH on cholesterol metabolism in the hamster adrenal is at the level of HMG-CoA reductase. In the hamster, therefore, where the main source of cholesterol for the adrenal gland is de-novo synthesis, it seems that a complex mechanism is involved in the control of LDL receptor gene expression.

Adrenal Glands↗

Atrial natriuretic peptide is involved in the ACTH response to stress and glucocorticoid negative feedback in the rat.

The role of atrial natriuretic peptide (ANP) in the ACTH response to stress and the glucocorticoid negative feedback control of ACTH release was investigated in adult male homozygous Brattleboro and adrenalectomized Wistar rats respectively, using the technique of immunoneutralization. The relatively low ACTH response to stress and the lack of arginine vasopressin make the homozygous Brattleboro rat a more rigorous and simpler preparation in which to test the hypothesis that ANP is involved in the ACTH response to stress. In both sets of experiments, blood sampling and injection of sheep anti-ANP or control serum were carried out in conscious animals through intra-atrial cannulae implanted 2 days previously under halothane anaesthesia. A 30-s exposure to ether resulted in a brisk twofold increase in the plasma ACTH concentrations in homozygous Brattleboro rats infused with anti-ANP, but not control serum. The injection of either dexamethasone, a potent glucocorticoid receptor agonist, or corticosterone resulted in a rapid and marked reduction in the plasma concentrations of ACTH in Wistar rats which had been adrenalectomized, under halothane anaesthesia, at least 21 days before experimentation. The inhibitory action of dexamethasone, but not corticosterone, was significantly reduced in animals infused with anti-ANP serum. These results show that the inhibition of ANP release into hypophysial portal blood is probably important for triggering the ACTH response to stress and that ANP may play a role in corticosteroid negative feedback control of ACTH release mediated by type II (glucocorticoid) receptors.

Adrenalectomy↗

Release of bioactive ACTH by perifused human placenta at early and late gestation.

This study assessed whether bioactive ACTH is released by the human placenta during perifusion in vitro at early and late gestation. Human placental villous fragments from early (8-12 weeks) and late (38-40 weeks) gestation were perifused at a constant rate for 6.5 h. To assess ACTH-like bioactivity released by this tissue, the perifusion effluent was redirected through adjacent chambers containing freshly dispersed adrenocortical cells obtained from adult rats. Baseline secretion of corticosterone by these adrenocortical cells averaged 95 +/- 26 (S.E.M.) fmol/min, and this increased at least fivefold (P < 0.01, two-way ANOVA) in response to placental effluent at early and late gestation. The magnitude of this increase, expressed as a percentage of the maximal response to a subsequent stimulus with ACTH(1-24), was similar for placentas obtained at early (41 +/- 12% of maximal response) and late (42 +/- 17%) gestation. Immunoreactive (I)-ACTH was readily detectable in placental effluent from all preparations (5.5 +/- 2.3 fmol/min per g tissue), and there was no apparent difference with stage of gestation. To determine whether all of the ACTH-like bioactivity released by the placenta was attributable to I-ACTH, a second series of placental/adrenal perfusions was conducted. In these, I-ACTH was selectively removed from placental effluent by immunoneutralization, and the residual bioactivity measured. Immunoneutralization involved preincubation of placental effluent with ACTH antiserum (1:100), and preincubation with normal rabbit serum (NRS) served as a control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗

Role of cortisol in the ACTH-induced suppression of testicular steroidogenesis in guinea pigs.

In order to investigate the role of cortisol in the regulation of testicular function, adult male guinea pigs were challenged with ACTH (20 IU), cortisol (8 or 16 mumol), or with ACTH plus dexamethasone (DEX, 2 mumol). The amounts of cortisol, testosterone, progesterone, and androstenedione present in the plasma or secreted by incubated adrenals or testes were determined by radioimmunoassay. The plasma concentrations of LH were determined using a radioimmunoassay for rat LH. ACTH treatment elevated cortisol plasma concentrations to 999% of control values, whereas it reduced testosterone plasma levels to 43% of control values. ACTH treatment did not affect LH plasma levels. A significant negative correlation was found in ACTH-treated animals, when the cortisol and testosterone plasma concentrations in serially taken blood samples (30-240 min after treatment) were compared (rs = -0.90 and rs = -0.99, P < 0.05). In addition to cortisol, ACTH raised progesterone and androstenedione plasma concentrations. If animals were treated with 2 mumol DEX + ACTH, the plasma levels of cortisol and androstenedione but not of progesterone, testosterone or LH were changed. ACTH stimulated the in vitro secretion of cortisol, progesterone and androstenedione by the adrenals but reduced the in vitro release of androstenedione and testosterone by the testes. In summary, treatment of guinea pigs resulted in elevated cortisol and in reduced testosterone plasma concentrations. The mechanism of the cortisol-induced inhibition of testicular function was independent of the LH plasma concentrations. The in vitro experiments indicate that cortisol directly interacts with the Leydig cells, presumably by inhibiting the activity of the testicular 17 alpha-hydroxylase and/or C17,20-lyase. Taking into account the results of comparable investigations in the rat, the inhibition of the testicular 17 alpha-hydroxylase and/or C17,20-lyase takes place if the intracellular cortisol exceeds the capacity of the 11 beta-hydroxysteroid dehydrogenase to inactivate it.

Adrenal Glands↗