Rise In Plasma ACTH Levels Research Articles

Altered Control of the Hypothalamo-Pituitary-Adrenal Axis in Adult Male Rats Exposed Perinatally to Food Deprivation and/or Dehydration

Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.

Role of prostaglandins E1, E2 and F2 alpha in the brain in interleukin 1 beta-induced adrenocorticotropin secretion in the rat.

It is well known that interleukin (IL)-1 is a potent activator of the hypothalamo-pituitary-adrenal axis in the rat. Many studies have reported that prostaglandins (PGs), especially PGE2, in the brain may mediate the IL-1 stimulation of corticotropin-releasing hormone release, which then leads to adrenocorticotropin (ACTH) secretion. However, a general consensus has yet to emerge regarding whether PGE2 is the only or the most important PG in the brain mediating IL-1-induced ACTH secretion in the rat. To address this question, we examined the effect of intracerebroventricular (icv) administration of antisera against PGE1, PGE2 or PGF2 alpha, or normal rabbit serum on the ACTH response induced by an icv injection of IL-1 beta in the rat. Each antibody or normal rabbit serum (as the control) was given icv 15 min before an icv administration of human recombinant IL-1 beta (50 ng). IL-1 beta produced a significant rise in plasma ACTH levels, and this response was significantly suppressed by either of the three PG antibodies. Interestingly, the inhibitory effect of anti-PGE2 antibody seemed to be somewhat weaker than those of the other two antibodies. We conclude that not only PGE2 but also PGE1 and PGF2 alpha in the brain may mediate the IL-1 beta stimulation of ACTH secretion in the rat.

Acute immobilization stress alters LH and ACTH release in response to administration of N-methyl-D,L-aspartic acid in peripubertal and adult male rats.

We have evaluated the effects of stress on the pituitary hormone response to N-methyl-D,L aspartic acid (NMA) in peripubertal (43 day old) and adult (80 day old) male rats. Animals were stressed by immobilization for 3 h. Fifteen min prior to the end of the stress period, animals were injected sc with either vehicle or increasing doses of NMA (10, 30 or 60 mg/kg BW). Animals were sacrificed 15 minutes later. A significant rise in plasma LH in response to NMA occurred at a lower dose (10 versus 60 mg/kg BW), and the magnitude of the response was greater overall in peripubertal than in adult unstressed rats. Stress altered the LH response to NMA in both age groups. In peripubertal stressed rats, NMA did not induce a rise in plasma LH levels. In adult rats exposed to stress, the magnitude of the LH response to 60 mg/kg BW of NMA was lower than in unstressed animals. NMA administration triggered a rise in plasma ACTH levels in unstressed rats of both age groups, but the magnitude of the rise was greater in adults than in peripubertal animals. Stress reduced the ACTH response to NMA administration in both age groups. Plasma FSH concentrations were higher in peripubertal animals than in adults. NMA and stress were without major effect on plasma FSH levels in either age group. These data suggest that excitatory amino acids (EAA) form an important component in the regulatory processes governing the release of LH and ACTH, and that the maturational stage of the central nervous system and exposure to stress alter the LH and ACTH response to EAA.

Adrenocorticotropic Hormone in Relation to Interrenal Function during Stress in Tilapia ( Oreochromis mossambicus)

This study examines ACTH-like immunoreactivity in the pituitary pars distalis and pars intermedia of the freshwater teleost Oreochromis mossambicus (tilapia). Two products (tACTH A and tACTH B) were present in both lobes. These two products also accounted for the majority of the ACTH i.r. when in vitro pars distalis incubation medium was analyzed by HPLC. In a homologous bioassay the two tilapia ACTH-like molecules and human ACTH 1-39 possessed similar corticotropic potency. The peptides were quantified using a newly validated radioimmunoassay, which was also used to measure ACTH in plasma of unstressed and stressed fish. Short-term (<12 min) stress rapidly increased plasma cortisol, reaching levels of around 300 ng/ml in 5 min. Surprisingly, this initial elevation was not accompanied by a rise in plasma ACTH levels. A more prolonged (3 hr) confinement in pairs resulted in high plasma cortisol and ACTH levels in one fish of every pair. The second fish had control ACTH levels and only marginally elevated cortisol levels. Therefore, in this species social interactions seem to influence the reaction of the pituitary-interrenal axis to stress. The short-term cortisol response to disturbance could be abolished completely by pretreating fish in vivo with cortisol for 48 hr. This treatment did not alter circulating ACTH levels. It is concluded that tilapia did not rely on circulating ACTH for a rapid elevation of plasma cortisol levels. Both neuronal mechanisms and cortisol feedback may regulate the pituitary-interrenal axis at the level of the interrenal.

The effect of salt-loading on corticotropin releasing hormone and arginine vasopressin mRNA levels in the mouse hypothalamus: A quantitative in situ hybridization analysis

Previously, we showed that during salt-loading in mice there was an acute rise in plasma ACTH levels after 2 days followed by a transient decrease after 4 and 9 days. Pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary increased after 2 days and returned to normal thereafter. In this study, changes in hypothalamic CRH and AVP mRNA levels during salt-loading were investigated using quantitative in situ hybridization histochemistry. CRH mRNA was expressed only in the paraventricular nucleus (PVN), while AVP mRNA was expressed in both the supraoptic (SON) and paraventricular nuclei. CRH mRNA levels were unchanged after 2 days salt-loading, but declined to 77% of control levels after 9 days. AVP mRNA levels rose to 260% and 634% of control levels in the SON, and to 352% and 522% of control levels in the PVN, after 2 and 9 days salt-loading, respectively. These data suggest a major role of AVP in the acute stimulation of ACTH secretion and POMC mRNA levels seen after 2 days salt-loading. Densitization of AVP receptors at the corticotroph level and a centrally mediated inhibition of CRH release may account for the decrease of ACTH secretion and POMC mRNA levels in the anterior pituitary with prolonged salt-loading.

Stimulatory effect of interleukin-1 on adrenocorticotropin secretion in the rat: is it modulated by prostaglandins?

The in vivo release of ACTH by interleukin-1 alpha (II-1 alpha) is reportedly blocked by acute treatment with indomethacin (indo), suggesting an involvement of endogenous prostaglandins in the effect of cytokines on the hypothalamic-pituitary-adrenal axis. However, indo also increases plasma corticosterone levels, raising the possibility that inhibition of ACTH release is due to suppressive effects of hypercorticolemia rather than to blockade of the stimulatory effects of II-1 alpha. We observed that the iv administration of indo (10 mg/kg) 15 min before II-1 alpha completely abolished the rise in plasma ACTH levels caused by the peripheral injection of this lymphokine to intact rats. At the time of II-1 alpha injection, plasma corticosterone levels were 39 +/- 12 ng/ml in controls and 121 +/- 22 ng/ml in indo-treated animals (P less than or equal to 0.01). In contrast, implantation of intact rats with indo pellets (which delivered 30 micrograms drug/h) 28 h before II-1 only partially interfered with II-1-induced ACTH secretion. In these rats plasma corticosterone levels before II-1 alpha injection were 29 +/- 14 ng/ml in controls and 66 +/- 18 ng/ml in rats implanted with indo pellets (P less than or equal to 0.05). To determine whether the effect of indo was due to corticosteroid feedback or represented a modulating action of prostaglandins themselves, a similar series of experiments was carried out in adrenalectomized rats. In the absence of corticoid replacement therapy, acute treatment with indo did not measurably interfere with the stimulatory effect of II-1 alpha. In contrast, indo blunted, but did not abolish, the effect of II-1a in ADX rats pretreated with corticosterone or dexamethasone to normalize basal ACTH levels. We conclude that the acute ability of indomethacin to totally block II-1-induced ACTH secretion by intact rats appears to be primarily mediated through corticosteroid feedback. However, results obtained when a similar experiment was carried out in adrenalectomized/corticosteroid-treated rats suggest, although they do not prove, that the ability of II-1 alpha to activate the hypothalamic-pituitary-adrenal axis may be partially dependent on the release of prostaglandins.

Adrenocorticotropin release induced by intracerebroventricular injection of recombinant human interleukin-1 in rats: possible involvement of prostaglandin.

ACTH release induced by iv and intracerebroventricular (icv) injection of recombinant human interleukin-1 beta (IL-1 beta) or alpha (IL-1 alpha) was studied in conscious, unrestrained rats. A dose as small as 3 ng of IL-1 beta injected icv induced a significant rise in plasma ACTH levels, whereas 100 ng/100 g body wt (approximately 300 ng/rat) was needed for a significant ACTH response when injected iv. Intracerebroventricular administration of 30 ng IL-1 alpha tended to increase plasma ACTH levels, but not significantly. Intravenous injection of 1000 ng/100 g IL-1 beta induced a maximal response with a pronounced elevation of plasma ACTH levels at 10 and 30 min after injection, but plasma ACTH levels fell at 60 min post injection. On the other hand, icv injection of 30 ng IL-1 beta raised plasma ACTH levels at 10 min, reaching peak values between 30 and 60 min post injection, and plasma ACTH levels remained elevated for 2-3 h after injection. Pretreatment with indomethacin completely prevented the ACTH response induced by either iv or icv injection of IL-1 beta. Administration of indomethacin did not alter the elevation of plasma ACTH levels induced by immobilization stress, however. On the other hand, vagotomy did not alter the ACTH response to iv administered IL-1 beta. Neither iv nor icv injection of IL-1 beta in a dose which induced a maximal ACTH response altered plasma PRL levels. These findings strongly suggest that the brain is the primary site of action of IL-1 beta, and that IL-1 beta transmits the message of the immune system to the brain and, possibly, CRF neurons. It is also suggested that prostaglandins may be involved in this central action of IL-1 beta.

Increase in plasma ACTH after dopaminergic stimulation in rats

The effects of a dopaminergic agonist, apomorphine, and a dopaminergic antagonist, haloperidol, on plasma ACTH, and corticosterone levels were evaluated in adult male rats. Subcutaneous administration of apomorphine in the dose range of 50-500 micrograms X kg-1 significantly increased plasma corticosterone levels. Acute treatment with apomorphine (250 micrograms X kg-1) resulted in an elevation of plasma ACTH concentration, peak values being reached 15 min after the injection. The apomorphine-induced rise in plasma ACTH levels was completely inhibited by pretreatment with haloperidol (1 mg X kg-1). A stimulatory role for dopamine receptors in the control of pituitary ACTH release in the rat is suggested.

Effect of norepinephrine on the pituitary adrenocorticotrophic activation by ether stress and on the in vitro release of ACTH by the adenohypophysis of male and female newborn rats.

The effect of norepinephrine (NOR) has been investigated in 8-day-old newborn rats of both sexes subjected to stress by 2 min ether inhalation or sham stress. The animals were sacrificed either before or 2 and 32 min after the stress or the sham stress procedure was started. Investigations were also performed on newborns bearing neurotoxic lesions of the arcuate nucleus by neonatal treatment with monosodium-L-glutamate. The effect of NOR was also investigated in vitro on incubated pars distalis. ACTH concentrations in the pituitary, plasma, and the incubation medium were determined by radioimmunoassay. NOR at the dose of 0.2 microgram/g was unable to affect plasma ACTH levels during a period of 60 min in unstressed newborns, in contrast to higher doses (0.5, 1, and 5.0 micrograms/g) which elicited a sharp rise in plasma ACTH levels. Then, NOR was injected (0.2 microgram/g) to male and female pups 15 min before the stress or sham stress procedure. 32 min after the beginning of ether inhalation, the pituitary response was greater in NOR-injected than in saline-injected males; in NOR-treated females the rise in plasma ACTH levels was higher at 2 and 32 min than in saline-injected animals. At this latter time, plasma ACTH levels were similar in NOR-treated males and females, while in saline-treated newborns, the response to ether stress was greater and more longlasting in females than in males. No significant rise in plasma ACTH levels was observed in sham-stressed pups.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticosterone secretion after inhibition of prostaglandin synthesis by indomethacin

Systemic indomethacin (Ind) administration decreased prostaglandin F (PGF) content of the rat adrenal to less than 1.4 pg/mg. This was less than 5% of the adrenal PGF content in the gelatin-treated (Gel) control group (34 pg/mg). Basal plasma corticosterone levels were increased by the Ind treatment. Since the calculated metabolic clearance rate for corticosterone was unchanged, this increase was attributed to an enhanced adrenal secretion rate that was secondary to elevated plasma ACTH concentration. Ether exposure in the presence of Ind did not stimulate a normal rise in plasma corticosterone or adrenal corticosteroidogenesis. Adrenal responsiveness to exogenous ACTH was reduced after Ind treatment. There was a normal rise in plasma ACTH levels following ether exposure confirming the adrenal as the site of inhibition. Systemic Ind treatment thus appears to have two sites of action in altering plasma corticosterone levels: 1) a direct effect on the adrenal, inhibiting normal secretion in response to acute elevations of plasma ACTH, and 2) an action at the pituitary or hypothalamic level, eliciting an increase in basal ACTH secretion.

Effect of hydrocortisone on ACTH, growth hormone, insulin and glucose in the blood of bilaterally adrenalectomized patients.

This study is aimed at elucidating the mechanism of paradoxical rise in plasma ACTH levels in response to glucocorticoids, observed by several authors in bilaterally adrenalectomized patients with Cushing's disease. Six control subjects and fourteen patients bilaterally adrenalectomized for Cushing's disease were given a dose of 200 mg hydrocortisone sodium succinate by 3-5 mm i.v. injection. Plasma ACTH (in 6 patients), serum cortisol, growth hormone (GH) and insulin and blood glucose levels were estimated at 0, 30, 60, 90, and 120 minutes. The administration of hydrocortisone significantly suppressed plasma ACTH levels only at 60 min. In one case a slight rise in ACTH level during the test was observed. A significant fall in blood glucose levels was found only in the adrenalectomized patients. No significant changes in serum insulin and GH levels were noted. The possible mechanisms are discussed, especially the potential role of transient glucose deficiency in the pathophysiology of plasma ACTH increase in response to hydrocortisone in the bilaterally adrenalectomized patients.

Simultaneous determinations of plasma ACTH and GH levels after an oral metyrapone.

The levels of plasma ACTH and GH were simultaneously measured in normal subjects every 30 min for 4 nr after an oral administration of metyrapone, either 1.0g or 1.5g. Both doses of metyrapone caused a significant decrease in plasma cortisol levels 90min later, when the mean values of plasma cortisol levels were not significantly different between both groups. An administration of 1.0g of metyrapone raised plasma ACTH levels in 2 out of 6 subjects within 90min, while an increase in plasma GH levels of 5.0ng/ml above the base line levels was observed in 2 subjects. In one of the subjects in whom the levels of plasma GH increased, plasma GH peak was preceded by that of plasma ACTH, but no rise in plasma ACTH levels was observed in another subject. When 1.5g of metyrapone was given, plasma ACTH levels increased in all 6 subjects. The response of plasma ACTH was quite different in each individual and there appeared one or two peaks within 240 min. The mean value of plasma ACTH was 69±17 pg/ml at 0 time and increased to 165±18 pg/ml at 60min (p<0.01 vs 0 time). An increment in plasma GH levels was observed in 5 out of 6 subjects. The mean peak value was reached at 90min and the difference between the values at 0 and 90 min was significant. There was also no correlation between the secretion of ACTH and that of GH. These results may indicate that a higher dose of metyrapone causes both ACTH and GH secretions within a short period not by a negative feedback mechanism of cortisol but presumably by acting directly on the pituitary and/or on the hypothalamus as a nonspecific stimulus.