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PubMed1981

Decreased adrenal androgen sensitivity to ACTH during aging.

During the human aging process, basal plasma levels of cortisol and aldosterone demonstrate little change, while concentrations of adrenal androgens (AA) such as dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and androstenedione (A) decrease dramatically in men and women. There is no age-related change in ACTH concentrations to explain this observation. In this study, ACTH (cosyntropin, alpha1-24 corticotropin) stimulation tests were performed on elderly subjects and controls to test the hypothesis that analogous to the aging testicular. Leydig cell, AA-producing cells of the aging adrenal gland may become less sensitive to physiological levels of ACTH, but still retain their sensitivity to elevated ACTH levels. Results showed that in the elderly subjects, basal levels and ACTH-stimulatability of cortisol and aldosterone were unchanged. In agreement with earlier studies, basal levels of AA were found to be decreased in the elderly. However, ACTH stimulation demonstrated impaired reserve in DHA and A, and a total lack of stimulatability of DHAS. These findings could be explained by an age-related loss of adrenal enzymes or cell populations which produce AA, a loss or decrease in a subpopulation of ACTH receptors specific for AA production, or loss of a pituitary factor necessary for AA secretion.

Adrenal Glands↗
PubMed1987

Influences of ACTH 4-10 on event-related potentials reflecting attention in man.

The present paper is concerned with effects of the 4-10 sequence of the endogenous ACTH on electrophysiological measures of attention in humans. It was attempted to replicate previous findings of an impaired selective attention following administration of an analog of ACTH 4-9. The effect of this analog had been found to dominate in the beginning of the blocks of an attention task, but to fade away with time on task. In the present study, fourteen male students were tested in a dichotic listening paradigm, 40 min after intranasal application of either 0.4 mg ACTH 4-10, or placebo. Averaged auditory evoked potentials (AEPs) to attended and inattended tone pips, EEG power spectra, heart rate and blood pressure, and behavioral performance were measured during task performance. ACTH 4-10 appeared to slightly impair selective attention as indicated by AEP responses. In particular, the positive shift of the AEP waveforms to inattended stimuli was reduced at the beginning of each block of tone pips under ACTH 4-10. The pattern of actions resembled the effects observed after administration of the more potent synthetic analog of ACTH 4-9 in the previous experiment. Effects of ACTH 4-10 on the AEPs to inattended stimuli, however, differed from influences of the synthetic analog in that they did not affect a rather wide latency range but concentrated on the latency range of the P200 component.

Adolescent↗
PubMed1988

ACTH: a single pretreatment enhances the analgesic efficacy of and prevents the development of tolerance to morphine.

Evidence suggests a close relationship between ACTH and opioids. They are derived from the same precursor molecule, released concomitantly in response to stress and are known to interact at receptor level. Acute exposure to endogenous opioids induces analgesia in the short-term yet shifts the morphine dose-response curve to the right for a period of several weeks. Therefore, the possibility exists that ACTH might also exert an influence extending beyond that suggested by its biological half-life. To investigate this further, DBA/2 mice were pretreated with porcine ACTH left undisturbed for 3 days, then challenged with morphine. Dose-response studies indicated that pretreatment with 10 but not 0, 0.1 or 1.0 IU ACTH influenced responsivity to morphine, rendering a sub-analgesic dose (1.0 mg/kg) effective and significantly enhancing the degree of analgesia observed following treatment with 5 mg/kg morphine, suggesting a shift in the dose-response curve to the left. Time-course analysis revealed 5 mg/kg morphine to induce an analgesic reaction with an onset of between 15-30 and lasting between 60 and 120 min post opiate administration. ACTH pretreatment did not influence this time course, however a significantly greater degree of analgesia was observed at 60 min post morphine injection in 10 IU ACTH pretreated animals than in saline pretreated controls. ACTH pretreatment further influenced subsequent responding to chronic morphine administration. Whilst saline pretreated animals demonstrated significant analgesia in response to the first administration, tolerance to this effect had developed following four days of repeated exposure to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Opioid modulation of the effects of repeated stress on ACTH, cortisol, prolactin, and growth hormone in pigs.

Prepubertal gilts (n = 16) were restrained with a nose snare for 15 min each day over 9 days. At the beginning of the first and last nose snare, the animals were also injected IV with 1 mg/kg of naloxone. Blood samples were taken before and after restraint at 15-min intervals and plasma assayed for ACTH, cortisol, prolactin, and GH. The initial restraint led to significant increases in ACTH, cortisol, prolactin, and GH concentrations. There was no evidence of a reduction in the magnitude of endocrine responses with repeated restraint. Indeed, the response of GH was more apparent after the final restraint. In the absence of the restraint, naloxone elevated cortisol and ACTH concentrations. Naloxone, given with the first restraint, enhanced the increase in ACTH, cortisol, and prolactin. Naloxone, given during the last restraint, inhibited the increase in GH, but had less effect upon cortisol and prolactin concentrations than during the initial restraint. Gilts genetically selected for a high cortisol response to ACTH injections had a higher basal cortisol concentration and a higher cortisol response to restraint than gilts selected for a low cortisol response to ACTH. However, there were no differences between these groups in ACTH, prolactin, or GH concentrations, or in any endocrine response to naloxone. Endogenous opioids can inhibit pituitary-adrenocortical responses and enhance GH responses of pigs to stress. Measures of cortisol concentrations are poor predictors of prolactin and GH responses to stress.

Adrenocorticotropic Hormone↗
PubMed1980

Steroid secretion by ACTH-stimulated human fetal adrenal tissue during the first week in organ culture.

Fetal adrenal tissue has been reported to lose its in vivo secretory pattern by virtue of a loss of fetal zone cells after the first week in culture. Consequently, we studied the steroidogenic capacity and the responsiveness to ACTH of human fetal adrenal tissue during the first week in organ culture. The culture medium was removed daily and assayed for cortisol and dehydroisoandrosterone sulfate (DS). First, as the concentration of ACTH in the medium was increased from 0 to 1 micrograms/ml steroid secretion increased. When tissue fragments were maintained in the absence of ACTH for 3 to 4 days, there was a striking increase in steroid secretion upon addition of ACTH to the medium, with larger rates of secretion of cortisol than DS being observed. Second, the steroidogenic capacity of the separate zones of the fetal adrenal gland was assessed. Tissue from the fetal zone secreted large amounts of DS and small amounts of cortisol, whereas neocortex tissue secreted similar quantities of DS and cortisol. Third, fetal zone tissue was maintained the absence of ACTH for 4 days and thereafter ACTH was added to the media for an additional 6 days. In this experiment, there was a marked increase in DS secretion rate after the addition of ACTH and a smaller increase in cortisol secretion.

Adrenal Glands↗
PubMed1976

Comparison of the analeptic potency of TRH, ACTH 4-10, LHRH, and related peptides.

Various peptide hormones appear to exert behavioral and pharmacologic effects apart from their classical endocrine actions. Thytrotopin-releasing hormone (TRH), for example, antagonizes the sedation and hypothermia produced by barbiturate and other depressant drugs and de Wied has shown that ACTH 4-10, TRH, LHRH and certain related substances show some activity in inhibition of extinction of a pole-jumping avoidance response in the rat. These data provided the impetus for screening ACTH 4-10, LHRH, and related peptides for analeptic activity. ACTH 4-10 and ACTH 4-7 were inactive in antagonizing pentobarbital whether administered peripherally or centrally. ACTH 4-7 amide and 4-Met(O2), 8-D-Lys,9-Phe-ACTH 4-9 were active regardless of route of administration LHRH and two tripeptide fragments (pGlu-His-Trp-NH, and pGlu-His-Phe-NH2) showed analeptic activity only after intracisternal administration. Thus, some peptide fragments related to ACTH 4-10 and LHRH were shown to share to some degree the analeptic properties previously demonstrated for TRH.

Adrenocorticotropic Hormone↗
PubMed1979

ACTH self-administration in rats.

The ability of rats to learn a lever pressing response reinforced by a contingent intravenous delivery of ACTH 1--24 and 4--10, was investigated. About 60% of the rats tested learned to press the lever for the two analogues that were infused at a rate of 2.08 microgram per second via a chronically implanted intrajugular catheter. Most of the animals exhibited sustained daily self-injections of 250 to 375 microgram of ACTH 1--24 and more variable amounts of ACTH 4--10. Comparisons with the self-administration of saline and altered responses following a change in the concentration of ACTH 1--24 solution indicated a positively reinforcing effect for the neuropeptide. The self-administration of the ACTH 4--10 analogue demonstrates that this reinforcing property of ACTH is not due to its adrenal stimulating activity. Brain targets possibly involved in the self-administration of ACTH are discussed.

Adrenocorticotropic Hormone↗
PubMed1980

Intraventricular ACTH reduces social interaction in male rats.

Intraventricular ACTH (1.25 microgram), ACTH (1.6 microgram) and ACTH:D-Phe (1.6 microgram) resulted in significant reductions in the time that pairs of male rats spent in active social interaction. This decrease in social behaviour was not accompanied by a decrease in motor activity. The results are similar to those previously found with peripheral administration of ACTH and suggest that these behavioural effects of ACTH are centrally mediated. None of the ACTH fragments had a significant effect on the latency with which thirsty rats started drinking in an unfamiliar environment. The results are discussed in relation to a possible anxiogenic action of ACTH.

Adrenocorticotropic Hormone↗
PubMed1987

Monosodium glutamate does not alter ACTH- or apomorphine-induced penile erection and yawning.

The effect of the intracerebroventricular (ICV) injection of ACTH 1-24 (1, 5 and 10 micrograms) or the subcutaneous administration of apomorphine (20 and 80 micrograms/kg SC) on spontaneous penile erection and yawning was studied in rats treated with monosodium glutamate (MSG), a treatment that depletes hypothalamic ACTH, alpha-MSH and endorphin-like peptides. Neonatal MSG treatment failed to antagonize either apomorphine- or ACTH-induced yawning in male and female rats, or to alter the number of penile erection episodes induced by the two substances in male rats. In contrast, hypophysectomy, that does not alter the concentration of hypothalamic ACTH and alpha-MSH, caused a marked prevention of apomorphine- and ACTH-induced responses, in agreement with previous studies. The results suggest that the integrity of opiomelanotropinergic neurons in the hypothalamus is not necessary for the induction of yawning and penile erection by ACTH-derived peptides, and that apomorphine and other dopamine agonists apparently do not induce penile erection and yawning by releasing an ACTH-derived peptide in brain.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Distribution and possible origin of beta-endorphin and ACTH in discrete brainstem nuclei of rats.

Immunoreactive ACTH and beta-endorphin in the lower brainstem nuclei of intact and brainstem-hemisected rats were quantified by radioimmunoassay. The distribution of these peptides was almost identical throughout the lower brainstem. The concentrations of ACTH and beta-endorphin were essentially equal when expressed on a molar basis. Both peptides were distributed unevenly in the lower brainstem. High concentrations were found in the periaqueductal central gray matter and the dorsal raphe nucleus, and moderate levels were present in the locus coeruleus, the parabrachial nuclei, the nucleus raphe magnus and in the nucleus of the solitary tract. beta-Endorphin was measurable in all 43 brainstem nuclei investigated; ACTH was non-detectable in the red and lateral cuneate nuclei. Except in certain areas in the medulla oblongata (nucleus of the solitary tract, lateral reticular nucleus, reticular formation) ACTH and beta-endorphin declined in brainstem nuclei 10 days after midbrain hemisections. Retrograde accumulation of ACTH and beta-endorphin was found in the arcuate nucleus 3 days after midbrain hemisection, which was mainly ipsilateral to the lesion. Data from brainstem-hemisected rats also indicated that ACTH and beta-endorphin in the nucleus of the solitary tract are primarily of local origin, whereas the lateral reticular nucleus (A1 and A5 catecholaminergic cell groups) and medullary reticular formation may receive ACTH and beta-endorphin innervation from both hypothalamic and medullary neurons.

Adrenocorticotropic Hormone↗
PubMed1996

Effect of cortisol and ACTH on corticosteroid-suppressed peripheral blood natural killer cells from healthy volunteers and patients with Crohn's disease.

Recently, we have shown that administration of adrenocorticotropic hormone (ACTH) to corticosteroid-treated Crohn's disease (CD) patients increased the peripheral blood natural killer (NK) cell activity which was suppressed by the corticosteroids. To elucidate this observation we analysed the in vitro effect of budesonide, prednisolone, cortisol, and ACTH on NK cells of healthy volunteers and corticosteroid-treated CD patients. Incubation of peripheral blood mononuclear cells (PBMNC) from healthy volunteers during the cytotoxicity assay caused a dose-dependent inhibition of NK cell activity by the three corticosteroids, while ACTH had hardly any effect. Pre-incubation for 18 h with high and low inhibiting concentrations also showed a significant inhibiting effect on NK cell activity of the corticosteroids. The percentage of CD56+ NK cells tended to increase after pre-incubation with a high inhibiting concentration of budesonide, prednisolone, and cortisol. Incubation of budesonide- or prednisolone-suppressed PBMNC from healthy volunteers and CD patients, with ACTH and/or cortisol, to mimic the in vivo situation, did not restore the corticosteroid-induced suppression of NK cell activity. The increase of the budesonide- or prednisolone-suppressed NK cell activity after in vivo administration of ACTH to the CD patients is therefore probably not a direct effect of cortisol or ACTH. Presumably other factors like cytokines and/or neurohormones must be involved in the in vivo interaction between corticosteroids, ACTH, and NK cells.

Adrenal Cortex Hormones↗
PubMed1986

Oxytocin inhibits ACTH and peripheral catecholamine secretion in the urethane-anesthetized rat.

Oxytocin (OT) generally has a stimulatory effect on ACTH secretion both in vitro and in vivo. As part of a study of ACTH-releasing factors in hypophysial portal blood, the effects of i.v. OT administration on plasma ACTH levels were tested in urethane-anesthetized rats. Surprisingly, i.v. injection of 10 micrograms OT lowered plasma ACTH levels by about 35% (P less than 0.01). It was reasoned that this paradoxical inhibition of ACTH secretion by OT might be mediated by inhibition of the unusually high rate of peripheral catecholamine secretion in this model. Measurement of plasma catecholamines before and after i.v. administration of 10 micrograms OT revealed a 53% inhibition of EPI (P less than 0.01) and 43% inhibition of NE (P less than 0.05). Administration of the beta-adrenergic antagonist propranolol (400 micrograms) 15 min before the beginning of the experiment completely blocked the inhibitory effects of OT on ACTH secretion and in fact unmasked the stimulatory effects of OT normally seen in conscious animals and in vitro. Superfused bisected adrenal glands exposed to 10(-6) M OT for 10 min secreted more than 30% less EPI and NE than control adrenals suggesting that the inhibition of EPI and NE secretion by OT in vivo occurs, at least in part, directly at the level of the adrenal. The data support the hypothesis that peripheral catecholamines may at times be directly involved in the control of ACTH secretion and also suggest that OT, which has recently been identified in the adrenal medulla, may have important paracrine functions in the regulation of adrenal catecholamine secretion.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Behavioral support for an ACTH receptor in the CNS.

In this report we present a series of experiments which have led us to support the notion of the presence of an ACTH receptor in the CNS. A short intense heat-stress (hot-plate) applied to the paws of rats will temporarily reduce activity. During the course of experimentation we were able to eliminate a number of logical mediators. Neither adrenalectomy, adrenal-medullectomy, naloxone administration, nor alpha-MSH-(1-12) were able to affect the observed akinesia. Hypophysectomy, however, was able to abolish or mask the behavior and the reduction in activity could be reinstated by the administration of ACTH-(4-10) to hypophysectomised rats. These data support the notion that a short intense stressor can release ACTH and that this ACTH can be responsible for mediating the short term reduction in activity. In addition, the fact that ACTH-(4-10) has only minimal steroidogenic properties and was able to reinstate the behavior led us to speculate that these effects were of central origin. Furthermore, since naloxone was not capable of altering the behavior, the suggestion is that ACTH in this paradigm acted at a receptor site apart from the naloxone sensitive receptor. This site may in fact be an ACTH specific receptor.

Adrenal Medulla↗
PubMedDate not supplied

Pressor, tachycardic and behavioral excitatory responses in conscious rats following ICV administration of ACTH and CRF are blocked by naloxone pretreatment.

Experiments were conducted to compare the blood pressure and heart rate responses of conscious rats given intracerebroventricular (ICV) injections of adrenocorticotropin (ACTH 1-24) and corticotropin releasing factor (CRF). Under sodium pentobarbital anaesthesia, rats were implanted with a stainless-steel cannula into the lateral cerebral ventricle and had their right femoral artery and vein cannulated. Upon recovery (24-48 hr later) conscious, unrestrained rats were given ICV injections (total volume 5 microliter by gravity flow) of sterile saline, ACTH (1-24) (0.85 and 1.7 nmoles) or CRF (0.55 and 1.1 nmoles) and blood pressure and heart rate were monitored over the next 2 hr (from the abdominal aorta via the femoral arterial catheter). Both ACTH and CRF caused mean arterial pressure (MAP) to increase, which was paralleled with increases in mean heart rate (MHR). Moreover, these elevations in MAP and MHR were temporally associated with excessive grooming (for ACTH) and locomotor activity (for CRF), which occurred before and lasted as long as MAP and MHR were enhanced. Intravenous (IV) pretreatment whereby naloxone was given 10 min before ICV administration of ACTH (1.7 nmoles) or CRF (1.1 nmoles), showed that naloxone blocked the behavioral, pressor and tachycardic effects of both ACTH and CRF. The results demonstrate that the pressor, tachycardic and locomotor effects evoked in conscious rats by ICV administration of ACTH or CRF are antagonized by naloxone and that their hemodynamic changes may, in part, be mediated by prior behavioral activation.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Neonatal ACTH and corticosterone alter hypothalamic monoamine innervation and reproductive parameters in the female rat.

Female Sprague-Dawley rat pups were injected SC with either ACTH(1-24) (0.5 mg/kg) or saline vehicle once daily from postnatal day 1 (day of birth) to day 7. Plasma corticosterone (CORT) levels were recorded via radioimmunoassay (RIA) on day 4 to measure adrenal response to these treatments. Hypothalamic 5-HT and DA fiber densities were assessed using high-affinity specific 3H-5-HT and 3H-DA uptake at days 7, 25, and at adulthood (80-90 days). Animals were checked daily for vaginal opening (starting on day 30) as a sign of sexual maturation and later tested for sexual behavior as virgins (60-70 days of age). Plasma estradiol and progesterone levels were measured via RIA. Plasma CORT levels were greatly increased among ACTH-treated animals during the treatment period. The 5-HT uptake was significantly increased in ACTH-treated animals at day 7 (p < 0.01) and at adulthood (p < 0.02) compared to controls. The DA uptake was significantly higher among ACTH-treated animals at day 7 (p < 0.01). The sexual maturation of ACTH-treated animals was delayed when compared to control animals (p < 0.01). The ACTH-treated animals displayed slight deficits in female sexual behavior compared to control animals (p < 0.05). No significant changes in plasma sex steroid levels were found. Based on this study, we suggest that monoamine innervation into the developing female hypothalamus is susceptible to early postnatal manipulation with ACTH and CORT, and that the resulting changes in these monoamine fiber densities may be responsible for the observed deficits in reproductive maturation and behavior.

Adrenocorticotropic Hormone↗
PubMed1978

On the role of protein synthesis in the response of adrenal tumor cells to ACTH.

Y-1 adrenal tumor cells were incubated with aminoglutethimide with and without ACTH. Greater production of pregnenolone from endogenous cholesterol was observed (after washing to remove aminoglutethimide) in mitochondria from cells incubated with aminoglutethimide and ACTH than in those from cells incubated with aminoglutethimide alone. This response was inhibited by cycloheximide and puromycin but not by chloramphenicol or actinomycin D. ACTH increased the incorporation of [3H]tyrosine into protein associated with mitochondria but not into total cell protein or protein of postmitochondrial supernatant. This response did not require aminoglutethemide block and was inhibited by cycloheximide and puromycin but not by chloramphenicol or actinomycin D. Dibutyryl cyclic AMP produced both of these responses (increased production of pregnenolone and synthesis of protein associated with mitochondria). The concentration of cycloheximide required to cause 50% inhibition of the responses to ACTH and dibutyryl cyclic AMP was approximately the same for steroidogenesis by whole cells, for production of pregnenolone by isolated mitochondria, for incorporation of [3H]tyrosine into Y-1 cell protein and for the increase in synthesis of protein associated with mitochondria produced by ACTH (0.08--0.2 microgram/ml). Disc gel electrophoresis revealed that the increased incorporation of [3H]tyrosine involved two proteins corresponding to molecular weight of approximately 27,000 and 13,000 respectively. These observations suggest that ACTH promotes synthesis of protein(s) by cytoplasmic ribosomes on stable messenger RNA, that the protein(s) becomes associated with mitochondria and that the protein(s) includes one or more which are associated with the increase in production of pregnenolone produced in mitochondria by the addition of ACTH to adrenal cells.

Adrenal Gland Neoplasms↗
PubMed1983

Induction of cultured bovine adrenocortical zona glomerulosa cell 17-hydroxylase activity by ACTH.

The induction of steroid 17-hydroxylase activity was examined in primary cultures of bovine adrenocortical zona glomerular cells. 17-Hydroxylase activity was determined by assaying the metabolism of [3H]pregnenolone to [3H]17-hydroxypregnenolone by high performance liquid chromatography (HPLC). Conversion of [3H]pregnenolone to [3H] progesterone and [3H]17-hydroxypregnenolone to [3H]17-hydroxyprogesterone was prevented by the addition of cyanoketone, an inhibitor of 3 beta-hydroxysteroid dehydrogenase. ACTH increased adrenal zona glomerulosa 17-hydroxylase activity 55-fold to 1750 pmoles/10(4) cells/2 h, an activity equivalent to that of ACTH-treated zona fasciculata cells. Maximal induction was seen after 4 days exposure to ACTH. The dose of ACTH which gave half-maximal induction was 0.25 nM. Previously, ACTH had been demonstrated to suppress bovine glomerulosa conversion of deoxycorticosterone to aldosterone by a steroid-induced oxygen-derived free radical process that was prevented by antioxidants. This process resulted in loss of the terminal cytochrome P-450 enzyme involved in aldosterone biosynthesis. However, induction of 17-hydroxylase activity is not affected by antioxidants or the addition of steroids, e.g. cortisol. ACTH-mediated induction of bovine zone glomerulosa 17-hydroxylase activity and suppression of glomerulosa aldosterone production results in effective conversion of functional glomerulosa cells to functional fasciculata cells. The actions of ACTH on glomerulosa 17-hydroxylase activity support the hypothesis of a steroid-induced functional zonation of the adrenal cortex.

Adrenal Cortex↗
PubMed1984

PHI stimulates ACTH release from pituitary tumor cell.

The identification of PHI (the 27-amino acid peptide (P) having an N-terminal histidine (H) and a C-terminal isoleucine amide (I] in median eminence suggested that PHI influences the secretory function of the anterior pituitary. The effects of PHI on ACTH release from clonal mouse pituitary corticotrophs were investigated. The secretory response to PHI was correlated with a prior increase in cyclic AMP accumulation. Both cyclic AMP synthesis and ACTH secretion were increased by PHI in a concentration-dependent manner. PHI was a less effective agonist of cyclic nucleotide synthesis and ACTH secretion than VIP. The secretory response to PHI was blocked by the calcium channel antagonist, nifedipine, and by dexamethasone. Somatostatin and oxotremorine blocked both PHI-stimulated cyclic AMP formation and ACTH secretion. The observation that VIP in high concentrations can elicit ACTH secretion from normal rat anterior pituitary suggested that a VIP-like substance may modulate ACTH secretion. However, the finding that PHI does not elicit ACTH release from primary cultures of dispersed anterior pituitary, coupled to its relatively lower potency compared to VIP, indicate that corticotrophs are not an important target for PHI.

1-Methyl-3-isobutylxanthine↗