Regulation Of Adrenocorticotropic Hormone Secretion Research Articles

The effect of vasopressin 1b receptors (V1bRs) blockade on the HPA axis activity in rats exposed to acute heat stress

Thermal stressors such as low and high ambient temperature elicit an abundance of neuroendocrine responses including activation of the hypothalamo-pituitary-adrenal (HPA) axis and arginine vasopressin (AVP) release. The exposure to heat is a particularly interesting model for studying AVP action because this kind of stressor represents not only an unpleasant experience but also a threat to osmotic homeostasis. As AVP has long been recognized as a hormone involved in the modulation of HPA axis activity, the aim of this study was to elucidate the role of AVP in acutely heat-exposed rats using Nelivaptan, a selective vasopressin 1b receptor (V1bR) antagonist. Rats were exposed to high ambient temperature (38°C) for 60 min. The circulating hormones were determined by ELISA or chemiluminescence, and intrapituitary adrenocorticotropic hormone (ACTH) and V1bR level were determined by western blot. The results obtained show that V1bR blockade negatively affected the increase in blood ACTH caused by heat exposure. This treatment alone, or in combination with Nelivaptan, decreased intrapituitary V1bR levels while circulating AVP concentration was increased under the same conditions. Furthermore, a strong correlation was observed between blood ACTH and corticosterone concentration. In conclusion, our results directly confirm the positive role of AVP in the regulation of ACTH secretion from the pituitary in animals exposed to heat. Moreover, the results suggest that AVP from the general circulation influences pituitary V1bR.

Dopamine-Regulated Adrenocorticotropic Hormone Secretion in Lactating Rats: Functional Plasticity of Melanotropes

Pro-opiomelanocortin (POMC) is processed to adrenocorticotropic hormone (ACTH) and β-lipotropin in corticotropes of the anterior lobe, and to α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in melanotropes of the intermediate lobe (IL) of the pituitary gland. While ACTH secretion is predominantly under the stimulatory influence of the hypothalamic factors, hormone secretion of the IL is tonically inhibited by neuroendocrine dopamine (NEDA) neurons. Lobe-specific POMC processing is not absolute. For example, D₂ type DA receptor (D2R)-deficient mice have elevated plasma ACTH levels, although it is known that corticotropes do not express D2R(s). Moreover, observations that suckling does not influence α-MSH release, while it induces an increase in plasma ACTH is unexplained. The aim of the present study was to investigate the involvement of the NEDA system in the regulation of ACTH secretion and the participation of the IL in ACTH production in lactating rats. Untreated and estradiol (E₂)-substituted ovariectomized (OVX) females were also studied. The concentration of ACTH in the IL was higher in lactating rats than in OVX rats, while the opposite change in α-MSH level of the IL was observed. DA levels in the IL and the neural lobe were lower in lactating rats than in OVX rats. Suckling-induced ACTH response was eliminated by pretreatment with the DA receptor agonist, bromocriptine (BRC). Inhibition of DA biosynthesis by α-methyl-p-tyrosine (αMpT) and blockade of D2R by domperidone (DOM) elevated plasma ACTH levels, but did not influence plasma α-MSH levels in lactating rats. The same drugs had opposite effects in OVX and OVX + E₂ animals. In lactating mothers, BRC was able to block ACTH responses induced by both αMpT and DOM. Surgical denervation of the IL elevated basal plasma levels of ACTH. Taken together, these data indicate that melanotropes synthesize ACTH during lactation and its release from these cells is regulated by NEDA neurons.

Regulation of adrenocorticotropic hormone secretion: lessons from mice deficient in corticotropin-releasing hormone.

Regulation of adrenocorticotropic hormone secretion: lessons from mice deficient in corticotropin-releasing hormone.

Role of inositol trisphosphate-sensitive calcium stores in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells [published erratum appears in Endocrinology 1996 Mar;137(3):1041

Role of inositol trisphosphate-sensitive calcium stores in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells [published erratum appears in Endocrinology 1996 Mar;137(3):1041

Role of inositol trisphosphate-sensitive calcium stores in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells.

Intracellular Ca2+ (Cai2+) stores contribute significantly to Ca2+ signaling in many types of cells. We studied the role of inositol trisphosphate (InsP3)-sensitive Ca2+ stores, a principal Cai2+ store that presumably is within the endoplasmic reticulum (ER), in cell signaling by examining the effect of thapsigargin (Tg), an ER Ca2+ pump inhibitor that depletes the ER Ca2+ pool, on ACTH secretion. Preincubation for 6-24 h with 2-20 nM Tg had no effect on the resting cytosolic free Ca2+ concentrations ([Cai2+]) but inhibited the ionomycin-stimulated spike-type increase in [Cai2+], which is mediated by InsP3-independent Cai2+ release from the ER, in a dose-dependent (IC50, 4 nM) and time-dependent manner. In ER Cai(2+)-depleted cells, the spike phase (initial 5 min) of the ACTH secretory response to arginine vasopressin (AVP), which is mediated by InsP3-induced Cai2+ release, was also attenuated (IC50, 7.3 nM). However, the spike phase of the ACTH secretory response to AVP was inhibited to a much greater degree than the spike-type response to ionomycin, suggesting that ER Cai2+ stores might have functions other than simply providing Ca2+ for InsP3-stimulated Cai2+ release. Tg pretreatment (IC50, 12 nM) also markedly inhibited the sustained plateau (final 15-min) phase of the ACTH secretory response to AVP, which is mediated by diacylglycerol-induced activation of protein kinase C and subsequent influx of extracellular Ca2+ via L-type voltage-sensitive Ca2+ channels (VSCC), but had no effect on the sustained (full 20 min) response to dioctanoylglycerol that directly activates protein kinase C. Tg had no effect on specific cell binding of [125I]AVP or on specific cell binding of [3H]phorbol 12,13-dibutyrate (except at 20 nM Tg), an index of protein kinase C concentration, or on protein kinase C activity. AVP significantly stimulated inositol trisphosphate accumulation, but pretreatment with Tg completely abolished this effect of AVP, whereas [3H]myoinositol incorporation into membrane-associated inositol lipids and inositol phosphates was unaffected. Thus, Tg-induced depletion of ER Cai2+ stores inhibited both the spike and plateau phases of the ACTH secretory response to AVP, presumably by inhibiting phospholipase C activity and the resulting generation of InsP3 and diacylglycerol. Preincubation with Tg inhibited, in a dose-dependent (IC50, 13 nM) and time-dependent manner, the sustained ACTH secretory response to corticotropin-releasing hormone (CRH) that is mediated by cAMP-induced activation of protein kinase A and Cae2+ influx via L-type VSCC, and the sustained response to forskolin, which directly activates adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of constant light on the concentration of catecholamines of the hypothalamus and adrenal glands, circulatory hadrenocorticotropin hormone and progesterone

The participation of adrenocorticotropic hormone (ACTH) in the control of adrenal glands and the regulation of ACTH secretion in female rats exposed to constant light for six weeks were studied. A significant increase of plasma ACTH (p < 0.05) in rats exposed to constant light is in correlation with an increase of epinephrine (E) synthesis in adrenal gland (p < 0.05) when compared to intact controls. On the other hand, ACTH secretion is in inverse relation with a significantly reduced concentration of dopamine (DA) and norepinephrine (NE) in hypothalamus (p < 0.05). In addition, higher concentration of plasma ACTH in rats exposed to constant light through its effect on the adrenal cortex is responsible for the appearance of polycystic ovaries. As a contribution to this assumption is the result showing an increased concentration of serum progesterone in rats exposed to constant light when compared to corresponding controls which is probably of adrenal origin. These results indicate an inverse relationship between plasma ACTH concentrations and DA and NE concentrations in hypothalamus and that the hypothalamo-pituitary-adrenal axis has a significant role in the regulation of ovarian function.

Role of lipoxygenase metabolites of arachidonic acid in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells.

Arachidonic acid metabolites have been implicated in the regulation of ACTH secretion. To define further which eicosanoid(s) is primarily involved, we examined the effects of both inhibitors of the three arachidonate metabolic pathways (cyclooxygenase, lipoxygenase, and epoxygenase) and specific eicosanoid products on ACTH secretion by rat pituitary corticotrophs in a microperifusion system. CRF stimulates sustained ACTH release that is mediated by protein kinase-A-induced extracellular Ca2+ (Cae2+) influx via L-type voltage-sensitive calcium channels (VSCC). Arginine vasopressin (AVP) stimulates an initial spike phase of ACTH release that presumably is mediated by inositol 1,4,5-trisphosphate-induced intracellular Ca2+ (Cai2+) release, followed by a sustained plateau phase of ACTH release that is mediated by protein kinase-C-induced Cae2+ influx via L-type VSCC. Pretreatment for 15 min with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 50 microM), but not the cyclooxygenase inhibitor indomethacin (10 microM) or the epoxygenase inhibitor SKF525A (100 microM) inhibited the sustained response to CRF by 48% and the initial spike response to AVP by 38%. NDGA-induced inhibition was not reversed by indomethacin or SKF525A, alone or in combination, precluding arachidonate shunting into other pathways. However, the results suggested that epoxygenase metabolites may have a minor stimulatory and cyclooxygenase metabolites may have a minor inhibitory effect on ACTH secretion. Preexposure to NDGA suppressed by 43% the sustained response to 8-bromo-cAMP, which directly activates protein kinase-A; by 57% the sustained response to dioctanolglycerol, which directly activates protein kinase-C; and by 59% the spike-type response to ionomycin, which releases Cai2+ by an inositol 1,4,5-trisphosphate-independent mechanism. These results suggest that NDGA either inhibits the production of a lipoxygenase metabolite involved in Cae2+ influx and/or Cai2+ release or acts other than by inhibiting lipoxygenase, such as by directly blocking membrane transport of Cae2+. The three major lipoxygenase metabolites tested, 5(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acid (HETE), all stimulated sustained ACTH release in a dose-dependent manner. At a concentration of 2 microM, 12(S)-HETE was 4.7 and 2.5 times more potent than 5(S)- and 15(S)-HETE, respectively, and completely reversed NDGA inhibition of both CRF- and AVP-stimulated ACTH secretion. The ACTH-releasing activity of 12(S)-HETE was inhibited 26% by removing Cae2+ and 54% by both removing Cae2+ and depleting Cai2+, indicating either that 12(S)-HETE facilitates transmembrane Ca2+ transfer or that increased cytosolic Ca2+ is necessary for 12(S)-HETE's action.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of lipoxygenase metabolites of arachidonic acid in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells

Role of lipoxygenase metabolites of arachidonic acid in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells

Regulation of adrenocorticotropin secretion from cultured canine anterior pituitary cells

Summary Pituitary cells, collected from five healthy dogs, were cultured and treated with various doses of ovine corticotropin-releasing hormone (crh), arginine vasopressin (avp), oxytocin (ot), or angiotensin II (aii) to determine which of these hypothalamic peptides affected adrenocorticotropin (acth) secretion. Of the 4 peptides, only crh significantly increased acth secretion from cultured canine anterior pituitary cells. The lowest dose of crh tested, 0.01 nM, significantly stimulated acth release. Co-addition of avp, ot, or aii with crh did not increase acth secretion beyond that caused by addition of crh alone. Similarly, neither co-addition of avp with ot, avp with aii, or ot with aii significantly stimulated acth secretion. These results support a role for crh in the physiologic regulation of acth secretion from the canine anterior pituitary, but do not support regulatory roles for avp, ot, or aii.

Electron-microscopic cytochemistry of the catecholaminergic innervation of ACTH-containing neurons in the rat hypothalamic arcuate nucleus.

The synaptic relationship between catecholamine terminals and adrenocorticotropic hormone (ACTH)-containing neurons in the arcuate nucleus (AN) of the rat hypothalamus was investigated by electron microscopy, using ACTH immunocytochemistry combined with autoradiography after 3H-dopamine (3H-DA) injection or 5-hydroxydopamine (5-OHDA) uptake in the same tissue section. ACTH-like (ACTH-LI) immunoreactive nerve cell bodies and fibers received synaptic inputs by axon terminals labeled with 3H-DA or 5-OHDA in the AN. This suggests that catecholaminergic neurons, at least DA- and 5-OHDA-containing neurons, may play an important role in the regulation of ACTH secretion or other functions of ACTH neurons via synapses in the AN of the rat hypothalamus.

Receptor-mediated actions of corticotropin-releasing factor in pituitary gland and nervous system.

High-affinity corticotropin-releasing factor (CRF) receptors which mediate the actions of the hypothalamic peptide on adrenocorticotropic hormone (ACTH) release have been identified in the rat anterior pituitary gland. Occupancy of the pituitary receptor by CRF agonists stimulates ACTH release via activation of adenylate cyclase and cyclic adenosine monophosphate dependent protein kinase. In the regulation of ACTH secretion, the effects of CRF on the corticotroph are integrated with the stimulatory actions of cyclic adenosine monophosphate-independent stimuli such as angiotensin II, vasopressin and norepinephrine, and the inhibitory effects of glucocorticoids and somatostatin. In contrast to the major importance of the inhibitory effect of glucocorticoid feedback on ACTH secretion, somatostatin has relatively little effect on CRF-stimulated ACTH release in the normal rat corticotroph. Following adrenalectomy, the progressive elevation of plasma ACTH levels is accompanied by a concomitant decrease in pituitary CRF receptors. The postadrenalectomy loss of CRF receptors, which is prevented by dexamethasone treatment, is caused by a combination of occupancy and processing of the pituitary sites during increased secretion of the hypothalamic peptide. Recently, specific receptors for CRF have been localized in the rat and monkey brain and adrenal medulla, where they are also coupled to adenylate cyclase. Brain CRF receptors are most abundant in the cerebral and cerebellar cortices and in structures related to the limbic system and control of the autonomic nervous system. The actions of CRF on the central and peripheral nervous systems, as well as on the pituitary gland, emphasize the role of CRF as a key hormone in the integrated response to stress.

Fast, rate-sensitive corticosteroid negative feedback during stress

Characteristics of the fast, rate-sensitive, negative-feedback regulation of adrenocorticotropin secretion during stress was quantitatively analyzed using rats anesthetized with pentobarbital sodium. Various levels of plasma corticosterone were achieved during morning hours by infusing corticosterone solutions of different concentrations. Blood was sampled serially from the carotid artery. An increase in plasma corticosterone concentration 15 min after intravenous, pulsed injection of histamine (230 microgram) during saline intravenous infusion was defined as the "control response". When plasma corticosterone was rising during corticosterone infusion, the response to histamine stimulus was distinctly inhibited (fast, rate-sensitive feedback inhibition), whereas such an inhibition was not observed when plasma corticosterone levels were not rising, regardless of the absolute level. The critical rate of rise of plasma corticosterone, at or above which the fast rate-sensitive feedback was manifested, was 4-6 microgram/100 ml per min. When three graded doses of histamine were injected while plasma corticosterone levels were increasing at a rate of 6 microgram/100 ml per min, the absolute value of the inhibition observed was independent of the administered dose of the stressor. A hypothetical model for the mechanism of this feedback inhibition, based on the assumption that the hormone effect was proportional to the rate of formation of hormone-receptor complex, satisfied the quantitative characteristics of the inhibition experimentally observed in this study.

The Role of “Short” Feedback Mechanisms in the Regulation of Adrenocorticotropin Secretion

Publisher Summary A short feedback mechanism may play a physiological role in the control of the secretion of the adrenocorticotropic hormone (ACTH). The existence of a control mechanism of the short type has been demonstrated for all the hormones manufactured in the anterior pituitary gland, as well as for the melanocyte stimulating hormone (MSH), which, in several species of animals, is secreted by the intermediate lobe. A short system is involved also in the control of the secretion of those pituitary hormones (growth hormone, prolactin, and MSH) that do not have a peripheral target gland and consequently are not regulated by traditional feedback mechanisms. In a study described in the chapter, ACTH proved effective in depressing blood corticosterone levels and in inhibiting the response to the mild stress, but only when placed in the median eminence (ME) region. Implants of ACTH in the frontal cerebral cortex or the pituitary were completely ineffective, as were implants of luteinizing hormone (LH) in the ME.