Basal Hormone Release Research Articles

Small GTPase control of pituitary hormone secretion: Evidence from studies in the goldfish (Carassius auratus) neuroendocrine model

The secretion of vertebrate pituitary hormones is regulated by multiple hypothalamic factors, which, while generally activating unique receptor systems, ultimately propagate signals through interacting intracellular regulatory elements to modulate hormone exocytosis. One important family of intracellular regulators is the monomeric small GTPases, a subset of which (Arf1/6, Rac, RhoA, and Ras) is highly conserved across vertebrates and regulates secretory vesicle exocytosis in many cell types. In this study, we investigated the roles of these small GTPases in basal and agonist-dependent hormone release from dispersed goldfish (Carassius auratus) pituitary cells in perifusion experiments. Inhibition of these small GTPases elevated basal LH and GH secretion, except for Ras inhibition which only increased basal LH release. However, variable responses were observed with regard to LH and GH responses to the two goldfish native gonadotropin-releasing hormones (GnRH2 and GnRH3). GnRH-dependent LH release, but not GH secretion, was mediated by Arf1/6 GTPases. In contrast, inhibition of Rac and RhoA GTPases selectively enhanced GnRH3- and GnRH2-dependent GH release, respectively, while Ras inhibition only enhanced GnRH3-evoked LH secretion. Together, our results reveal novel divergent cell-type- and ligand-specific roles for small GTPases in the control of goldfish pituitary hormone exocytosis in unstimulated and GnRH-evoked release.

β-Arrestin-dependent signaling in GnRH control of hormone secretion from goldfish gonadotrophs and somatotrophs

In goldfish, two native isoforms of gonadotropin-releasing hormone (GnRH2 and GnRH3) stimulate luteinizing hormone (LH) and growth hormone (GH) release from pituitary cells through activation of cell-surface GnRH-receptors (GnRHRs) on gonadotrophs and somatotrophs. Interestingly, GnRH2 and GnRH3 induce LH and GH release via non-identical post-receptor signal transduction pathways in a ligand- and cell-type-selective manner. In this study, we examined the involvement of β-arrestins in the control of GnRH-induced LH and GH secretion from dispersed goldfish pituitary cells. Treatment with Barbadin, which interferes with β-arrestin and β2-adaptin subunit interaction, reduced LH responses to GnRH2 and GnRH3, as well as GH responses to GnRH2; but enhanced GnRH3-induced GH secretion. Barbadin also had positive influences on basal hormone release, and basal GH release in particular, as well as basal activity of extracellular signal-regulated kinase (ERK) and GnRH-induced ERK activation. These findings indicate that β-arrestins play permissive roles in the control of GnRH-stimulated LH release. However, in somatotrophs, β-arrestins, perhaps by mediating agonist-selective endosomal trafficking of engaged GnRHRs, participate in GnRH-isoform-specific GH release responses (stimulatory and inhibitory for GnRH2-GnRHR and GnRH3-GnRHR activation, respectively). The correlative stimulatory influences of Barbadin on basal hormone release and ERK activation suggest that β-arrestins may negatively regulate basal secretion through modulation of basal ERK activity. These results provide the first direct evidence of a role for β-arrestins in hormone secretion from an untransformed primary pituitary cell model, and establish these proteins as important receptor-proximal players in mediating functional selectivity downstream of goldfish GnRHRs.

The Role of Uron and Chlorobenzene Derivatives, as Potential Endocrine Disrupting Compounds, in the Secretion of ACTH and PRL.

Uron herbicides polluting the environment represent a serious concern for environmental health and may be regarded as endocrine-disrupting compounds (EDCs), which influence the regulation of human homeostasis. We aimed to investigate the effect of EDC urons (phenuron: PU, monuron: MU, and diuron: DU) and chlorobenzenes on the basal release of the adrenocorticotropic hormone (ACTH), which is a part of the adenohypophysis-adrenocortical axis. Hormone secretion in the presence of EDC was studied in two cell types: normal adenohypophysis cells (AdH) and cells of prolactinomas (PRLOMA). PRLOMA was induced in female Wistar rats by subcutaneously injecting them with estrone acetate for 6 months. AdH and PRLOMA were separated from treated and untreated experimental animals, dissociated enzymatically and mechanically in order to create monolayer cell cultures, which served as an experimental in vitro model. We investigated the effects of ED agents separately and in combination on ACTH and prolactin (PRL) release through the hypophyseal-adrenal axis. Hormone determination was carried out by the luminescent immunoassay and the radioimmunoassay methods. Our results showed that (1) uron agents separately did not change ACTH and PRL release in AdH culture; (2) ACTH secretion in arginine vasopressin- (AVP-) activated AdH cells was significantly increased by EDC treatment; (3) ED agents increased the basal hormone release (ACTH, PRL) in PRLOMA cells; and (4) EDC exposure increased ACTH release in AVP-activated PRLOMA cells. We conclude that the herbicides PU, MU, and DU carry EDC effects and show human toxicity potential.

Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells.

SummaryHuman pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.

Transplantation of bovine adrenocortical cells encapsulated in alginate

Current treatment options for adrenal insufficiency are limited to corticosteroid replacement therapies. However, hormone therapy does not replicate circadian rhythms and has unpleasant side effects especially due to the failure to restore normal function of the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal cell transplantation and the restoration of HPA axis function would be a feasible and useful therapeutic strategy for patients with adrenal insufficiency. We created a bioartificial adrenal with 3D cell culture conditions by encapsulation of bovine adrenocortical cells (BACs) in alginate (enBACs). We found that, compared with BACs in monolayer culture, encapsulation in alginate significantly increased the life span of BACs. Encapsulation also improved significantly both the capacity of adrenal cells for stable, long-term basal hormone release as well as the response to pituitary adrenocorticotropic hormone (ACTH) and hypothalamic luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6]LHRH. The enBACs were transplanted into adrenalectomized, immunodeficient, and immunocompetent rats. Animals received enBACs intraperitoneally, under the kidney capsule (free cells or cells encapsulated in alginate slabs) or s.c. enclosed in oxygenating and immunoisolating βAir devices. Graft function was confirmed by the presence of cortisol in the plasma of rats. Both types of grafted encapsulated cells, explanted after 21-25 d, preserved their morphology and functional response to ACTH stimulation. In conclusion, transplantation of a bioartificial adrenal with xenogeneic cells may be a treatment option for patients with adrenocortical insufficiency and other stress-related disorders. Furthermore, this model provides a microenvironment that ensures 3D cell-cell interactions as a unique tool to investigate new insights into cell biology, differentiation, tissue organization, and homeostasis.

Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective.

Managing precocious puberty (PP) has been a challenge due to lack of standardized definition, gonadotrophins assay, gonadotrophin stimulation, timings for blood sampling, and parameters for assessing outcomes. This review evaluated available literature to simplify the algorithm for managing gonadotrophin dependent/central PP (CPP), with an Indian perspective. CPP is one of the commonest forms of PP and mimics the normal course of puberty, at an age <8 and 9 years for girls and boys respectively. Basal and post gonadotrophin hormone releasing hormone analog (GnRHa) luteinizing hormone (LH) ≥0.3–0.6 IU/L and ≥4–5 IU/L (30–60 min after GnRH/GnRHa administration) respectively, using modern ultrasensitive automated chemiluminescence assays, can be considered positive for central puberty initiation. Uterine length of >3.5 cm and uterine volume of >1.8 ml are two most specific indicators for true CPP. Therapy is indicated in children with CPP with accelerated bone age, height advancement, or psychosocial stress. Treatment goal is to halt puberty progression to a socially acceptable age, allowing the child to attain optimal height potential. GnRHa is the treatment of choice, with best height outcomes when initiated <6 years age. Treatment is recommended till 11 years age. LH suppression to <3 U/L may be a reasonable target in patients on GnRHa therapy. Medroxyprogesterone acetate holds an important place in managing PP in India, cause of high costs associated with GnRHa therapy. There is an urgent need for clinical trials from India, for establishing Indian cut-off for diagnosis, treatment and follow-up of children with PP.

Morphological study of adrenal glands in Wistar rat subjected to chronic dehydration : Comparison with a desert rodent Gerbillus tarabuli

Diet constitutes an important source of water in desert environments. For rodents surviving under such drastic conditions suggests a state of permanent stress. So, we investigated the effect of chronic dehydration on plasma parameters and adrenal gland structure compared to that of Gerbillus tarabuli. 12 male rats were divided into control and dehydrated group submitted to ingestion of 2 % saline solution for 7 days. Gerbils (n = 6) group was fed with barely grain. Osmolality, and hematocrit were determined and adrenal glands were treated by histological technique. Dehydrated rats show a significant increase in hematocrit and osmolality ; confirming hypovolemic state. Gerbil presented low hematocrit suggesting that their blood contains more water. However, its osmolality was similar to that of dehydrated rats. Dehydration induced degranulation of adrenaline chromaffine cells and enlargement of capillaries, suggesting strong adrenalin release. However, gerbils showed the same structure as that of controls, indicating basal stress hormone release. Parallely, the zona fasciculata (ZF) of dehydrated rats and gerbils, show a loss of the spongy appearance and capillary dilatations which can be related to an increased production of glucocorticoides. Considering all results, it appears that the chronic dehydration constitutes a stress condition in Wistar rats, but shortage of water, which characterizes the arid environment of gerbil is not a stress factor for this specie. In gerbil, morphological features of ZF, don’t seem to be a stress response ; it would be rather an indication of metabolic strategy, probably for metabolic water production.

PI3K signalling in GnRH actions on dispersed goldfish pituitary cells: Relationship with PKC-mediated LH and GH release and regulation of long-term effects on secretion and total cellular hormone availability

Goldfish pituitary cells are exposed to two GnRHs, salmon (s)GnRH and chicken (c)GnRH-II. Phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) both participate in acute sGnRH- and cGnRH-II-stimulated LH and GH release. Using goldfish pituitary cells, we examined the relationship between PI3K and PKC in acute LH and GH secretion, and PI3K involvement in chronic hormone release and total LH and GH availability. The PI3K inhibitor LY294002 did not affect PKC agonists-induced LH or GH release, and PKC agonists did not alter PI3K p85 phosphorylation, suggesting PKC activation is not upstream of PI3K in acute hormone release. In 2, 6, 12 and 24h treatments, LY294002 did not affect LH release but stimulated total LH availability at 6h. sGnRH stimulatory actions on LH release and total availability at 12 and 24h, and cGnRH-II effects on these parameters at 6h were inhibited by LY294002. LY294002 enhanced basal GH release at 2 and 6h, but reduced total GH at 12 and 24h. Increased GH release was seen following 6, 12 and 24h of sGnRH, and 2, 6 and 24h of cGnRH-II treatment but total GH availability was only elevated by 24h cGnRH-II treatment. Whereas LY294002 inhibited GH release responses to sGnRH at 12h and cGnRH-II at 6h, it attenuated cGnRH-II-elicited, but not sGnRH-induced, effects on total GH. These results indicate that PI3K differentially modulates long-term basal and GnRH-stimulated hormone release, and total hormone availability, in a time-, cell-type-, and GnRH isoform-selective manner.

Effect of Inhaled Corticosteroids on Growth and Puberty in Egyptian Asthmatic Children and Adolescents

Growth suppression and delayed puberty may be major concerns for Inhaled Corticosteroids (ICS) treatment in children. Thus, we aimed to assess the effect of long-term ICS on growth and pubertal status in 30 asthmatic children and adolescents in comparison to 20-matched healthy subjects. Auxological measurements, Tanner staging and bone age assessment were performed. Measurements of basal and Lutenizing hormone releasing hormone (LHRH) stimulated follicle stimulating hormone (FSH) and Lutenizing hormone (LH) were done for patients only. In addition, pelvic ultrasound for measurements of uterine length and right ovarian volume was done for females aged > 11 years. Patients' height, bone age and their Standard Deviation Scores (SDSs) were significantly lower, while weight SDSs were significantly higher than controls. ICS at doses > 400 microg/day negatively affected height and its SDS (OR: 8.5, 95% CI: 2.15-33.8), whereas the use of ICS for > 1 year significantly affected all auxological parameters with a particular risk on height SDS (OR: 9, 95% CI = 3.10-10.64) and weight for height SDS (OR: 6.82, 95% CI: 1.36-34.27). Significantly lower stimulated gonadotropins were encountered at doses > 400 microg/day, while a duration > 1 year was associated with significantly lower basal and stimulated gonadotropins. Logistic analysis revealed that the use of ICS for > 1 year carried the highest risk of association with low stimulated FSH (OR: 5.80, 95%, CI: 1.54-33.70) and LH (OR: 8.31, 95% CI: 1.83-50.47). In conclusion, ICS at doses > 400 microg/day carry a significant risk of retarding height of asthmatic children while their continuous use for > 1 year carries significant risks of short stature, weight gain and delayed puberty.

In vivo fluorescence imaging of glutamate in sensory cortex

Human pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.

T3-release from autonomously functioning thyroid nodules in vitro.

Toxic thyroid nodules have been shown to be of clonal origin. In a portion of them, point mutations affecting either the gene of the TSH receptor (TSHr) or the alpha-subunit of stimulating G-protein, consecutively leading to enhanced cAMP levels, which may enhance growth or functional activity of the thyrocyte or both, were recently found. To complement these studies, we evaluated hormone response (i.e. T3 release) in vitro from tissues derived from toxic thyroid nodules as compared directly to the surrounding paranodular tissues as well as tissues derived from euthyroid goiter and from patients with Graves' disease. Experiments were conducted in the presence and absence of bTSH or Graves' immunoglobulines. Tissues obtained during surgery were incubated over 5 h, followed by equilibrium dialysis for 24 h, and determination of free T3 in an aliquot by RIA. Basal T3 release in nodular tissues (n = 10) was significantly higher (median: 7.3 ng/l) compared to paranodular tissues (3.2 ng/l; P < 0.01), tissues derived from euthyroid goiter (1.3 ng/l; n = 12; P < 0.001) and thyroid tissues derived from patients with Graves' disease (2.5 ng/l; n = 6; P < 0.001). Upon stimulation with bTSH (1 IU/l), median T3 concentrations markedly increased to 11.5 ng/l (P < 0.05), 7.3 ng/l (P < 0.05), 4.2 ng/l (P < 0.01) and 3.2 ng/l (P = N.S.), respectively. Stimulation over basal values was 1.6-fold in nodular tissues, 2.3-fold in paranodular tissues, 3.2-fold in euthyroid goiter and 1.3-fold in Graves' disease. In toxic thyroid nodules basal hormone-releasing activities were stimulated by fifteen out of twenty (75%) Graves' sera tested. For comparison, stimulation in other tissues occurred in 45% (paranodular), 80% (euthyroid goiter) and 35% (Graves' disease), respectively. In conclusion, tissue derived from toxic thyroid nodules exhibits enhanced basal hormone release as compared to both, the surrounding paranodular tissues and tissues from euthyroid goiter in vitro, which may reflect constitutional activation of TSHr, alpha-subunit of stimulating G-protein or other so far unknown intermediate by point mutations affecting the respective genes. Hyperactivities in toxic thyroid nodules may be even further enhanced by external stimulators such as TSH or TSH receptor antibodies. The first stimulator may have clinical relevance in patients with toxic thyroid nodules and not yet suppressed TSH; the latter could play a role in the rare Marine Lenhart syndrome.

Erythropoietin Inhibits Basal and Stimulated Corticotropin-Releasing Hormone Release from the Rat Hypothalamus via a Nontranscriptional Mechanism

Brain hypoxia-ischemia induces a local increase in the levels of erythropoietin (EPO) and vascular endothelial growth factor (VEGF); this condition is also associated with acute activation of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that increased levels of EPO and VEGF in the hypothalamus may play a role in the control of HPA function. Thus, in this study we used rat hypothalamic explants to investigate whether EPO and VEGF can directly modulate CRH release; the latter was assessed by RIA measurement of the peptide in the incubation medium and hypothalamic tissue. EPO and VEGF effects were studied in short-term (1-3 h) experiments under basal conditions or after stimulation with 56 mM KCl or 10 microM veratridine. We observed that EPO (1-10 nm) significantly reduced CRH release and, in parallel, increased intrahypothalamic CRH content. VEGF tended to reduce CRH release without reaching statistical significance. Moreover, EPO, but not VEGF, inhibited KCl- and veratridine-stimulated CRH release and counteracted the parallel decrease in intrahypothalamic CRH induced by the two secretagogues. EPO effects were not mediated by modification of CRH gene expression, either in the absence or the presence of KCl or veratridine; in this paradigm, KCl and veratridine per se did not modify CRH gene expression. Our findings suggest that EPO contributes to the regulation of the HPA axis activation; in pathological conditions such as brain ischemia, this growth factor may control the HPA axis function, preventing possible detrimental effects of HPA overactivation.

Effects of testosterone on hormonal content and calcium-dependent basal secretion in female rat pituitary cells

In vivo and in vitro effects of elevated androgens on agonist-induced gonadotropin secretion have been addressed previously. Here we investigated the effects of testosterone on hormonal content and basal (in the absence of agonists) hormone release in pituitary lactotrophs, somatotrophs and gonadotrophs from female rats. Furthermore we tested the hypothesis that testosterone action is dependent on the pattern of spontaneous and Bay K 8644 (a L-type calcium channel agonist) -induced calcium signalling. Mixed anterior pituitary cells were cultured in steroid containing or depleted media, and testosterone (1 pM to 10 nM) was added for 48 h. Cells were studied for their spontaneous and Bay K 8644-induced calcium signalling pattern and total hormone levels (release and hormonal content). In lactotrophs, somatotrophs and gonadotrophs testosterone did not affect the pattern of spontaneous calcium signalling. Bay K 8644-induced calcium signalling and hormone release were not affected by testosterone. In both steroid-depleted and -containing medium, testosterone inhibited prolactin (PRL), luteinizing hormone (LH) and growth hormone (GH) cellular content and release in a dose-dependent manner, with IC 50s in a sub-nanomolar concentration range. These results indicate that testosterone inhibits basal hormone release from lactotrophs, somatotrophs and gonadotrophs without affecting intracellular calcium signalling. This action of testosterone is not dependent on the presence of other steroid hormones.

SV2A and SV2C are not vesicular Ca2+ transporters but control glucose-evoked granule recruitment

Synaptic vesicle protein 2 (SV2) is expressed in neuroendocrine cells as three homologous isoforms, SV2A, SV2B and SV2C. Ca2+-dependent function in exocytosis has been attributed to SV2A and SV2B, without elucidation of the mechanism. The role of SV2C has not yet been addressed. Here we characterize the three SV2 isoforms and define their involvement in regulated insulin secretion. SV2A and SV2C are associated with insulin-containing granules and synaptic-like-microvesicles (SLM) in INS-1E insulinoma and primary beta-cells, whereas SV2B is only present on SLM. Neither overexpression nor isoform-specific silencing of SV2A or SV2C by RNA interference modifies depolarization-triggered cytosolic [Ca2+] rises or secretory granule [Ca2+], measured with a VAMP-2 aequorin chimera. This strongly argues against any Ca2+ transport function of SV2. Moreover, up- or downregulation of these isoforms has no influence on K+-induced insulin release suggesting that SV2 does not affect the Ca2+-dependent step(s) of exocytosis. By contrast, glucose-elicited secretion is inhibited during the sustained rather than the early phase, placing the action of SV2 on the recruitment of granules from the reserve pool to the plasma membrane. This conclusion is reinforced by capacitance measurements in glucose-stimulated SV2C-deficient cells. Like capacitance, evoked and basal hormone release are attenuated more by silencing of SV2C compared with SV2A. This indicates only partial redundancy and highlights a key role for SV2C in the secretory process.

Structural organization and biological relevance of oscillatory parathyroid hormone secretion

Parathyroid gland secretory activity exhibits seasonal and circadian fluctuations, which are in synchrony with changes in serum calcium, phosphate, and bone turnover. In addition, an ultradian rhythm exists, which comprises seven pulses per hour, accounts for 30% of basal parathyroid hormone (PTH) release, and is highly sensitive to changes in ionized calcium. Acute hypocalcemia induces a selective, severalfold increase in pulse frequency and amplitude, whereas hypercalcemia suppresses the pulsatile secretion component, as does prolonged calcitriol therapy. Chronic renal failure is associated with a GFR dependent decrease in metabolic PTH clearance accounting for a two- to threefold increase in plasma PTH concentrations, a consistent increase of PTH burst mass and frequency, and a markedly reduced capacity to counteract changes in ionized calcium by modulation of pulsatile PTH release. Continuous PTH excess destroys bone, whereas intermittent administration of pharmacological doses of PTH improves bone morphology and strength in experimental and clinical settings. The molecular mechanisms of the exposure pattern dependent, contrasting biological effects of PTH may involve differential regulation of osteoblastic G protein signaling feedback circuits. In this context, calcimimetic and calcilytic agents are promising new therapeutic tools allowing for tight control of plasma PTH and restoration of circadian PTH rhythmicity.

Slow spontaneous secretion from single large dense-core vesicles monitored in neuroendocrine cells.

Hormones are released from cells by passing through an exocytotic pore that forms after vesicle and plasma membrane fusion. In stimulated exocytosis vesicle content is discharged swiftly. Although rapid vesicle discharge has also been proposed to mediate basal secretion, this has not been studied directly. We investigated basal hormone release by preloading fluorescent peptides into single vesicles. The hormone discharge, monitored with confocal microscopy, was compared with the simultaneous loading of vesicle by FM styryl dye. In stimulated vesicles FM 4-64 (4 microM), loading and hormone discharge occurs within seconds. In contrast, in approximately 50% of spontaneously releasing vesicles, the vesicle content discharge and the FM 4-64 loading were slow (approximately 3 min). These results show that in peptide secreting neuroendocrine cells the elementary vesicle content discharge differs in basal and in stimulated exocytosis. It is proposed that the view dating back for some decades, which is that, at rest, the vesicle discharge of hormones and neurotransmitters is similar to that occurring after stimulation, needs to be extended. In addition to the classical paradigm that secretory capacity of a cell is determined by controlling the probability of occurrence of elementary exocytotic events, one will have to consider activity modulation of elementary exocytotic events as well.

Deconvolution Analysis as a Hormone Pulse-Detection Algorithm

This chapter describes an iterative parametric deconvolution technique to identify and quantitate basal and pulsatile hormone release, while concurrently estimating endogenous hormone half lives. Simulated examples of the application of this methodology indicate that at least for plausible synthetic time series, this parametric deconvolution approach is superior to the CLUSTER method in locating hormone secretion events. PULSE4 also provides crucial information about secretion-event burst mass, elimination half-lives, and basal secretion. The accompanying simulations also offer guidelines about the features of the experimental data that are required for an accurate characterization of the pulsatile nature of hormone release. The sampling frequency should be such that there are approximately four or more data points per elimination half-life. Parametric deconvolution-based hormone pulse identification methods also have specific limitations in the maximum detectable hormone pulse frequency. After each secretion event, the concentration of the hormone begins to decrease according to the elimination kinetics. To accurately parameterize the elimination process and basal secretion, a significant amount of elimination must take place before the next secretion event.

Taurine and the control of basal hormone release from rat neurohypophysis

Pituicytes of pituitary neural lobe are rich in the amino acid taurine, which they release upon hypoosmotic stimulation. As a generally inhibitory amino acid, taurine is thought to activate receptors on neural lobe nerve terminals and exert some control over hormone release. Previous work has shown the presence of glycine and GABA A receptors in neural lobe, both of which have affinity for taurine. Using a perifused explant system, we studied the effects of taurine activation of glycine and GABA A receptors on basal hormone release. Somewhat surprisingly, taurine induced increases in basal release of both vasopressin and oxytocin. Taurine-induced increases in oxytocin release were blocked by bicuculline, suggesting involvement of GABA A receptors. Increases in vasopressin release were not blocked by bicuculline, indicating involvement of receptors other than GABA A. Although combined bicuculline and strychnine, an antagonist at most glycine receptors, also did not block increased vasopressin release, picrotoxin (a Cl − channel blocker) was effective in blocking increases in both vasopressin and oxytocin release. The other receptor(s) involved in taurine actions is postulated to be strychnine-insensitive glycine receptors. Thus, taurine in neural lobe may act via both a GABA A receptor and one or more types of glycine receptors to depolarize nerve terminal membranes under basal conditions. Taurine-induced partial depolarization resulting in Na + channel inactivation is probably responsible for its previously observed inhibition of stimulated hormone release from neural lobe.

Neuroendocrine adaptations in renal disease.

Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion. At the hypothalamo-pituitary level, experimental evidence suggests that CRF reduces the synthesis and/or release of the cognate hypothalamic releasing factors, GHRH and LHRH, and enforces excessive inhibition by somatostatin. Parathyroid hormone (PTH) and insulin are secreted in both basal and pulsatile modes, wherein the latter is putatively coordinated by autonomic innervation. Amplitude and frequency-dependent adaptations of PTH and insulin outflow fail in CRF, as assessed under steady-state conditions and during metabolic drive (i.e., calcium for PTH and glucose for insulin). A common feature in CRF is a diminished mass of hormone released per burst, due in principle to attenuation of feedforward signals and/or accentuation of (unknown) feedback signals. Damping of neuronal control and/or prolonged network response times may contribute to aberrant pulse frequency, disproportionate basal (nonpulsatile) hormone release, and consistent erosion of secretory process regularity in the uremic state. The homeostatic consequences of distorted secretory dynamics, tissue resistance, impaired hormone clearance, and altered mean agonist concentrations are evident in certain therapeutic interventions, such as GH supplementation in CRF.

Mechanisms Involved in Glucagon-Like Peptide-1 (7–36) Amide Action on the Rat Hypothalamo-Neurohypophysial System

Glucagon-like peptide-1 (7–36) amide (tGLP-1) has been shown to modify the secretory function of the rat hypothalamo-neurohypophysial complex (HNC). However, mechanisms underlying this action are still unclear. Using explants containing the HNC obtained from euhydrated rats, possible interactions of tGLP-1 with angiotensin II (Ang II), forskolin-induced cAMP synthesis or calcium ions were investigated. In addition, explants taken from rats given 2% saline were used in order to examine whether chronic osmotic stimulation affects tGLP-1 action on vasopressin and oxytocin neurons. tGLP-1 did not modify Ang II- or forskolin-evoked hormone release. Incubation of the HNC in calcium-free medium inhibited the tGLP-1-dependent vasopressin/oxytocin secretion. Prolonged salt loading in vivo completely changed the neurohypophysial response to tGLP-1 in vitro; it did not only abolish the stimulatory effect of tGLP-1 on basal hormone release, but reduced K⁺-stimulated vasopressin/oxytocin secretion. Consequently, the neurohypophysial response to tGLP-1 may depend on the functional status of the HNC and on the presence of calcium ions, but not cAMP.