Biomedical subjects

J Epelbaum

Publications and source records attributed to J Epelbaum.

At least 55 records · Page 3Linked to original sources

PubMed1998

Hypothalamic and hypophyseal regulation of growth hormone secretion.

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex steroid receptors in the ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5. Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on ARC neurons. 6. At the pituitary level, major neurotransmitters regulating GH cells act on receptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and several neuropeptides, for instance, vasoactive intestinal peptide, angiotensin 2, endothelin, and activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and dwarfism, diabetes, and acromegaly, as well as during inflammatory processes.

Animals↗

PubMed1998

Profiles of amyloid precursor and presenilin 2-like proteins are correlated during development of the mouse hypothalamus.

The amyloid precursor protein (APP) and APP-like (APLP) material, as visualized with the Mab22C11 antibody, have previously been shown to be associated with radial glia in hypothalamus, which are known to promote neurite outgrowth. By Northern blot analysis, APP 695 mRNA levels increased steadily over hypothalamic development, APP 770 mRNA was transiently expressed at 12 days postnatally, and APLP mRNA was only weakly expressed in the hypothalamus. The developmental pattern of APP moeities in mouse hypothalamus and in fetal hypothalamic neurons in culture was compared with a presenilin 2 (PS2) related protein using an antibody developed against the N-terminal part of PS2. By Western blot analysis, APP and PS2-like immunoreactivity were visualized as a 100-130 and 52 kDa bands, respectively. An APP biphasic increase was observed during hypothalamic development in vivo. APP immunoreactivity was equally detected in neuronal and glial cultures, while PS2-like material was more concentrated in neurons. A correlation between APP/APP-like and PS2-like levels was observed during development in vivo. While APP was mostly associated with membrane fractions, a significant portion of PS2-like material was also recovered from cytosolic fractions in vitro. In contrast to native PS2 in COS-transfected cells, the PS2-like material did not aggregate after heating for 90 s at 90 degrees C. These results indicate a close association between APP and PS2-like material during hypothalamic development in vivo, and suggest that neuronal and glial cultures may provide appropriate models to test their interactions.

Amyloid beta-Protein Precursor↗

PubMed1998

Interrelations between hypothalamic somatostatin and proopiomelanocortin neurons.

Somatostatin receptors were visualized by [125I]-Tyr0-DTrp8-somatostatin radioautography on 35% of arcuate neurons containing proopiomelanocortin (POMC) mRNA, as identified by in situ hybridization using a [35S] labelled riboprobe on 5 microm-thick consecutive sections. Furthermore, double immunohistochemical staining revealed contacts of beta-endorphin or alpha-MSH containing fibres with a majority of somatostatin perikarya in the anterior hypothalamic periventricular nucleus. Taken together, these data indicate that hypothalamic somatostatin and POMC neurons are interconnected. The results are discussed in term of intrahypothalamic control of GH secretion.

Animals↗

PubMed1998

Somatostatin receptor subtypes sst1 and sst2 elicit opposite effects on the response to glutamate of mouse hypothalamic neurones: an electrophysiological and single cell RT-PCR study.

We have previously shown that somatostatin can either enhance or decrease AMPA/kainate receptor-mediated responses to glutamate in mouse-dissociated hypothalamic neurones grown in vitro. To investigate whether this effect is due to differential activation of somatostatin (SRIF) receptor subtypes, we compared modulation of the response to glutamate by SRIF with that induced by CH-275 and octreotide, two selective agonists of sst1 and sst2/sst5 receptors, respectively. Somatostatin either significantly decreased (49%) or increased (30%) peak currents induced by glutamate, and was ineffective in the remaining cells. Only the decreased response was obtained with octreotide, whereas only increased responses were elicited by CH-275 (47 and 35% of the tested cells, respectively). Mean amplitude variations under somatostatin or octreotide on the one hand, and under somatostatin or CH-275 on the other hand, were equivalent. Pertussis toxin pretreatment significantly decreased the number of cells inhibited by somatostatin or octreotide, but had no effect on the frequency of neurones showing increased sensitivity to glutamate during somatostatin or CH-275 application. About half of the neurones tested by single cell reverse transcriptase polymerase chain reaction (RT-PCR) expressed only one sst receptor (sst1 in 26% and sst2 in 22% of studied cells). Out of the remaining neurones, 34% displayed neither sst1 nor sst2 mRNAs, whereas 18% showed a simultaneous expression of both mRNA subtypes. Expression of sst1 or sst2 mRNA subtypes matched totally with the effects of somatostatin on sensitivity to glutamate in 79% of the neurones processed for PCR after recordings. These data show that pertussis toxin-insensitive activation of the sst1 receptor subtype mediates somatostatin-induced increase in sensitivity to glutamate, whereas decrease in the response to glutamate is linked to pertussis toxin-sensitive activation of the sst2 receptor subtype.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1998

Effects of damage to the basal forebrain on brain glucose utilization: a reevaluation using positron emission tomography in baboons with extensive unilateral excitotoxic lesion.

Neuronal loss in the basal forebrain cholinergic structures and frontotemporal hypometabolism are two characteristics of Alzheimer's disease, but their interrelations still are unsettled. We previously reported that unilateral electrolytic lesions of the nucleus basalis of Meynert in baboons were associated with marked but transient cortical hypometabolism. The current study reevaluates this issue using improved methodology. Baboons with unilateral ibotenic acid lesion of all three basal forebrain cholinergic structures (IBO group) were compared with sham-operated animals. The CMRglc was measured with high-resolution coronal positron emission tomography scanning coregistered with magnetic resonance imaging, before surgery and serially between 4 and 72 days afterward. Severe histologic basal forebrain damage and a decrease of more than 50% in cortical choline acetyltransferase activity were found postmortem in the IBO group. Transient and nonspecific hypometabolism was found in the needle track area in both groups. Compared with the sham-operated group, only marginally significant decreases in ipsilateral-contralateral CMRglc ratios were observed in the IBO group, affecting only 1 of 14 neocortical areas investigated (the anterior temporal cortex) at a single postsurgical time (day 14), and the posterior hippocampal region at days 14 and 38. Furthermore, there was no consistently significant correlation between ipsilateral-contralateral CMRglc ratios and cortical choline acetyltransferase activity values in any of the four regions analyzed. These results suggest that cholinergic deafferentation play at best a marginal role in the brain hypometabolism observed in Alzheimer's disease.

Alzheimer Disease↗

PubMed1998

Long-term inhibitory effects of somatostatin and insulin-like growth factor 1 on growth hormone release by serum-free primary culture of pituitary cells from European eel (Anguilla anguilla).

To investigate the ability of hypothalamic and peripheral factors to directly regulate growth hormone (GH) release in a primitive teleost, the European eel (Anguilla anguilla L.), we used primary cultures of dispersed pituitary cells. When cultured for 12 days in a serum-free medium, pituitary cells continuously released large amounts of GH, which exceeded the initial cellular content. Somatotropin-release inhibiting hormone (SRIH-14) dose-dependently inhibited GH release (EC50 0.75 nM) up to a maximal inhibitory effect of 95%. No desensitization of somatotropes to SRIH was observed over the 12 days of culture. Use of receptor subtype-selective SRIH agonists suggests the existence on eel somatotropes of SRIH receptor(s) related to the mammalian sst2/sst3/sst5 class rather than to the sst1/sst4 class. Insulin-like growth factor 1 (IGF1) dose-dependently inhibited GH release (EC50 0.03 nM) up to a maximal inhibitory effect of 85%, without desensitization. IGF1 and IGF2 were equipotent in inhibiting GH release, whereas insulin was 1,000 times less active, suggesting the implication of a receptor related to the mammalian IGF type 1 receptor. These results indicate that eel somatotropes are active in vitro without any specific additional factors, and suggest the existence of a dominant inhibitory control of GH release in vivo. Two potential candidates for this chronic negative regulation are a neurohormone, SRIH and a circulating factor, IGF1. These data underline the early evolutionary origin of the molecular and functional SRIH-GH-IGF1 neuroendocrine axis in vertebrates.

Anguilla↗

PubMed1998

Effect of 17beta-estradiol on somatostatin receptor expression and inhibitory effects on growth hormone and prolactin release in rat pituitary cell cultures.

In the present study, we tested whether 17beta-estradiol (E2)-induced PRL sensitivity to somatostatin-14 (SRIF) involves selective up-regulation of discrete somatostatin receptor subtypes (ssts) in primary cultures of female rat pituitary cells. The efficacy of the endogenous peptide SRIF to inhibit GH and PRL secretion and cAMP accumulation was compared with those of octreotide (OCT), BIM-23052, BIM-23056, and BIM-23268, which have been reported to be relatively selective for rat sst2, sst3, and sst5. Experiments were performed in steroid-depleted media supplemented or not with 1 nM E2 for 96 h. SRIF, OCT, and BIM-23052 inhibited cAMP accumulation and GH release independently of E2. In contrast, all three agonists affected PRL release in E2-treated cultures only. Inhibition of cAMP accumulation by SRIF, OCT, and BIM-23052 was enhanced by exposure of cells to E2. The rank of potency of the agonists, OCT = SRIF > BIM-23052, was similar for GH and PRL inhibition. BIM-23268 was a weak agonist on GH, but not on PRL, secretion. BIM-23056 had no effect on the release of either hormone, but slightly inhibited cAMP formation in E2-treated cells. To verify whether SRIF receptor gene expression correlated with these observations, messenger RNA (mRNA) transcripts corresponding to the five ssts were measured by quantitative RT-PCR in the presence or absence of E2. Control cells expressed predominantly sst2 and sst3 transcripts; sst1 mRNA was present in moderate amounts, whereas sst4 and sst5 were only weakly expressed. E2 had a differential effect on distinct ssts; it increased mRNA concentrations corresponding to sst2 and sst3, and decreased that of sst1. These results indicate that sst2 and sst3 receptors are the major somatostatin receptors expressed in the female rat pituitary, and that both of them are positively regulated by estradiol. However, the capacity of lactotropes to respond to SRIF after exposure to E2 seems to depend more upon E2-induced up-regulation of the sst2 than of the sst3 receptor subtype.

Animals↗

PubMed1998

Somatostatin as a neurotrophic factor. Which receptor/second messenger transduction system is involved?

A variety of studies support a trophic role for somatostatin in the developing nervous system, evidenced as stimulation of neurite outgrowth and axonal or neuronal migration in both in vivo and culture models. Cloning experiments have now demonstrated the existence of five subtypes of somatostatin receptor, differentially distributed in the nervous system, differentially linked to specific signal transduction systems and in certain cases differentially expressed during development. The combination of the differential and developmental regulation of expression of both the somatostatin peptides and their receptors thus provides great potential in terms of trophic effects. To substantiate trophic effects of somatostatin, data are presented from two different model systems, cultures of cerebellar granule cells as well as transgenic mice in which somatostatin is expressed under the control of the glial fibrillary acidic protein promoter. Finally, potential receptor subtypes and second messenger systems involved in these trophic effects are addressed.

Animals↗

PubMed1998

[Somatostatin: a ubiquitous peptide].

Somatostatin (SRIF) was discovered in 1973, in Roger Guillemin's laboratory as a Growth Hormone (GH) inhibiting neurohormone. It is widely distributed in mammals where it acts also as a peripheral hormone, an autocrine or paracrine factor and a neuropeptide. SRIF receptors are located on several human tumours and SRIF agonists are in clinical use to monitor GH secretion in acromegalic patients. This short review summarizes the properties of the central and peripheral somatostatinergic systems, the three peptides belonging to the somatostatin family: (SRIF14, SRIF28 and cortistatin), the pharmacology of the five SRIF receptor subtypes, some ontogenetic and phylogenetic aspects, as well as pathological findings.

Amino Acid Sequence↗

PubMed1997

Ultrastructural localization of galanin and galanin receptors in the guinea pig median eminence.

The aim of this work was to compare the localization of galanin and galanin receptors in the guinea pig median eminence at the light and electron microscopic level. Concerning galanin the highest labeling was shown in the external part of the median eminence. At the ultrastructural level, galanin immunoreactivity was observed only in nerve terminals containing granular vesicles of approximately 120 nm in diameter. Light microscopic autoradiographs of semithin sections exhibited a moderate labeling in the external part of the median eminence. Galanin receptors were labeled in vitro on semithin sections (2 microm) using the highly specific radioligand [125I]galanin. Ultrastructural data showed that most of galanin binding sites overlaid membrane appositions between nerve terminals and also between nerve terminal and tanycyte. By considering the percentages in the distribution of the binding it appeared that galanin receptors were located on some nerve ending membranes. Our observations were not really in favor of a presence of receptors in tanycytes. The presence of galanin nerve endings in the external part suggests that like in the rat the peptide may have a direct hypophysiotrophic role. In contrast, the occurrence of numerous binding sites gives additional arguments in favor of a local action (paracrine and/or autocrine) of galanin occurring via galanin receptors located essentially on the pericapillary nerve terminals in the guinea pig median eminence.

Animals↗

PubMed1997

Mab22C11 antibody to amyloid precursor protein recognizes a protein associated with specific astroglial cells of the rat central nervous system characterized by their capacity to support axonal outgrowth.

Amyloid precursor protein (APP) is a transmembrane glycoprotein which is believed to promote neural cell adhesion, neural survival, and neuritogenesis. The present study was undertaken to determine whether APP could be detected within different types of astroglial cells present in the central nervous system (CNS) of neonatal or adult rats. The localization of this protein within glial cells was studied by using a monoclonal antibody (Mab22C11) that recognizes all APP isoforms and in addition cross-reacts with APP-like proteins. In the brain of neonatal rats, Mab22C11 immunostaining was associated with numerous elongated radial glia-like structures. In the intact brain and spinal cord of adult rats, Mab22C11 immunostaining was associated with (i) numerous neuron-like structures and (ii) glial structures immunostained for glial fibrillary acidic protein (GFAP) and/or vimentin, including tanycytes mostly located in the mediobasal hypothalamus, fibrous astrocytes located in the white matter and ependymocytes bordering the ventricles. On the other hand, all the GFAP-immunostained astrocytes located in the grey matter were Mab22C11 negative. In the lesioned brain and spinal cord of adult rats, Mab22C11 immunostaining was associated with intensely GFAP-immunostained reactive astrocytes located close to a surgical lesion, but not with those induced by Wallerian degeneration that appear at a distance from a lesion. Electron microscopic observations further indicated that in all these labeled astroglial cells, Mab22C11 immunostaining was mainly localized to the limiting plasma membrane and the membrane of intracytoplasmic cisternae and vesicles. These data indicate that Mab22C11 antibody induces strong immunostaining of specific astroglial cells of the neonatal and adult rat CNS that support axonal outgrowth, therefore suggesting that an APP-like protein associated with these cells participates in their axonal outgrowth promoting properties.

Amyloid beta-Protein Precursor↗

PubMed1997

Distribution and pharmacological characterization of somatostatin receptor binding sites in the sheep brain.

Somatostatin binding sites have been localized and quantified in the sheep brain using 125I-Tyr0-DTrp8-somatostatin, by quantitative high resolution light microscopic autoradiography. Sections were analyzed by densitometry on radioautographic film, and subsequently on slides coated with photoemulsion. Specific somatostatin binding sites were concentrated in the medial habenula, superior colliculus, dorsal motor nucleus of the vagus nerve, inferior olive, spinal trigeminal nucleus, and cerebellum. In competition experiments, octreotide, a sst2/sst3/sst5 selective agonist only partially displaced 125I-Tyr0-DTrp8-somatostatin in the three cerebellar layers while it was fully active as compared to somatostatin 14 and 28 in the deeper layers of the parietal cortex. Moderate to low somatostatin receptor densities were present in the mesencephalic periaqueductal gray, dorsal raphe, thalamic paraventricular nucleus, interpeduncular nucleus, pineal gland, dorsal tegmental, dorsolateral tegmental and parabrachial nuclei, nucleus of the solitary tract. The distribution of somatostatin binding sites generally correlates with the data obtained on slides dipped in photoemulsion which provided better resolution and more precise localization. In most of the labeled areas, 125I-Tyr0-DTrp8-somatostatin receptor binding was distributed between both neuropil and perikarya. Perikarya bearing 125I-Tyr0-DTrp8-somatostatin receptors were observed in areas which did not display detectable binding sites on film such as the preoptic-anterior hypothalamic complex and arcuate nucleus and in the locus coeruleus. In conclusion, the distribution of 125I-Tyr0-DTrp8-somatostatin binding sites in sheep brain is very reminiscent of other mammals being closer to the human than to rodents.

Animals↗

PubMed1997

Somatostatin receptor imaging in somatotroph and non-functioning pituitary adenomas: correlation with hormonal and visual responses to octreotide.

OBJECTIVE: A multicentre study was undertaken to determine the value of somatostatin receptor (sst) scintigraphy in predicting hormonal and visual responses to octreotide treatment in GH-secreting and non-functioning pituitary adenomas. SUBJECTS AND METHODS: Somatostatin receptor scintigraphy was performed in 48 patients (19 acromegaly, 29 non-functioning pituitary adenomas with ophthalmological defects). Results were expressed as an uptake index of the pituitary area. A threshold for positivity was determined in 23 subjects considered as controls. Thirty-five patients were treated for 1 month with octreotide (300 micrograms daily). The therapeutic response was assessed on GH and IGF-I suppression or evolution of the ophthalmological defects. The relationships between the somatostatin receptor scintigraphy result, the therapeutic effect of octreotide and in vitro studies performed in 12 tumours were studied. RESULTS: From the results of control subjects the uptake index threshold for positivity was 2. In patients, somatostatin receptor scintigraphy was positive in 64% and there was no relationship between uptake index and tumour size. In GH tumours, somatostatin receptor scintigraphy was positive in 68%; uptake index was related to octreotide-induced GH and IGF I suppression. The positive predictive value was 100% and the negative predictive value was 50%. In vitro studies showed detectable binding sites for somatostatin with sst2 and sst5 expression in the 4 GH tumours studied although somatostatin receptor scintigraphy was negative in 2 cases. In non-functioning pituitary adenomas somatostatin receptor scintigraphy was positive in 62%. Based on visual effects, the positive predictive value was 61% and the negative predictive value was 100%. A wide distribution of somatostatin binding sites was found in 8 non-functioning pituitary adenomas with expression of sst2 only. CONCLUSION: In the conditions of the study, in patients with acromegaly, positive somatostatin receptor scintigraphy predicts a hormonal response but the value of somatostatin receptor scintigraphy is limited by its low negative predictive value. In patients with non-functioning pituitary adenomas, negative somatostatin receptor scintigraphy predicts that there will be no visual improvement during octreotide treatment.

Acromegaly↗

PubMed1997

Differential expression of multiple somatostatin receptors in the rat cerebellum during development.

The present study describes the expression pattern of somatostatin receptor genes during the development of rat cerebellum. Characterization of somatostatin receptors was carried out by binding studies using receptor subtype-selective ligands in the germinative epithelium and granule cell layer of the cerebellum from postnatal day 4 (P4) to P21 and in granule cell cultures. Quantitative reverse transcription-PCR carried out for the five receptor subtype mRNAs in cerebellar extracts showed that sst1 mRNAs are predominant at the end of gestation. A transient high expression of the sst2 gene was observed from P7 to P14. In parallel, high levels of binding sites sensitive to sst2 ligands were detected in the granule cell germinative epithelium and in granule cell cultures. sst3 mRNAs rapidly increased from P14 and became the predominant form at P21, but respective binding sites were not detected. Whereas sst4 mRNA levels were generally low, those of sst5 were nearly undetectable. Reverse transcription-PCR carried out in granule cell cultures revealed the relative abundance of sst mRNAs as follows: sst2 > sst1 > sst3 = sst4. sst5 mRNA was undetectable. The results show the expression of four somatostatin receptor genes, but only three receptors (sst1, sst4, and mainly sst2) were detected as binding sites during cerebellar development.

Animals↗

PubMed1997

Distinct patterns of expression and physiological effects of sst1 and sst2 receptor subtypes in mouse hypothalamic neurons and astrocytes in culture.

Somatostatin (SRIF) receptor subtypes (sst) were characterized in hypothalamic neurons and astrocytes by quantitative reverse transcription-polymerase chain reaction and radioreceptor assays using [125I-Tyr0,D-Trp8]SRIF-14 as a ligand in ionic conditions discriminating between SRIF-1 (sst2, -3, and -5 receptors) and SRIF-2 (sst1 and -4 receptors) binding sites. In neurons, sstl mRNA levels were twofold higher than those of sst2, and sst3-5 expression was only minor. Astrocytes expressed 10-fold less sst mRNAs than neurons, which corresponded mostly (80%) to sst2. SRIF-1 binding site radioautography indicated that 10% of hypothalamic neurons were labelled on both cell bodies and neuritic processes, as were 35% of astrocytes. On neuronal and glial membranes, SRIF-14 and octreotide, an sst2/sst3/sst5-selective analogue, completely displaced SRIF-1 binding, whereas des-AA(1,2,5)[D-Trp8,IAmp9]SRIF (CH-275), an sst1-selective analogue, was ineffective. Using SRIF-2 conditions, only SRIF-14 and CH-275 displaced the binding on neurons. No SRIF-2 binding was observed on glia. SRIF-14 and octreotide inhibited forskolin-stimulated adenylyl cyclase activity in neurons and glia, whereas CH-275 was effective in neurons only. In patch-clamp experiments, SRIF-14 modulated the glutamate sensitivity of hypothalamic neurons with either synergistic or antagonistic effects; CH-275 was only stimulatory and octreotide inhibitory. It is concluded that hypothalamic neurons express primarily sst1 and sst2, sst2 predominates in astrocytes, and both receptors induce distinct biological effects.

Adenylyl Cyclase Inhibitors↗

PubMed1997

Semiquantitative distribution of galanin-receptor (GAL-R1) mRNA-containing cells in the male rat hypothalamus.

The semiquantitative distribution of mRNA encoding for rat galanin receptor (GAL-R1) was examined by in situ hybridization in the rat hypothalamus using a 35S-riboprobe. Most hypothalamic nuclei expressed GAL-R1 mRNA. In the anterior hypothalamus, high levels of expression were found in the medial preoptic area, paraventricular and supraoptic nuclei. Numerous cells also expressed the GAL-R1 mRNA with a moderate level of expression in the periventricular region. Very few GAL-R1-expressing cells were present in the suprachiasmatic nucleus. In the medial hypothalamus, numerous expressing cells were detected in the dorsomedial and ventromedial nuclei. The arcuate nucleus was moderately labeled throughout its rostrocaudal extent; labeled cell bodies were visible in the ventromedial and ventrolateral subdivisions as well. These results indicate that the GAL-R1 mRNA is not only expressed in anterior hypothalamic nuclei but also in the mediobasal hypothalamus and periventricular region. This hypothalamic distribution correlates well with that of 125I-GAL-binding sites and GAL-immunoreactive fibers. This distribution represents the morphological substrate for GAL roles in the hypothalamic regulation of neuroendocrine, behavioral and autonomic functions.

Animals↗

PubMed1997

Intrahypothalamic growth hormone feedback: from dwarfism to acromegaly in the rat.

Two different dwarf rat models with primary (dw/dw, DW) or secondary (transgenic growth retarded, WF/Tgr) GH deficiency and contrasting hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) expression were implanted sc with GC cells. These form encapsulated rat GH-secreting tumors that maintain high plasma rat GH levels for several weeks. In both strains, GC cell tumors stimulated growth and raised GHBP levels, without affecting pituitary GH content. In DW rats, GC cell implants increased SRIH expression in the periventricular nucleus (PeV), but not in the arcuate nucleus (ARC), whereas their high GHRH expression in ARC was decreased by GC cells. In contrast, GC cell implants in WF/Tgr rats had little effect on the already high SRIH expression in PeV or low GHRH expression in ARC, although they reduced SRIH expression in ARC. GC cell implants also reduced GH receptor expression in both ARC and PeV in the WF/Tgr dwarves. Thus, chronic GH overexposure stimulates rapid growth in both dwarf strains, but has differential hypothalamic effects in these models. This experimental approach now makes it possible to study the effects of pathophysiological concentrations of GH ranging from dwarfism to acromegaly in the same animal model.

Acromegaly↗

PubMed1997

Species differences between male rat and ram pituitary somatostatin receptors involved in the inhibition of growth hormone secretion.

The sheep is a valuable model in which to study GH neuroregulation as its pattern of GH secretion is very close to that in humans. Furthermore, important differences in somatostatin (SRIH) action between rats and sheep have been found previously. Our goal was to compare in male rat and ram pituitaries the binding characteristics of somatostatin receptors and the effect of SRIH and 17 analogues on GH release. Using radioautography, SRIH binding was seen to be evenly distributed over the anterior pituitary of both species. In the binding assay, binding sites were three times more concentrated in rats than in sheep. Important interspecies differences in the action of SRIH and its analogues were found: they inhibited GH at lower concentrations in rats than in sheep. Seven peptides displayed greater inhibitory ability in sheep than in rats while three were more potent in rats. Agonistic potencies to inhibit GH release in rats were correlated with somatostatin receptors subtype 2 (sst2) affinities. Our data confirm and extend the quantitative differences between rat and sheep in SRIH inhibitory action on GH secretion and confirm that ligand-binding properties of a given receptor subtype cannot be extrapolated across species.

Animals↗