scholarly journals Novel Long-Acting Somatostatin Analog with Endocrine Selectivity: Potent Suppression of Growth Hormone But Not of Insulin

Endocrinology ◽  
2001 ◽  
Vol 142 (1) ◽  
pp. 477-486 ◽  
Author(s):  
Michel Afargan ◽  
Eva Tiensuu Janson ◽  
Garry Gelerman ◽  
Rakefet Rosenfeld ◽  
Offer Ziv ◽  
...  
Keyword(s):  
Insulin Release ◽  
Cyclic Peptide ◽  
Hormone Secretion ◽  
Integrated Approach ◽  
Cell System ◽  
Binding Assays ◽  
Gh Secretion ◽  
Long Acting ◽  
Glucagon And Insulin

Abstract Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1–5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively.

Differential effects of passive immunization with somatostatin antiserum on adenohypophysial hormone secretions in starved rats

1986 ◽  
Vol 109 (2) ◽  
pp. 169-174 ◽  
Author(s):  
J. N. Hugues ◽  
A. Enjalbert ◽  
E. Moyse ◽  
C. Shu ◽  
M. J. Voirol ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Hormone Secretion ◽  
Plasma Concentrations ◽  
Passive Immunization ◽  
Negative Control ◽  
Prolactin Secretion ◽  
Male Rats ◽  
Minimal Effective Dose ◽  
Gh Secretion

ABSTRACT The role of somatostatin (SRIF) on adenohypophysial hormone secretion in starved rats was reassessed by passive immunization. Because of the absence of pulsatile GH secretion in starved rats, the effects of the injection of SRIF antiserum on GH levels can be clearly demonstrated. To determine whether starvation modifies the sensitivity of the adenohypophysis to SRIF, we measured 125I-labelled iodo-N-Tyr-SRIF binding. There was no difference in the dissociation constant (Kd) nor in the maximal binding capacity (Bmax) in fed (n = 15) and starved (n = 15) animals (Kd = 0·38 ± 0·09 (s.e.m.) and 0·45 ± 0·09 nmol; Bmax = 204 ± 39 and 205 ± 30 fmol/mg protein respectively). Administration of SRIF antiserum resulted in a dose-dependent increase in plasma concentrations of GH, TSH and prolactin. The minimal effective dose of SRIF antiserum was 50 μl for GH, 100 μl for TSH and 200 μl for prolactin. Our results show that: (1) starvation does not modify adenohypophysial SRIF-binding sites, (2) in starved male rats endogenous SRIF exerts a negative control on prolactin secretion in vivo and (3) sensitivity to endogenous SRIF seems to be different for each hypophysial cell type. J. Endocr. (1986) 109, 169–174

Evidence of a paracrine role for pancreatic somatostatin in vivo

1983 ◽  
Vol 245 (6) ◽  
pp. E598-E603 ◽  
Author(s):  
G. J. Taborsky
Keyword(s):  
Insulin Release ◽  
Glucagon Secretion ◽  
Base Line ◽  
Anesthetized Dogs ◽  
D Cells ◽  
Glucagon And Insulin ◽  
Line P ◽  
A And B Cells

Somatostatin (SS) in the D cells of the pancreatic islets has been hypothesized to tonically inhibit the secretion of glucagon and insulin from the neighboring A and B cells. To test this hypothesis directly, a nonimmunoreactive analogue of somatostatin [( D-Ala5-D-Trp8]SS) was infused intravenously at 0.55–17 micrograms/min into anesthetized dogs to suppress the secretion of pancreatic somatostatin and observe the effects of that suppression on glucagon and insulin release. Infusions of this analogue into anesthetized dogs at both a low dose (1.7 micrograms X min-1 X 30 min iv, n = 7) and at a medium dose (5.5 micrograms X min-1 X 30 min iv, n = 7) suppressed the release of somatostatin-like immunoreactivity (SLI) from the in situ canine pancreas by 31 +/- 10% of base line (P less than 0.025) and 45 +/- 6% of base line (P less than 0.0005), respectively. These doses increased glucagon secretion markedly (by 179 +/- 39 and 250 +/- 60% of base line, both P less than 0.005) and increased insulin secretion moderately (by 35 +/- 17 and 62 +/- 27% of base line, respectively, both P less than 0.05). The highest dose of analogue (17 micrograms/min, n = 9) produced less stimulation of glucagon release (delta = +95 +/- 35% of basal, P less than 0.025) and marked inhibition of insulin release (delta = -61 +/- 9% of basal, P less than 0.0005) despite a larger inhibition of pancreatic SLI release (delta = -84 +/- 3% of basal, P less than 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Obestatin Partially Affects Ghrelin Stimulation of Food Intake and Growth Hormone Secretion in Rodents

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1648-1653 ◽  
Author(s):  
Philippe Zizzari ◽  
Romaine Longchamps ◽  
Jacques Epelbaum ◽  
Marie Thérèse Bluet-Pajot
Keyword(s):  
Food Intake ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Male Rats ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Freely Moving ◽  
Stimulation Of

Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 μg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.

A possible relationship between serum transferrin, growth hormone secretion and height velocity in children

1980 ◽  
Vol 93 (2) ◽  
pp. 134-138 ◽  
Author(s):  
M. Donnadieu ◽  
R. M. Schimpff ◽  
P. Garnier ◽  
J. L. Chaussain ◽  
J. C. Job
Keyword(s):  
Growth Hormone ◽  
Growth Regulation ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Height Velocity ◽  
Obese Children ◽  
Gh Secretion ◽  
Growth Promoting

Abstract. Since transferrin (Tf) in vitro has a growth-promoting activity and is associated with NSILA properties, the aim of this work was to study in vivo the relationships between Tf, somatomedin activity (SM), growth hormone (GH) secretion, and height velocity in children. An iv infusion of ornithine hydrochloride was given to 23 controls; the induced rise of GH was accompanied by a simultaneous fall of SM (r = −0.711, P < 0.001) and was preceded by a fall of Tf (r = −0.610, P < 0.01). In 17 obese children SM was within the normal range, when Tf levels were higher and arginineinduced GH peaks lower than in the controls, and a negative correlation was found between Tf basal levels and GH peaks (r = −0.608, P < 0.01). In 9 children with confirmed hypopituitarism the Tf levels were significantly lower than in the controls. In 14 children with confirmed or suspected hypopituitarism a single im injection of hGH (6 mg) failed to induce Tf variations over 24 h. In 39 of these children the height velocity was significantly correlated with Tf basal levels (r = 0.701, P < 0.001). These data suggest that transferrin is involved in growth regulation, and that GH secretion is related to transferrin levels by a feed-back mechanism.

Dichotomic action of glucocorticoids on growth hormone secretion

1987 ◽  
Vol 116 (2) ◽  
pp. 165-171 ◽  
Author(s):  
Koji Nakagawa ◽  
Tatsuya Ishizuka ◽  
Takao Obara ◽  
Miyao Matsubara ◽  
Kazumasa Akikawa
Keyword(s):  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Normal Rat ◽  
Rat Pituitary Cells

Abstract. The mechanism of apparently discrepant actions of glucocorticoids (GC) on GH secretion, in vivo suppression and in vitro potentiation, was studied in rats. Dexamethasone (Dex), at the concentration of 50 nmol/l, Potentiated basal and GHRH-stimulated GH release from monolayer culture of normal rat pituitary cells in 48 h. On the other hand, in vivo administration of Dex, 165 μg daily for 3 days, consistently suppressed serum GH levels in female rats. In these rats, the hypothalamic content of immunoreactive (IR) SRIH was significantly increased, whereas that of IR-GHRH was significantly decreased in comparison with the untreated rats. Bioassayable GH-releasing activity was also lower in Dex-treated rats. These findings indicate that the suppressing effect of GC on GH release in vivo is, at least partially, due to the increase in hypothalamic SRIH release and probably also to the decrease in GHRH release, and these effects surpass the potentiating effect of GC on GH release at the pituitary level, resulting in a net inhibitory effect in vivo.

Glucocorticoid modulation of growth hormone secretion in vitro. Evidence for a biphasic effect on GH-releasing hormone mediated release

1987 ◽  
Vol 114 (4) ◽  
pp. 465-469 ◽  
Author(s):  
Gian Paolo Ceda ◽  
Robert G. Davis ◽  
Andrew R. Hoffman
Keyword(s):  
Growth Hormone ◽  
Prolonged Exposure ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Inhibitory Effect ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Glucocorticoid Action

Abstract. Glucocorticoids have been shown to have both stimulatory and suppressive effects on GH secretion in vitro and in vivo. In order to study the kinetics of glucocorticoid action on the somatotrope, cultured rat pituitary cells were exposed to dexamethasone for varying periods of time. During short-term incubations (≤ 4 h), dexamethasone inhibited GHRH and forskolin-elicited GH secretion, but during longer incubation periods, the glucocorticoid enhanced both basal and GHRH-stimulated GH release. The inhibitory effect of brief dexamethasone exposure was also seen in cells which previously had been exposed to dexamethasone. In addition, growth hormone secretion from cultured rat and human somatotropinoma cells was inhibited by a brief exposure to dexamethasone. Thus, the nature of glucocorticoid action on the isolated cultured somatotrope is biphasic, with brief exposure inhibiting, and more prolonged exposure stimulating GH secretion.

INFLUENCE OF INDOMETHACIN AND OF POLYPHLORETIN PHOSPHATE FRACTIONS ON IN VIVO SECRETION OF THYROID HORMONE IN MICE

1977 ◽  
Vol 86 (2) ◽  
pp. 330-335 ◽  
Author(s):  
A. Melander ◽  
U. Westgren ◽  
S. H. Ingbar
Keyword(s):  
Molecular Weight ◽  
Thyroid Hormone ◽  
De Novo ◽  
Hormone Secretion ◽  
Receptor Site ◽  
Graves Disease ◽  
Endogenous Prostaglandins ◽  
Small Increments ◽  
Long Acting

ABSTRACT Previous in vivo studies in mice have shown that polyphloretin phosphate (PPP), a polyionic polyester of phosphoric acid and the dihydrochalcone phloretin, can inhibit thyroid hormone secretion induced by TSH and by the long-acting thyroid stimulator of Graves' disease (LATS), but not that induced by catecholamines or 5-hydroxytryptamine (5-HT). The present study was undertaken to explore further the mechanism of this effect, particularly the possibility that PPP interferes with the synthesis of endogenous prostaglandins (PG). Therefore, the effects of PPP and some of its subfractions and congeners were compared with those of indomethacin, a known inhibitor of PG synthesis, with respect to their influence on the blood radioiodine (BRI) increase in response to TSH, 5-HT, and isoprenaline (IPNE) in 125I- and T4-pre-treated mice. When given alone, neither indomethacin nor PPP or its subfractions reduced the BRI levels. Instead, small increments were seen in occasional experiments. Indomethacin did not inhibit the BRI increase in response to any of the thyroid-stimulating agents, but rather enhanced the responses in occasional experiments. PPP and some of its high-molecular weight subfractions reduced the BRI increases in response to TSH but not those to 5-HT or IPNE. The findings do not support the concept that de novo synthetized PG mediates TSH activation of thyroid hormone secretion, but they favour the view that PPP inhibits the action of TSH at its receptor site.

Physiological control of growth hormone secretion by thyrotrophin-releasing hormone in the domestic fowl

1985 ◽  
Vol 105 (3) ◽  
pp. 351-355 ◽  
Author(s):  
H. Klandorf ◽  
S. Harvey ◽  
H. M. Fraser
Keyword(s):  
Domestic Fowl ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Physiological Control ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Gh Secretion ◽  
Normal Sheep Serum ◽  
Plasma Gh

ABSTRACT Immature cockerels (4- to 5-weeks old) were passively immunized, with antiserum raised in sheep, against thyrotrophin-releasing hormone (TRH). The administration of TRH antiserum (anti-TRH) at doses of 0·5, 1·0 or 2·0 ml/kg lowered, within 1 h, the basal concentration of plasma GH for at least 24 h. The administration of normal sheep serum had no significant effect on the GH concentration in control birds. Although the GH response to TRH (1·0 or 10·0 μg/kg) was not impaired in birds treated 1 h previously with anti-TRH, prior incubation (at 39 °C for 1 h) of TRH (20 μg/ml) with an equal volume of anti-TRH completely suppressed the stimulatory effect of TRH (10 pg/kg) on GH secretion in vivo. These results suggest that TRH is physiologically involved in the hypothalamic control of GH secretion in the domestic fowl. J. Endocr. (1985) 105, 351–355

Lack of refractoriness to stimulation with long acting thyroid stimulator of thyroid hormone synthesis and thyroid hormone secretion in mice in vivo

1983 ◽  
Vol 102 (3) ◽  
pp. 392-395 ◽  
Author(s):  
Hitoshi Ikeda ◽  
Shigenobu Nagataki
Keyword(s):  
Thyroid Hormone ◽  
Weight Control ◽  
Hormone Secretion ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis ◽  
Positive Serum ◽  
Ad Libitum ◽  
Long Acting ◽  
Prior Administration

Abstract. The present study was undertaken to examine whether long acting thyroid stimulator (LATS) induces refractoriness of thyroid hormone synthesis and thyroid hormone secretion to the stimulator in vivo. Male DDY mice fed with a low iodine diet and given 5 μg/ml of triiodothyronine (T3) in drinking water ad libitum for 4 days were injected with 0.25 ml of LATS positive serum (1000%/0.25 ml in the McKenzie bioassay) ip every 24 h for 9 days. Groups of 5 mice were sacrificed before and 1, 3, 5, 7 and 9 days after the first injection of LATS for the determinations of serum thyroxine (T4) concentrations, the 1 h thyroid 131I uptake and thyroid weight. Control mice were injected with LATS negative pooled normal sera. Serum T4 concentrations elevated significantly 24 h after the 3rd injection of LATS and remained elevated until the end of the experiment. One hour thyroid 131I uptake elevated about 3-fold 24 h after the first injection of LATS. It further increased 24 h after the 3rd injection of LATS to 10-fold of the value for control animals and stayed elevated at this same level for the remainder of the study. These results indicate that stimulating effects of LATS on thyroid hormone synthesis assessed by thyroid 131I uptake and thyroid hormone secretion assessed by serum T4 concentrations were not diminished by the prior administration of the stimulator. These findings suggest that LATS does not induce refractoriness of either thyroid hormone synthesis or thyroid hormone secretion to the stimulator in mice in vivo.

Growth hormone-releasing factor does not stimulate phosphoinositides breakdown in primary cultures of rat and human pituitary cells

1986 ◽  
Vol 112 (3) ◽  
pp. 345-350 ◽  
Author(s):  
Dolores Collado Escobar ◽  
Lucia M. Vicentini ◽  
Ezio Ghigo ◽  
Enrica Ciccarelli ◽  
Luciana Usellini ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Inositol Phosphates ◽  
Primary Cultures ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Cell System ◽  
Pituitary Cells ◽  
Human Pituitary ◽  
Growth Hormone Releasing Factor

Abstract. It has been reported that rat growth hormone releasing factor (rat GRF-43), similarly to the two human GRFs (GRF-40 and 44) stimulates adenylate cyclase activity in pituitary cells. Controversial findings have been presented by two different groups on the action of GRF on phosphoinositides (PI) metabolism, a phenomenon linked to Ca++ – mediated intracellular mechanisms. In the work to be reported, we evaluated the accumulation of inositol phosphates induced by GRF exposure in primary cultures of rat and human pituitary cells. Addition of rat GRF-43 to rat pituitary cells at doses up to 1 μm had no effect on inositol phosphates accumulation, while already at a dose as low as 0.05 nm it increased growth hormone secretion in the incubation medium significantly. In the same cell system, TRH, a known activator of PI breakdown, significantly increased [3H]inositol phosphates. In primary cultures of human somatotrophs from acromegalic subjects as in rats, addition of hpGRF-40 and also of TRH did not elicit any modification in the accumulation of [3H]inositol phosphates. Consistent with in vivo findings, both peptides induced a significant release of GH in the medium. Our results show that the GH releasing effect of GRF does not involve the hydrolysis of phosphatidylinositol in normal rat as well as in tumoral human somatotrophs. In addition it appears that the anomalous response of TRH on adenomatous cells from acromegalic patients is differently mediated in respect to the action of the tripeptide on normal lactotrophs and thyrotrophs.

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