Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats

2005 ◽  
Vol 153 (3) ◽  
pp. R7-R10 ◽  
Author(s):  
A P Silva ◽  
P Schoeffter ◽  
G Weckbecker ◽  
C Bruns ◽  
H A Schmid
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Plasma Concentrations ◽  
Inhibitory Effect ◽  
Corticotropin Releasing Hormone ◽  
Acth Secretion ◽  
Releasing Hormone ◽  
Corticosterone Secretion ◽  
Corticosterone Release ◽  
Acth Release

Objective: Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is biochemically characterized by increased plasma concentrations of ACTH inducing hypersecretion of cortisol. Somatostatin is known to inhibit ACTH secretion, and in vitro data have shown the inhibition of ACTH secretion by agonists activating sst2 and sst5 receptors. The present study aimed to determine the inhibitory effect of the multireceptor ligand SOM230, compared with the sst2-preferring agonist octreotide, on corticotropin-releasing hormone (CRH)-stimulated secretion of ACTH and corticosterone in rats. Methods: Secretion of ACTH and corticosterone was induced by i.v. application of CRH (0.5 μg/kg) in rats pretreated 1 h before by i.v. application of SOM230 (1, 3, or 10 μg/kg), octreotide (10 μg/kg) or NaCl 0.9%. Results: SOM230 (3 and 10 μg/kg) inhibited CRH-induced ACTH release by 45±3% and 51±2%, respectively, and corticosterone release by 43±5% and 27±16%, respectively. 10 μg/kg of octreotide tended to be less potent at inhibiting ACTH release (34±6% inhibition) and did not alter the secretion of corticosterone. Conclusion: SOM230 has a stronger inhibitory effect on ACTH and corticosterone secretion than octreotide in rats. This difference can be explained by its higher affinity to sst1, sst3 and especially sst5 receptors compared with octreotide.

Effects of endothelin-1 and endothelin-3 on rat hypothalamic corticotrophin-releasing hormone and pituitary ACTH release in vitro

1994 ◽  
Vol 140 (3) ◽  
pp. 419-424 ◽  
Author(s):  
A E Calogero ◽  
F Raiti ◽  
G Nicolosi ◽  
N Burrello ◽  
R D'Agata ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Endocrine Function ◽  
Male Rat ◽  
Detectable Effect ◽  
Releasing Hormone ◽  
Potent Vasoconstrictor ◽  
Endothelin 3 ◽  
The Brain ◽  
Acth Release

Abstract Endothelins (ETs) are potent vasoconstrictor peptides that also participate in the regulation of endocrine function. Indeed, immunoreactive ET, ET mRNA and ET receptors have been found in the brain and the pituitary gland and ETs stimulate arginine vasopressin, LH, FSH, TSH and gonadotrophin-releasing hormone and inhibit prolactin release in vitro. The present study was undertaken to evaluate the effects of ET-1 and ET-3, two members of this family, on corticotrophin-releasing hormone (CRH) release by explanted male rat hypothalami in vitro and on ACTH release by primary pituitary cell culture. ET-3 decreased basal CRH release in a concentration-related manner. The lowest effective concentration tested was 3 nmol/l but a more pronounced inhibitory effect was obtained at a concentration of 10 nmol/l. On the other hand, ET-1 did not have any detectable effect on basal CRH release. Neither ET-1 nor ET-3 had any effect on the release of CRH stimulated by potassium chloride. ET-1 increased basal ACTH release, whereas ET-3 did not have any effect. Both ET-1 and ET-3 suppressed the release of ACTH stimulated by 1 nmol CRH/l. These data suggest that both ET-1 and ET-3 are able to modulate the hypothalamic-pituitary-adrenal axis function in vitro. However, they act at different levels and seem to have opposite effects. Indeed, while ET-1 stimulated pituitary ACTH release, ET-3, the peptide produced mainly in the brain, inhibited hypothalamic CRH release in vitro. Journal of Endocrinology (1994) 140, 419–424

Interleukin-1β Stimulates Corticotropin-Releasing Hormone (CRH) and Adrenocorticotropin (ACTH) Release by Rat Adrenal Gland in Vitro

1993 ◽  
Vol 4 (3) ◽  
pp. 267-270 ◽  
Author(s):  
Giuseppina Mazzocchi ◽  
Francesco G. Musajo ◽  
Ludwik K. Malendowicz ◽  
Paola G. Andreis ◽  
Gastone G. Nussdorfer
Keyword(s):  
Adrenal Gland ◽  
Interleukin 1Β ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Acth Release

Isolated pituitary cells: glucocorticoids do not rapidly suppress ACTH secretion in response to CRF

1989 ◽  
Vol 256 (1) ◽  
pp. E145-E151 ◽  
Author(s):  
M. Familari ◽  
J. W. Funder
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Suppressive Effect ◽  
Inhibitory Response ◽  
Pituitary Cells ◽  
Concomitant Treatment ◽  
Inhibitory Effects ◽  
Acth Secretion ◽  
Acth Release

The possibility of a direct rapid suppressive effect of glucocorticoids on stimulated adrenocorticotropic hormone (ACTH) release was investigated in perifused normal pituitary cells attached to microcarriers. Forty-eight hours after attachment to Cytodex beads, cells were transferred to two columns (one experimental, one control), perifused at a rate of 300-350 microliters/min, and equilibrated for 3 h. Either rat or ovine corticotropin-releasing factor (CRF; 2 nM) were used to stimulate ACTH release, and fractions collected every 5 min were assayed for immunoreactive ACTH. Concomitant treatment with CRF and glucocorticoids (dexamethasone 100 nM or corticosterone 1 microM), or glucocorticoid pretreatment for up to 2 h, did not affect the release of ACTH occasioned by repetitive 5-min exposures to CRF at 30-min intervals. In addition, when ovine CRF was given as two 30-min infusions 1 h apart, neither concomitant steroid administration nor steroid pretreatment for 90 min affected the release of ACTH compared with controls. The lack of rapid steroid inhibition was not an artifact of enzymatic dispersion or microcarrier attachment, since no rapid inhibitory response was seen with acutely perifused rat anterior pituitary quarters. We thus conclude that in vitro rapid inhibitory effects of glucocorticoids on ACTH release do not occur at the level of the pituitary. Accordingly such action in vivo presumably reflects acute steroid-induced effects on the hypothalamus or higher centers.

scholarly journals The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5

2005 ◽  
Vol 152 (4) ◽  
pp. 645-654 ◽  
Author(s):  
Leo J Hofland ◽  
Joost van der Hoek ◽  
Richard Feelders ◽  
Maarten O van Aken ◽  
Peter M van Koetsveld ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Inhibitory Effect ◽  
Cushing's Disease ◽  
Somatostatin Analogue ◽  
Receptor Subtypes ◽  
Acth Secretion ◽  
Corticotroph Adenoma ◽  
Corticotroph Adenomas ◽  
Acth Release

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst1, sst2, sst3 and sst5 was recently introduced. We compared the in vitro effects of the sst2-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. Results: Corticotroph adenomas expressed predominantly sst5 mRNA (six out of six adenomas), whereas sst2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range −30 to −40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (− 28%). In AtT20 cells, expressing sst2, sst3 and sst5, SOM230 inhibited ACTH secretion with high potency (IC50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst5 is relatively resistant to negative control by glucocorticoids. Conclusions: The selective expression of sst5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing’s disease.

Hypothalamic peptide regulation of ACTH secretion from sheep pituitary

1993 ◽  
Vol 265 (4) ◽  
pp. R840-R845 ◽  
Author(s):  
R. J. Kemppainen ◽  
T. P. Clark ◽  
J. L. Sartin ◽  
C. A. Zerbe
Keyword(s):  
Angiotensin Ii ◽  
Anterior Pituitary ◽  
Adrenocorticotropic Hormone ◽  
Corticotropin Releasing Factor ◽  
Pituitary Cells ◽  
Ang Ii ◽  
Acth Secretion ◽  
Low Concentrations ◽  
Acth Release

The relative abilities of the hypothalamic peptides corticotropin-releasing factor (CRF), arginine vasopressin (AVP), oxytocin (OT), and angiotensin II (ANG II) to stimulate adrenocorticotropic hormone (ACTH) secretion from cultured sheep anterior pituitary cells were studied. Incubation of cells with CRF, AVP, and OT, but not ANG II, was associated with increased ACTH secretion. CRF and AVP were equally effective in stimulating ACTH release at 0.1 nM, but larger doses of each resulted in distinctly different ACTH secretory patterns. The minimally effective dose of OT was 10 nM; greater doses of this peptide resulted in ACTH secretory responses similar to those measured after addition of AVP. Cotreatment with ANG II did not affect the ACTH-secretory response to CRF, AVP, or OT. These data confirm that AVP is a potent stimulus for ACTH secretion from sheep anterior pituitary in vitro and also show that CRF is effective in low concentrations in releasing ACTH. In contrast, the data do not support a regulatory role for ANG II in stimulating ACTH release directly from sheep corticotroph cells.

Chronic stress and pituitary–adrenocortical responses to corticotropin-releasing hormone and vasopressin in female pigs

1995 ◽  
Vol 132 (4) ◽  
pp. 479-486 ◽  
Author(s):  
Cecile JJG Janssens ◽  
Frans A Helmond ◽  
Victor M Wiegant
Keyword(s):  
Chronic Stress ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Concomitant Administration ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Releasing Effect ◽  
Adrenocortical Responses ◽  
Acth Release

Janssens CJJG, Helmond FA, Wiegant VM. Chronic stress and pituitary–adrenocortical responses to corticotropin-releasing hormone and vasopressin in female pigs. Eur J Endocrinol 1995;132:479–86. ISSN 0804–4643 Effects of long-term tethered housing (a condition of chronic stress) on pituitary-adrenocortical responsiveness to exogenous corticotropin-releasing hormone (CRH) and lysine8-vasopressin (LVP) were investigated in female pigs. Intravenous administration of CRH (dose range 10–440 pmol/kg body wt) or LVP (10–880 pmol/kg body wt) elicited transient and dose-related increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol. Comparison of the responses induced by the peptides indicated that CRH is a more potent ACTH secretagogue than LVP. Treatment with LVP produced a fivefold greater plasma cortisol/ACTH ratio than treatment with CRH, suggesting that in addition to stimulating pituitary ACTH release it enhanced the ability of the adrenal cortex to secrete cortisol in response to ACTH. Whereas concomitant administration of 10 pmolCRH/kg body wt and 20 pmol LVP/kg body wt revealed an additive effect on ACTH release, synergism between both peptides was found with respect to their cortisol-releasing effect. Ten to thirteen weeks of chronic stress did not alter significantly the absolute ACTH and cortisol responses to the two peptides. In tethered pigs, the cortisol/ACTH ratio after CRH treatment, calculated from the area under the curve, was twofold that in loose-housed pigs. From these observations we conclude that after chronic stress the sensitivity of the adrenocortex to circulating ACTH was increased, whereas the sensitivity of the pituitary to CRH and/or LVP remained unaltered. Frans A Helmond, Department of Human and Animal Physiology, Wageningen Agricultural University, Haarweg 10, 6709 PJ Wageningen, The Netherlands

Responsiveness to corticotropin-releasing hormone and vasopressin in canine Cushing's syndrome

1994 ◽  
Vol 130 (4) ◽  
pp. 410-416 ◽  
Author(s):  
Petra A van Wijk ◽  
Ad Rijnberk ◽  
Ronald JM Croughs ◽  
Jeannette Wolfswinkel ◽  
Paulus J Selman ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Adrenocorticotropic Hormone ◽  
Companion Animals ◽  
Cushing's Syndrome ◽  
Adrenocortical Tumor ◽  
Corticotropin Releasing Hormone ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Releasing Hormone ◽  
Lysine Vasopressin

Van Wijk PA, Rijnberk A, Croughs RJM, Wolfswinkel J, Selman PJ, Mol JA. Responsiveness to corticotropin-releasing hormone and vasopressin in canine Cushing's syndrome. Eur J Endocrinol 1994;130:410–16. ISSN 0804–4643 Corticotropin-releasing hormone (CRH) and vasopressin are the most important hypothalamic factors regulating adrenocorticotropic hormone (ACTH) secretion. In this study we have investigated the responsiveness of the pituitary–adrenocortical axis to intravenous administration of CRH or lysine vasopressin (LVP) in 16 control dogs, 22 dogs with pituitary-dependent hyperadrenocorticism and five dogs with hyperadrenocorticism due to an adrenocortical tumor, using doses of CRH and LVP that caused equivalent ACTH responses in the control dogs. After CRH administration, the increment in plasma ACTH was significantly (p < 0.05) lower in dogs with pituitary-dependent hyperadrenocorticism (221 ± 53 ng/l) than that in control dogs (279 ± ng/l). In the dogs with pituitary-dependent hyperadrenocorticism, the relative increases in ACTH after CRH were significantly (p < 0.05) lower than those after LVP. Despite the absence of an increase in ACTH following LVP administration in dogs with hyperadrenocorticism due to an adrenocortical tumor, there was a significant increase in plasma cortisol, the increment (790 ±238 nmol/l) being not statistically different from that in the control dogs (412 ± 37 nmol/l). We conclude that in spite of the changes inherent to pituitary-dependent hyperadrenocorticism, i.e. neoplastic transformation of corticotropic cells and hypercortisolism, there is persistence of responsiveness to hypophysiotropic hormones. The ACTH secretion by corticotropic cells in pituitary-dependent hyperadrenocorticism was relatively less sensitive to stimulation with CRH than with LVP. Adrenocortical tumors develop an aberrant sensitivity to LVP. A Rijnberk, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80.154, 3508 TD, Utrecht, The Netherlands

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

2006 ◽  
Vol 291 (2) ◽  
pp. E395-E403 ◽  
Author(s):  
Raul M. Luque ◽  
Manuel D. Gahete ◽  
Ute Hochgeschwender ◽  
Rhonda D. Kineman
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Inhibitory Effect ◽  
Mrna Levels ◽  
Adrenal Axis ◽  
Ghrelin Gene ◽  
Total Ghrelin ◽  
The Impact ◽  
Circulating Levels ◽  
Acth Release

Corticosterone and total ghrelin levels are increased in somatostatin (SST) knockout mice ( Sst −/−) compared with SST-intact controls ( Sst +/+). Because exogenous ghrelin can increase glucocorticoids, the question arises whether elevated levels of ghrelin contribute to elevated corticosterone levels in Sst −/− mice. We report that Sst −/− mice had elevated mRNA levels for pituitary proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), whereas mRNA levels for hypothalamic corticotropin-releasing hormone (CRH) did not differ from Sst +/+ mice. Furthermore, SST suppressed pituitary POMC mRNA levels and ACTH release in vitro independently of CRH actions. In contrast, it has been reported that ghrelin increases glucocorticoids via a central effect on CRH secretion and that n-octanoyl ghrelin is the form of ghrelin that activates the GHS-R1a and modulates CRH neuronal activity. Consistent with elevations in total ghrelin levels, Sst −/− mice displayed an increase in stomach ghrelin mRNA levels, whereas hypothalamic and pituitary expression of ghrelin was not altered. Despite the increase in total ghrelin levels, circulating levels of n-octanoyl ghrelin were not altered in Sst −/− mice. Because glucocorticoids and ghrelin increase in response to fasting, we examined the impact of fasting on the adrenal axis and ghrelin in Sst +/+ and Sst −/− mice and found that endogenous SST does not significantly contribute to this adaptive response. We conclude that endogenous SST inhibits basal ghrelin gene expression in a tissue specific manner and independently and directly inhibits pituitary ACTH synthesis and release. Thus endogenous SST exerts an inhibitory effect on ghrelin synthesis and on the adrenal axis through independent pathways.

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