Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-1, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles

Jacks, T. J.; Hickey, Gerard J.; Judith, F. R.; Taylor, J. E.; Chen, H; Krupa, David; Feeney, William P.; Schoen, William R.; Ok, Dmitrieva; Fisher, M. H.; Wyvratt, Matthew J.; Smith, Roy G.

doi:10.1677/joe.0.1430399

Cited by 84 publications

(48 citation statements)

References 6 publications

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“…T max is about 10 min, which is also in agreement with other GHSs in different species, including man (26)(27)(28)(29).…”

Section: Discussionsupporting

confidence: 88%

Pharmacological characterisation of a new oral GH secretagogue, NN703

Hansen¹,

Raun²,

Nielsen³

et al. 1999

European Journal of Endocrinology

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NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist.Binding of 35S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of 35 S-MK677. However, the observed K i value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells.The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155 Ϯ 23 nmol/kg and 91 Ϯ 7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown.The effect of NN703 on GH release after i.v. and oral dosing in beagle dogs was studied. NN703 dosedependently increased the GH release after oral administration. At the highest dose (20 mmol/kg), a 35-fold increase in peak GH concentration was observed (49.5 Ϯ 17.8 ng/ml, mean Ϯ S.E.M.). After a single i.v. dose of 1 mmol/kg the peak GH plasma concentration was elevated to 38.5 Ϯ 19.6 ng/ml (mean Ϯ S.E.M.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1 Ϯ 0.4 h.A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 mmol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group.In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.

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“…T max is about 10 min, which is also in agreement with other GHSs in different species, including man (26)(27)(28)(29).…”

Section: Discussionsupporting

confidence: 88%

Pharmacological characterisation of a new oral GH secretagogue, NN703

Hansen¹,

Raun²,

Nielsen³

et al. 1999

European Journal of Endocrinology

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“…The identification of a specific GHRP receptor in the pituitary, the hypothalamus and other areas of the central nervous system (CNS) (Ong et al 1998, Yokote et al 1998, Chen 2000 has suggested, in the past, the existence of an endogenous ligand for these compounds and this ligand, ghrelin, has been recently identified (Bowers 2001, Kojima et al 2001. The actions of these GHRPs, however, are not specific for GH, as they also stimulate prolactin, adrenocorticotropin (ACTH) and cortisol release in humans and other animals (Jacks et al 1994, Chang et al 1995, Copinschi et al 1996, Arvat et al 1997b. The sites of action for the release of GH by GHRPs are both in the hypothalamus and the pituitary, although the former is seemingly the privileged area (Müller et al 1999).…”

Section: Introductionmentioning

confidence: 99%

GH and cortisol rebound rise during and following a somatostatin infusion: studies in dogs with the use of a GH-releasing peptide

Rigamonti

Bonomo²,

Cella³

et al. 2002

Journal of Endocrinology

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GH-releasing peptides (GHRPs), a class of small synthetic peptide and non-peptide compounds, act on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in both humans and other animals. GHRPs, like corticotropin-releasing hormone (CRH), also possess acute ACTH-and cortisol-releasing activity, although the mechanisms underlying the stimulatory effect of GHRPs on the hypothalamo-pituitary-adrenal (HPA) axis are still unclear. In recent years, studies in humans and other animals have provided evidence that the rebound GH rise which follows withdrawal of an infusion of somatostatin (SS) (SSIW) is due, at least in part, to the functional activation of GH-releasing hormone (GHRH) neurons of the recipient organism. Unexpectedly, in humans, SS infusion, at a dose inhibiting basal GH secretion, has been associated with an activation of the HPA axis, leading to the hypothesis that this response was mediated, at least in part, by a central nervous system ACTH-releasing mechanism activated by the SS-induced decrease in GH secretion. Interestingly, the rebound GH rise which follows SSIW was magnified by the administration, before SS withdrawal, of a GHRP, implying that the SSIW approach could also be exploited to investigate in vivo the functional interaction in the process of GH and/or ACTH/cortisol secretion between endogenous GHRH (and/or other ACTH-releasing mechanisms) and GHRPs.In the present study, six young beagle dogs were given, on different occasions, at the beginning and at the end of a 3-h i.v. infusion of SS or saline (SAL), a bolus of physiological SAL or a GHRP compound, EP51216.SSIW induced a GH rebound rise without affecting plasma cortisol concentrations, while the withdrawal of SAL infusion was ineffective on either hormone paradigm. Administration of EP51216 at the beginning of SAL infusion evoked release of both GH and cortisol, whereas EP51216 administration at the withdrawal of SAL infusion evoked somatotroph and cortisol responses which were reduced in amplitude and duration. SS infusion significantly reduced the secretion of GH elicited by EP51216 but did not affect the rise of plasma cortisol levels. Interestingly, SSIW resulted in a marked enhancement of the somatotroph and cortisol responses evoked by EP51216.The marked rise of plasma GH levels induced by the GHRP after SSIW recalled that occurring after acute combined administration of recombinant human GHRH and EP51216, implying that exogenously delivered GHRP had synergized with the endogenous GHRH release triggered by SSIW. In contrast, acute combined administration of GHRH and the GHRP induced a cortisol response not different from that induced by GHRP alone, indicating that endogenous GHRH release was not involved in the enhanced cortisol response following EP51216 administration after SSIW. Similarly, the direct involvement of endogenous CRH could be ruled out, since i.v. administration of ovine CRH after SSIW evoked cortisol peak levels not different from those evoked by CRH at the withdrawa...

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“…These synthetic GH secretagogues (sGHS), although modelled from Met-enkephalins, have lost the opioid activity and stimulate GH secretion of pituitary somatotroph cells both in vitro and in vivo in a variety of species, including rat, pig and human (Momany et al 1981, Bowers et al 1984, Bowers 1993, Ghigo et al 1994, Arvat et al 1995. Since all these peptides have an oral bioavailability lower than 1%, a number of non-peptidyl sGHS 429,653 and MK 0677), with structures more amenable to chemical modification and optimization of oral bioavailability, have been developed and studied in both animals and man (Cheng et al 1993, Gertz et al 1993, Smith et al 1993, Jacks et al 1994, Chang et al 1995. Among them, the spiroindoline derivative, MK 0677, proved to be the strongest stimulator of GH secretion (Patchett et al 1995).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms of action underlying the GH-releasing activity of peptidyl and non-peptidyl sGHS seem to involve the antagonism of somatostatinergic pathways at both the pituitary and hypothalamic level as well as the stimulation of GHRH-secreting neurones (Conley et al 1995, Hickey et al 1996. Interestingly, the activity of sGHS is not fully specific since a slight stimulatory effect on prolactin, adrenocorticotrophin and cortisol levels as well as influences on the control of sleep and food intake have also been demonstrated ( Jacks et al 1994, Locke et al 1995, Frieboes et al 1995. These actions could take place via activation of specific receptors at levels other than the hypothalamo-pituitary system.…”

Section: Introductionmentioning

confidence: 99%

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland

Muccioli

Ghè²,

Ghigo³

et al. 1998

Journal of Endocrinology

143

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In vitro studies have been performed to demonstrate and characterize specific binding sites for synthetic GH secretagogues (sGHS) on membranes from pituitary gland and different human brain regions. A binding assay for sGHS was established using a peptidyl sGHS (Tyr-Ala-hexarelin) which had been radioiodinated to high specific activity at the Tyr residue. Specific binding sites for 125 I-labelled Tyr-Ala-hexarelin were detected mainly in membranes isolated from pituitary gland and hypothalamus, but they were also present in other brain areas such as choroid plexus, cerebral cortex, hippocampus and medulla oblongata with no sex-related differences. In contrast, negligible binding was found in the thalamus, striatum, substantia nigra, cerebellum and corpus callosum. The binding of 125 I-labelled Tyr-Ala-hexarelin to membrane-binding sites is a saturable and reversible process, depending on incubation time and pH of the buffer. Scatchard analysis of the binding revealed a finite number of binding sites in the hypothalamus and pituitary gland with a dissociation constant (K d ) of (1·5 0·3) 10 9 and (2·1 0·4) 10 9 mol/l respectively. Receptor activity is sensitive to trypsin and phospholipase C digestion, suggesting that protein and phospholipids are essential for the binding of 125 I-labelled Tyr-Ala-hexarelin. The binding of 125 Ilabelled Tyr-Ala-hexarelin to pituitary and hypothalamic membranes was displaced in a dose-dependent manner by different unlabelled synthetic peptidyl (Tyr-Ala-hexarelin, GHRP2, hexarelin, GHRP6) and non-peptidyl (MK 0677) sGHS. An inhibition of the specific binding was also observed when binding was performed in the presence of [-Arg 1 --Phe 5 --Trp 7,9 -Leu 11 ]-substance P, a substance P antagonist that has been found to inhibit GH release in response to sGHS. In contrast, no competition was observed in the presence of other neuropeptides (GHRH, somatostatin, galanin or Met-enkephalin) which have a known influence on GH release.In conclusion, the present data demonstrate that sGHS have specific receptors in human brain and pituitary gland and reinforce the hypothesis that these compounds could be the synthetic counterpart of an endogenous GH secretagogue involved in the neuroendocrine control of GH secretion and possibly in other central activities.

show abstract

Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-1, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles

Cited by 84 publications

References 6 publications

Pharmacological characterisation of a new oral GH secretagogue, NN703

Pharmacological characterisation of a new oral GH secretagogue, NN703

GH and cortisol rebound rise during and following a somatostatin infusion: studies in dogs with the use of a GH-releasing peptide

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland

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