Twenty-four-hour growth hormone (GH)-releasing peptide (GHRP) infusion enhances pulsatile GH secretion and specifically attenuates the response to a subsequent GHRP bolus.

Hühn, W; Hartman, Mark L.; Pezzoli, Suzan S.; Thorner, Michael O.

doi:10.1210/jcem.76.5.8496311

Cited by 63 publications

(36 citation statements)

References 29 publications

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“…This finding is very much in keeping with the lowered pulse amplitude observed in the present study following inhibition of GHS-1a receptor activation. Several studies have also demonstrated that administration of GH-releasing peptides or GHSs will amplify the normal pulsatile pattern of GH in both young and elderly human subjects (23,24). These findings are consistent with the concept that endogenous ghrelin acts through the GHS-1a receptor to amplify the normal pulsatile pattern of GH secretion.…”

Section: Use Of Bim-28163 To Dissect the Role Of Endogenous Ghrelin -supporting

confidence: 73%

Novel analogs of ghrelin: physiological and clinical implications

Halem¹,

Taylor²,

Dong³

et al. 2004

European Journal of Endocrinology

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Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.European Journal of Endocrinology 151 S71-S75

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Section: Use Of Bim-28163 To Dissect the Role Of Endogenous Ghrelin -supporting

confidence: 73%

Novel analogs of ghrelin: physiological and clinical implications

Halem¹,

Taylor²,

Dong³

et al. 2004

European Journal of Endocrinology

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“…The effects of continuous peripheral infusion of synthetic GHS on pulsatile GH release in the human mirror the foregoing outcomes (11,41,45,73).…”

Section: Simulation Of Continuous Peripheral Ghrelin Stimulationmentioning

confidence: 72%

“…Fifth, continuous intravenous GHS infusion amplifies GH pulse amplitude (but not frequency) 5-to 30-fold in both men and women (11,41,45,73). Therefore, augmentation of GH peak height is an expectation of valid model performance.…”

Section: Ghrelin and Gh Network: Basis Of Model Structurementioning

confidence: 99%

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

Farhy

Veldhuis

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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(GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments. somatotropic axis; growth hormone secretagogues; feedback; mathematical model; hormone pulsatility; hypothalamus; pituitary GHRELIN AND SYNTHETIC GROWTH HORMONE SECRETAGOGUES (GHS) stimulate pulsatile growth hormone (GH) secretion via combined hypothalamohypophyseal mechanisms. The GHS receptor is expressed by somatotrope cells and arcuate nucleus (ArC) neurons containing GHRH and other peptides (40,44). Ghrelin and GHS act directly on GH-secreting (somatotrope) cells and indirectly on the inhibitory signal somatostatin (SRIF) and the peptidyl agonist GH-releasing hormone (GHRH) (13,27,44,51). In particular, GHS stimulate somatotropes in vitro but are synergistic with GHRH, induce ArC GHRH release, and antagonize certain hypothalamic actions of SRIF in vivo (3,10,13,27,37,40,51). GHRH potentiates feedforward drive by GHS because passive immunoneutralization or pharmacological antagonism of GHRH and truncational mutation of the GHRH receptor attenuate GHS-evoked GH secretion markedly in the rat, mouse, and human (31,35,63,65,68,78). In contradistinction, GHS and GHRH do not synergize in vitro (70, 89). Pituitary portal vein sampling studies have indicated that GHS infusion elicits ArC GHRH release in the conscious sheep (31, 35). Other experiments have established that GHS can oppose inhibition by SRIF and octreotide in the anterior pituitary gland and the hypothalamus (25)(26)(27)71). No formalism incorporates these multilocus actions of GHS into available constructs of self-renewable GH pulses mediated by GHRH-SRIF-GH feedback interactions (34,53,61,72).Current models of the basic properties of the GH pulse renewal process assume reciprocal interactions among GHRH, SRIF,. In the present work, we have used this foundation in an effort to incorporate the known effects of GHS in a simple network-l...

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“…GH administered by osmotic minipumps induces a continuous increase in circulating GH concentrations, whereas the GHSs, also when administered continuously, increase the amplitude of the endogenous GH pulses (Huhn et al 1993, Jaffe et al 1993. Furthermore, it has been suggested that different subtypes of the recently cloned GHS receptor may exist and that different GHSs may differ in their binding affinity for the different subtypes (Ong et al 1998).…”

Section: Tablementioning

confidence: 99%

The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats

Svensson

Lall²,

Dickson³

et al. 2000

Journal of Endocrinology

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Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0·5 mg/kg per day; n=7), GHRP-6 (0·5 mg/kg per day; n=8), GH (3·5 mg/kg per day; n=7), or vehicle administered continuously s.c. via osmotic minipumps for 12 weeks. The animals were followed in vivo by dual X-ray absorptiometry (DXA) measurements every 4th week. After the animals were killed, femurs were analysed in vitro by mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans. After this, excised femurs and vertebrae L6 were analysed by the use of Archimedes' principle and by determinations of ash weights. All treatments increased body weight and total tibial and vertebral BMC measured by DXA in vivo compared with vehicle-treated controls. However, total BMC corrected for the increase in body weight (total BMC:body weight ratio) was unaffected. Tibial area bone mineral density (BMD, BMC/area) was increased, but total and vertebral area BMDs were unchanged. The pQCT measurements in vitro revealed that the increase in the cortical BMC was due to an increased cross-sectional bone area, whereas the cortical volumetric BMD was unchanged. Femur and vertebra L6 volumes were increased but no effect was seen on the volumetric BMDs as measured by Archimedes' principle. Ash weight was increased by all treatments, but the mineral concentration was unchanged. We conclude that treatment of adult female rats with the GHSs ipamorelin and GHRP-6 increases BMC as measured by DXA in vivo. The results of in vitro measurements using pQCT and Archimedes' principle, in addition to ash weight determinations, show that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged.

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Twenty-four-hour growth hormone (GH)-releasing peptide (GHRP) infusion enhances pulsatile GH secretion and specifically attenuates the response to a subsequent GHRP bolus.

Cited by 63 publications

References 29 publications

Novel analogs of ghrelin: physiological and clinical implications

Novel analogs of ghrelin: physiological and clinical implications

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats

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