Peptidomimetic Regulation of Growth Hormone Secretion

Smith, Roy G.; Ploeg, Lex H.T. Van der; Howard, Andrew D.; Feighner, Scott D.; Cheng, Kang; Hickey, Gerard J.; Wyvratt, Matthew J.; Fisher, M. H.; Nargund, Ravi P.; Patchett, Arthur A.

doi:10.1210/edrv.18.5.0316

Cited by 426 publications

(284 citation statements)

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“…The GH-releasing activity of ghrelin is more marked in humans than in animals (Kojima et al, 1999;Seoane et al, 2000;Smith et al, 1997;Takaya et al, 2000). In humans, the GH response to ghrelin was considerably greater than that observed following administration of GHRH or synthetic GHSs (Arvat et al, 2001;Bowers, 2001;Seoane et al, 2000;Takaya et al, 2000), whereas in rats the GH-releasing potency of ghrelin was similar to that of GHRH (Kojima et al, 1999).…”

Section: Introductionmentioning

confidence: 95%

“…Studies in dogs have shown that orally (e.g., MK-0677, capromorelin) and intravenously (IV) (e.g., hexarelin) administered GHSs are also effective GH releasers (Carpino et al, 2003;Cella et al, 1995;Jacks et al, 1996;Rigamonti et al, 1999). However, the action of synthetic GHSs is not always confined to the promotion of GH release (Casanueva and Dieguez, 1999;Lamberts, 1999;Smith et al, 1997). In man, synthetic GHSs such as GHRP-6 also stimulates the secretion of Prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol (Arvat et al, 2001;Casanueva and Dieguez, 1999;Lamberts, 1999;Massoud et al, 1996;Smith et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…However, the action of synthetic GHSs is not always confined to the promotion of GH release (Casanueva and Dieguez, 1999;Lamberts, 1999;Smith et al, 1997). In man, synthetic GHSs such as GHRP-6 also stimulates the secretion of Prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol (Arvat et al, 2001;Casanueva and Dieguez, 1999;Lamberts, 1999;Massoud et al, 1996;Smith et al, 1997). Moreover in rats, GHRP-6 activates the pituitary-adrenocortical axis (Thomas et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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The effects of three growth hormone secretagogues (GHSs), ghrelin, growth hormone-releasing peptide-6 (GHRP-6), and growth hormone-releasing hormone (GHRH), on the release of adenohypophyseal hormones, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinising hormone (LH), prolactin (PRL) and on cortisol were investigated in young and old healthy Beagle dogs.Ghrelin proved to be the most potent GHS in young dogs, whereas in old dogs GHRH administration was associated with the highest plasma GH concentrations. The mean plasma GH response after administration of ghrelin was significantly lower in the old dogs compared with the young dogs. The mean plasma GH concentration after GHRH and GHRP-6 administration was lower in the old dogs compared with the young dogs, but this difference did not reach statistical significance. In both age groups, the GHSs were specific for GH release as they did not cause significant elevations in the plasma concentrations of ACTH, cortisol, TSH, LH, and PRL. It is concluded that in young dogs, ghrelin is a more powerful stimulator of GH release than either GHRH or GHRP-6. Ageing is associated with a decrease in GH-releasing capacity of ghrelin, whereas this decline is considerably lower for GHRH or GHRP-6.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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“…GHS were discovered as a family of non-natural peptidyl and non-peptidyl molecules able to strongly stimulate GH secretion acting on a specific Gprotein coupled receptor, namely GHS type 1a receptor, that is different from the GHRH-receptor (Smith et al, 1997;Muccioli et al, 1998Muccioli et al, , 2002. Theoretically, GHS would therefore influence cardiac structure and function via enhanced GH and IGF-I secretion.…”

Section: Introductionmentioning

confidence: 99%

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

169

116

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The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

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“…A third independent pathway responsible for regulation of GH release has recently emerged from studies of artificial GH secretagogues (GHSs) (3,4). GHSs are synthetic compounds that are potent stimulators of pituitary GH release, acting through the GHS receptor (GHS-R) (5)(6)(7).…”

mentioning

confidence: 99%

Structural Divergence of Human Ghrelin

Hosoda¹,

Kojima²,

Mizushima³

et al. 2003

Journal of Biological Chemistry

282

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Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser 3 , was isolated from rat stomach and found to be an endogenous ligand for the growthhormone secretagogue receptor (GHS-R). This octanoyl modification is essential for ghrelin-induced GH release. We report here the purification and identification of human ghrelin from the stomach, as well as structural analysis of the human ghrelin gene and quantitation of changes in plasma ghrelin concentration before and after gastrectomy. Human ghrelin was purified from the stomach by gel filtration and high performance liquid chromatography, using a ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a stable cell line expressing GHS-R to test the fractions. In the course of purification, we isolated human ghrelin of the expected size, as well as several other ghrelin-derived molecules. Classified into four groups by the type of acylation observed at Ser 3 ; these peptides were found to be non-acylated, octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All peptides found were either 27 or 28 amino acids in length, the former lacking the C-terminal Arg 28, and are derived from the same ghrelin precursor through two alternative pathways. The major active form of human ghrelin is a 28-amino acid peptide octanoylated at Ser 3 , as was found for rat ghrelin. Synthetic octanoylated and decanoylated ghrelins produce intracellular calcium increases in GHS-R-expressing cells and stimulate GH release in rats to a similar degree. Both ghrelin and the ghrelin-derived molecules were found to be present in plasma as well as stomach tissue. Plasma levels of immunoreactive ghrelin after total gastrectomy in three patients were reduced to approximately half of their pre-gastrectomy values, after which they gradually increased. This suggests that the stomach is the major source of circulating ghrelin and that other tissues compensate for the loss of ghrelin production after gastrectomy.

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Peptidomimetic Regulation of Growth Hormone Secretion

Cited by 426 publications

References 130 publications

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Structural Divergence of Human Ghrelin

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