Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.

Hickey, Gerard J.; Jacks, T. J.; Judith, F. R.; Taylor, J. E.; Schoen, William R.; Krupa, David; Cunningham, Patrick N.; Clark, Janet A.; Smith, Roy G.

doi:10.1210/endo.134.2.8299565

Cited by 52 publications

(29 citation statements)

References 21 publications

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“…Among the effects of GHS-R ligands unrelated to GH release, moderate but consistent elevation of serum adrenocorticotropin (ACTH) and glucocorticoid levels have been reported for a variety of GHSs in different species (2,5,6,8,9,23). In good agreement, it was shown recently that ghrelin is able to elicit ACTH and cortisol responses in humans (18,20), as well as ACTH and corticosterone release in rats and mice respectively (19,24).…”

Section: Introductionmentioning

confidence: 72%

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Barreiro

Pinilla²,

Aguilar³

et al. 2002

European Journal of Endocrinology

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Objective: GH secretagogues (GHSs) elicit a variety of biological effects in several endocrine and nonendocrine target tissues, including activation of the hypothalamic -pituitary-adrenal axis. The latter is mainly carried out through a central hypothalamic action; yet the possibility of additional effects directly at the adrenal level cannot be ruled out. The aims of this study were to evaluate the expression and homologous regulation of the GHS-receptor (GHS-R) gene in rat adrenal and to assess the effects of synthetic (GH releasing peptide-6 -GHRP-6) and natural (ghrelin) ligands of GHS-R upon basal and ACTH-stimulated corticosterone secretion in vitro. Design and Methods: Analysis of adrenal expression of target mRNAs (GHS-R, GHS-R1a, ghrelin, and several steroidogenic factors) was conducted by means of primer-specific, semi-quantitative RT-PCR. Evaluation of corticosterone secretion by incubated adrenal tissue was carried out by specific RIA. Results: RT-PCR analysis demonstrated expression of the GHS-R gene, but not of the gene encoding the cognate ligand ghrelin, in rat adrenal. Moreover, expression of the mRNA coding for the type 1a GHS-R (GHS-R1a), i.e. the biologically active receptor form, was demonstrated. The adrenal expression of the GHS-R message appeared under the regulation of homologous signals in vitro, as short-term incubation of adrenal samples in serum-free medium induced a significant increase in GHS-R mRNA levels that was inhibited by exposure to different doses of GHRP-6 (10 29 -10 25 mol/l) or ghrelin (10 27 mol/l). Notably, an opposite pattern of homologous regulation of GHS-R gene expression was observed at the pituitary. Finally, short-term stimulation with increasing concentrations of GHRP-6 (10 29 -10 25 mol/l) or ghrelin (10 27 mol/l) failed to alter basal and ACTHstimulated corticosterone secretion in vitro, neither did it modify ACTH-stimulated mRNA expression levels of several upstream elements in the steroidogenic route: the steroidogenic acute regulatory (StAR) protein, and the enzymes P450 cholesterol side-chain cleavage (P450scc) and 3b-hydroxysteroid dehydrogenase (3b-HSD). Conclusions: Our study provides novel evidence for the expression and homologous regulation of the GHS-R gene in rat adrenal. However, our results cast doubts on the possibility of direct adrenal actions of ligands of the GHS-R in the regulation of corticosterone secretion in the rat.

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Section: Introductionmentioning

confidence: 72%

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Barreiro

Pinilla²,

Aguilar³

et al. 2002

European Journal of Endocrinology

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“…In dogs (Hickey et al, 1994) and rats (Kojima et al, 1999), synthetic GHSs do not stimulate PRL release. This species-related difference may be explained by different numbers of somatomammotrophs in various species (Raun et al, 1998), with humans having a high proportion of these cells (Frawley and Boockfor, 1991).…”

Section: Discussionmentioning

confidence: 99%

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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“…Reportedly, some GHRPs can release corticosteroids (Hickey et al 1994, Friboes et al 1995, Clark et al 1997 and although the mechanism by which GHRPs stimulate the HPA axis is unknown, it probably underlies a hypothalamic action since no effect on adrenocorticotropin release from isolated pituitary cells has been observed (Smith et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Gennaro-Colonna

Rossoni²,

Cocchi³

et al. 2000

Journal of Endocrinology

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Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 µg/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 µg, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexarelin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

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Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.

Cited by 52 publications

References 21 publications

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

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

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

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