Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release

It has previously been reported that growth hormone secretagogues (GHS) may have a role in the regulation of bone metabolism in animals and humans. In this study we evaluated the effect of ghrelin, the endogenous ligand of GHS receptors, on the proliferation rate and on osteoblast activity in primary cultures of rat calvaria osteoblasts. In the same experiments, we compared the effects of ghrelin with those of hexarelin (HEXA) and EP-40737, two synthetic GHS with different characteristics. Both ghrelin and HEXA (10 11 -10 8 M) significantly stimulated osteoblast proliferation at low concentrations (10 10 M). Surprisingly, EP-40737 demonstrated an antiproliferative effect at 10 9 -10 8 M, whereas lower concentrations had no effect on cell proliferation. Ghrelin and HEXA significantly increased alkaline phosphatase (ALP) and osteocalcin (OC) production. At variance with these peptides, EP-40737 did not significantly stimulate ALP and OC. The mRNA for GHS-R1a receptors and the corresponding protein were detected in calvarial osteoblasts by RT-PCR and Western blot respectively, indicating that ghrelin and GHS may bind and activate this specific receptor. We conclude that endogenous ghrelin and synthetic GHS modulate proliferation and differentiation of rat osteoblasts, probably by acting on their specific receptor.

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“…Accordingly EP-40737 does not share all the biological activities of ghrelin and HEXA (Torsello et al 1998(Torsello et al , 2000.…”

Section: Discussionmentioning

confidence: 93%

Ghrelin regulates proliferation and differentiation of osteoblastic cells

Maccarinelli¹,

Sibilia²,

Torsello³

et al. 2005

Journal of Endocrinology

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170

121

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“…In this context, it is noteworthy that in the rat the orexigenic activity of some GHRPs appears to be divorced from the GH-releasing effect (36), pointing to the existence of different receptor or sub-receptor systems for GHRPs (53).…”

Section: Discussionmentioning

confidence: 99%

“…To ensure that the rats were satiated, they were given a freshly prepared diet consisting of standard pellets. After administration of the above compounds, the cumulative food intake was carefully evaluated every hour for 6 h, according to a standard procedure (36).…”

Section: Food Intake Experimentsmentioning

confidence: 99%

Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide

Rigamonti

Cella²,

Cavallera

et al. 2001

European Journal of Endocrinology

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Objective: Among the many actions of nitric oxide (NO) are those on endocrine and feeding behaviour. Based on NO involvement in the GH-releasing effect of the GH-releasing peptides (GHRPs) and the reported orexigenic activity of these compounds, we sought to evaluate the effect of the combined administration of a long-acting NO donor, molsidomine, and the newly synthesized GHRP EP92632 on food intake and GH secretion in rats. Moreover, to verify the specificity of a potential NO involvement, we evaluated whether or not the effects of GHRPs were abolished by a pre-treatment with an inhibitor of NO synthase, N-nitro-arginine-methyl-ester (NAME). Methods: In the food intake experiments, adult Sprague±Dawley male rats underwent acute administration of: (1) EP92632 (160 mg/kg, s.c.); (2) molsidomine (100 mg/kg, i.p.); (3) EP92632+molsidomine; (4) L-NAME (40 and 60 mg/kg, i.p.); (5) EP92632+L-NAME (60 mg/kg, i.p.); (6) EP92632+molsidomine+L-NAME (60 mg/kg, i.p.); and (7) 0.9% saline (0.1 ml/kg, i.p.). After treatments, the cumulative food intake in the 6 post-treatment hours was carefully evaluated. In the neuroendocrine experiments, rats were given the same compounds according to the above reported schedule, except for the use of one dose of NAME (60 mg/kg, i.p.) and a lower EP92632 dose (80 mg/kg, s.c.), and were sampled via atrial cannula. Results: EP92632 significantly stimulated food intake, an effect which was further enhanced by molsidomine, though the latter did not elicit per se any orexigenic effect. L-NAME given alone significantly decreased food intake and abolished the orexigenic effect of the GHRP and the enhancing effect of molsidomine. Plasma GH levels increased significantly following administration of EP92632 but, in contrast to the food intake experiments, molsidomine significantly inhibited both basal and EP92632-stimulated GH secretion; moreover, NAME had a biphasic effect on the EP92632-stimulated GH release: initially inhibitory and then, from 45 min on, stimulatory. NAME did not affect basal GH levels but, surprisingly, combined administration of molsidomine and NAME induced a striking inhibition of both basal and the peptide-stimulated GH release. Conclusions: In summary, these data indicate that NO in the rat is physiologically involved in a stimulatory way in the GHRP-mediated effect on food intake, but exerts a dual action, probably stimulatory at hypothalamic and inhibitory at pituitary levels, on basal and GHRP-stimulated GH secretion. European Journal of Endocrinology 144 155±162

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“…17 ± 19 The present study was aimed at pursuing the identi®cation of other EP 60761-andaor EP50885-related peptides endowed with proerectile activity when injected into the PVN and to compare their structure ± activity relationship with that of those peptides well characterized for their effects on GH release and eating behaviour. 20 A comparison of the proerectile effects of these EP peptides with those of apomorphine, oxytocin and NMDA, and the effect they induced on penile erection when given systemically (endovenously) are also reported.…”

Section: Introductionmentioning

confidence: 99%

EP 60761- and EP 50885-induced penile erection: structure–activity studies and comparison with apomorphine, oxytocin and N-methyl-D-aspartic acid

Succu

et al. 2000

Int J Impot Res

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The effect of 10 peptides structurally related to the growth hormone (GH) releasing peptide hexarelin, injected into the paraventricular nucleus of the hypothalamus (PVN), on penile erection was studied in male rats. Six out of the 10 peptides tested induced penile erection in a dosedependent manner. Among them, the most potent were EP 80661, EP 60761 and EP 91072, which were active at doses of 20 ± 200 ng. The potency of these peptides in inducing penile erection is comparable to that of apomorphine, oxytocin and N-methyl-D-aspartic acid similarly injected into the PVN. Other peptides found active were EP 50885, EP 90101 and EP 91071, which induced penile erection at doses of 200 ± 2000 ng. In contrast, EP 51322, EP 70555, EP 51216 and EP 91073 were inactive, as were hexarelin, EP 40904 and EP 40737 in a previous study. The majority of EP peptides found active when injected into the PVN induced penile erection, although to a lesser extent, also when given systemically (endovenously). The proerectile effect of EP peptides was prevented by the oxytocin receptor antagonist [d(CH 2 ) 5 Tyr(Me) 2 -Orn 8 ]-vasotocin given into the lateral ventricles but not into the PVN, by the nitric oxide (NO) synthase inhibitor N G -nitro-larginine methyl ester given either into the lateral ventricles or into the PVN, by the N-type Ca 2 channel blocker o o-conotoxin GVIA and by morphine, but not by the dopamine receptor antagonist cis-¯upenthixol or by the N-methyl-D-aspartic acid receptor antagonist dizolcipine, given into the PVN. As the structure ± activity relationship of EP peptides for proerectile activity is different from those of other biological actions of these compounds, ie for GH release and eating behaviour, the present results suggest that EP peptides induce penile erection by acting on speci®c hypothalamic receptor sites that activate paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas that mediate this sexual function by a mechanism similar to that of dopamine receptor agonists, oxytocin and N-methyl-D-aspartic acid.

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Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release

Cited by 91 publications

References 27 publications

Ghrelin regulates proliferation and differentiation of osteoblastic cells

Ghrelin regulates proliferation and differentiation of osteoblastic cells

Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide

EP 60761- and EP 50885-induced penile erection: structure–activity studies and comparison with apomorphine, oxytocin and N-methyl-D-aspartic acid

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