Involvement of Nitric Oxide in the Regulation of Growth Hormone Secretion in Dogs

Valverde, I Salar; Peñalva, A; Ghigo, Ezio; Casanueva, Felipe F.; Diéguez, Carlos

doi:10.1159/000054688

Cited by 22 publications

(22 citation statements)

References 31 publications

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“…Similarly, the releasing activity of GHRP-6 has been proven NO dependent in dogs [36]. In good agreement with these results, our data show that the stimulatory effect of ghrelin requires the presence of NO; it is blocked by pretreatment with NAME, an inhibitor of NO synthases.…”

Section: Discussionsupporting

confidence: 89%

Role of Ghrelin in the Control of Growth Hormone Secretion in Prepubertal Rats: Interactions with Excitatory Amino Acids

et al. 2003

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Ghrelin is a 28-amino-acid peptide, with an essential n-octanoyl modification at Ser3, that elicits growth-hormone (GH) secretion in rats and humans. At present, the mechanisms of ghrelin action and its interactions with other systems controlling GH secretion remain poorly characterized. In this context, the present study was undertaken to obtain information about ontogeny and possible gender differences in the GH-releasing activity of ghrelin, and to delineate its primary site(s) of action at the hypothalamus and/or pituitary. In addition, the interactions between ghrelin and other relevant signals in the control of GH secretion, such as excitatory amino acids (EAAs), nitric oxide (NO) and serotonin, were assessed. Experiments were carried out in infantile-prepubertal animals, when GH pulsatility is not yet established. Systemic administration of ghrelin (25 nmol/rat, i.p.) to 5-, 10- and 23-day-old male and female rats increased plasma GH levels from day 10 onwards. This action was NO dependent, since it disappeared in 23-day-old males after pretreatment with an inhibitor of NO synthase (NAME). Similarly, central infusion of ghrelin (3 nmol/rat, i.c.v.) elicited GH responses in 10- and 23-day-old animals significantly higher than after systemic administration. By contrast, in vitro challenge of pituitary tissue with increasing doses of ghrelin (10^–9–10^–7M) failed to enhance GH release into the incubation medium, whereas stimulation with GH-releasing hormone (GHRH; 10^–7M) or GHRP-6 (10^–7M) was effective. Finally, effects of ghrelin were blocked by pretreatment with MK-801 and NBQX antagonists of EAA ionotropic receptors and after manipulation of endogenous serotoninergic tone. In addition, the potent releasing activity of EAA agonists NMDA and AMPA was blunted by pretreatment with D-Lys3-GHRP-6, a selective antagonist of the cognate ghrelin receptor, i.e. the GH-secretagogue receptor. In conclusion, our results demonstrate that GH-releasing activity of ghrelin appears early in the infantile period, is NO dependent and involves a primary hypothalamic site of action. The data also demonstrate for the first time the existence of a cross-talk between ghrelin and other neurotransmitter systems, such as EAAs and serotonin, in precise control of GH secretion.

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Section: Discussionsupporting

confidence: 89%

Role of Ghrelin in the Control of Growth Hormone Secretion in Prepubertal Rats: Interactions with Excitatory Amino Acids

et al. 2003

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“…NO donors show an inhibitory effect on GH secretion, probably because they release high nitrite levels [14]. In addition, NO inhibition may act by increasing the hypothalamic somatostatinergic tone and blunting endogenous GHRH secretion [27]. Hall and Garthwaite [28] reported that physiological NO concentration ranged to be 100 pM (or below) up to approximately 5 nM.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide inhibits ghrelin-induced cell proliferation and ERK1/2 activation in GH3 cells

Tian

Wang

et al. 2010

Endocr

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Ghrelin stimulates growth hormone release and cell proliferation, which strongly supports a significant role for this peptide in the control of growth hormone-releasing adenomas function and growth. Nitric oxide can influence the stimulatory effects of ghrelin on growth hormone secretion in growth hormone-releasing adenomas. However, the effect of nitric oxide (NO) on ghrelin-induced cell proliferation and the mechanism of this effect in the adenoma were not clarified. In this study, we observed that ghrelin, at a concentration of 10⁻⁹ to 10⁻⁶ M, significantly increased BrdU incorporation into rat GH3 cells. A NO donor, S-nitroso-N-acetylpenicillamine (SNAP), blunted basal, and ghrelin-induced cell proliferation. A blocker of NO synthase, Nw-nitro-L-arginine methyl ester hydrochloride (NAME), had no influence on these actions. The activation of extracellular signal-regulated kinase (ERK) 1/2 was examined by western blotting. The results showed that SNAP reduced ghrelin-stimulated ERK1/2 activation but NAME had no influence on this activation. Together, this study indicates that NO inhibited ghrelin-induced cell proliferation by blocking ERK1/2 activation in GH3 cells.

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“…It has been postulated that pituitary iNOS activation decreases GH secretion, since its inhibition by L-N(6)-(l-iminoethyl)lysine administration prevents the inhibitory effect of IFN-␥ on GH release in pituitary cell cultures (45). However, other data in the literature suggest that NO has a stimulatory effect on GH release in vitro (3,34), and in vivo (43). These discrepancies have been explained by a biphasic action of NO on GH secretion: a positive effect at low concentrations and a negative effect at high concentrations (7).…”

Section: Discussionmentioning

confidence: 99%

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

Priego

Cáceres²,

Martín³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Priego, Teresa, Inmaculada Ibáñez de Cáceres, Ana Isabel Martín, M. Á ngeles Villanú a, and Asunción López-Calderón. NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver. Am J Physiol Endocrinol Metab 286: E50-E56, 2004. First published September 16, 2003 10.1152/ajpendo.00149.2003In this study, we administered aminoguanidine, a relatively selective inducible nitric oxide synthase (iNOS) inhibitor, to study the role of nitric oxide (NO) in LPSinduced decrease in IGF-I and IGFBP-3. Adult male Wistar rats were injected intraperitoneally with LPS (100 g/kg), aminoguanidine (100 mg/kg), LPS plus aminoguanidine, or saline. Rats were injected at 1730 and 0830 the next day and killed 4 h after the last injection. LPS administration induced an increase in serum concentrations of nitrite/ nitrate (P Ͻ 0.01) and a decrease in serum concentrations of growth hormone (GH; P Ͻ 0.05) and IGF-I (P Ͻ 0.01) as well as in liver IGF-I mRNA levels (P Ͻ 0.05). The LPS-induced decrease in serum concentrations of IGF-I and liver IGF-I gene expression seems to be secondary to iNOS activation, since aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver. In contrast, LPS-induced decrease in serum GH was not prevented by aminoguanidine administration. LPS injection decreased IGFBP-3 circulating levels (P Ͻ 0.05) and its hepatic gene expression (P Ͻ 0.01), but endotoxin did not modify the serum IGFBP-3 proteolysis rate. Aminoguanidine administration blocked the inhibitory effect of LPS on both IGFBP-3 serum levels and its hepatic mRNA levels. When aminoguanidine was administered alone, IGFBP-3 serum levels were increased (P Ͻ 0.05), whereas its hepatic mRNA levels were decreased. This contrast can be explained by the decrease (P Ͻ 0.05) in serum proteolysis of this binding protein caused by aminoguanidine. These data suggest that iNOS plays an important role in LPS-induced decrease in circulating IGF-I and IGFBP-3 by reducing IGF-I and IGFBP-3 gene expression in the liver. nitric oxide; inducible nitric oxide synthase; lipopolysaccharide; growth hormone; insulin-like growth factor I; insulin-like growth factor-binding protein-3; proteolysis; aminoguanidine SEPSIS INDUCES PROTEOLYSIS and negative nitrogen balance, which leads to lean body mass loss and cachexia. Sepsis is also associated with a wide range of hormonal changes that contribute to the catabolic state; among these there is an alteration of the somatotropic axis (47). A decrease in serum concentrations of IGF-I in septic patients and in different inflammatory diseases has also been observed (12,28).Lipopolysaccharide (LPS), or endotoxin, triggers the initiation of host responses to sepsis by gram-negative bacterial infection. Endotoxin administration in rats increases plasma concentrations of corticosterone, whereas it decreases circulating growth hormone (GH) and IGF-I (20, 27). The decrease in circulating IGF-I is secondary to a decrease in IGF-I gene expres...

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Involvement of Nitric Oxide in the Regulation of Growth Hormone Secretion in Dogs

Cited by 22 publications

References 31 publications

Role of Ghrelin in the Control of Growth Hormone Secretion in Prepubertal Rats: Interactions with Excitatory Amino Acids

Role of Ghrelin in the Control of Growth Hormone Secretion in Prepubertal Rats: Interactions with Excitatory Amino Acids

Nitric oxide inhibits ghrelin-induced cell proliferation and ERK1/2 activation in GH3 cells

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

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