scholarly journals Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model

2009 ◽  
Vol 43 (3) ◽  
pp. 105-119 ◽  
Author(s):  
Clemens Wagner ◽  
S Roy Caplan ◽  
Gloria S Tannenbaum
Keyword(s):  
Growth Hormone ◽  
Vagus Nerve ◽  
Present Model ◽  
Male Rat ◽  
Extended Model ◽  
Growth Hormone Releasing Hormone ◽  
Hypothalamic Neuropeptides ◽  
Neuroendocrine Axis ◽  
The Brain

Growth hormone (GH) is secreted in a pulsatile fashion from the pituitary gland into the circulation. Release is governed by two hypothalamic neuropeptides, growth hormone-releasing hormone (GHRH) and somatostatin (SRIF), resulting in secretion episodes with a periodicity of 3.3 h in the male rat. Ghrelin is an additional recently identified potent GH-secretagogue. However, its in vivo interactions with the GH neuroendocrine axis remain to be elucidated. Moreover, two different sites of ghrelin synthesis are involved, the stomach and the hypothalamus. We used our previously developed core model of GH oscillations and added the sites of ghrelin action at the pituitary and in the hypothalamus. With this extended model, we simulated the effects of central and peripheral ghrelin injections, monitored the GH profile and compared it with existing experimental results. Systemically administered ghrelin elicits a GH pulse independent of SRIF, but only in the presence of GHRH. The peripheral ghrelin signal is mediated to the brain via the vagus nerve, where it augments the release of GHRH and stimulates the secretion of neuropeptide-Y (NPY). By contrast, centrally administered ghrelin initiates a GH pulse by increasing the GHRH level and by antagonizing the SRIF block at the pituitary. In addition, NPY neurons are activated, which trigger a delayed SRIF surge. The major novel features of the present model are a) the role played by NPY, and b) the dissimilar functions of ghrelin in the hypothalamus and at the pituitary. Furthermore, the predictions of the model were experimentally examined and confirmed.

Periodic interactions of GH-releasing factor and somatostatin can augment GH release in vitro

1987 ◽  
Vol 253 (5) ◽  
pp. E508-E514
Author(s):  
J. Weiss ◽  
M. J. Cronin ◽  
M. O. Thorner
Keyword(s):  
Growth Hormone ◽  
Human Growth Hormone ◽  
Human Growth ◽  
Male Rat ◽  
Base Line ◽  
Additive Effects ◽  
Growth Hormone Releasing Factor ◽  
The Impact

Growth hormone (GH) is secreted as pulses in vivo. To understand the signals governing this periodicity, we have established a perifusion-based model of pulsatile GH release. Male rat anterior pituitaries were dispersed and perifused with pulses of human growth hormone-releasing factor-(1--40) (GHRF), with or without a continuous or discontinuous somatostatin tonus. An experiment was composed of a 1-h base-line collection followed by four 3-h cycles; each contained single or paired 10-min infusion(s) of 3 nM GHRF. In testing the impact of somatostatin, the protocol was identical except that 0.3 nM somatostatin was added 30 min into the base-line period and then was either continued throughout the study or withdrawn during the periods of GHRF infusion. GH base lines with somatostatin were lower than vehicle base lines (P less than 0.05). GHRF pulses generated consistent peaks of GH release between 200 and 300 ng. min-1. (10(7) cells)-1, and these peaks were not altered by continuous somatostatin. In contrast, withdrawal of somatostatin during GHRF administration elicited markedly higher GH peaks (P less than 0.05) and more total GH release (P less than 0.05). This response could not be accounted for by the additive effects of GHRF and somatostatin withdrawal.

scholarly journals Genesis of the ultradian rhythm of GH secretion: a new model unifying experimental observations in rats

1998 ◽  
Vol 275 (6) ◽  
pp. E1046-E1054 ◽  
Author(s):  
Clemens Wagner ◽  
S. Roy Caplan ◽  
Gloria S. Tannenbaum
Keyword(s):  
Time Course ◽  
Male Rat ◽  
Peripheral Tissues ◽  
Feedback Mechanisms ◽  
Gh Secretion ◽  
Metabolic Functions ◽  
Neuroendocrine Axis ◽  
Two Peaks ◽  
The Brain ◽  
Gh Receptors

Growth hormone (GH) induces growth in animals and humans and also has important metabolic functions. The GH neuroendocrine axis consists of a signaling cascade from the hypothalamus to the pituitary, the liver, and peripheral tissues, including two major feedback mechanisms. GH is secreted from the pituitary into the circulating blood according to the effect on the somatotrophs of two hypothalamic peptides, GH-releasing hormone (GHRH) and its antagonist, somatostatin (SRIF). The typical GH profile in the male rat shows secretory episodes every 3.3 h, which are subdivided into two peaks. Focusing on the mechanisms for generation of this ultradian GH rhythm, we simulated the time course of GH secretion under a variety of conditions. The model that we propose is based on feedback of GH on its own release mediated both by GH receptors on SRIF neurons in the brain and by a delayed SRIF release into both the brain and portal blood. SRIF, with a resultant periodicity of 3.3 h, affects both the somatotroph cells in the pituitary and the GHRH neurons in the hypothalamus. The secretion of GHRH is postulated to occur in an ∼1-h rhythm modulated by the level of SRIF in the hypothalamus. The model predicts a possible mechanism for the feminization of the male GH rhythm by sex steroids and vice versa, and suggests experiments that might reveal the proposed intrinsic 1-h GHRH rhythm.

scholarly journals Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

2017 ◽  
Vol 114 (45) ◽  
pp. 12033-12038 ◽  
Author(s):  
Iacopo Gesmundo ◽  
Michele Miragoli ◽  
Pierluigi Carullo ◽  
Letizia Trovato ◽  
Veronica Larcher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Therapeutic Potential ◽  
Growth Hormone Releasing Hormone ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

scholarly journals Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

2019 ◽  
Vol 116 (6) ◽  
pp. 2226-2231 ◽  
Author(s):  
Tania Villanova ◽  
Iacopo Gesmundo ◽  
Valentina Audrito ◽  
Nicoletta Vitale ◽  
Francesca Silvagno ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Antagonists

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

scholarly journals Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2331
Author(s):  
Chongxu Zhang ◽  
Tengjiao Cui ◽  
Renzhi Cai ◽  
Medhi Wangpaichitr ◽  
Mehdi Mirsaeidi ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Lung Physiology ◽  
Extracellular Signal ◽  
P21 Activated Kinase

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.

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