The Growth Hormone Secretagogue, L-692,429, Induces Phosphatidylinositol Hydrolysis and Hormone Secretion by Human Pituitary Tumors

Adams, Eric F.; Petersen, Beate; Lei, Ting; Buchfelder, Michael; Fahlbusch, Rudolf

doi:10.1006/bbrc.1995.1374

Cited by 57 publications

(32 citation statements)

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“…In the present investigation, U73122 decreased the transient increase in [Ca 2+ ] i evoked by L-585. Consistent with activation of this pathway were the observations that GHRP-6 and non-peptidergic GHS increased phosphoinositide turnover, and caused translocation of protein kinase C (Adams et al 1995, Mau et al 1995. The activation and interplay of several pathways of signal transduction mediate the effect of GHS in mobilizing Ca 2+ , cAMP, protein kinase A and C, and phospholipase C (Smith et al 1997, Muller et al 1999.…”

Section: Casupporting

confidence: 50%

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Glavaski-Joksimovic¹,

Jeftinija²,

Jeremić³

et al. 2002

Journal of Endocrinology

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The effects of a GH secretagogue, L-692,585 (L-585), and human GH-releasing hormone (hGHRH) on calcium transient and GH release were investigated in isolated porcine pituitary cells using calcium imaging and the reverse hemolytic plaque assay (RHPA). Somatotropes were functionally identified by the application of hGHRH. All cells that responded to hGHRH responded to L-585 application. Perfusion application of 10 µM hGHRH and L-585 for 2 min resulted in an increase in intracellular calcium concentrations ([Ca 2+ ] i ) of 53 1 nM (mean S.E.M.) (P<0·01) and 68 2 nM (P<0·01) respectively. The L-585 response was characterized by an initial increase in [Ca )-GRF (1-29) amide) decreased the stimulatory effect of hGHRH. These failed to block the stimulatory effect of L-585, suggesting a different receptor for L-585 from the GHRH receptor. The hGHRHinduced calcium transients and initial peak increase induced by L-585 were significantly decreased by removal of calcium from the bathing medium or the addition of nifedipine, an L-calcium channel blocker. The plateau component of L-585-induced calcium change was abolished by removal of calcium and nifedipine. These results suggest an involvement of calcium channels in GH release. Either SQ-22536, an adenylate cyclase inhibitor, or U73122, a phospholipase C (PLC) inhibitor, blocked the stimulatory effects of hGHRH and L-585 on [Ca 2+ ] i transient, indicating the involvement of adenylate cyclasecAMP and PLC-inositol triphosphate pathways. These results further suggested that calcium mobilization from internal stores during the first phase of the L-585 response induced an increase in [Ca 2+ ] i whereas calcium influx during the second phase is a consequence of somatotrope depolarization.

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Section: Casupporting

confidence: 50%

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Glavaski-Joksimovic¹,

Jeftinija²,

Jeremić³

et al. 2002

Journal of Endocrinology

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“…The latter observation is consistent with the absence of synergy between GHRH and GHRP with respect to PRL or ACTH secretion (20). The mechanism for PRL release by GHRP is largely unknown, although direct somatomammotroph stimulation has been implicated (3,21). ACTH secretion is thought to be effected via hypothalamic activation of CRH and/or vasopressin release by GHRP (22,23).…”

Section: Discussionsupporting

confidence: 67%

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹

Maheshwari¹,

Rahim²,

Shalet³

et al. 1999

The Journal of Clinical Endocrinology & Metabolism

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The mechanism of the synergistic relationship between GH-releasing peptide (GHRP) and GHRH with respect to GH secretion is poorly understood. We report the response to hexarelin, a potent GHRP, in patients affected with a homozygous mutation in the GHRH receptor gene, with consequent GHRH resistance and GH-deficient dwarfism. This newly described syndrome is the human homolog of the little (lit/lit) mouse. Intravenous administration of hexarelin (2 g/kg) to four male adult patients (dwarfs of Sindh) resulted in a complete lack of elevation in plasma GH levels (Ͻ1 ng/mL), an at least 50-to 100-fold deviation from the normal response. In contrast, plasma PRL, ACTH, and cortisol levels rose in a normal manner in response to hexarelin. We conclude that an intact GHRH signaling system is critical for GHRPs to exert their effect on GH release, but that the GHRH system is not necessary for the effect of GHRP on PRL and ACTH secretion. Hexarelin (and probably other GHRPs) are not effective agents for the treatment of patients with GHRH resistance due to GHRH receptor deficiency. (J Clin Endocrinol Metab 84: 956 -959, 1999) T HE GH-RELEASING peptides (GHRP) are a class of small peptides that stimulate GH and, to a lesser degree, PRL and ACTH secretion from the pituitary gland (1-3). They interact with a recently cloned specific receptor that is expressed in the hypothalamus and pituitary (4). Orally active nonpeptide GHRP mimetics that bind to the same receptor and act as GH/PRL/ACTH secretagogues have been developed (3). The GHRPs are believed to represent analogs of a still unknown endogenous ligand for the GHRP receptor. This putative ligand is thought to participate in the regulation of GH secretion, in conjunction with GHRH and somatostatin. GHRPs synergize with GHRH in releasing GH by an unknown, primarily hypothalamic mechanism; coadministration of GHRP with GHRH in vivo results in a large potentiation of the GHRH effect (5, 6). The effect of GHRP on GHRH action at the pituitary level is smaller and additive rather than synergistic (7,8). Despite efforts at elucidating the GHRH-GHRP relationship, the nature of their interaction remains poorly understood, partly because of the difficulty in isolating the effects of GHRH, somatostatin, and GHRP in vivo.To shed further light on the cross-talk between GHRH and GHRP, we studied individuals with a unique new syndrome of genetic GHRH receptor (GHRH-R) deficiency (dwarfism of Sindh) (9, 10) to determine the efficacy of GHRP in elaborating GH, PRL, and ACTH release in the absence of GHRH signaling. Patients affected by this mutation in the GHRH-R are profoundly GH deficient because of GHRH resistance at the pituitary level (9 -12). A practical aim of the study was to determine whether GHRP or its oral analogs may represent a therapeutic modality for the affected patients who live in a rural area of Pakistan where medical services are limited. Hexarelin, the GHRP used in this study, is a potent GHRP whose effects in normal human subjects are well characterized (1...

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“…This is in line with the mechanism of action of GHS described in the pituitary (Smith et al, 1997). The activity of GHS in the CNS is mediated by a specific G-protein-coupled receptor whose stimulation generates GH release through a series of events, including IP 3 -dependent release of Ca 2+ and activation of PKC (BressonBepoldin & Dufy-Barbe, 1994;Adams et al, 1995;Chen et al, 1996). A similar mechanism may be responsible for GHS action in rat skeletal muscle.…”

Section: S Pierno Et Alsupporting

confidence: 56%

Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin‐specific receptor

Pierno

Desaphy

et al. 2003

British J Pharmacology

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1 Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. 2 By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [DLys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. 3 Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca 2+ ] i increase, which was reversible and not blocked by nifedipine or removal of external Ca 2+ . 4 Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. 5 Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.

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The Growth Hormone Secretagogue, L-692,429, Induces Phosphatidylinositol Hydrolysis and Hormone Secretion by Human Pituitary Tumors

Cited by 57 publications

References 0 publications

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹

Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin‐specific receptor

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The Growth Hormone Secretagogue, L-692,429, Induces Phosphatidylinositol Hydrolysis and Hormone Secretion by Human Pituitary Tumors

Cited by 57 publications

References 0 publications

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated porcine somatotropes

Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency1

Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin‐specific receptor

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Product

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Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹