Administration Of Growth Hormone Secretagogues Research Articles

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia.

BackgroundCachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose‐limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium‐dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS‐R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood.MethodsBy a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast‐twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin‐induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention.ResultsCisplatin‐treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up‐regulation of atrogin1/Murf‐1 genes and a down‐regulation of Pgc1‐a gene, all indexes of muscle atrophy, and by a two‐fold increase in resting intracellular calcium, [Ca2+]i, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store‐operated calcium entry were ~50% significantly reduced in cisplatin‐treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin‐induced alteration of calcium homeostasis by both common as well as drug‐specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis.ConclusionsOur findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin‐induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin‐induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy‐associated cachexia.

Intracerebroventricular and intravenous administration of growth hormone secretagogue L-692,585, somatostatin, neuropeptide Y and galanin in pig: Dose-dependent effects on growth hormone secretion

Central regulation of growth hormone (GH) secretion by the GH secretagogue, L-692,585 (585), was determined in Yorkshire barrows (40–45 kg BW) with intracerebroventricular (icv) stainless steel cannulas placed by stereotaxic coordinates and indwelling external jugular vein (iv) cannulas for injecting 585 or saline during 3 h serial blood sampling. Dose-dependent effects of 585 were determined by icv injections of saline vehicle, 3, 10, and 30 μg/kg BW by once daily increment. A switchback study of iv and icv 585 treatment determined central and peripheral regulation of GH secretion by the secretagogue at 30 μg/kg BW. When administered icv, 585 increased GH concentration in a dose-dependent manner, with a return to baseline by 60 min. GH secretion was attenuated by increased numbers of icv 585 injections ( p < 0.05); however, it was not affected by increased numbers of iv 585 injections. Icv administration of somatostatin (SRIF) decreased ( p < 0.05) GH secretion compared with saline-treated controls, and decreased ( p < 0.05) peak GH response when given in combination with 585 as compared with 585 alone. Porcine galanin (pGAL) modestly increased ( p < 0.05) GH levels compared with saline controls, but when given icv in combination with 585 peak GH response was lower ( p < 0.05) compared with 585 alone. Porcine neuropeptide Y (pNPY) administered icv was without effect on GH levels compared with saline controls and decreased ( p < 0.05) peak GH response when given in combination with 585 as compared with 585 alone. The pharmacological actions by icv administration indicate that the GH secretagogue and neuropeptides act at the level of both porcine pituitary and hypothalamus.

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

Ghrelin is a native ligand for the growth hormone secretagogue (GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments.

Anabolic strategies in critical illness.

Critical illness precipitates a marked catabolic response, with protein wasting and loss of lean body mass. Prolongation of this response leads to impaired immunity, poor wound healing, loss of intestinal barrier function and muscle weakness, thereby increasing morbidity and perhaps mortality. Conventional nutritional support only partially ameliorates this process. Disappointingly, specific anabolic and anticatabolic strategies have so far met with only limited success, although recent findings, in particular studies demonstrating the potential value of aggressive insulin therapy and the administration of growth hormone secretagogues, have been encouraging.

Daily low-dose administration of growth hormone secretagogue stimulates pulsatile growth hormone secretion and elevates plasma insulin-like growth factor-1 levels in pigs.

Repeated administration of growth hormone secretagogues (GHSs) has proven to be a delicate matter owing to development of tolerance. The aim of the present study was to define conditions during which the responsiveness to the orally active NN703 was maintained over several days. Growing pigs were fitted with stomach and vascular catheters, permitting unstressed intragastric administrations and blood sampling. NN703 or vehicle was administered once daily. When NN703 was given at a dose of 18 mg/kg, there was a massive acute increase in plasma growth hormone (GH) levels, but this was only seen on the first day of administration. A dose of 1.8 mg/kg did not cause a significant acute increase in plasma GH concentrations, whereas stimulation of pulsatile GH release was sustained over a 4-d period. During the first 7 h following injection of vehicle, the area under the curve of plasma GH was 1211+/-144 (microg/[L x 7 h]), but increased to 1770+/-269 and 1824+/-198 (microg/[L x 7 h]) on the first and fourth day of NN703 administration, respectively. Deconvolution analysis of the 7-h profiles revealed that the GH mass per burst as well as the GH burst amplitude were significantly (p < 0.001) increased during treatment with NN703, which led to an increase in pulsatile GH secretion rate (p < 0.001). Insulin-like growth factor-1 plasma concentrations increased steadily during NN703 administration (p < 0.01) and decreased after termination of treatment. The sustained increase in GH pulsatility observed with low-dose NN703 treatment suggests that development of tolerance to this GHS may be obviated by minimization of dose.

Glucocorticoid regulation of growth hormone (GH) secretagogue-induced growth responses and GH secretagogue receptor expression in the rat

Synthetic GH-releasing peptides such as GHRP-6 are potent GH secretagogues (GHSs) in several species, but attempts to stimulate growth by continuous GHS exposure have had limited success. GHSs also release ACTH and adrenal steroids. Since glucocorticoid excess is associated with poor linear growth, stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by continuous GHS administration may compromise their growth-promoting effects. We have now examined the effects of continuous GHRP-6 infusion (100 mg/day, s.c. for 14 days) in normal 150-day-old female rats, and in adrenalectomized (Adx) rats with or without dexamethasone (Dex) replacement. Infusion of GHRP-6 did not significantly affect body weight gain compared with excipient-treated controls in either intact rats (controls, 9.0 +/- 1.6 vs GHRP-6, 11.8 +/- 0.9 g) or Adx rats (4.4 +/- 1.5 vs 7.9 +/- 2.7 g). However, GHRP-6 significantly increased weight gain in Adx rats treated with Dex (controls, 3.5 +/- 1.4 vs GHRP-6, 15.4 +/- 1.6 g;P<0.01). Adrenalectomy decreased plasma triglycerides (P<0.01), and Dex treatment increased plasma cholesterol (P<0.001), GHRP-6 treatment did not affect these plasma lipids. Dex treatment also reduced plasma GH-binding protein levels and hepatic GH binding (P<0.05). Pituitary GH content was decreased in Adx rats (P<0.05) but not in Dex-treated Adx rats. Adrenalectomy markedly decreased GHS-receptor mRNA expression in the arcuate (P<0. 001) and ventromedial nuclei (P<0.01), whilst Dex treatment normalized GHS-receptor expression. These results suggest that adrenal steroids are necessary for normal GHS-receptor expression and GHRP-6-induced weight gain, but long-term stimulation of the HPA axis by continuous GHS exposure may be detrimental to the growth response.

Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat

Growth hormone secretagogues (GHS) are small, synthetic compounds which have the potential of releasing growth hormone (GH) from the pituitary. The mechanism of action of GHS has not been fully elucidated. A specific GHS receptor (GHS-R) is expressed in the pituitary gland and in several areas of the brain including the hypothalamus. We have characterized the GHS-R-mRNA-expressing neurons with respect to co-expression of selected neurotransmitters in the hypothalamus. This was done by dual chromogenic and autoradiographic in situ hybridization with riboprobes for GHS-R mRNA and neuropeptide Y (NPY), pro-opiomelanocortin (POMC), somatostatin (SRIH) or GH-releasing hormone (GHRH) mRNA. In the arcuate nucleus, GHS-R mRNA was expressed in 94 ± 1% of the neurons expressing NPY, 8 ± 2% of those expressing POMC and 30 ± 6% expressing SRIH mRNA. 20–25% of the GHRH- mRNA-expressing neurons contained GHS-R mRNA, whereas the vast majority of the arcuate GHS-R-mRNA-containing cells did not contain GHRH mRNA. The finding of a significant co-expression of GHS-R and NPY mRNA in the arcuate nucleus is in accordance with the previous demonstration by Dickson et al. that c-Fos is induced in NPY neurons following GHS administration. These results indicate that GHS have other effects on neuroendocrine regulation than GH release via GHRH neurons. Stimulation of the arcuate NPY neurons via GHS-R may explain the increased appetite and the cortisol release seen after administration of some GHS compounds.

Growth Hormone-Releasing Hormone and Morphine Attenuate Growth Hormone Secretagogue-Induced Activation of the Arcuate Nucleus in the Male Rat

Growth hormone secretagogues (GHS) administered systemically selectively induce growth hormone (GH) release from the pituitary and the expression of Fos protein in arcuate nucleus neurons. Both the control of GH release and the expression of the GHS receptor in the arcuate nucleus are thought to be regulated, at least in part, by the negative feedback actions of GH. In this study, we utilized the immunocytochemical detection of Fos protein to examine the effects of morphine- and GH-releasing hormone (GHRH)-induced GH release on the activation of arcuate nucleus neurons following GHS administration. Given alone, two structurally different GHS induced significant amounts of Fos-LI in the arcuate nucleus of male rats, suggesting activation of cells in this region. Prior administration of morphine or GHRH significantly reduced the number of Fos-positive cells in the arcuate nucleus of rats injected with either GHS, although when given together, morphine and GHRH did not produce a greater reduction in Fos expression than when given alone. In no case was there a complete reduction in Fos expression, indicating that some arcuate nucleus neurons are not subject to the feedback effects of endogenous GH. These results provide evidence that, in the male rat, GH can feedback to the hypothalamus, altering the responsiveness of neurons involved in the central response to GHS.