Showing papers on "Growth hormone secretagogue published in 2003"

Developmental, Stage-Specific, and Hormonally Regulated Expression of Growth Hormone Secretagogue Receptor Messenger RNA in Rat Testis

Abstract: Recent evidence from our research suggested the direct role of ghrelin in the control of testicular function. However, the pattern of expression and hormonal regulation of the gene encoding its cognate receptor (i.e., the growth hormone-secretagogue receptor [GHS-R]) in the male gonad remains to be fully elucidated. In this paper, overall expression of GHS-R mRNA in rat testis was compared with that of the functional receptor form, namely GHS-R type 1a, in different developmental and experimental settings. In addition, cellular distribution of GHS-R within adult testis tissue was assessed. Our analyses demonstrated persistent expression of the GHS-R gene in rat testis throughout postnatal development. In contrast, testicular expression of GHS-R type 1a mRNA remained undetectable before puberty and sharply increased thereafter. In adult testis, GHS-R1a mRNA expression presented a scattered pattern of cellular distribution, including Sertoli and Leydig cells that also showed specific GHS-R1a immunoreactivity. Expression of total GHS-R and specific GHS-R1a mRNAs was detected in isolated seminiferous tubule preparations, with varying levels throughout the defined stages of the spermatogenic cycle. In addition, testicular expression of total GHS-R and GHS-R1a mRNAs was up-regulated by exposure to ghrelin in vitro and after stimulation with FSH in vivo. In conclusion, our data demonstrate that expression of the GHS-R gene in rat testis takes place in a developmental, stage-specific, and hormonally regulated manner. Divergent expression of total GHS-R and type 1a specific mRNAs was detected at certain stages of postnatal development and spermatogenic cycle, thus raising the possibility that, in addition to net changes in GHS-R gene expression, the balance between receptor subtypes may represent a novel mechanism for the tuning of ghrelin sensitivity in rat testis.

Cyclical Cushing's syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors.

Abstract: A 56-yr-old woman was referred with a diagnosis of Cushing’s disease. Hypertension and severe hypokalemia were present and high urinary free cortisol/cortisone ratio was detected, raising a suspicion of an ectopic ACTH syndrome. Inferior petrosal sinus sampling, thoracic computed tomography, and octreotide scans were negative. Remission and relapse periods lasting 3–4 months were observed during the 3.5 yr of follow-up. Finally a thoracic computed tomography scan showed a basal paracardic nodule in the left lung. After surgery, a well-differentiated neuroendocrine tumor (typical bronchial carcinoid) was diagnosed, staining positively for ACTH. RT-PCR revealed expression of proopiomelanocortin, CRH receptor, and V3 vasopressin receptor. Somatostatin receptor type 1, 2, 3, and 5 mRNA was detected only in tumoral tissue. Interestingly, we observed the simultaneous presence of ghrelin and both GH secretagogue (GHS) receptors (1a and 1b) mRNA in tumoral tissue but not in the normal lung. This finding correlate...

New Active Series of Growth Hormone Secretagogues

Abstract: New growth hormone secretagogue (GHS) analogues were synthesized and evaluated for growth hormone releasing activity. This series derived from EP-51389 is based on a gem-diamino structure. Compounds that exhibited higher in vivo GH-releasing potency than hexarelin in rat (subcutaneous administration) were then tested per os in beagle dogs and for their binding affinity to human pituitary GHS receptors and to hGHS-R 1a. Compound 7 (JMV 1843, H-Aib-(d)-Trp-(d)-gTrp-formyl) showed high potency in these tests and was selected for clinical studies.(1)

Regulation of ghrelin secretion and action

Abstract: The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHS-R1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK-293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3-dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.

Stimulatory effect of ghrelin on isolated porcine somatotropes.

Abstract: Research on the mechanism for growth hormone secretagogue (GHS) induction of growth hormone secretion led to the discovery of the GHS receptor (GHS-R) and later to ghrelin, an endogenous ligand for GH

Ghrelin: update 2003.

Abstract: Ghrelin is a recently described peptide hormone that is secreted by endocrine cells in the gastrointestinal tract. Although its initial discovery was as a novel growth hormone secretagogue, it has been found to regulate feeding behavior by modulating expression levels of orexigenic peptides in the hypothalamus. Ghrelin has been implicated in the coordination of energy balance and weight regulation, and its dysregulation may be important in obesity. Ghrelin also has several other physiologic actions besides potential regulation of food intake that are described in this brief review.

A growth hormone secretagogue prevents ischemic-induced mortality independently of the growth hormone pathway in dogs with chronic dilated cardiomyopathy.

Abstract: To determine the functional role of growth hormone (GH) secretagogue in myocardium with ischemia, left ventricular (LV) pressure gauge, wall thickness crystals, coronary occluder, pacers, and catheters were implanted in 26 dogs Beginning 1 week after ventricular pacing (240 beats/min) was initiated, dogs were treated (sc) with GH releasing peptide-6 (GHRP-6, n = 8, 02 mg/kg/day), GH (n = 7, 006 mg/kg/day), or vehicle (n = 11) Two weeks of pacing was associated with similar decreases in LV pressure, rate of change of LV pressure, systolic wall thickening (WT), and an increase in left atrial pressure in all groups Coronary artery occlusion (CAO) resulted in a similar loss of WT in ischemic regions, which did not recover during reperfusion period in all groups WT in nonischemic regions, however, was enhanced in the GHRP-6 group compared with the GH and vehicle groups, eg, increase of WT after 1 h of reperfusion was greater (p <005) in the GHRP-6 (+53 +/- 8%) than in the GH (+14 +/- 12%) or (+14 +/- 6%) There were no differences in myocardial blood flow, hemodynamics, or arrhythmic beats among all groups during CAO and reperfusion periods Strikingly, no dogs in the GHRP-6 group died during CAO, whereas the survival rates for GH and vehicle groups were 57 and 55%, respectively Our data demonstrate, for the first time, that chronic therapy with a GH secretagogue prevents sudden death in dogs with dilated cardiomyopathy subjected to acute ischemia This seems to be related to an enhanced nonischemic compensatory mechanism mediated by the GH secretagogue receptors rather than via the GH/insulin growth factor-1 pathway

A convergent asymmetric synthesis of a growth hormone secretagogue

Abstract: Described herein is a convergent asymmetric synthesis of growth hormone secretagogue (GHS) suitable for large-scale preparations. Key features include: (1) an improved method for α-iodination of a lactam; (2) a novel synthesis of a disubstituted urea using Ti(O i -Pr) 4 and NaBH 4 ; (3) construction of biphenyl ureas via an unprecedented Suzuki coupling; (4) an in situ mesylation/ N -alkylation of a benzolactam.

Ghrelin mRNA and GH secretagogue receptor mRNA in human GH‐producing pituitary adenomas is affected by mutations in the α subunit of G protein

Abstract: Summary objective Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma. Somatic mutations in the subunit of Gs α protein (gsp), which led to a constitutive activation of adenylyl cyclase, are reported in GH-producing pituitary adenomas. We analysed the relationship between ghrelin mRNA and GHSR mRNA expression levels in gsp mutation-positive and -negative GH-producing pituitary adenomas. patients Pituitary adenoma tissue was obtained at surgery from 20 patients with acromegaly. methods The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT–PCR method. To detect the gsp mutations, amplified Gs α subunit cDNA fragments were sequenced directly using RT–PCR method. results There was no significant difference in the expression of ghrelin mRNA between mutation-positive and -negative adenomas. The expression of GHSR mRNA was significantly lower in gsp mutation-positive than -negative adenomas. There was a significant negative correlation between the levels of ghrelin mRNA and GHSR mRNA expression in mutation-negative adenomas; no such correlation was found in mutation-positive adenomas. conclusion These results suggest that GHSR mRNA expression is downregulated by ghrelin in gsp mutation-negative GH-producing pituitary adenomas, and that changes in intracellular signalling pathways in gsp mutation-positive GH-producing pituitary adenomas affect the expression of G protein-coupled receptors such as GHSR. The absence of negative correlation between ghrelin and GHSR expression might be induced by lowered GHSR expression in gsp mutation-positive GH-producing adenomas.

Compositions and methods for stimulating gastrointestinal mobility

Abstract: The present invention is directed to methods for stimulating the motility of the gastrointestinal system in a patient which comprises administering a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said secretagogue or said prodrug. More particularly, the present invention provides methods for stimulating the motility of the gastrointestinal system in a patient which comprises administering a compound of Formula I: a prodrug thereof or a pharmaceutically acceptable salt of said secretagogue or said prodrug.

The effect of treatment with the oral growth hormone (GH) secretagogue MK-677 on GH isoforms

Abstract: Growth hormone (GH) consists of several isoforms. We have studied the proportion, expressed as percentage of total GH concentration, of non-22kDa (non-22K) GH isoforms and 20K GH during 8-week oral treatment with MK-677 25mg daily in 12 obese males. The proportion of non-22K GH isoforms in peak total GH samples after the initial MK-677 administration was higher than that after 2 and 8 weeks (p<0.01 and p<0.05, respectively). In selected non-peak total GH samples after the initial MK-677 administration, however, the proportion of non-22K GH isoforms was similar to that in the peak total GH samples after 2 and 8 weeks. The proportion of 20K GH in 2-h samples after the initial MK-677 administration was lower than that after 2 and 8 weeks (p<0.01 and p<0.05, respectively). We concluded that the proportion of non-22K GH isoforms was higher in peak, but not in non-peak, total GH samples after the initial MK-677 administration than that observed after multiple doses. The proportion of 20K GH in 2-h samples after the initial MK-677 administration was lower than that after 2 and 8 weeks. These moderate changes in the proportion non-22K GH isoforms are likely of small importance for the clinical response to MK-677 treatment.

Growth hormone secretagogue and functional food containing dioscin or extracts of plants therewith

Abstract: PURPOSE: A composition containing as an effective ingredient diosin, a derivative thereof or a plant extract containing the same which stimulate secretion of growth hormone by acting on the pituitary gland is provided. The composition is low in toxicity and thus can be used as a therapeutic agent caused by a deficiency in growth hormone secretion and a food for stimulating secretion of growth hormone. CONSTITUTION: The therapeutic agent for treatment of diseases caused by a deficiency in growth hormone secretion, a functional food, health supplementary food or special nutritious food contains diosin of the formula 1 and derivatives thereof. The methanol extract of Smilax china and a butanol fraction thereof contains the diosin and derivatives thereof and is obtained by extracting in methanol or a mixed solvent, filtering and then concentrating under reduced pressure. The methanol extract of Dioscorea quinqueloba Thunb. and a butanol fraction thereof contains the diosin and derivatives thereof and is obtained by extracting in methanol or a mixed solvent, filtering and then concentrating under reduced pressure. The mixed solvent is methanol and water.

Physiological Function of Growth Hormone Secretagogue Receptors in the Cardiovascular System

Abstract: Growth hormone secretagogues (GHS) consist of a series of small enkephalin derived peptides identified as growth hormone-releasing peptides (GHRPs) (Bowers, 1993) and non-peptidyl derivatives modeled from GHRPs (Smith et al., 1997). To this class of compounds is recently added a new member, ghrelin, an endogenous 28 amino acid polypeptide isolated from the stomach (Kojima et al., 1999). GHS share a common activity in stimulating the release of growth hormone (GH) from the pituitary in several animal species and in man (Ghigo et al., 2001). The GH release is mediated through the binding of GHS to a G protein-coupled receptor identified by expression cloning as GHS-Ria or ghrelin receptor, for which mRNA expression as well as protein receptor localization are mainly confined to the hypothalamus and the pituitary (Howard et al., 1996).

Endocrine and Extraendocrine Activity of Ghrelin and the GHS: Basic Research

Abstract: Until few years ago it was generally accepted that the secretion of growth hormone (GH) was mainly regulated by stimulatory and inhibitory influences of two hypothalamic hypophysiotropic hormones, the growth hormone releasing hormone (GHRH) and somatostatin (SS), respectively. GHRH and SS were considered the final common pathway by which neurotransmitters, peripheral hormone, and environmental, metabolic and immune stimuli could influence the secretion of GH (Locatelli and Torsello, 1997; Muller et al., 1999). However, at the end of 1970s, the observation that several synthetic peptidyl and non-peptidyl molecules, derived from the pentapeptide met-enkephalin and named “growth hormone secretagogues” (GHS), were able to potently stimulate GH secretion from cultured pituitary cells (Bowers et al., 1980), experimental animals (Bowers et al., 1984), and humans (Ilson et al., 1989; Bowers et al., 1990) was suggestive of the existence of another endogenous factor physiologically involved in the regulation of GH release. In 1996, the identification of a specific GHS receptor (GHS-R) distinct from that of GHRH (Howard et al., 1996; Pong et al., 1996) further supported this hypothesis, and made possible the recent discovery of its endogenous agonist. The endogenous natural ligand of the GHS-R was isolated from a peripheral tissue, the stomach, and not, as generally expected, from the hypothalamus, and was named “ghrelin” (ghre is the Proto-Indo-European root of the word “grow”) (Kojima et al., 1999).