Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867

SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6⋅3 3⋅4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GHreleasing hormone antagonist. SM-130686 dosedependently inhibited the binding of radiolabeled ligand, 35 S-MK-677, to human GHS receptor 1a (IC 50 =1⋅2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19⋅5 2⋅1 and 18⋅1 7⋅5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor.In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.

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“…in five different experiments with rat pituitary primary culture ( Fig. 2A) (Cheng et al 1997). As shown in Fig.…”

Section: Gh-releasing Activity Of Sm-130686 Through the Ghs Receptormentioning

confidence: 96%

Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686

Nagamine¹,

Nagata²,

Seki³

et al. 2001

Journal of Endocrinology

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“…[D-Lys-3]-GHRP-6 (Bachem), a classical but not highly selective GHS-R antagonist (12)(13)(14), was freshly diluted in 100 mL of saline and intraperitoneal injections were performed every 12 h during five consecutive days followed by a 16-h fasting period before sacrifice or intraperitoneal glucose tolerance tests (IPGTTs) (2 g D-glucose/kg). The optimal dose of GHS-R antagonist (200 nmol/30 g) was determined according to previous published work (15,16). For metabolic analyses, mice were individually placed in metabolic cages, provided with the same quantities of food and water, and housed on a reverse light-dark cycle.…”

Section: Animals and Analytical Proceduresmentioning

confidence: 99%

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

et al. 2015

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Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non–insulin-dependent diabetes.

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“…4A). The ghrelin-induced calcium responses were inhibited by the known hGHSR1a antagonist, L-756,867 (19). Activation of hGHSR1a caused a rapid increase in fluorescence that reached a maximum in about 15 s and completely decayed to baseline level in about 100 s. Remarkably, the addition of BAPTA (30 M BAPTA-AM) delayed the peak fluorescence re-…”

Section: Delayed Calcium Kinetics In Functional Gpcr Assaysmentioning

confidence: 99%

Delay of Intracellular Calcium Transients Using a Calcium Chelator: Application to High-Throughput Screening of the Capsaicin Receptor Ion Channel and G-Protein-Coupled Receptors

Grant¹,

Bansal²,

Mitra³

et al. 2001

Analytical Biochemistry

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Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867

Cited by 22 publications

References 4 publications

Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686

Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

Delay of Intracellular Calcium Transients Using a Calcium Chelator: Application to High-Throughput Screening of the Capsaicin Receptor Ion Channel and G-Protein-Coupled Receptors

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