Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Ljungqvist, Anders; Feng, Da Hsuan; Hook, W. Alexander Van; Shen, Zhencai; Bowers, Cyril Y.; Folkers, Karl

doi:10.1073/pnas.85.21.8236

Cited by 59 publications

(19 citation statements)

References 15 publications

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“…These findings (demonstrating that apoptotic cell death by blockade of the gonadotropin action by immunoneutralization (54). Thus we treated BDL rats with antide, a third-generation Gonadotropin-releasing hormone (GnRH) antagonist (that inhibits gonadotropin secretion) (43) and demonstrated inhibition of cholangiocyte proliferation and increased apoptosis similar to what was observed with anti-FSH antibody. Parallel to our findings, antide has been shown to have antiproliferative effects by binding to GnRH receptor, which results in termination of receptor function (34).…”

Section: Discussionmentioning

confidence: 99%

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Mancinelli¹,

Onori²,

Gaudio³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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mones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP3 levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. (8), prolactin (58), and progesterone (25). The cAMP/ERK1/2/Elk-1 signaling has been shown to play a key role in the regulation of cholangiocyte proliferation (18,20,24,27,37). For example, whereas increased cAMP levels sustain cholangiocyte growth (20,24,27,37), decreased cAMP synthesis results in inhibition of cholangiocyte hyperplasia (24,27,37).Follicle-stimulating hormone (FSH) is the central hormone of the mammalian reproduction (55). FSH, also called gonadotropin because it stimulates the gonads, is produced from the anterior pituitary gland of the brain (60). FSH is a large glycoprotein composed of alpha and beta subunits, similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (1). The alpha subunits of FSH, LH, TSH, and hCG are identical, whereas the beta subunit is unique and endows each hormone with the ability to binds to its own receptor (60). FSH interacts with a receptor protein that has seven transmembrane-spanning domains; its binding is transduced into an intracellular signal via the heterotrimeric G proteins (61). Following coupling of the FSHR to G␣ s adenylyl cyclase is stimulated, followed by production of cAMP and activation of PKA, which phosphorylates structural proteins, enzymes, and transcriptional activators (32,66). Whether the FSH receptor is also linked to G␣ i has not yet been completely defined. In fact, the treatment of Sertoli cells with pertussis toxin (PTX, a G␣ i inhib...

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Section: Discussionmentioning

confidence: 99%

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Mancinelli¹,

Onori²,

Gaudio³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…To determine whether GnRH-II required the mammalian GnRH receptor (GnRH-I receptor) to stimulate LH release, animals were treated with antide (Bachem; Torrance, CA), a potent GnRH-I receptor antagonist (19), either alone or in combination with GnRH-I and GnRH-II during the midluteal phase, determined as described in experiment 1. GnRH forms were administered iv at a 1-g/kg body weight dose, and antide was administered iv at 100 g/kg body weight.…”

Section: Methodsmentioning

confidence: 99%

Relative Effect of Gonadotropin-Releasing Hormone (GnRH)-I and GnRH-II on Gonadotropin Release

Densmore

Urbanski

2003

The Journal of Clinical Endocrinology & Metabolism

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Two forms of GnRH (GnRH-I and GnRH-II) are expressed in the hypothalamus of humans and rhesus monkeys, but their relative abilities to stimulate LH and FSH release are unknown. Therefore, young (8 -12 yr) and old (21-23 yr) female rhesus monkeys were treated iv with bolus injections of either GnRH-I or GnRH-II (dose range, 0.01-10 g/kg body weight); serial blood samples were remotely collected through a vascular catheter for up to 2 h after injection. Overall, plasma LH concentrations were similarly elevated after treatment with GnRH-I and GnRH-II, and the responses were slightly greater in the younger animals. Although plasma FSH concentrations were unaffected by a single exposure to GnRH-I or GnRH-II, they showed a similar significant increase after repeated exposures (every 2 h for 24 h). In a subsequent experiment, antide, a GnRH-I receptor antagonist, was administered (100 g/kg body weight) together with a single injection of GnRH-I or GnRH-II (1 g/kg body weight). As expected, GnRH-Iinduced LH release was significantly attenuated by this combined treatment; moreover, GnRH-II-induced LH release was completely blocked. Taken together, these data show that GnRH-II can potently stimulate gonadotropin release in vivo and that this action is likely mediated through the GnRH-I receptor. (J Clin Endocrinol Metab 88: 2126 -2134, 2003)

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“…However, no accumulation of cGMP was observed in any pituitary cellular compartment. How ever, in a second set of experiments we studied the effect of a potent and long-lasting GnRH antagonist, antide [23], on expression of NOS in the anterior pituitary in vivo. The results show that this decapeptide completely abolished the increase in NOS mRNA induced by castra tion.…”

Section: Discussionmentioning

confidence: 99%

“…Scr, Lys(Nic), D-Lys(Nic), Leu. Lvs(iPr), Pro, DAIa-NH2], a powerful and long-acting GnRH antagonist [23], and 3 rats subcutaneous injections of saline. Six further rats were sham oper ated and 3 received antide (as above) and 3 saline (as above).…”

Section: Tissue Preparationmentioning

confidence: 99%

“…We have used an immunohistochemical technique to visualize cGMP [20][21][22] in slices of rat anterior pituitary glands after treatment with GnRH and several NO donors in vitro. Moreover, we have administered a powerful GnRH antagonist, antide [23], in vivo, and analyzed to what extent the castra tion-induced increase in NOS mRNA levels can be in fluenced by this drug.…”

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confidence: 99%

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Nitric Oxide Synthase and cGMP in the Anterior Pituitary Gland: Effect of a GnRH Antagonist and Nitric Oxide Donors

Yamada

Xu²,

Zhang³

et al. 1997

Neuroendocrinology

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Using immunohistochemistry and in situ hybridization, it has been previously shown that gonadotropes and folliculo-stellate cells in the rat anterior pituitary gland express nitric oxide (NO) synthase (NOS), and that NOS expression is increased by gonadectomy. Using the indirect immunofluorescence technique in conjunction with antibodies raised to conjugated cGMP, we have attempted to establish the target cells for NO in the anterior pituitary and to define the mediator of NO regulation. After incubation of pituitary slices with several NO donors, numerous endocrine cells, but no folliculo-stellate cells, expressed cGMP. Most of these cells stained for LH, that is they were gonadotropes. However, there were apparently cGMP-positive, LH-negative and LH-positive, cGMP-negative endocrine cells. The increase in cGMP could be virtually completely blocked by a guanylyl cyclase inhibitor. cGMP was not expressed in corticotropes, but cGMP-positive cells often contained NOS-like immunostaining. Incubation with GnRH did not result in detectable levels of cGMP. However, when castrated rats were pretreated with a potent long-lasting GnRH antagonist, antide, the castration-induced increase in NOS was completely blocked. This suggests that GnRH is involved in the in vivo upregulation of NOS after castration, but that GnRH cannot induce cGMP accumulation in normal pituitary slices in vitro. Taken together, the present results give further evidence for a role of NO in the control of, in particular, LH secretion from the anterior pituitary gland in the rat.

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Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Cited by 59 publications

References 15 publications

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Relative Effect of Gonadotropin-Releasing Hormone (GnRH)-I and GnRH-II on Gonadotropin Release

Nitric Oxide Synthase and cGMP in the Anterior Pituitary Gland: Effect of a GnRH Antagonist and Nitric Oxide Donors

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