Endocrine effects of new bombesin/gastrin-releasing peptide antagonists in rats

1992 ◽  
Vol 263 (4) ◽  
pp. E712-E717
Author(s):  
J. Pinski ◽  
T. Yano ◽  
K. Groot ◽  
R. Z. Cai ◽  
S. Radulovic ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
Antagonistic Effect ◽  
Receptor Subtypes ◽  
Serum Growth Hormone ◽  
Gastrin Releasing Peptide ◽  
Gastrin Secretion ◽  
Brain Ventricle ◽  
Grp Receptors ◽  
Serum Gh ◽  
Grp Receptor

Four new and specific pseudononapeptide bombesin/gastrin-releasing peptide (GRP) receptor antagonists, containing the D-forms of Trp or Trp analogue (Tpi) at position 6, were studied for their effects on the endocrine pancreas and GRP-(14-27)-induced gastrin release in pentobarbital-anesthetized rats. One of the analogues, D-Tpi6,Leu13-psi (CH2NH)Leu14-bombesin-(6-14) (RC-3095), was injected into the lateral brain ventricle just preceding intracerebroventricular administration of GRP-(14-27) to evaluate its antagonistic effect on GRP-induced serum growth hormone (GH) suppression. Analogues RC-3095, D-Trp6,Leu13-psi (CH2NH)Leu14-bombesin-(6-14) (RC-3125), and D-Trp6,Leu13-psi (CH2NH)Phe14-bombesin-(6-14) (RC-3420), but not D-Tpi6,Leu13-psi (CH2NH)Phe14-bombesin-(6-14) (RC-3105), significantly (P < 0.01) inhibited GRP-(14-27)-stimulated serum gastrin secretion. Analogues RC-3095, RC-3420, and RC-3105, but not RC-3125, demonstrated significant (P < 0.05) antagonistic activities on GRP-(14-27)-stimulated plasma glucagon secretion. Intracerebroventricular injection of RC-3095 (10 micrograms) immediately before GRP-(14-27) (1 microgram) completely prevented the GRP-(14-27)-induced serum GH suppression. These results indicate that 1) marked differences exist in the ability of these analogues to antagonize GRP-(14-27)-induced gastrin or glucagon release, suggesting the existence of different bombesin/GRP receptor subtypes, and 2) the central effect of bombesin/GRP on GH release from the pituitary is probably mediated through specific bombesin/GRP receptors.

scholarly journals Overexpression of Gastrin-Releasing Peptide Receptors in Tumor-Associated Blood Vessels of Human Ovarian Neoplasms

2007 ◽  
Vol 29 (5) ◽  
pp. 421-433 ◽  
Author(s):  
Achim Fleischmann ◽  
Beatrice Waser ◽  
Jean Claude Reubi
Keyword(s):  
Ovarian Neoplasms ◽  
Ovarian Tumors ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Peptide Receptors ◽  
Gastrin Releasing Peptide ◽  
Bombesin Receptor ◽  
Grp Receptors ◽  
Grp Receptor

Background: Peptide receptors, overexpressed in specific cancers, represent new diagnostic and therapeutic targets. In this study, receptors for the gastrin-releasing peptide (GRP), and other members of the bombesin-family of peptides, were evaluated in ovarian neoplasms. Methods: 75 primary, secondary and metastatic ovarian tumors were investigated for their bombesin-receptor subtype expression, incidence, localization and density using in vitro autoradiography on tissue sections with the universal radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]-bombesin(6-14) and the GRP-receptor subtype-preferring 125I-[Tyr4]-bombesin. Results: GRP-receptors were detected in 42/61 primary ovarian tumors; other bombesin-receptor subtypes (BB1, bb3) were rarely present (3/61). Two different tissue compartments expressed GRP-receptors: the tumoral vasculature was the predominant site of GRP-receptor expression (38/61), whereas neoplastic cells more rarely expressed GRP-receptors (14/61). GRP-receptor positive vessels were present in the various classes of ovarian tumors; generally, malignant tumors had a higher incidence of GRP-receptor positive vessels compared to their benign counterparts. The prevalence of such vessels was particularly high in ovarian carcinomas (16/19) and their metastases (5/5). The GRP-receptors were expressed in high density in the muscular vessel wall. Normal ovary (n=10) lacked GRP-receptors. Conclusions: The large amounts of GRP-receptors in ovarian tumor vessels suggest a role in tumoral vasculature and possibly angiogenesis. Further, these vessels might be targeted in vivo with bombesin analogs for diagnosis or for therapy.

[Ala6]gastrin-releasing peptide-10: an analogue with dissociated biological activities

1989 ◽  
Vol 257 (2) ◽  
pp. E235-E240
Author(s):  
H. Mukai ◽  
K. Kawai ◽  
S. Suzuki ◽  
H. Ohmori ◽  
K. Yamashita ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Biological Activities ◽  
Glucagon Secretion ◽  
Gastrin Releasing Peptide ◽  
Gastrin Secretion ◽  
Insulin And Glucagon Secretion ◽  
Mammalian Tissues ◽  
Stimulation Of

COOH-terminal decapeptide of gastrin-releasing peptide (GRP-10) is a bombesin-like peptide, which has bioactivities to stimulate gastrin, insulin, and glucagon secretion. We have synthesized an analogue of GRP-10 that inhibits GRP-10's stimulation of insulin secretion both in vivo and in vitro and glucagon secretion in vivo, while potentiating the stimulation of gastrin secretion. The amino acid sequence of this peptide is H-Gly-Asn-Trp-Ala-Ala-Gly-His-Leu-Met-NH2 ([Ala6]GRP-10). Because the stimulation of insulin and gastrin secretion by GRP-10 has been ascribed to a direct effect on B- and G-cells, these findings suggest that there are two subtypes of receptors for bombesin-like peptides in mammalian tissues.

Gastrin-releasing peptide receptors in the tumor vascular bed of various human cancers: high incidence in urinary tract cancers

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14575-e14575
Author(s):  
A. M. Fleischmann ◽  
B. Waser ◽  
J. C. Reubi
Keyword(s):  
Urinary Tract ◽  
Biliary Tract ◽  
Vascular Targeting ◽  
Gastrin Releasing Peptide ◽  
Tract Cancer ◽  
Vascular Bed ◽  
Urinary Tract Cancer ◽  
Tumor Types ◽  
Grp Receptors ◽  
Grp Receptor

e14575 Background: Tumoral Gastrin-releasing peptide (GRP) receptors are potential targets for diagnosis and therapy using radiolabeled or cytotoxic GRP analogs. GRP-receptor overexpression has been detected in cancer cells and, more recently, also in the vascular bed of selected tumors. More information on vascular GRP-receptors in cancer is required to asses their potential for vascular targeting applications. Methods: Frequent human cancers from the breast (n=134), lung (n=57), prostate (n=50), kidney (n=32), colon (n=46), urinary tract (n=26) and biliary tract (n=23) were analyzed using in vitro GRP-receptor autoradiography on tissue sections with the 125I-[Tyr4]-bombesin radioligand and/or the universal radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]-bombesin(6–14). GRP-receptor expressing tumoral vessels were evaluated in each tumor group for prevalence, quantity (vascular score) and GRP-receptor density. Results: Prevalence of vascular GRP-receptors is variable, ranging from 13% (prostate cancer) to 92% (urinary tract cancer). Different tumor-types within a given site may have divergent prevalence of vascular GRP-receptors (e.g. lung: small cell cancer: 0%; adenocarcinoma: 59%; squamous carcinoma: 83%). Also the vascular score varies widely, with highest score in urinary tract cancer (1.69), moderate scores in lung (0.91), colon (0.88), kidney (0.84) and biliary tract (0.69) cancers and low scores in breast (0.39) and prostate (0.14) cancers. Vascular GRP-receptors are expressed in the muscular vessel wall in moderate to high densities. Normal non- neoplastic control tissues from these organs lack vascular GRP-receptors. Conclusions: Tumoral vessels in all evaluated sites overexpress GRP-receptors, suggesting a major biological function of GRP-receptors in the tumor vascular bed. Vascular GRP-receptor expression varies between the tumor-types indicating tumor-specific mechanisms in their regulation. Urinary tract cancers express vascular GRP-receptors so abundantly, that they are promising candidates for vascular targeting applications. No significant financial relationships to disclose.

scholarly journals High expression of gastrin-releasing peptide receptors in the vascular bed of urinary tract cancers: promising candidates for vascular targeting applications

2009 ◽  
Vol 16 (2) ◽  
pp. 623-633 ◽  
Author(s):  
Achim Fleischmann ◽  
Beatrice Waser ◽  
Jean Claude Reubi
Keyword(s):  
Urinary Tract ◽  
Receptor Expression ◽  
Vascular Targeting ◽  
Gastrin Releasing Peptide ◽  
Tract Cancer ◽  
Vascular Bed ◽  
Urinary Tract Cancer ◽  
Tumor Types ◽  
Grp Receptors ◽  
Grp Receptor

Tumoral gastrin-releasing peptide (GRP) receptors are potential targets for diagnosis and therapy using radiolabeled or cytotoxic GRP analogs. GRP-receptor overexpression has been detected in endocrine-related cancer cells and, more recently, also in the vascular bed of selected tumors. More information on vascular GRP-receptors in cancer is required to asses their potential for vascular targeting applications. Therefore, frequent human cancers (n=368) were analyzed using in vitro GRP-receptor autoradiography on tissue sections with the 125I-[Tyr4]-bombesin radioligand and/or the universal radioligand 125I-[d-Tyr6, β-Ala11, Phe13, Nle14]-bombesin(6–14). GRP-receptor expressing vessels were evaluated in each tumor group for prevalence, quantity (vascular score), and GRP-receptor density. Prevalence of vascular GRP-receptors was variable, ranging from 12% (prostate cancer) to 92% (urinary tract cancer). Different tumor types within a given site had divergent prevalence of vascular GRP-receptors (e.g. lung: small cell cancer: 0%; adenocarcinoma: 59%; squamous carcinoma: 83%). Also the vascular score varied widely, with the highest score in urinary tract cancer (1.69), moderate scores in lung (0.91), colon (0.88), kidney (0.84), and biliary tract (0.69) cancers and low scores in breast (0.39) and prostate (0.14) cancers. Vascular GRP-receptors were expressed in the muscular vessel wall in moderate to high densities. Normal non-neoplastic control tissues from these organs lacked vascular GRP-receptors. In conclusion, tumoral vessels in all evaluated sites express GRP-receptors, suggesting a major biological function of GRP-receptors in neovasculature. Vascular GRP-receptor expression varies between the tumor types indicating tumor-specific mechanisms in their regulation. Urinary tract cancers express vascular GRP-receptors so abundantly, that they are promising candidates for vascular targeting applications.

scholarly journals Characterization of ligand binding and processing by gastrin-releasing peptide receptors in a small-cell lung cancer cell line

1992 ◽  
Vol 281 (1) ◽  
pp. 115-120 ◽  
Author(s):  
C Cardona ◽  
N M Bleehen ◽  
J G Reeve
Keyword(s):  
Lung Cancer ◽  
Ligand Binding ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Gastrin Releasing Peptide ◽  
Grp Receptors ◽  
Grp Receptor

The ligand-binding properties of the gastrin-releasing peptide (GRP) receptor and the cellular processing of GRP have been studied in the small-cell lung cancer (SCLC) cell line COR-L42. Scatchard analysis of GRP receptor expression indicated a single class of high-affinity receptors (Kd 1.5 nM) and approx. 6700 receptors/cell. GRP bound to its receptor with a Ki of 2.4 nM. The bombesin-related peptides neuromedin B (NMB) and phyllolitorin also bound to GRP receptors with Ki values of 22.7 and 59.1 nM respectively. Binding of 125I-GRP to COR-L42 cells increased rapidly at 37 degrees, achieved a maximum at 10 min and declined rapidly thereafter. At 4 degrees C, maximum binding was achieved at 30 min and the subsequent decline in cell-associated radioactivity was slower than that seen at 37 degrees C. Acid/salt extraction, to separate surface-bound ligand from internalized GRP, indicated that after receptor binding 125I-GRP was rapidly internalized. To determine the pathway of 125I-GRP degradation, binding studies were carried out with the lysosomotropic agent chloroquine (5 mM), and with phosphoramidon (10 microM), an inhibitor of the membrane-bound enzyme (EC 3.4.24.11). Both agents markedly inhibited the degradation of GRP, indicating that this process involves a lysosomal pathway and a phosphoramidon-sensitive pathway, possibly involving the EC 3.4.24.11 enzyme. GRP receptor down-regulation was observed following a 10 min exposure to 100 nM-GRP. With longer pretreatment times the number of binding sites recovered to 80% of control values. Treatment with 5 mM-chloroquine plus GRP or cycloheximide (10 micrograms/ml) plus GRP demonstrated that the majority of GRP receptors are recycled. NMB and phyllolitorin pretreatment did not influence the subsequent binding of 125I-GRP, suggesting that these peptides do not down-regulate GRP receptors.

THU0072 Gastrin-Releasing Peptide (GRP) and RC-3095, a GRP Receptor Antagonist, Regulates Arthritic Mice Synovial Fibroblasts

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 218.1-218
Author(s):  
V.S. Clarimundo ◽  
M. Farinon ◽  
C. Nör ◽  
L.I. Filipin ◽  
P.S. Gulko ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Synovial Fibroblasts ◽  
Gastrin Releasing Peptide ◽  
Grp Receptor

NSILA AND FOETAL GROWTH

1979 ◽  
Vol 90 (3) ◽  
pp. 534-543 ◽  
Author(s):  
U. E. Heinrich ◽  
D. S. Schalch ◽  
M. H. Jawadi ◽  
C. J. Johnson
Keyword(s):  
Gestational Age ◽  
Serum Growth Hormone ◽  
Premature Newborns ◽  
Foetal Growth ◽  
Protein Binding Assay ◽  
Competitive Protein Binding Assay ◽  
Term Newborns ◽  
Competitive Protein Binding ◽  
Cortisol Levels ◽  
Serum Gh

ABSTRACT Employing a sensitive competitive protein binding assay for NSILA (non-suppressible insulin-like activity), circulating levels of this somatomedin (SM) have been measured throughout pregnancy, at parturition, and in foetal and newborn sera. Acid-dissociable serum NSILA (mean ± sem) in 57 women was significantly higher during pregnancy (1106 ± 46 μU/ml), than in 11 adult non-pregnant control subjects (844 ± 22 μU/ml), but not correlated with week of gestation or with serum growth hormone (GH) or cortisol levels. At parturition, the NSILA concentration in 28 cord sera (598 ± 38 μU/ml) was significantly less than in the corresponding maternal sera (1039 ± 63 μU/ml). The NSILA levels in 23 premature newborns (370 ± 20 μU/ml) and 8 smallfor-gestational-age newborns (310 ± 46 μU/ml) were significantly less than in 33 term newborns (494 ± 18 μU/ml). Serum NSILA in 56 term and premature newborns exhibited a significant positive correlation both with gestational age and birth weight but not with serum GH or cortisol levels. These data suggest that the maternal-foetal growth-promoting system is a highly complex one in which NSILA levels both in maternal and foetal circulations appear to be under multifactorial control.

scholarly journals Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 737 ◽  
Author(s):  
Hyun-Joo Park ◽  
Yeon Kim ◽  
Mi-Kyoung Kim ◽  
Jae Joon Hwang ◽  
Hyung Joon Kim ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Vascular System ◽  
Ex Vivo ◽  
Calcium Deposition ◽  
Gastrin Releasing Peptide ◽  
Cardiovascular Morbidity And Mortality ◽  
Potential Strategy ◽  
Grp Receptor

Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.

Concurrent elevation of fundic somatostatin prevents gastrin stimulation by GRP

1999 ◽  
Vol 276 (1) ◽  
pp. G21-G27 ◽  
Author(s):  
Yana Zavros ◽  
William R. Fleming ◽  
Arthur Shulkes
Keyword(s):  
Normal Animal ◽  
Differential Regulation ◽  
Local Source ◽  
Major Influence ◽  
Plasma Gastrin ◽  
Gastrin Releasing Peptide ◽  
Gastrin Secretion ◽  
Stimulation Of

Gastrin-releasing peptide (GRP) can stimulate both gastrin and somatostatin (SOM) secretion, but, as gastrin increases SOM and SOM in turn inhibits gastrin, the overall endpoint in terms of gastrin output is variable. To examine the mechanisms involved, we compared the effects of GRP on gastrin secretion in normal sheep and sheep chronically immunized against SOM. In the normal animal, GRP had no effect on either plasma gastrin or SOM. However, in sheep immunized against SOM, GRP stimulated gastrin secretion, suggesting that the concurrent stimulation of SOM prevents the increase in gastrin secretion. To determine the local source of SOM, GRP was then infused into nonimmunized sheep with cannulas draining blood from the fundus and antrum. GRP stimulated fundic SOM output but inhibited antral SOM and gastrin secretion, demonstrating that the fundus was the source of the SOM. Because cholinergic interactions have a major influence on the effects of GRP, a cholinergic stimulus was administered, and we found that the responses were different: SOM output was inhibited in both the antrum and fundus, and antral gastrin secretion was increased. The present study demonstrates two further instances of the differential regulation of SOM from the antrum and fundus. GRP fails to stimulate gastrin because of an increase in fundic SOM, whereas gastrin levels increase following a cholinergic stimulus because of inhibition of both antral and fundic SOM secretion.

scholarly journals Roles for substance P and gastrin-releasing peptide as neurotransmitters released by primary afferent pruriceptors

2013 ◽  
Vol 109 (3) ◽  
pp. 742-748 ◽  
Author(s):  
Tasuku Akiyama ◽  
Mitsutoshi Tominaga ◽  
Auva Davoodi ◽  
Masaki Nagamine ◽  
Kevin Blansit ◽  
...  
Keyword(s):  
Substance P ◽  
Receptor Antagonist ◽  
Sensory Neurons ◽  
Intrathecal Administration ◽  
Primary Sensory Neurons ◽  
Gastrin Releasing Peptide ◽  
Behavioral Studies ◽  
Neurokinin 1 ◽  
Protease Activated Receptor 2 ◽  
Grp Receptor

Recent studies support roles for neurokinin-1 (NK-1) and gastrin-releasing peptide (GRP) receptor-expressing spinal neurons in itch. We presently investigated expression of substance P (SP) and GRP in pruritogen-responsive primary sensory neurons and roles for these neuropeptides in itch signaling. Responses of dorsal root ganglion (DRG) cells to various pruritogens were observed by calcium imaging. DRG cells were then processed for SP, GRP, and isolectin B-4 (IB4; a marker for nonpeptidergic neurons) immunofluorescence. Of pruritogen-responsive DRG cells, 11.8–26.8%, 21.8–40.0%, and 21.4–26.8% were immunopositive for SP, GRP, and IB4, respectively. In behavioral studies, both systemic and intrathecal administration of a NK-1 receptor antagonist significantly attenuated scratching evoked by chloroquine and a protease-activated receptor 2 agonist, SLIGRL, but not histamine, bovine adrenal medulla peptide 8-22 (BAM8-22), or serotonin. Systemic or intrathecal administration of a GRP receptor antagonist attenuated scratching evoked by chloroquine and SLIGRL but not BAM8-22 or histamine. The GRP receptor antagonist enhanced scratching evoked by serotonin. These results indicate that SP and GRP expressed in primary sensory neurons are partially involved as neurotransmitters in histamine-independent itch signaling from the skin to the spinal cord.

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