Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta.
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ABSTRACT:
SUBMITTER: Patacchini R
PROVIDER: S-EPMC1574141 | biostudies-other | 2003 Dec
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. METHODS:Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1-750?mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750?mg GSK1440115 or placebo and given a methacholine challenge. RESULTS:Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50?mg dose. In the presence of food at the 750?mg dose, the time to maximal concentration was between 2 and 6?h and the terminal half-life was short at approximately 2?h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ?3?h (between 4 and 7?h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. CONCLUSION:While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.
| S-EPMC3638148 | biostudies-literature
Project description:In this study, we investigated the effects of a selective urotensin II (UII) receptor antagonist, SB-657510, on the inflammatory response induced by UII in human umbilical vein endothelial cells (EA.hy926) and human monocytes (U937). UII induced inflammatory activation of endothelial cells through expression of proinflammatory cytokines (IL-1? and IL-6), adhesion molecules (VCAM-1), and tissue factor (TF), which facilitates the adhesion of monocytes to EA.hy926 cells. Treatment with SB-657510 significantly inhibited UII-induced expression of IL-1?, IL-6, and VCAM-1 in EA.hy926 cells. Further, SB-657510 dramatically blocked the UII-induced increase in adhesion between U937 and EA.hy926 cells. In addition, SB-657510 remarkably reduced UII-induced expression of TF in EA.hy926 cells. Taken together, our results demonstrate that the UII antagonist SB-657510 decreases the progression of inflammation induced by UII in endothelial cells.
| S-EPMC3819900 | biostudies-literature
Project description:This study was designed to evaluate the effects of DS37001789, a novel and highly potent urotensin II (U-II) receptor (GPR14) antagonist, against mortality, hypertrophy, and cardiac dysfunction in pressure-overload hypertrophy by transverse aortic constriction (TAC) in mice. In addition, we analyzed the phenotype of GPR14 knockout (KO) mice after TAC induction to confirm the contribution of the U-II/GPR14 system. The oral administration of 0.2% DS37001789 to TAC mice for 12 weeks significantly ameliorated the mortality rate and 0.2% DS37001789 for 4 weeks significantly improved cardiac function by pressure-volume analysis. GPR14 expression was significantly upregulated in the left ventricle in the TAC mice treated with 0.2% DS37001789. Moreover, we confirmed that the significant amelioration of mortality was accomplished by the inhibition of cardiac enlargement and the improvement of cardiac function in GPR14 KO mice after TAC surgery. These results suggest that the U-II/GPR14 system contributes to the progression of heart failure and its blockade ameliorates the mortality via improved cardiac function. The U-II/GPR14 system may thus be an attractive target for treating heart failure with pathological cardiac hypertrophy and DS37001789 may be a novel therapeutic agent for heart failure in patients with pressure-overload conditions such as hypertension and aortic valve stenosis.
| S-EPMC7005433 | biostudies-literature
Project description:BACKGROUND AND PURPOSE During the past decade, a few GPCRs have been characterized at the nuclear membrane where they exert complementary physiological functions. In this study, we investigated (1) the presence of a functional urotensin-II (U-II) receptor (UT) in rat heart nuclear extracts and (2) the propensity of U-II and U-II-related peptide (URP) to cross the plasma membrane in a receptor-independent manner. EXPERIMENTAL APPROACH Biochemical and pharmacological methods including competitive binding assays, photoaffinity labelling, immunoblotting as well as de novo RNA synthesis were used to characterize the presence of functional UT receptors in rat heart nuclei. In addition, confocal microscopy and flow cytometry analysis were used to investigate the cellular uptake of fluorescent U-II and URP derivatives. KEY RESULTS The presence of specific U-II binding sites was demonstrated in rat heart nuclear extracts. Moreover, such subcellular localization was also observed in monkey heart extracts. In vitro transcription initiation assays on rat, freshly isolated, heart nuclei suggested that nuclear UT receptors are functional, and that U-II, but not URP, participates in nuclear UT-associated gene expression. Surprisingly, hU-II and URP efficiently crossed the plasma membrane in a receptor-independent mechanism involving endocytosis through caveolin-coated pits; this uptake of hU-II, but not that of URP, was dependent on extracellular pH. CONCLUSION Our results suggest that (1) U-II and URP can differentially modulate nuclear UT functions such as gene expression, and (2) both ligands can reach the internal cellular space through a receptor-independent mechanism.
| S-EPMC3415652 | biostudies-literature
Project description:Urotensin-II (U-II) has been shown to be the most potent mammalian vasoconstrictor known. Thus, a U-II antagonist might be of therapeutic value in a number of cardiovascular disorders. However, interspecies variability of several nonpeptidic ligands complicates the interpretation of in vivo studies of such antagonists in preclinical animal disease models. ACT058362 is a selective antagonist for the human U-II receptor (hUT2R) with a reported K(d) value of approximately 4 nM in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with a K(d) value of approximately 1 500 nM. In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (K(d)= approximately 9 nM) and rUT2R (K(d)= approximately 21 nM). To understand the species selectivity of the UT2R, we investigated the binding site of ACT058362 and SB706375 in both hUT2R and rUT2R to explain the dramatically lower (approximately 400-fold) affinity of ACT058362 for rUT2R and the similar affinity (approximately 10 nM) of SB706375 for both UT2Rs. These studies used MembStruk and MSCDock to predict the UT2R structure and the binding site of ACT058362 and SB706375. Based on binding energies, we found two binding modes each with D130(3.32) as the crucial anchoring point (Ballesteros-Weinstein numbering given in superscript). We predict that ACT058362 (an aryl-amine-aryl or ANA ligand) binds in the transmembrane (TM) 3456 region, while SB706375 (an aryl-aryl-amine or AAN ligand) binds in the TM 1237 region. These predicted sites explain the known differences in binding of the ANA ligand to rat and human receptors, while explaining the similar binding of the AAN compound to rat and human receptors. Moreover the predictions explain currently available structure-activity relationship (SAR) data. To further validate the predicted binding sites of these ligands in hUT2R and rUT2R, we propose several mutations that would help define the structural origins of differential responses between UT2R of different species, potentially indicating novel UT2R antagonists with cross-species high affinity.
| S-EPMC3517062 | biostudies-literature
Project description:Drug repositioning research using transcriptome data has recently attracted attention. In this study, we attempted to identify new target proteins of the urotensin-II receptor antagonist, KR-37524 (4-(3-bromo-4-(piperidin-4-yloxy)benzyl)-N-(3-(dimethylamino)phenyl)piperazine-1-carboxamide dihydrochloride), using a transcriptome-based drug repositioning approach. To do this, we obtained KR-37524-induced gene expression profile changes in four cell lines (A375, A549, MCF7, and PC3), and compared them with the approved drug-induced gene expression profile changes available in the LINCS L1000 database to identify approved drugs with similar gene expression profile changes. Here, the similarity between the two gene expression profile changes was calculated using the connectivity score. We then selected proteins that are known targets of the top three approved drugs with the highest connectivity score in each cell line (12 drugs in total) as potential targets of KR-37524. Seven potential target proteins were experimentally confirmed using an in vitro binding assay. Through this analysis, we identified that neurologically regulated serotonin transporter proteins are new target proteins of KR-37524. These results indicate that the transcriptome-based drug repositioning approach can be used to identify new target proteins of a given compound, and we provide a standalone software developed in this study that will serve as a useful tool for drug repositioning.
| S-EPMC8384862 | biostudies-literature
Project description:New findingsWhat is the central question of this study? Urotensin II is upregulated in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis. Could treatment with a urotensin II receptor antagonist slow progression of renal disease? What is the main finding and its importance? In the rat, expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end-stage renal failure. Subchronic treatment with a urotensin receptor antagonist slowed but did not prevent progression of CKD. This suggests that urotensin II contributes to the decline in renal function in CKD.AbstractElevated serum and urine urotensin II (UII) concentrations have been reported in patients with end-stage chronic kidney disease (CKD). Similar increases in UII and its receptor, UT, have been reported in animal models of CKD, but only at much earlier stages of renal dysfunction. The aim of this study was to characterize urotensin system expression as renal disease progresses to end-stage failure in a ⅚ subtotal nephrectomy (SNx) rat model. Male Sprague-Dawley rats underwent SNx or sham surgery and were killed at 8 weeks postsurgery [early (E)] or immediately before end-stage renal failure [30 ± 3 weeks postsurgery; late (L)]. Systolic blood pressure, urinary albumin:creatinine ratio and glomerulosclerosis index were all increased in SNx-E rats compared with sham-E by 8 weeks postsurgery. These changes were associated with an increase in renal immunoreactive UII staining but little change in UT expression. As CKD progressed to end-stage disease in the SNx-L group, markers of renal function deteriorated further, in association with a marked increase in immunoreactive UII and UT staining. Subchronic administration of a UT antagonist, SB-611812, at 30 mg kg-1 day-1 for 13 weeks, in a separate group of SNx rats resulted in a 2 week delay in the increase in both systolic blood pressure and urinary albumin:creatinine ratio observed in vehicle-treated SNx but did not prevent the progression of renal dysfunction. The urotensin system is upregulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD.
| S-EPMC6492238 | biostudies-literature
Project description:Blockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676).Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI).KR36676 displayed high binding affinity for the UT receptor (Ki : 0.7?nM), similar to that of U-II (0.4?nM), and was a potent antagonist at that receptor (IC50 : 4.0?nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (?0.01??M). Oral administration of KR36676 (30?mg·kg(-1) ) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy.A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy.
| S-EPMC4409911 | biostudies-literature
Project description:In order to analyze the regulatory effects of UII and GPR14 on gene transcription in Mc903-induced atopic dermatitis skin, ear skin collected from MC903 chronic itch mouse model on day 13 was used for in-depth analysis and sequencing of skin gene expression. The effect of GSK1562590 on the expression of pruritus and inflammatory factors in dermatitis was detected by RNA-seq.
2023-06-16 | GSE226669 | GEO
Project description:BackgroundThe expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn's disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation.MethodsWe employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid). We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture.ResultsIn the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFN? by 89%, IL-1? by 63%, IL-6 by 43% and tumor necrosis factor (TNF) by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40%) and gp96-II peptide (35%). Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%), lipopolysaccharide-induced TNF (48%), IL-6 (81%) and in Staphylococcus epidermidis-induced TNF (67%) and IL-6 (81%), as well as IL-12/IL-18-induced IFN? (75%). gp96-II peptide reduced IL-1?, IL-6, TNF and GM-CSF in human peripheral blood mononuclear cells to a similar degree without affecting cell viability, whereas RANTES, IL-25 and MIF were twofold to threefold increased.Conclusiongp96-II peptide protects against murine intestinal inflammation by regulating inflammation in vivo and in vitro, pointing to its promise as a novel treatment for inflammatory bowel disease.
| S-EPMC5732239 | biostudies-literature