The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform

Martine Clozel - One of the best experts on this subject based on the ideXlab platform.

  • the Urotensin ii Receptor antagonist palosuran improves pancreatic and renal function in diabetic rats
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Martine Clozel, Shuangshuang Ding, Patrick Hess, Changbin Qiu, Markus Rey
    Abstract:

    Urotensin-II (U-II) is a cyclic peptide that acts through a specific G-protein-coupled Receptor, UT Receptor. Urotensin-II and UT Receptors have been described in pancreas and kidney, but their function is not well understood. We studied the effects of chronic treatment of diabetic rats with the orally active selective U-II Receptor antagonist palosuran. Streptozotocin treatment causes pancreatic β-cell destruction and leads to the development of hyperglycemia, dyslipidemia, and renal dysfunction. Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. The U-II system is unique in that it plays a role both in insulin secretion and in the renal complications of diabetes. Urotensin Receptor antagonism might be a new therapeutic approach for the treatment of diabetes.

  • pharmacology of the Urotensin ii Receptor antagonist palosuran act 058362 1 2 4 benzyl 4 hydroxy piperidin 1 yl ethyl 3 2 methyl quinolin 4 yl urea sulfate salt first demonstration of a pathophysiological role of the Urotensin system
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Martine Clozel, Christophe Binkert, Magdalena Birkerrobaczewska, Celine Boukhadra, Shuangshuang Ding, Walter Fischli, Patrick Hess, Boris Mathys, Keith Morrison, Celia Muller
    Abstract:

    Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to a specific G protein-coupled Receptor, formerly the orphan Receptor GPR14, now renamed Urotensin Receptor (UT Receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT Receptor. ACT-058362 antagonizes the specific binding of 125I-labeled U-II on natural and recombinant cells carrying the human UT Receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT-058362 also inhibits U-II-induced calcium mobilization and mitogen-activated protein kinase phosphorylation. The binding inhibitory potency of ACT-058362 is more than 100-fold less on the rat than on the human UT Receptor, which is reflected in a pD′2 value of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U-II. In functional assays of short incubation times, ACT-058362 behaves as an apparent noncompetitive inhibitor. In vivo, intravenous ACT-058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT Receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia. As a selective renal vasodilator, ACT-058362 may be effective in other renal diseases.

Henry Krum - One of the best experts on this subject based on the ideXlab platform.

  • chronic Urotensin ii Receptor antagonist treatment does not alter hypertrophy or fibrosis in a rat model of pressure overload hypertrophy
    Peptides, 2010
    Co-Authors: Andrew R Kompa, David J. Behm, Darren J Kelly, Bing H Wang, Arintaya Phrommintikul, Stephen A Douglas, Henry Krum
    Abstract:

    Urotensin II (UII) is a potential mediator in the pathogenesis of cardiovascular disease, and inhibition of its actions at the Urotensin Receptor (UT) has been shown to improve cardiac function and structural changes of the myocardium in a model of myocardial infarction. In this study we utilized a model of pressure-overload hypertrophy induced by abdominal aortic constriction (AAC) which resulted in hypertrophy, increased fibrosis and impaired diastolic and systolic function. These changes were associated with a 4-fold increase in UII protein expression in the myocardium. Treatment of animals with a selective UT (SB-657510) antagonist for 20 weeks at a dose of 1500 ppm did not improve cardiac function as assessed by echocardiography and pressure-volume loop analysis, nor did it inhibit left ventricular hypertrophy or fibrosis. We hypothesize that other neurohumoral pathways may have a greater involvement in the pathogenesis of this model. Targeting the UII system appears to be insufficient to observe a beneficial outcome.

  • effect of the Urotensin Receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy
    Hypertension, 2010
    Co-Authors: Liffert Vogt, Carlos Chiurchiu, Harbajan Chadhaboreham, Parisa Danaietash, Jasper Dingemanse, Samy Hadjadj, Henry Krum, Gerjan Navis, Eric Neuhart, Aneliya Parvanova
    Abstract:

    The Urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the Urotensin Receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and 135 and 85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether Urotensin Receptor antagonism represents a new treatment strategy in this high-risk patient population.

Aneliya Parvanova - One of the best experts on this subject based on the ideXlab platform.

  • effect of the Urotensin Receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy
    Hypertension, 2010
    Co-Authors: Liffert Vogt, Carlos Chiurchiu, Harbajan Chadhaboreham, Parisa Danaietash, Jasper Dingemanse, Samy Hadjadj, Henry Krum, Gerjan Navis, Eric Neuhart, Aneliya Parvanova
    Abstract:

    The Urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the Urotensin Receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and 135 and 85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether Urotensin Receptor antagonism represents a new treatment strategy in this high-risk patient population.

Markus Rey - One of the best experts on this subject based on the ideXlab platform.

  • the Urotensin ii Receptor antagonist palosuran improves pancreatic and renal function in diabetic rats
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Martine Clozel, Shuangshuang Ding, Patrick Hess, Changbin Qiu, Markus Rey
    Abstract:

    Urotensin-II (U-II) is a cyclic peptide that acts through a specific G-protein-coupled Receptor, UT Receptor. Urotensin-II and UT Receptors have been described in pancreas and kidney, but their function is not well understood. We studied the effects of chronic treatment of diabetic rats with the orally active selective U-II Receptor antagonist palosuran. Streptozotocin treatment causes pancreatic β-cell destruction and leads to the development of hyperglycemia, dyslipidemia, and renal dysfunction. Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. The U-II system is unique in that it plays a role both in insulin secretion and in the renal complications of diabetes. Urotensin Receptor antagonism might be a new therapeutic approach for the treatment of diabetes.

David J. Behm - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Urotensin II Receptor antagonist, GSK1440115, in asthma
    Frontiers Media S.A., 2013
    Co-Authors: Alison D Portnoy, David J. Behm, Sanjay Ekumar, Kelly M Mahr, Robert B Noble, John Ethroup, Steven F Russ
    Abstract:

    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 Receptor (UT) 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 2-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 hours and the terminal half-life was short at approximately 2 hours. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% Receptor occupancy for >=3 hours (between 4-7 hours 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

  • genetic and pharmacological manipulation of Urotensin ii ameliorate the metabolic and atherosclerosis sequalae in mice
    Arteriosclerosis Thrombosis and Vascular Biology, 2012
    Co-Authors: Zhipeng You, David J. Behm, Jacques Genest, Pierreolivier Barrette, Anouar Hafiane, Pedro Dorleansjuste, Adel Schwertani
    Abstract:

    Objective— Urotensin II (UII) is a potent vasoactive peptide that binds to the Urotensin Receptor–coupled Receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis. Methods and Results— We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type ( P P P Conclusion— These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.

  • chronic Urotensin ii Receptor antagonist treatment does not alter hypertrophy or fibrosis in a rat model of pressure overload hypertrophy
    Peptides, 2010
    Co-Authors: Andrew R Kompa, David J. Behm, Darren J Kelly, Bing H Wang, Arintaya Phrommintikul, Stephen A Douglas, Henry Krum
    Abstract:

    Urotensin II (UII) is a potential mediator in the pathogenesis of cardiovascular disease, and inhibition of its actions at the Urotensin Receptor (UT) has been shown to improve cardiac function and structural changes of the myocardium in a model of myocardial infarction. In this study we utilized a model of pressure-overload hypertrophy induced by abdominal aortic constriction (AAC) which resulted in hypertrophy, increased fibrosis and impaired diastolic and systolic function. These changes were associated with a 4-fold increase in UII protein expression in the myocardium. Treatment of animals with a selective UT (SB-657510) antagonist for 20 weeks at a dose of 1500 ppm did not improve cardiac function as assessed by echocardiography and pressure-volume loop analysis, nor did it inhibit left ventricular hypertrophy or fibrosis. We hypothesize that other neurohumoral pathways may have a greater involvement in the pathogenesis of this model. Targeting the UII system appears to be insufficient to observe a beneficial outcome.

  • targeted overexpression of the human Urotensin Receptor transgene in smooth muscle cells effect of ut antagonism in apoe knockout mice fed with western diet
    Atherosclerosis, 2009
    Co-Authors: Panayiota Papadopoulos, David J. Behm, Zhipeng You, Stephen A Douglas, Nicolas Bousette, Wisam Alramli, Eliot H Ohlstein, Stephen M Harrison, Adel Giaid
    Abstract:

    Abstract Urotensin II (UII) and its Receptor UT are upregulated in the pathological setting of various cardiovascular diseases including atherosclerosis. However, their exact role in atherosclerosis remains to be determined. In the present study we used four strains of mice; wild-type (WT), UT + (a transgenic strain expressing human UT driven by the α-smooth muscle-specific, SM22, promoter), ApoE knockout (ko), and UT + /ApoE ko. All animals were fed high fat diet for 12 weeks. Western blot analysis revealed a significant increase in aortic UT expression in UT + relative to WT mice ( P + . Immunohistochemistry revealed the presence of strong expression of UT and UII proteins in the atheroma of UT + , ApoE ko and UT + /ApoE ko mice, particularly in foam cells. Serum cholesterol and triglyceride levels were significantly increased in ApoE ko and in UT + /ApoE ko but not in UT + mice when compared to WT mice ( P + , ApoE ko and UT + /ApoE ko compared to WT mice ( P P P