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Sample records for at1b angiotensin receptor

  1. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Directory of Open Access Journals (Sweden)

    Courtney Premer

    2013-01-01

    Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

  2. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Science.gov (United States)

    Premer, Courtney; Lamondin, Courtney; Mitzey, Ann; Speth, Robert C.; Brownfield, Mark S.

    2013-01-01

    Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors. PMID:23573410

  3. Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.

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    Irina Bogdarina

    2010-02-01

    Full Text Available Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.

  4. Heterogeneous Downregulation of Angiotensin II AT1-A and AT1-B Receptors in Arterioles in STZ-Induced Diabetic Rat Kidneys

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    Zsolt Razga

    2014-01-01

    Full Text Available Introduction. The renin granulation of kidney arterioles is enhanced in diabetes despite the fact that the level of angiotensin II in the diabetic kidney is elevated. Therefore, the number of angiotensin II AT1-A and AT1-B receptors in afferent and efferent arteriole’s renin-positive and renin-negative smooth muscle cells (SMC was estimated. Method. Immunohistochemistry at the electron microscopic level was combined with 3D stereological sampling techniques. Results. In diabetes the enhanced downregulation of AT1-B receptors in the renin-positive than in the renin-negative SMCs in both arterioles was resulted: the significant difference in the number of AT1 (AT1-A + AT1-B receptors between the two types of SMCs in the normal rats was further increased in diabetes and in contrast with the significant difference observed between the afferent and efferent arterioles in the normal animals, there was no such difference in diabetes. Conclusions. The enhanced downregulation of the AT1-B receptors in the renin-negative SMCs in the efferent arterioles demonstrates that the regulation of the glomerular filtration rate by the pre- and postglomerular arterioles is changed in diabetes. The enhanced downregulation of the AT1-B receptors in the renin-positive SMCs in the arterioles may result in an enhanced level of renin granulation in the arterioles.

  5. Regional variation in aortic AT1b receptor mRNA abundance is associated with contractility but unrelated to atherosclerosis and aortic aneurysms.

    Directory of Open Access Journals (Sweden)

    Aruna Poduri

    Full Text Available Angiotensin II (AngII, the main bioactive peptide of the renin angiotensin system, exerts most of its biological actions through stimulation of AngII type 1 (AT1 receptors. This receptor is expressed as 2 structurally similar subtypes in rodents, termed AT1a and AT1b. Although AT1a receptors have been studied comprehensively, roles of AT1b receptors in the aorta have not been defined.We initially compared the regional distribution of AT1b receptor mRNA with AT1a receptor mRNA in the aorta. mRNA abundance of both subtypes increased from the proximal to the distal aorta, with the greatest abundance in the infra-renal region. Corresponding to the high mRNA abundance for both receptors, only aortic rings from the infra-renal aorta contracted in response to AngII stimulation. Despite the presence of both receptor transcripts, deletion of AT1b receptors, but not AT1a receptors, diminished AngII-induced contractility. To determine whether absence of AT1b receptors influenced aortic pathologies, we bred AT1b receptor deficient mice into an LDL receptor deficient background. Mice were fed a diet enriched in saturated fat and infused with AngII (1,000 ng/kg/min. Parameters that could influence development of aortic pathologies, including systolic blood pressure and plasma cholesterol concentrations, were not impacted by AT1b receptor deficiency. Absence of AT1b receptors also had no effect on size of aortic atherosclerotic lesions and aortic aneurysms in both the ascending and abdominal regions.Regional abundance of AT1b receptor mRNA coincided with AngII-induced regional contractility, but it was not associated with AngII-induced aortic pathologies.

  6. Angiotensin II Receptor Blockers

    Science.gov (United States)

    ... a chemical in your body that affects your cardiovascular system in various ways, including narrowing your blood vessels. This narrowing can increase your blood pressure and force your heart to work harder. Angiotensin ...

  7. Angiotensin receptors in the cardiovascular system

    NARCIS (Netherlands)

    Wagenaar, L.J.; Voors, AA; Buikema, H; van Gilst, WH

    2002-01-01

    The angiotensin II receptors mediate the effects of the renin-angiotensin system, which has an important role in cardiovascular (patho)physiology. Four types of angiotensin receptors are known, of which the type 1 (AT,) and the type 2 (AT(2)) receptors are the most important. Stimulation of the AT,

  8. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...... the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1...

  9. Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

    Science.gov (United States)

    Crowley, Steven D; Vasievich, Matthew P; Ruiz, Phillip; Gould, Samantha K; Parsons, Kelly K; Pazmino, A Kathy; Facemire, Carie; Chen, Benny J; Kim, Hyung-Suk; Tran, Trinh T; Pisetsky, David S; Barisoni, Laura; Prieto-Carrasquero, Minolfa C; Jeansson, Marie; Foster, Mary H; Coffman, Thomas M

    2009-04-01

    Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

  10. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Kristensen, Karl Emil; Torp-Pedersen, Christian; Gislason, Gunnar Hilmar

    2015-01-01

    OBJECTIVE: The renin-angiotensin system is thought to play a pivotal role in the pathogenesis of abdominal aortic aneurysms (AAAs). However, effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) on human AAAs remain unclear. We therefore ex...

  11. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis

    National Research Council Canada - National Science Library

    Healey, Jeff S; Baranchuk, Adrian; Crystal, Eugene; Morillo, Carlos A; Garfinkle, Michael; Yusuf, Salim; Connolly, Stuart J

    2005-01-01

    This study was designed to identify all randomized clinical trial data evaluating angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for the prevention of atrial fibrillation (AF...

  12. Angiotensin II receptors in the gonads

    Energy Technology Data Exchange (ETDEWEB)

    Aguilera, G.; Millan, M.A.; Harwood, J.P.

    1989-05-01

    The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AII receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.

  13. Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

    LENUS (Irish Health Repository)

    Wan Md Adnan, Wan A H

    2011-03-01

    (i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

  14. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists.

    Science.gov (United States)

    Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P

    2015-12-15

    The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Quantitative autoradiography of angiotensin II receptors in the SHR brain

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    Gehlert, D.R.; Speth, R.C.; Wamsley, J.K.

    1986-11-01

    Several lines of evidence indicate brain angiotensin II is associated with the elevation of blood pressure seen in the spontaneously hypertensive rat (SHR). These include an increased pressor response to intracerebroventricularly administered angiotensin II and a reduction of blood pressure in response to centrally administered angiotensin II receptor antagonists. Using quantitative receptor autoradiography, we have detected greater angiotensin II receptor binding in a number of discrete brain nuclei of the 6-week-old SHR when compared to age-matched Wistar-Kyoto controls. Tissue sections from various brain regions were labeled with (/sup 125/I)-angiotensin II according to a previously described method. Autoradiograms were generated by apposing the labeled tissue sections to LKB Ultrofilm along with brain paste standards which contained known amounts of (/sup 125/I). Quantitation of the binding, utilizing computer-assisted microdensitometry, indicated greater (/sup 125/I)-angiotensin II binding in several brain areas implicated in cardiovascular control including the subfornical organ, nucleus of the solitary tract, dorsal motor nucleus of the vagus, locus coeruleus, supraoptic nucleus and the organum vasculosum of the lamina terminalis. Scatchard analysis of the binding in the nucleus of the solitary tract indicated an increased receptor number (Bmax) was responsible for the change while binding in two forebrain structures, the subfornical organ and supraoptic nucleus, showed alterations in receptor number and affinity (Kd). Several other brain regions, unrelated to cardiovascular control, exhibited no change in (/sup 125/I)-angiotensin II binding.

  16. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2004-01-01

    Roč. 22, č. 12 (2004), s. 2253-2261 ISSN 0263-6352 R&D Projects: GA ČR GA301/03/0751 Grant - others:HHMI(US) HHMI55000331 Institutional research plan: CEZ:AV0Z5011922 Keywords : angiotensin II receptors * metabolic syndrome * peroxisome proliferator activated receptors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.871, year: 2004

  17. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, L.

    2008-01-01

    The mechanism behind the positive response to the inhibition of the angiotensin II receptor AT(1) in conjunction with stroke is elusive. Here we demonstrate that cerebrovascular AT(1) receptors show increased expression (upregulation) after cerebral ischemia via enhanced translation. This enhanced...

  18. Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation

    NARCIS (Netherlands)

    Groenewegen, Hendrik C.; van der Harst, Pim; Roks, Anton J. M.; Buikema, Hendrik; Zijlstra, Felix; van Gilst, Wiek H.; de Smet, Bart J. G. L.

    2008-01-01

    Background: To evaluate the effect of supraphysiological levels of angiotensin II and selective angiotensin II type 1 receptor ( AT1-receptor) blockade on neointimal formation and systemic endothelial function after stent implantation in the rat abdominal aorta. Methods: Male Wistar rats were

  19. Cardiovascular effects of the angiotensin type 2 receptor.

    Science.gov (United States)

    Faria-Costa, Gabriel; Leite-Moreira, Adelino; Henriques-Coelho, Tiago

    2014-01-01

    The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angiotensin type 1 receptor, AT1R. Although the quantities of the AT2R found in the adult are low, its expression rises in pathological situations. The AT2R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT2R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT1R inhibitor). After myocardial infarction, the AT2R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT2R promotes natriuresis. Until now, treatment directed at the renin-angiotensin-aldosterone system has been based on angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT2R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  20. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS

    DEFF Research Database (Denmark)

    Leonhardt, Julia; Villela, Daniel C.; Teichmann, Anke

    2017-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may......, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked...

  1. The Angiotensin AT2 Receptor

    DEFF Research Database (Denmark)

    Unger, Thomas; Steckelings, Ulrike M.; Dzau, Victor J.

    2015-01-01

    Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin-angiotensi...

  2. Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

    DEFF Research Database (Denmark)

    Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...... describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation.......Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report...

  3. Comparing the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal function decline in diabetes

    NARCIS (Netherlands)

    Huang, Yunyu; Haaijer-Ruskamp, Flora M.; Voorham, Jaco

    Aim: To compare effectiveness of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) for protecting Type 2 diabetes mellitus (DM2) patients from renal function decline in a real-world setting. Methods: Retrospective cohort study of new ACEi/ARB users in 2007-2012 in

  4. Angiotensin II type 1 receptor (A1166C) gene polymorphism in ...

    African Journals Online (AJOL)

    angiotensin system (RAS) is likely to contribute for its heterogenous association in renal diseased patients. Among the candidate genes of RAS, angiotensin II type 1 receptor gene polymorphism (AT1R A1166C) seems to be particularly ...

  5. Angiotensin-converting enzyme inhibitors reduce mortality compared to angiotensin receptor blockers: Systematic review and meta-analysis.

    Science.gov (United States)

    Salvador, Gabriel Lo; Marmentini, Vinicius M; Cosmo, Willian R; Junior, Emilton L

    2017-12-01

    Background There are few reviews comparing the long-term outcomes of the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in a hypertensive population because both are effective in reducing blood pressure. None of them compared angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with a placebo group in patients with essential hypertension, because few studies exist with this design. Methods A systematic search of PUBMED, LILACS, SCIELO, ICTRP, Cochrane, EMBASE and ClinicalTrials.gov from 1 January 2000 until 31 December 2015 selected prospective studies that reported an association between the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in the following cardiovascular outcomes: heart failure/hospitalisation, stroke, acute myocardial infarction, total cardiovascular deaths, total deaths and total outcomes. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were combined by using a fixed-effects model. Results Seventeen studies ( n = 73,761) were included of which 12 studies were randomly assigned to angiotensin II receptor blocker therapy ( n = 24,697) and five to angiotensin-converting enzyme inhibitors ( n = 12,170). Angiotensin-converting enzyme inhibitors proved to be significant in reducing total deaths (OR 0.85, 95% CI 0.78-0.93) and cardiovascular deaths (OR 0.77, 95% CI 0.69-0.87). Angiotensin II receptor blocker therapy did not show a reduction in total deaths (OR 1.02, 95% CI 0.96-1.09) or cardiovascular deaths (OR 0.95, 95% CI 0.86-1.06). For acute myocardial infarction, stroke and heart failure/hospitalisation, the reductions were significant for both classes. Conclusion Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use is similar in preventing major cardiovascular outcomes regarding acute myocardial infarction, stroke and heart failure/hospitalisation. However, the use of angiotensin-converting enzyme

  6. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

    Directory of Open Access Journals (Sweden)

    Miroslav Radenkovic

    2016-01-01

    Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

  7. Molecular determinants of angiotensin II type 1 receptor functional selectivity

    DEFF Research Database (Denmark)

    Aplin, Mark; Bonde, Marie Mi; Hansen, Jakob Lerche

    2008-01-01

    The angiotensin AT(1) receptor is an important pharmacological target in the treatment of cardiovascular disorders, such as hypertension, diabetic nephropathy, cardiac hypertrophy, arrhythmia and failure. Simultaneously, the AT(1) receptor has emerged to be a prominent model for the emerging......-dependent and -independent behaviour. While G protein activation is known to be detrimental, G protein-independent signalling by the AT(1) receptor has been associated with phenotypes such as cell survival and renewal, regulation of cardiac contraction and cell migration. It is therefore currently hypothesized...

  8. Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

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    Salwa R. El-Shaboury

    2012-02-01

    Full Text Available A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA's, namely Losartan potassium (Los-K, Irbesartan (Irb, Valsartan (Val and Candesartan cilexetil (Cand in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9982–0.9991 were obtained over the concentration range from 0.006 μg/mL to 1.7 μg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ without interferences from the co-formulated HCTZ or the additives commonly present in tablets. Keywords: Angiotensin II receptor antagonists, Spectrofluorimetry, Determination

  9. Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers

    Directory of Open Access Journals (Sweden)

    Georg Nickenig

    2006-03-01

    Full Text Available Targeting the renin-angiotensin-aldosterone system (RAAS, specifically the effector peptide angiotensin II (Ang II, represents a major opportunity for slowing the progression of cardiovascular disease (CVD and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors (ACE-Is in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough. By blocking Ang II at the AT1 receptor lever, Ang II receptor blockers (ARBs provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but may also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor. Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.

  10. Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers

    Directory of Open Access Journals (Sweden)

    Georg Nickenig

    2006-03-01

    Full Text Available Targeting the renin-angiotensin-aldosterone system (RAAS, specifically the effector peptide angiotensin II (Ang II, represents a major opportunity for slowing the progression of cardiovascular disease (CVD and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors P, (ACE-Is in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough. By blocking Ang II at the AT1 receptor level, Ang II receptor blockers (ARBs provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but may also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor. Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.

  11. Reappraisal of role of angiotensin receptor blockers in cardiovascular protection

    Directory of Open Access Journals (Sweden)

    Ram CV

    2011-05-01

    Full Text Available C Venkata S RamTexas Blood Pressure Institute, Clinical Research Institute of Dallas Nephrology Associates; and Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USAAbstract: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor blockers (ARBs have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT and Olmesartan and Calcium Antagonists Randomized (OSCAR studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.Keywords: angiotensin receptor blockers, hypertension, outcomes, clinical trials

  12. A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Quitterer, Ursula, E-mail: ursula.quitterer@pharma.ethz.ch [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland); Pohl, Armin; Langer, Andreas; Koller, Samuel; AbdAlla, Said [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland)

    2011-06-10

    Highlights: {yields} A new FRET-based method detects AT1/B2 receptor heterodimerization. {yields} First time application of AT1-Cerulean as a FRET donor. {yields} Method relies on signal peptide-enhanced cell surface delivery of AT1-Cerulean. {yields} A high FRET efficiency revealed efficient heterodimerization of AT1/B2R proteins. {yields} AT1/B2R heterodimers were functionally coupled to desensitization mechanisms. -- Abstract: Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R

  13. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral...... circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control...

  14. The Fetal Safety of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

    Directory of Open Access Journals (Sweden)

    Myla E. Moretti

    2012-01-01

    Full Text Available Angiotensin converting enzyme (ACE inhibitors and angiotensin II receptor blockers (ARBs are known to cause fetal renal damage in pregnancy. Due to conflicting reports in the literature, their safety after first trimester exposure has been debated. Our aim was to determine whether the use of ACE inhibitors or ARBs in the first trimester of pregnancy is associated with an increased risk for major malformations or other adverse outcomes. All subjects were prospectively enrolled from among women contacting a teratogen information service. At initial contact, details of maternal medical history and exposures were collected and follow-up interviews were conducted to ascertain pregnancy outcomes. Two comparator groups, women with hypertension treated with other antihypertensives, and healthy controls were also recruited. Baseline maternal characteristics were not different among the three groups. There were no differences in rates of major malformations. Both the ACE-ARBs and disease-matched groups exhibited significantly lower birth weight and gestational ages than the healthy controls (P<0.001 for both variables. There was a significantly higher rate of miscarriage noted in the ACE/ARB group (P<0.001. These results suggest that ACE inhibitors/ARBs are not major human teratogens; however, they may be associated with an increased risk for miscarriage.

  15. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease

    NARCIS (Netherlands)

    Wiesmann, M.; Roelofs, M.; Lugt, R. Van Der; Heerschap, A.; Kiliaan, A.J.; Claassen, J.A.H.R.

    2017-01-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced

  16. Angiotensin AT1 Receptor-associated protein Arap1 in the Kidney Vasculature is Suppressed by Angiotensin II

    DEFF Research Database (Denmark)

    Doblinger, Elisabeth; Hoecherl, Klaus; Mederle, Katharina

    2012-01-01

    Arap1 is a protein that interacts with angiotensin II type 1 (AT1) receptors and facilitates increased AT1 receptor surface expression in vitro. In the present study we assessed the tissue localization and regulation of Arap1 in vivo. Arap1 was found in various mouse organs with highest expression...... in the heart, kidney, aorta, and adrenal gland. Renal Arap1 protein was restricted to the vasculature and to glomerular mesangial cells and was absent from tubular epithelia. A similar localization was found in human kidneys. To test the hypothesis that angiotensin II may control renal Arap1 expression, mice...

  17. Determination of the exact molecular requirements for type 1 angiotensin receptor epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy.

    Science.gov (United States)

    Smith, Nicola J; Chan, Hsiu-Wen; Qian, Hongwei; Bourne, Allison M; Hannan, Katherine M; Warner, Fiona J; Ritchie, Rebecca H; Pearson, Richard B; Hannan, Ross D; Thomas, Walter G

    2011-05-01

    Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein-mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and β-arrestin-dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [(32)P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the β-arrestin-biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a β-arrestin-uncoupled receptor retained these properties. We also found angiotensin II-mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or β-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor.

  18. Protective Angiotensin Type 2 Receptors in the Brain and Hypertension.

    Science.gov (United States)

    de Kloet, Annette D; Steckelings, Ulrike M; Sumners, Colin

    2017-06-01

    The goal of this review is to assess the evidence that activation of angiotensin type 2 receptors (AT2R) in the brain can lower blood pressure and possibly constitute an endogenous anti-hypertensive mechanism. Recent studies that detail the location of AT2R in the brain, particularly within or near cardiovascular control centers, mesh well with findings from pharmacological and gene transfer studies which demonstrate that activation of central AT2R can influence cardiovascular regulation. Collectively, these studies indicate that selective activation of brain AT2R causes moderate decreases in blood pressure in normal animals and more profound anti-hypertensive effects, along with restoration of baroreflex function, in rodent models of neurogenic hypertension. These findings have opened the door to studies that can (i) assess the role of specific AT2R neuron populations in depressing blood pressure, (ii) determine the relevance of such mechanisms, and (iii) investigate interactions between AT2R and depressor angiotensin-(1-7)/Mas mechanisms in the brain.

  19. Angiotensin III stimulates high stretch-induced ANP secretion via angiotensin type 2 receptor.

    Science.gov (United States)

    Park, Byung Mun; Oh, Young-Bin; Gao, Shan; Cha, Seung Ah; Kang, Kyung Pyo; Kim, Suhn Hee

    2013-04-01

    Angiotensin III (Ang III) is metabolized from Ang II by aminopeptidase (AP) A and in turn, Ang III is metabolized to Ang IV by APN. Ang III is known to have a similar effect to Ang II on aldosterone secretion, but the effect of Ang III on atrial natriuretic peptide (ANP) secretion from cardiac atria is not known. The aim of the present study is to define the effect of Ang III on ANP secretion and its receptor subtype using isolated perfused beating atria. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5 cmH2O to 7.5 cmH2O. Atrial stretch by volume load increased atrial contractility and ANP secretion. Ang III stimulated stretch-induced ANP secretion in a dose-dependent manner without change in atrial contractility. The stimulated effect of Ang III (1 μM) on stretch-induced ANP secretion was blocked by the pretreatment of Ang II type 2 (AT2) receptor antagonist but not by AT1 or Mas receptor antagonist. Pretreatment with inhibitor of phosphoinositide 3-kinase (PI3K), Akt, nitric oxide synthase, soluble guanylyl cyclase, or protein kinase G (PKG) attenuated Ang III-stimulated ANP secretion. When Ang III (40 nM) or Ang II (4nM) was infused for 10 min into anesthetized rats, mean arterial pressure was increased about 10%. However, Ang III increased plasma ANP level by 35.81±10.19% but Ang II decreased plasma ANP level by 30.41±7.27%. Therefore, we suggest that Ang III, opposite to Ang II, stimulated stretch-induced ANP secretion through AT2 receptor/PI3K/Akt/nitric oxide/PKG pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy

    DEFF Research Database (Denmark)

    Tarnow, L; Cambien, Francois; Rossing, P

    1996-01-01

    BACKGROUND: Genotypic abnormalities of the renin-angiotensin system have been suggested as risk factors for the development of hypertension, diabetic nephropathy and proliferative retinopathy. Most of the known actions of angiotensin-II are exerted through the angiotensin-II type 1 receptor, which...... is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied...... the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74...

  1. Quantitative autoradiography of angiotensin II receptors in brain and kidney: focus on cardiovascular implications

    Energy Technology Data Exchange (ETDEWEB)

    Gehlert, D.R.; Speth, R.C.; Wamsley, J.K.

    1985-01-01

    Quantitative techniques of receptor autoradiography have been applied to localize (/sup 125/I)-angiotensin II binding sites in brain and kidney. High densities of autoradiographic grains, indicating the presence of angiotensin II receptors, have been localized to several rat brain nuclei including the dorsal motor nucleus of the vagus, nucleus of the solitary tract, anterior pituitary, locus coeruleus and several hypothalamic nuclei. Cat thoracic spinal cord exhibited a high density of sites over the intermedio-lateral cell column. In sections of rat kidney, angiotensin II receptors were detected in the glomerulus, vasa recta and ureter. The cardiovascular implications of these results are apparent and relate angiotensin II to hypertensive mechanisms. Thus, angiotensin II represents an endocoid which is involved in control of blood pressure through its effects on peripheral organs as well as the central nervous system.

  2. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    Science.gov (United States)

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  3. Use of angiotensin II receptor blockers in children- a review of ...

    African Journals Online (AJOL)

    2015-05-19

    May 19, 2015 ... teinuria in renal disease. Safety pharmacokinetic, dosage, and palatability of adult formulations for the paediatric age group are highlighted. Conclusion: Angiotensin receptor antagonists are useful effective and safe alternatives to available antihypertensive therapy in paedi- atric population. Angiotensin re-.

  4. Angiotensin II type 1 receptor (A1166C) gene polymorphism in ...

    African Journals Online (AJOL)

    H. El-banawy

    2015-01-05

    Jan 5, 2015 ... sure and body fluids, via renin-angiotensin–aldosterone system. (RAAS).1 This enzymatic cascade acts as an endocrine and paracrine system that results in the production of angiotensin. II (AngII). 2,3 Angiotensin II type 1 receptor (AT1R) mediates most of the action of AngII and therefore modulates the.

  5. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS.

    Science.gov (United States)

    Leonhardt, Julia; Villela, Daniel C; Teichmann, Anke; Münter, Lisa-Marie; Mayer, Magnus C; Mardahl, Maibritt; Kirsch, Sebastian; Namsolleck, Pawel; Lucht, Kristin; Benz, Verena; Alenina, Natalia; Daniell, Nicholas; Horiuchi, Masatsugu; Iwai, Masaru; Multhaup, Gerhard; Schülein, Ralf; Bader, Michael; Santos, Robson A; Unger, Thomas; Steckelings, Ulrike Muscha

    2017-06-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other. © 2017 American Heart Association, Inc.

  6. Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor.

    Science.gov (United States)

    Cha, Seung Ah; Park, Byung Mun; Gao, Shan; Kim, Suhn Hee

    2013-12-05

    Angiotensin-(1-9) [Ang-(1-9)] and Ang-(1-7) are cleaved by Ang converting enzyme 2 forming Ang I and Ang II, respectively, and the truncated Angs play a role in regulating atrial natriuretic peptide (ANP) secretion. Previously, we found that Ang-(1-7) stimulates ANP secretion via the Mas receptor. However, the effect of Ang-(1-9) on ANP secretion is still unknown. The aim of the present study is to determine whether Ang-(1-9) stimulates ANP secretion and to characterize the signaling pathway involved in stimulating secretion. We examined the effects of Ang-(1-9) on ANP secretion and atrial contractility with and without inhibitors in isolated perfused atria. Ang-(1-9) stimulated ANP secretion and concentration without change in atrial contractility. Ang-(1-9)-induced-ANP secretion was increased from 5% to 60% by 3 μM Ang-(1-9) during the low-stretch state of the atrium. This stimulatory effect of Ang-(1-9) on ANP secretion was attenuated by pretreatment with an Ang II type 2 receptor (AT2R) antagonist but not by AT1R or Mas receptor antagonist. In addition, pretreatment with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) blocked Ang-(1-9)-induced ANP secretion. In the high-stretch atrial state, Ang-(1-9)-induced ANP secretion was increased more than in the low-stretch state following addition of 1 μM Ang-(1-9) (from 108% to 170%). In an in vivo experiment, acute infusion of Ang-(1-9) increased plasma ANP level without altering arterial blood pressure. This effect was attenuated by pretreatment with AT2R antagonist but not by Mas receptor antagonist. These results suggest that Ang-(1-9) stimulates ANP secretion via the AT2R-PI3K-Akt-NO-cGMP pathway. © 2013.

  7. Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus

    DEFF Research Database (Denmark)

    Pena, Michelle J; Heinzel, Andreas; Rossing, Peter

    2016-01-01

    BACKGROUND: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response...

  8. Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders

    DEFF Research Database (Denmark)

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R...... in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production...

  9. Angiotensin-(1-5), an active mediator of renin-angiotensin system, stimulates ANP secretion via Mas receptor.

    Science.gov (United States)

    Yu, Lamei; Yuan, Kuichang; Phuong, Hoang Thi Ai; Park, Byung Mun; Kim, Suhn Hee

    2016-12-01

    Angiotensin-(1-5) [Ang-(1-5)], which is a metabolite of Angiotensin-(1-7) [Ang-(1-7)] catalyzed by angiotensin-converting enzyme (ACE), is a pentapeptide of the renin-angiotensin system (RAS). It has been reported that Ang-(1-7) and Ang-(1-9) stimulate the secretion of atrial natriuretic peptide (ANP) via Mas receptor (Mas R) and Ang II type 2 receptor (AT 2 R), respectively. However, it still remains unknown whether Ang-(1-5) has a similar function to Ang-(1-7). We investigated the effect of Ang-(1-5) on ANP secretion and to define its signaling pathway using isolated perfused beating rat atria. Ang-(1-5) (0.3, 3, 10μM) stimulated high pacing frequency-induced ANP secretion in a dose-dependent manner. Ang-(1-5)-induced ANP secretion (3μM) was attenuated by the pretreatment with an antagonist of Mas R (A-779) but not by an antagonist of AT 1 R (losartan) or AT 2 R (PD123,319). An inhibitor for phosphatidylinositol 3-kinase (PI3K; wortmannin), protein kinase B (Akt; API-2), or nitric oxide synthase (NOS; L-NAME) also attenuated the augmentation of ANP secretion induced by Ang-(1-5). Ang-(1-5)-induced ANP secretion was markedly attenuated in isoproterenol-treated hypertrophied atria. The secretagogue effect of Ang-(1-5) on ANP secretion was similar to those induced by Ang-(1-9) and Ang-(1-7). These results suggest that Ang-(1-5) is an active mediator of renin-angiotensin system to stimulate ANP secretion via Mas R and PI3K-Akt-NOS pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca2+-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy

    NARCIS (Netherlands)

    Flesch, M; Schiffer, F; Zolk, O; Pinto, Y; Stasch, JP; Knorr, A; Ettelbruck, S; Bohm, M

    Background Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure, Objective To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT(1)-RA) is sufficient to prevent the

  11. Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy

    NARCIS (Netherlands)

    Flesch, M.; Schiffer, F.; Zolk, O.; Pinto, Y.; Stasch, J. P.; Knorr, A.; Ettelbrück, S.; Böhm, M.

    1997-01-01

    BACKGROUND: Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure. OBJECTIVE: To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the

  12. Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Prakash C Deedwania

    2006-03-01

    Full Text Available It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP and dyslipidaemia as a method of reducing global cardiovascular risk.Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR trial.Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be an important addition to the management of vulnerable patients at high risk of cardiovascular events.

  13. Predicting Kinase Activity in Angiotensin Receptor Phosphoproteomes Based on Sequence-Motifs and Interactions

    DEFF Research Database (Denmark)

    Bøgebo, Rikke; Horn, Heiko; Olsen, Jesper V

    2014-01-01

    Recent progress in the understanding of seven-transmembrane receptor (7TMR) signalling has promoted the development of a new generation of pathway selective ligands. The angiotensin II type I receptor (AT1aR) is one of the most studied 7TMRs with respect to selective activation of the β-arrestin ......Recent progress in the understanding of seven-transmembrane receptor (7TMR) signalling has promoted the development of a new generation of pathway selective ligands. The angiotensin II type I receptor (AT1aR) is one of the most studied 7TMRs with respect to selective activation of the β...

  14. Reduction of amiodarone pulmonary toxicity in patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

    Science.gov (United States)

    Kosseifi, Semaan G; Halawa, Ahmad; Halawa, Ahmed; Bailey, Beth; Micklewright, Melinda; Roy, Thomas M; Byrd, Ryland P

    2009-12-01

    Amiodarone (AM) is a widely used anti-arrhythmic medication. Its utility is, however, limited by adverse side effects. The mechanism of amiodarone-induced toxicity (APT) in the lungs is attributed primarily to stimulation of the angiotensin enzyme system leading to lung cell apoptosis and cell death. This mechanism has been demonstrated by in vitro and in vivo experimental animal studies. To date, however, no in vivo human studies have confirmed this mechanism for APT. This study was undertaken to determine whether angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) offer a protective effect against APT in humans. Demonstration of a protective effect of an ACE-I or ARB would suggest that stimulation of the angiotensin enzyme system may be a key process in APT. An 8-year retrospective analysis of all patients on AM therapy at the James H. Quillen Veterans Affairs Medical Center was undertaken. A total of 1000 patients on AM were identified. One-hundred-and-seventeen were excluded from the study. Five-hundred-and-twenty-four patients were simultaneously on an ACE-I or ARB. The remaining 359 patients were not. Pulmonary toxicity attributed to AM was identified in five and 14 patients with and without concomitant ACE-I or ARB therapy, respectively. The APT rate for the entire patient sample was 2.2%. APT occurred in 1% of patients on an ACE-I or ARB and in 3.9% of patients not taking an ACE-I or ARB. This observed difference in percentage of APT was statistically significant. The concomitant use of ACE-I or ARB in patients taking AM appears to offer a protective effect against APT. This observation suggests that the stimulation of the angiotensin enzyme system may play an important role in APT in humans.

  15. Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

    Science.gov (United States)

    Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

    2012-01-01

    The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

  16. Effect of angiotensin II type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Ik Soo Byon

    2017-06-01

    Full Text Available AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB and angiotensin converting enzyme inhibitor (ACEI on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS: Forty Sprague-Dawley rats were divided into 4 groups: control, diabetes mellitus (DM, candesartan-treated DM, and enalapril-treated DM (each group, n=10. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/(kg·d] and enalapril [ACEI, 10 mg/(kg·d] were administered to rats orally for 4wk. Vascular endothelial growth factor (VEGF and angiotensin II (Ang II concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor (AT1R levels were assessed at week 4 by Western blotting. RESULTS: Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control (P=0.04 and 0.005, respectively. Vitreous AT1R increased significantly in DM compared to the other three groups (P<0.007. Candesartan-treated DM rats showed higher vitreal AT1R concentration than the enalapril-treated DM group and control (P<0.001 and P=0.005, respectively. No difference in vitreous Ang II and AT1R concentration was found between the enalapril-treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION: Increased Ang II and AT1R in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

  17. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Andersen, S; Tarnow, L; Rossing, P

    2000-01-01

    and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM...... inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy....

  18. Sex-specific influence of angiotensin type 2 receptor stimulation on renal function

    DEFF Research Database (Denmark)

    Hilliard, Lucinda M; Jones, Emma S; Steckelings, Ulrike Muscha

    2012-01-01

    The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT(2)R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore......)R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT(2)R blockade (PD123319; 1 mg/kg per hour). Direct AT(2)R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent...

  19. Angiotensin-converting enzyme inhibitor increases angiotensin type 1A receptor gene expression in aortic smooth muscle cells of spontaneously hypertensive rats.

    Science.gov (United States)

    Negoro, N; Kanayama, Y; Iwai, J; Umetani, N; Nishimura, M; Konishi, Y; Okamura, M; Inoue, T; Takeda, T

    1994-04-12

    To examine the regulation of angiotensin receptors in vascular smooth muscle cells, we studied the effects of antihypertensive drugs on angiotensin type 1A (AT1A) receptor gene expression in aortic smooth muscle cells (ASMCs) from spontaneously hypertensive rats (SHRs) using both ribonuclease protection assay and reverse-transcription polymerase chain reaction. An increase in AT1A receptor gene expression in ASMCs of SHRs was induced by treatment with an angiotensin converting enzyme inhibitor (enalapril) for 2 weeks and 4 weeks, but not by other types of antihypertensive drugs such as alpha-blocker (doxazosin), alpha, beta-blocker (arotinolol), Ca antagonist (nicardipine) or vascular smooth muscle relaxant (hydralazine). Since all antihypertensive drugs lowered the blood pressure of the rats almost equally, our results suggest that AT1A receptor gene expression in ASMCs of SHRs may be regulated by the vascular renin-angiotensin system.

  20. Differential clinical profile of candesartan compared to other angiotensin receptor blockers.

    Science.gov (United States)

    Cernes, Relu; Mashavi, Margarita; Zimlichman, Reuven

    2011-01-01

    The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1]) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8-32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.

  1. Vascular Contraction and Preeclampsia Downregulation of the Angiotensin Receptor 1 by Hemopexin In Vitro

    NARCIS (Netherlands)

    Bakker, Winston W.; Henning, Rob H.; van Son, Willem J.; van Pampus, Maria; Aarnoudse, Jan G.; Niezen-Koning, Klary E.; Borghuis, Theo; Jongman, Rianne M.; van Goor, Harry; Poelstra, Klaas; Navis, Gerjan; Faas, Marijke M.

    During normal pregnancy, in contrast to preeclampsia, plasma hemopexin activity is increased together with a decreased vascular angiotensin II receptor (AT1) expression. We now tested the hypothesis that hemopexin can downregulate the AT1 receptor in vitro. Analysis of human monocytes or endothelial

  2. Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis.

    Science.gov (United States)

    Li, Yonghong; Cai, Shanglang; Wang, Qixin; Zhou, Jingwei; Hou, Bo; Yu, Haichu; Ge, Zhiming; Guan, Renyan; Liu, Xu

    2016-05-15

    The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P Mas receptor mRNA/protein expression but decreased the angiotensin II level, ACE and AT1 receptor mRNA/protein expression, as well as the p-ERK protein expression, compared to the injured group (all P Mas axis as well as inhibition of the ACE-angiotensin II-AT1 and p-ERK pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality.

    Science.gov (United States)

    Pernomian, Larissa; do Prado, Alejandro F; Gomes, Mayara S; Pernomian, Laena; da Silva, Carlos H T P; Gerlach, Raquel F; de Oliveira, Ana M

    2015-10-05

    AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin

  4. Heart Failure Therapeutics on the Basis of a Biased Ligand of the Angiotensin-2 Type 1 Receptor Rationale and Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure)

    NARCIS (Netherlands)

    Felker, G. Michael; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Soergel, David G.; Teerlink, John R.; Violin, Jonathan D.; Voors, Adriaan A.; Pang, Peter S.

    The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and

  5. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels

    2015-01-01

    . Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline. INTERPRETATION: Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other......BACKGROUND: No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which...... are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged...

  6. Differential clinical profile of candesartan compared to other angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    Zimlichman R

    2011-12-01

    Full Text Available Relu Cernes1,2, Margarita Mashavi1,3, Reuven Zimlichman1,31The Brunner Institute for Cardiovascular Research, Wolfson Medical Center and Tel Aviv University, Tel Aviv, Israel; 2Department of Nephrology, Wolfson Medical Center, Holon, Israel; 3Department of Medicine, Wolfson Medical Center, Holon, IsraelAbstract: The advantages of blood pressure (BP control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1] receptor antagonist (angiotensin receptor blocker [ARB] that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.Keywords: angiotensin receptor blockers, candesartan, candesartan cilexetil, clinical trials, efficacy studies, safety, blood pressure

  7. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S; van Geel, PP; Willenbrock, R; Pagel, [No Value; Pinto, YM; Buikema, H; van Gilst, WH; Lindschau, C; Paul, M; Inagami, T; Ganten, D; Urata, H

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT(1) receptors. However, the role of myocardial AT(1) receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  8. Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

    Indian Academy of Sciences (India)

    Analysis of genetic and biochemical data revealed that in this population the CT and TT genotypes of aldosterone synthase C-344T polymorphism, frequency of alcohol consumption and aldosterone levels were significantly high among the total as well as male hypertensives, while the AC and CC genotypes of angiotensin ...

  9. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure.

    Science.gov (United States)

    Li, Huiping; Weatherford, Eric T; Davis, Deborah R; Keen, Henry L; Grobe, Justin L; Daugherty, Alan; Cassis, Lisa A; Allen, Andrew M; Sigmund, Curt D

    2011-10-01

    All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to generate mice with either overexpression of a constitutively active angiotensin type 1A receptor transgene or depletion of endogenous angiotensin type 1A receptors. Androgen administration to female transgenic mice caused a robust induction of the transgene in the kidney and increased baseline blood pressure. In the receptor-depleted mice, androgen administration to females resulted in a Cre recombinase-mediated deletion of angiotensin type 1A receptors in the proximal tubule and reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of ANG II in either experimental model. These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions.

  10. Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders

    DEFF Research Database (Denmark)

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R......) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even...... in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production...

  11. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

    NARCIS (Netherlands)

    Lambers Heerspink, Hiddo J.; Holtkamp, Frank A.; Parving, Hans-Henrik; Navis, Gerjan J.; Lewis, Julia B.; Ritz, Eberhard; de Graeff, Pieter A.; de Zeeuw, Dick

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of

  12. Erratum Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

    Indian Academy of Sciences (India)

    Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. Manisha Patnaik, Pallabi Pati, Surendra N. Swain, Manoj K. Mohapatra, Bhagirathi Dwibedi, Shantanu K. Kar.

  13. Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

    DEFF Research Database (Denmark)

    Steckelings, U Muscha; Kloet, Annette de; Sumners, Colin

    2017-01-01

    Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent...

  14. Uptake of angiotensin II receptor blockers in the treatment of hypertension

    NARCIS (Netherlands)

    Greving, JP; Denig, P; van der Veen, WJ; Beltman, FW; Sturkenboom, MCJM; de Zeeuw, D; Haaijer-Ruskamp, FM

    Objective: To examine trends in prescribing of angiotensin II receptor blockers (ARBs) as initial and second-line treatment of hypertension. Methods: We performed a cohort study in the Integrated Primary Care Information database, a general practice research database in The Netherlands. We included

  15. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

    DEFF Research Database (Denmark)

    Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik

    2012-01-01

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of...

  16. Functional antagonism of different angiotensin II type I receptor blockers in human arteries

    NARCIS (Netherlands)

    Voors, AA; Buikema, H; van Buiten, A; Lubeck, RH; Boonstra, PW; van Veldhuisen, DJ; van Gilst, WH

    Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type I receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary

  17. Pre- and postsynaptic inhibitory potencies of the angiotensin AT(1) receptor antagonists eprosartan and candesartan

    NARCIS (Netherlands)

    Nap, Alexander; Mathy, Marie-Jeanne; Balt, Jippe C.; Pfaffendorf, Martin; van Zwieten, Pieter A.

    2003-01-01

    The aim of the present study was to determine the inhibitory potency of two selective angiotensin AT, receptor antagonists, eprosartan and candesartan, at the level of the sympathetic nerve terminal and the vascular smooth muscle. Male New Zealand White rabbits, weighing 2100-2550 g, were used. To

  18. Role of angiotensin receptor blockers in patients with left ventricular dysfunction : lessons from CHARM and VALIANT

    NARCIS (Netherlands)

    Voors, AA; van Veldhuisen, DJ

    2004-01-01

    The role of angiotensin receptor blockers (ARBs) in patients with left ventricular dysfunction has changed after the VALIANT and CHARM trials. CHARM proved that candesartan is a good alternative for patients with chronic heart failure who cannot tolerate ACE-inhibitors. Moreover, VALIANT

  19. The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

    DEFF Research Database (Denmark)

    Joseph, Jason P; Mecca, Adam P; Regenhardt, Robert W

    2014-01-01

    Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we...

  20. How does angiotensin AT2 receptor activation help neuronal differentiation and improve neuronal pathological situations?

    Science.gov (United States)

    Guimond, Marie-Odile; Gallo-Payet, Nicole

    2012-01-01

    The angiotensin type 2 (AT2) receptor of angiotensin II has long been thought to be limited to few tissues, with the primary effect of counteracting the angiotensin type 1 (AT1) receptor. Functional studies in neuronal cells have demonstrated AT2 receptor capability to modulate neuronal excitability, neurite elongation, and neuronal migration, suggesting that it may be an important regulator of brain functions. The observation that the AT2 receptor was expressed in brain areas implicated in learning and memory led to the hypothesis that it may also be implicated in cognitive functions. However, linking signaling pathways to physiological effects has always proven challenging since information relative to its physiological functions has mainly emerged from indirect observations, either from the blockade of the AT1 receptor or through the use of transgenic animals. From a mechanistic standpoint, the main intracellular pathways linked to AT2 receptor stimulation include modulation of phosphorylation by activation of kinases and phosphatases or the production of nitric oxide and cGMP, some of which are associated with the Gi-coupling protein. The receptor can also interact with other receptors, either G protein-coupled such as bradykinin, or growth factor receptors such as nerve growth factor or platelet-derived growth factor receptors. More recently, new advances have also led to identification of various partner proteins, thus providing new insights into this receptor’s mechanism of action. This review summarizes the recent advances regarding the signaling pathways induced by the AT2 receptor in neuronal cells, and discussed the potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2 receptor activation by non-peptide and selective agonists could represent new pharmacological tools that may help to improve impaired cognitive performance in Alzheimer’s disease and other

  1. Renal medullary (pro)renin receptor contributes to angiotensin II-induced hypertension in rats via activation of the local renin-angiotensin system.

    Science.gov (United States)

    Wang, Fei; Lu, Xiaohan; Liu, Mi; Feng, Yumei; Zhou, Shu-Feng; Yang, Tianxin

    2015-11-10

    (Pro)renin receptor (PRR) is a new component of the renin-angiotensin system and regulates renin activity in vitro. Within the kidney, PRR is highly expressed in the renal medulla where its expression is induced by angiotensin II infusion. The objective of the present study was to test a potential role of renal medullary PRR during angiotensin II-induced hypertension. A rat AngII infusion model (100 ng/kg/min) combined with renal intramedullary infusion of PRO20, a specific inhibitor of PRR, was builded. And the intravenous PRO20 infusion serve as control. Mean arterial pressure was recorded by radiotelemetry for one week. Further analysis of kidney injury, inflammation, biochemical indices and protein localization were performed in vivo or in vitro. Radiotelemetry demonstrated that AngII infusion elevated the mean arteria pressure from 108 ± 5.8 to 164.7 ± 6.2 mmHg. Mean arterial pressure decreased to 128.6 ± 5.8 mmHg (P renin activity following angiotensin II infusion were all remarkably attenuated by intramedullary PRO20 infusion. Following one week of angiotensin II infusion, increased PRR immunoreactivity was found in vascular smooth muscle cells. In cultured rat vascular smooth muscle cells, angiotensin II induced parallel increases in soluble PRR and renin activity, and the latter was significantly reduced by PRO20. Renal medullary PRR mediates angiotensin II-induced hypertension, likely by amplifying the local renin response.

  2. Vascular Contraction and Preeclampsia Downregulation of the Angiotensin Receptor 1 by Hemopexin In Vitro

    OpenAIRE

    Bakker, Winston W.; Henning, Rob H.; Willem J van Son; Pampus, Maria; Aarnoudse, Jan G; Niezen-Koning, Klary E; Borghuis, Theo; Jongman, Rianne M.; van Goor, Harry; Poelstra, Klaas; Navis, Gerjan; Faas, Marijke M.

    2009-01-01

    During normal pregnancy, in contrast to preeclampsia, plasma hemopexin activity is increased together with a decreased vascular angiotensin II receptor (AT1) expression. We now tested the hypothesis that hemopexin can downregulate the AT1 receptor in vitro. Analysis of human monocytes or endothelial cells by flow cytometry showed decreased membrane density of AT1 exclusively after incubation with active hemopexin, whereas in supernatants of these cell cultures, AT1 molecules could be detected...

  3. Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors.

    Science.gov (United States)

    Linares, Andrea; Couling, Leena E; Carrera, Eduardo J; Speth, Robert C

    2016-06-07

    This protocol describes receptor binding patterns for Angiotensin II (Ang II) in the rat brain using a radioligand specific for Ang II receptors to perform receptor autoradiographic mapping. Tissue specimens are harvested and stored at -80 °C. A cryostat is used to coronally section the tissue (brain) and thaw-mount the sections onto charged slides. The slide-mounted tissue sections are incubated in (125)I-SI-Ang II to radiolabel Ang II receptors. Adjacent slides are separated into two sets: 'non-specific binding' (NSP) in the presence of a receptor saturating concentration of non-radiolabeled Ang II, or an AT1 Ang II receptor subtype (AT1R) selective Ang II receptor antagonist, and 'total binding' with no AT1R antagonist. A saturating concentration of AT2 Ang II receptor subtype (AT2R) antagonist (PD123319, 10 µM) is also present in the incubation buffer to limit (125)I-SI-Ang II binding to the AT1R subtype. During a 30 min pre-incubation at ~22 °C, NSP slides are exposed to 10 µM PD123319 and losartan, while 'total binding' slides are exposed to 10 µM PD123319. Slides are then incubated with (125)I-SI-Ang II in the presence of PD123319 for 'total binding', and PD123319 and losartan for NSP in assay buffer, followed by several 'washes' in buffer, and water to remove salt and non-specifically bound radioligand. The slides are dried using blow-dryers, then exposed to autoradiography film using a specialized film and cassette. The film is developed and the images are scanned into a computer for visual and quantitative densitometry using a proprietary imaging system and a spreadsheet. An additional set of slides are thionin-stained for histological comparisons. The advantage of using receptor autoradiography is the ability to visualize Ang II receptors in situ, within a section of a tissue specimen, and anatomically identify the region of the tissue by comparing it to an adjacent histological reference section.

  4. Binding of Losartan to Angiotensin AT1 Receptors Increases Dopamine D1 Receptor Activation

    Science.gov (United States)

    Li, Dong; Scott, Lena; Crambert, Susanne; Zelenin, Sergey; Eklöf, Ann-Christine; Di Ciano, Luis; Ibarra, Fernando

    2012-01-01

    Signaling through both angiotensin AT1 receptors (AT1R) and dopamine D1 receptors (D1R) modulates renal sodium excretion and arterial BP. AT1R and D1R form heterodimers, but whether treatment with AT1R antagonists functionally modifies D1R via allosterism is unknown. In this study, the AT1R antagonist losartan strengthened the interaction between AT1R and D1R and increased expression of D1R on the plasma membrane in vitro. In rat proximal tubule cells that express endogenous AT1R and D1R, losartan increased cAMP generation. Losartan increased cAMP in HEK 293a cells transfected with both AT1R and D1R, but it did not increase cAMP in cells transfected with either receptor alone, suggesting that losartan induces D1R activation. Furthermore, losartan did not increase cAMP in HEK 293a cells expressing AT1R and mutant S397/S398A D1R, which disrupts the physical interaction between AT1R and D1R. In vivo, administration of a D1R antagonist significantly attenuated the antihypertensive effect of losartan in rats with renal hypertension. Taken together, these data imply that losartan might exert its antihypertensive effect both by inhibiting AT1R signaling and by enhancing D1R signaling. PMID:22193384

  5. Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells.

    Science.gov (United States)

    Amaya, Koji; Ohta, Tetsuo; Kitagawa, Hirohisa; Kayahara, Masato; Takamura, Hiroyuki; Fujimura, Takashi; Nishimura, Gen-Ichi; Shimizu, Koichi; Miwa, Koichi

    2004-10-01

    Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.

  6. Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

    DEFF Research Database (Denmark)

    Oprisiu-Fournier, Roxana; Faure, Sébastien; Mazouz, Hakim

    2009-01-01

    First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data...... AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary...

  7. Bradykinin antagonist counteracts the acute effect of both angiotensin-converting enzyme inhibition and of angiotensin receptor blockade on the lower limit of autoregulation of cerebral blood flow

    DEFF Research Database (Denmark)

    Sigurdsson, Sigurdur T; Paulson, Olaf B; Høj Nielsen, Arne

    2014-01-01

    The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague......-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination...

  8. beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations

    DEFF Research Database (Denmark)

    Sanni, S J; Hansen, J T; Bonde, M M

    2010-01-01

    The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often i...

  9. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

    Directory of Open Access Journals (Sweden)

    Podda Mauro

    2010-05-01

    Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

  10. Angiotensin AT1 receptors modulate the anxiogenic effects of angiotensin (5-8) injected into the rat ventrolateral periaqueductal gray.

    Science.gov (United States)

    Genaro, Karina; Fabris, Débora; Fachim, Helene A; Prado, Wiliam A

    2017-10-01

    Losartan and PD 123,319 are non-peptide angiotensin (Ang) receptor antagonists for the AT1 and AT2 subtypes of Ang II receptors, respectively. The tetrapeptide Ang (5-8) is the smallest Ang-peptide that elicits anxiogenic effects on unconditioned and conditioned experimental models upon injection into the ventrolateral column of the periaqueductal gray (vlPAG), and Ang (5-8) can be synthesized (from Ang II or Ang III) and inactivated in this mesencephalic structure. The vlPAG is also known to play a central role in mechanisms of fear and anxiety. We therefore utilized male Wistar rats to examine the effects of losartan and PD 123,319 injections, selective antagonists of the AT1 and AT2 receptors, respectively, into the vlPAG in the elevated plus-maze, a classic rat model of anxiety, and against the anxiogenic effect of Ang (5-8) (0.4 nmol/0.25μL) upon injection into the same region. The anxiolytic profile was dependent on the dose of intra-vlPAG losartan, whereas no effects on experimental anxiety were observed in the plus-maze following PD 123,319 injection. The anxiogenic effect of Ang (5-8) injection into the vlPAG remained unchanged in the PD 123,319-pretreated rats, but the effect did not occur in losartan-pretreated rats. The results led us to suggest that the anxiogenic effect of Ang (5-8) injection into the vlPAG may depend on the local activation of AT1, but not AT2 receptors. Activation of AT1 receptors in structures nearby vlPAG may be tonically involved in fear and experimental anxiety. Copyright © 2017. Published by Elsevier Inc.

  11. The effect of serum angiotensin II and angiotensin II type 1 receptor ...

    African Journals Online (AJOL)

    Objective: To measure serum Ang II and the frequency of AT1 receptor CC genotype among a group of Egyptian patients with pediatric onset lupus nephritis (pLN). Methods: This is a case-control cross sectional study which included 24 patients with pLN and 24 age and sex-matched healthy subjects as controls. Clinical ...

  12. Prospects for angiotensin receptor blockers in diabetic retinopathy

    DEFF Research Database (Denmark)

    Sjølie, Anne Katrin

    2007-01-01

    Retinopathy is the most common microvascular complication of diabetes mellitus, and is an important cause of blindness worldwide. Clinical trials have demonstrated that tight metabolic control inhibits the progression of retinopathy. Good blood pressure control has been shown to be protective...... in type 2 diabetes, and it may also reduce proliferative retinopathy in type 1 diabetes. However, such control is often difficult to achieve in clinical practice, and may be associated with problems such as hypoglycaemia. New therapies are therefore needed to reduce the risk of retinopathy....... There is growing evidence that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of diabetic retinopathy, and this has led to interest in RAS inhibitors as agents to prevent retinopathy. Several trials have suggested that ACE inhibitor therapy can inhibit progression of retinopathy...

  13. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced dementia risk in patients with diabetes mellitus and hypertension.

    Science.gov (United States)

    Kuan, Yi-Chun; Huang, Kuang-Wei; Yen, Der-Jen; Hu, Chaur-Jong; Lin, Cheng-Li; Kao, Chia-Hung

    2016-10-01

    The effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) on dementia risk in patients with type 2 diabetes mellitus (DM) and hypertension remain unknown. We investigated the effects of ACEIs and ARBs on dementia risk in patients with type 2 DM and hypertension. We conducted a cohort study by using the Taiwan National Health Insurance Research Database. We included 2377 patients receiving ACEIs and 1780 patients receiving ARBs in the ACEI and ARB cohorts, respectively. We included a comparable number of patients not receiving ACEIs and ARBs as controls in the non-ACEI and non-ARB cohorts through propensity score matching. The effect of ACEIs and ARBs on dementia risk was estimated through multivariate Cox proportional hazard regression after adjustment for several confounding factors. During the 12-year follow-up period, compared with the non-ACEI cohort, all-cause dementia risk decreased by 26% in the ACEI cohort [hazard ratio (HR)=0.74, 95% confidence interval (CI)=0.56-0.96]. The all-cause dementia risk was nearly 40% lower in the ARB cohort than in the non-ARB cohort (HR=0.60, 95% CI=0.37-0.97). These drugs prevented the occurrence of vascular dementia (VD), however, this effect was nonsignificant for Alzheimer's dementia (AD). Treatment duration- and dosage-related protection effects on dementia occurrence were observed. ACEIs and ARBs may effectively prevent all-cause dementia, particularly VD, in patients with type 2 DM and hypertension. Moreover, compared with ACEIs, ARBs appear to be more advantageous in dementia prevention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Evaluation of the effect of angiotensin converting enzyme inhibitors and angiotensin receptors blockers on aspirin antiplatelet effect.

    Science.gov (United States)

    Al-Azzam, Sayer I; Alzoubi, Karem H; Khabour, Omar F; Quttina, Maram; Zayadeen, Raya

    2016-02-01

    Cardiovascular disease (CVD) is one of the major burdens on societies and healthcare systems. Antiplatelet aspirin is used to prevent the occurrence or reoccurrence of cardiovascular events. However, studies have shown that a good portion of patients still suffer from cardiovascular events in spite of using aspirin (also called aspirin nonresponders). On the other hand, angiotensin-converting enzyme inhibitors (ACEIs) as well as angiotensin-receptor blockers (ARBs) are widely used in patients with different spectrums of cardiovascular diseases. In this study, the possible interactive effect of ACEIs and ARBs on aspirin response was evaluated in vitro. A multiplate analyzer was used to assay the possible interactions between ACEIs and ARBs drugs on antiplatelet effect of aspirin using blood obtained from 6 healthy volunteers. Means of area under the aggregation curves (AUCs) of the blood samples treated with 10 μg/mL aspirin were calculated before and after exposure to captopril, lisinopril, candesartan, or losartan. Results showed potential antithrombotic effect of ACEIs and ARBs only at high concentrations (3.3 μg/mL).The antiplatelet effect of aspirin 10 μg/mL was significantly enhanced by the addition of captopril or lisinopril at high dose (3.3 μg/mL), candesartan at all tested doses (0.03 μg/mL, 0.33 μg/mL, 3.3 μg/mL), and losartan at doses of 0.33 μg/mL and 3.3 μg/m. Treatment with ACEIs (captopril and lisinopril) and ARBs (candesartan and losartan) improved the antiplatelet response to aspirin. Further studies are needed to confirm this action and potentially apply it to clinical practice.

  15. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Wiesmann, Maximilian; Roelofs, Monica; van der Lugt, Robert; Heerschap, Arend; Kiliaan, Amanda J; Claassen, Jurgen Ahr

    2017-07-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.

  16. Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries

    NARCIS (Netherlands)

    van Geel, P. P.; Pinto, Y. M.; Voors, A. A.; Buikema, H.; Oosterga, M.; Crijns, H. J.; van Gilst, W. H.

    2000-01-01

    An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT(1)R) gene is associated with the incidence of essential hypertension and increased coronary artery vasoconstriction. However, it is still unknown whether this polymorphism is associated with a

  17. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

    2015-01-01

    of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high...... densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

  18. Altered genes profile of renin-angiotensin system, immune system, and adipokines receptors in leukocytes of children with primary hypertension.

    Science.gov (United States)

    Litwin, Mieczysław; Michałkiewicz, Jacek; Trojanek, Joanna; Niemirska, Anna; Wierzbicka, Aldona; Szalecki, Mieczysław

    2013-02-01

    Renin-angiotensin system, metabolic abnormalities, and immune activity have a role in the pathogenesis of primary hypertension. We assessed the leukocyte mRNA expression of angiotensinogen, angiotensin converting enzyme, renin, angiotensin 2 type 1 receptor, CD14 molecule, adiponectin type 1 receptor, and leptin receptor in hypertensive children before and after nonpharmacological treatment. Leukocyte mRNA expression was measured by means of quantitative real-time reverse transcriptase-polymerase chain reaction in 23 hypertensive children before and after 6 months of nonpharmacological treatment based on dietary advice and physical activities. Twenty-three normotensive children matched for age, sex, and body mass index served as a control group. Before treatment patients had elevated expression of angiotensin converting enzyme and CD14 mRNA, decreased expression of angiotensinogen and angiotensin type 1 receptor mRNA, and unchanged expression of renin, adiponectin, and leptin receptors mRNA as compared with controls. Renin mRNA negatively correlated with 24-hour mean arterial pressure and carotid intima-media thickness. Six months of nonpharmacological treatment caused decrease of blood pressure and normalization of metabolic abnormalities. Renin, adiponectin, and leptin receptors mRNA expression decreased and were lower than in control group. Changes in blood pressure, left ventricular mass, carotid intima-media thickness, body mass index, and waist circumference did not correlate with changes in the expression of renin-angiotensin system genes, CD14, leptin, and adiponectin receptors mRNA. We conclude that leukocytes of hypertensive children displayed alterations in the expression of renin-angiotensin system genes as well as those of CD14. Nonpharmacological treatment resulted in downregulation of genes involved in renin-angiotensin activation and those engaged in leukocyte responses to adipokines.

  19. The expression of Mas-receptor of the renin-angiotensin system in the human eye.

    Science.gov (United States)

    Vaajanen, A; Kalesnykas, G; Vapaatalo, H; Uusitalo, H

    2015-07-01

    The local renin-angiotensin system has been held to be expressed in many organs, including the eye. It has an important role in the regulation of local fluid homeostasis, cell proliferation, fibrosis, and vascular tone. Mas-receptor (Mas-R) is a potential receptor acting mainly opposite to the well-known angiotensin II receptor type 1. The aim of this study was to determine if Mas-R is expressed in the human eye. Seven enucleated human eyes were used in immunohistochemical detection of Mas-R and its endogenous ligand angiotensin (1-7) [Ang(1-7)]. Both light microscopy and immunofluorescent detection methods were used. A human kidney preparation sample was used as control. The Mas-R was found to have nuclear localization, and localized in the retinal nuclear layers and in the structures of the anterior segment of the eye. A cytoplasmic immunostaining pattern of Ang(1-7) was found in the inner and outer nuclear and plexiform layers of the retina and in the ciliary body. To the best of our knowledge, this is the first report showing Mas-R expression in the human eye. Its localization suggests that it may have a role in physiological and pathological processes in the anterior part of the eye and in the retina.

  20. Functional interactions between 7TM receptors in the renin-angiotensin system--dimerization or crosstalk?

    DEFF Research Database (Denmark)

    Lyngsø, Christina; Erikstrup, Niels; Hansen, Jakob L

    2008-01-01

    be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very......The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure...

  1. New basic science initiatives with the angiotensin II receptor blocker valsartan

    Directory of Open Access Journals (Sweden)

    Marc de Gasparo

    2000-06-01

    Full Text Available Summary Angiotensin II (Ang II plays a key role in the regulation of blood pressure and fluid homeostasis. Valsartan is a highly selective Ang II receptor blocker that specifically and selectively blocks Ang II at the AT1-receptor. In animal models, valsartan has shown positive effects on vasoconstriction, proliferation, remodelling, endothelial function and thrombogenesis, inflammation and atherosclerosis. These data are likely to be confirmed by the results of current clinical trials and valsartan is set to provide improved cardiovascular therapy in the future.

  2. Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Hansen, Jakob Lerche

    2008-01-01

    such as aldosterone secretion, vasoconstriction, and detrimental cardiac hypertrophy are known to result from G protein-dependent or -independent signal transduction, whereas mechanisms have been connected with more adaptive cardiac cell survival, migration, and regeneration phenotypes. Selective blockade of G......The angiotensin II type 1 (AT(1)) receptor plays a key role in cardiovascular pathophysiology, and it is a major pharmacologic target in the treatment of many cardiovascular disorders. However, AT(1) receptor activation is also involved in adaptive responses to altered hemodynamic demands...

  3. Nrf2 Deficiency Upregulates Intrarenal Angiotensin-converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.

    Science.gov (United States)

    Zhao, Shuiling; Ghosh, Anindya; Lo, Chao-Sheng; Chenier, Isabelle; Scholey, James W; Filep, Janos G; Ingelfinger, Julie R; Zhang, Shao-Ling; Chan, John S D

    2017-12-01

    We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout (KO) mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined immortalized rat RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2) or angiotensin 1-7 receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 attenuated hypertension, renal injury, and tubulointerstitial fibrosis, and lowered the urinary albumin/creatinine ratio as well as upregulated RPTC Ace2 and MasR expression, increased urinary angiotensin 1-7 levels parallel with down-regulation of Agt, ACE and pro-fibrotic gene expression compared to non-treated Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose-stimulation of Nrf2 nuclear translocation, Agt and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes. Copyright © 2017 Endocrine Society.

  4. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  5. The Prorenin and (Prorenin Receptor: New Players in the Brain Renin-Angiotensin System?

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2012-01-01

    Full Text Available It is well known that the brain renin-angiotensin (RAS system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (prorenin receptor (PRR, a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases.

  6. AVE 0991-angiotensin-(1-7) receptor agonist, inhibits atherogenesis in apoE-knockout mice.

    Science.gov (United States)

    Toton-Zuranska, J; Gajda, M; Pyka-Fosciak, G; Kus, K; Pawlowska, M; Niepsuj, A; Wolkow, P; Olszanecki, R; Jawien, J; Korbut, R

    2010-04-01

    Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.

  7. A combined role of calcium channel blockers and angiotensin receptor blockers in stroke prevention

    Directory of Open Access Journals (Sweden)

    Ji-Guang Wang

    2009-07-01

    Full Text Available Ji-Guang WangCentre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaAbstract: Stroke is a leading cause of death and disability worldwide. The importance of lowering blood pressure for reducing the risk of stroke is well established. However, not all the benefits of antihypertensive treatments in stroke can be accounted for by reductions in BP and there may be differences between antihypertensive classes as to which provides optimal protection. Dihydropyridine calcium channel blockers, such as amlodipine, and angiotensin receptor blockers, such as valsartan, represent the two antihypertensive drug classes with the strongest supportive data for the prevention of stroke. Therefore, when combination therapy is required, a combination of these two antihypertensive classes represents a logical approach.Keywords: stroke, angiotensin, calcium channel, cerebrovascular, hypertension, blood pressure

  8. Caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion.

    Science.gov (United States)

    Oh, Young-Bin; Gao, Shan; Lim, Jung Min; Kim, Hyung Tae; Park, Byung-Hyun; Kim, Suhn Hee

    2011-07-01

    Caveolae may act as mechanosensors and function as binding sites for calcium ions. The intracaveolar localization of atrial natriuretic peptide (ANP) derived from the direct interaction of atrial granules with caveolae has been demonstrated. The aim of this study was to define the effect of caveolae on ANP secretion induced by stretch and angiotensin II. The isolated perfused beating atria from Sprague-Dawley rats were used. To disrupt caveolae, 10mM methyl-β-cyclodextrin (MbCD) was applied for 1h and the number of caveoli were markedly decreased. MbCD increased basal ANP secretion and atrial diastolic pressure. The molecular profile of ANP in perfusate from control atria showed mainly one major peak corresponded to synthetic ANP whereas that from MbCD-treated atria showed two major immunoreactive peaks corresponded to synthetic rat ANP and proANP. High atrial stretch induced by elevating the height of outflow catheter from 5 cm H₂O to 7.5 cm H₂O increased atrial contractility and ANP secretion. The response of ANP secretion to high stretch was attenuated in MbCD-pretreated atria. Pretreatment with MbCD abolished angiotensin II-induced suppression and losartan-induced stimulation of ANP secretion. However, the effect of angiotenisin (1-7) on ANP secretion was not altered by MbCD treatment. The expression of angiotensin II type 1 receptor protein was reduced by MbCD treatment. These data suggest that caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion and relate to the processing of proANP. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats.

    Science.gov (United States)

    Chinnathambi, Vijayakumar; More, Amar S; Hankins, Gary D; Yallampalli, Chandra; Sathishkumar, Kunju

    2014-07-01

    Pre-eclampsia is a life-threatening pregnancy disorder whose pathogenesis remains unclear. Plasma testosterone levels are elevated in pregnant women with pre-eclampsia and polycystic ovary syndrome, who often develop gestational hypertension. We tested the hypothesis that increased gestational testosterone levels induce hypertension via heightened angiotensin II signaling. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate from Gestational Day 15 to 19 to induce a 2-fold increase in plasma testosterone levels, similar to levels observed in clinical conditions like pre-eclampsia. A subset of rats in these two groups was given losartan, an angiotensin II type 1 receptor antagonist by gavage during the course of testosterone exposure. Blood pressure levels were assessed through a carotid arterial catheter and endothelium-independent vascular reactivity through wire myography. Angiotensin II levels in plasma and angiotensin II type 1 receptor expression in mesenteric arteries were also examined. Blood pressure levels were significantly higher on Gestational Day 20 in testosterone-treated dams than in controls. Treatment with losartan during the course of testosterone exposure significantly attenuated testosterone-induced hypertension. Plasma angiotensin II levels were not significantly different between control and testosterone-treated rats; however, elevated testosterone levels significantly increased angiotensin II type 1 receptor protein levels in the mesenteric arteries. In testosterone-treated rats, mesenteric artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K(+) depolarization and phenylephrine were unaffected. The results demonstrate that elevated testosterone during gestation induces hypertension in pregnant rats via heightened angiotensin II type 1 receptor-mediated signaling, providing a molecular mechanism linking elevated maternal testosterone levels with gestational

  10. Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPARγ Activation

    DEFF Research Database (Denmark)

    Ohshima, Kousei; Mogi, Masaki; Jing, Fei

    2012-01-01

    The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type...

  11. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    J. Deinum (Jacob); J.M. van Gool (Jeanette); M.J.M. Kofflard (Marcel); A.H.J. Danser (Jan); F.J. ten Cate (Folkert)

    2001-01-01

    textabstractThe development of left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. Angiotensin II mediates both trophic and antitrophic effects, via angiotensin II type 1

  12. Local renin-angiotensin system regulates the differentiation of mesenchymal stem cells into insulin-producing cells through angiotensin type 2 receptor.

    Science.gov (United States)

    Sadik, Nermin Abdel-Hamid; Metwally, Nadia Said; Shaker, Olfat Gamil; Soliman, Mahmoud Sanad; Mohamed, Ahmed Abdelaziz; Abdelmoaty, Mai Mohamed

    2017-06-01

    Differentiation of stem cells into insulin-producing cells (IPCs) suitable for therapeutic transplantation offers a desperately needed approach for the diabetic patients. Elucidation of the molecular mechanisms during the differentiation of mesenchymal stem cells (MSCs) into IPCs assists the successful production of IPCs and provides an important insight into the improvement of the role of MSCs as a therapeutic tool for diabetes mellitus (DM). The present study aimed to investigate the role of local renin-angiotensin system (RAS) on MSCs differentiation into IPCs by measuring the expression of local RAS in MSCs during the differentiation into IPCs and assessing the effect of angiotensin type 1 receptor (AT1R) blocker and angiotensin type 2 receptor (AT2R) blocker on the differentiation process. Our data showed that the differentiation of MSCs into IPCs was associated with an increase in cellular angiotensinogen, angiotensin-converting enzyme (ACE), renin, and AT2R expression and undetectable expression of AT1R. The net effect was an increase in cellular angiotensin II (Ang II) during the differentiation process. AT1R blockade allowed the differentiation of MSCs into IPCs, whereas AT2R blockade alone and blockade of both AT1R and AT2R inhibited the differentiation of MSCs into IPCs. Our data demonstrated an important role of local RAS in the regulation of MSCs differentiation into IPCs and that Ang II mainly orchestrates this role through AT2R activation. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  13. ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS: IS THERE A REASON TO CONSIDER AN EQUIVALENCE OF TWO DRUG CLASSES FROM THE EVIDENCE BASED MEDICINE STANDPOINT

    Directory of Open Access Journals (Sweden)

    S. Yu. Martsevich

    2013-01-01

    Full Text Available The results of the main large controlled trials that had proven effect of ACE inhibitors (ACEi and angiotensin receptor blockers (ARB on cardiovascular diseases outcomes are evaluated. Data of the recent meta-analyzes comparing ACEi and ARB effects on the life prognosis in patients of the high cardiovascular risk are presented. Better validity of ACEi efficacy versus this of ARB is concluded.

  14. Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney

    Energy Technology Data Exchange (ETDEWEB)

    Zober, Tamas G. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Semmelweis University, Department of Pathophysiology, Budapest (Hungary); Fabucci, Maria E.; Zheng, Wei; Sandberg, Kathryn [Georgetown University, Department of Medicine, Washington, DC (United States); Brown, Phillip R.; Seckin, Esen; Mathews, William B. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Szabo, Zsolt [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Johns Hopkins Outpatient Center, Division of Nuclear Medicine, Baltimore, MD (United States)

    2008-06-15

    PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT{sub 1}R) in vivo. The goal of the present study was to investigate the effects of acute and chronic exposure to angiotensin converting enzyme inhibitors (ACEI) on the AT{sub 1}R in the dog kidney. Animals were imaged at baseline, after acute intravenous ACEI treatment and after a chronic 2-week exposure to an oral ACEI. Control animals were imaged at identical time points in the absence of ACEI treatment. In vivo AT{sub 1}R binding expressed by K{sub i} was increased in the renal cortex by chronic ACEI treatment (p < 0.05). In vitro measurements of AT{sub 1}R density (B{sub max}) also revealed significant increases in AT{sub 1}R in isolated glomeruli (p < 0.05). Plasma renin activity was increased, but angiotensin II (Ang II) and the Ang II/Ang I ratio showed a weak correlation with chronic ACEI treatment, consistent with an Ang II escape phenomenon. This study reveals, for the first time, that chronic ACEI treatment increases AT{sub 1}R binding in vivo in the dog renal cortex. (orig.)

  15. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    Science.gov (United States)

    2012-01-01

    Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005), we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088) and in ARBs after price adjustments in 2001 (173.4%, p price adjustment (−156.9%, p drugs showed long-term trend increases after price adjustments in 2001 (72.2%, p Price adjustments did not achieve long-term cost

  16. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    Directory of Open Access Journals (Sweden)

    Huang Shiou-Huei

    2012-05-01

    Full Text Available Abstract Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs] to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005, we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088 and in ARBs after price adjustments in 2001 (173.4%, p  Conclusions Price adjustments did not achieve long-term cost savings for overall renin-angiotensin drugs. Possible switching from ACEIs to ARBs

  17. Biased signaling of the angiotensin II type 1 receptor can be mediated through distinct mechanisms

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Hansen, Jonas Tind; Sanni, Samra Joke

    2010-01-01

    receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R). It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of β-arrestins without activation of G proteins. However, the underlying...... molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit β-arrestins. Since uncoupling of G proteins by increased ability...... to recruit β-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms....

  18. Differential involvement of hippocampal angiotensin 1 receptors in learning and memory processes in bulbectomized rats

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    Tashev E. Roman

    2016-04-01

    Full Text Available There is conflicting evidence regarding the effect of AT1 receptor antagonists on learning and memory processes. The effects of angiotensin II and losartan administration into CA1 hippocampal area on the avoidance performance in olfactory bulbectomized (OBX rats using active avoidance (shuttle box test and passive avoidance (step through test were investigated. Rats were microinjected unilaterally through implanted guide cannulas into the CA1 area of the dorsal hippocampus and the drugs were administered separately, 5 minutes before each training session. The microinjections of losartan into the left, but not the right CA1 hippocampal area improved the acquisition and retention of active and passive avoidance learning, thus suggesting dependence on the side of injection. The unilateral (left or right administration of angiotensin II did not significantly affect the performance of OBX rats in the avoidance tasks. A differential distribution of the AT1 receptors in the left and right hemisphere could contribute for the asymmetry in the behavioral effects of the AT receptor antagonist.

  19. Randomised trial on episodic cluster headache with an angiotensin II receptor blocker

    DEFF Research Database (Denmark)

    Tronvik, Erling; Wienecke, Troels; Monstad, Inge

    2013-01-01

    OBJECTIVES: The aim of this study was to evaluate the angiotensin II receptor antagonist candesartan as prophylactic medication in patients with episodic cluster headache. METHODS: This study comprised a prospective, placebo-controlled, double-blind, parallel-designed trial performed in seven...... the candesartan and placebo group was not significant with the pre-planned non-parametric ranking test, but a post-hoc exact Poisson test, which takes into account the temporal properties of the data, revealed a significant result ( P  ...

  20. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Murray, Gordon; Boysen, Gudrun

    2010-01-01

    BACKGROUND: Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large......-European countries: Norway, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland. STUDY OUTCOMES: There are two co-primary effect variables: • Functional status at 6-months, measured by the modified Rankin Scale, and • vascular death, myocardial infarction or stroke during the first 6-months...

  1. ANGIOTENSIN RECEPTOR BLOCKERS WITH PLEIOTROPIC PROPERTIES: A NEW STANDARD IN CARDIOVASCULAR RISK MANAGEMENT AND TREATMENT OF HYPERTENSION

    Directory of Open Access Journals (Sweden)

    V. I. Podzolkov

    2017-01-01

    Full Text Available An increase in the activity of the renin-angiotensin-aldosterone system is one of the most important mechanisms for the realization of the cardiovascular continuum. The role that angiotensin receptor blockers play in achieving target figures of blood pressure and reducing cardiovascular risk is discussed. The importance of pleiotropic properties of angiotensin receptor blockers (in particular, activation of peroxisome proliferator-activated receptors gamma – PPAR-γ in the management of patients with insulin resistance, obesity, dyslipidemia is also covered. The evidence base for the use of telmisartan as a drug with pleiotropic effect in patients with arterial hypertension and associated diseases (diabetes mellitus, obesity, renal dysfunction is discussed. 

  2. Inhibition of (prorenin Receptor Contributes to Renoprotective Effects of Angiotensin II Type 1 Receptor Blockade in Diabetic Nephropathy

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    Lin Zhang

    2017-10-01

    Full Text Available Aims: Renal renin-angiotensin system (RAS plays a pivotal role in the development of diabetic nephropathy (DN. Angiotensin II (Ang II type 1 receptor (AT1R blockade elevates (prorenin, which may bind to (prorenin receptor (PRR and exert receptor-mediated, angiotensin-independent profibrotic effects. We therefore investigated whether PRR activation leads to the limited anti-fibrotic effects of AT1R blockade on DN, and whether PRR inhibition might ameliorate progression of DN.Methods: To address the issue, the expression of RAS components was tested in different stages of streptozotocin (STZ-induced diabetic rats (6, 12, and 24 weeks and 6-week AT1R blockade (losartan treated diabetic rats. Using the blocker for PRR, the handle region peptide (HRP of prorenin, the effects of PRR on high glucose or Ang II-induced proliferative and profibrotic actions were evaluated by measurement of cell proliferation, matrix metalloproteinase-2 (MMP-2 activity, activation of extracellular signal-regulated kinase 1/2 (ERK1/2 and transforming growth factor-β1 (TGF-β1 expression in rat mesangial cells (MCs.Results: PRR was downregulated in the kidneys of different stages of diabetic rats (6, 12, and 24 weeks. Moreover, 6-week losartan treatment further suppressed PRR expression via upregulating AT2R, and ameliorated diabetic renal injury. HRP inhibited high glucose and Ang II-induced proliferative and profibrotic effects in MCs through suppressing TGF-β1 expression and activating MMP-2. Meanwhile, HRP enhanced losartan's anti-fibrotic effects through further inhibiting phosphorylation of ERK1/2 and TGF-β1 expression. Moreover, the inhibitive effect of HRP on Ang II-induced TGF-β1 expression depended on the regulation of PRR expression by AT2R.Conclusions: Our findings suggest that inhibition of PRR contributes to renoprotection against diabetic nephropathy by AT1R blockade.

  3. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor.

    Science.gov (United States)

    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2015-09-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Central angiotensin II stimulates cutaneous water intake behavior via an angiotensin II type-1 receptor pathway in the Japanese tree frog Hyla japonica.

    Science.gov (United States)

    Maejima, Sho; Konno, Norifumi; Matsuda, Kouhei; Uchiyama, Minoru

    2010-08-01

    Angiotensin II (Ang II) stimulates oral water intake by causing thirst in all terrestrial vertebrates except anurans. Anuran amphibians do not drink orally but absorb water osmotically through ventral skin. In this study, we examined the role of Ang II on the regulation of water-absorption behavior in the Japanese tree frog (Hyla japonica). In fully hydrated frogs, intracerebroventricular (ICV) and intralymphatic sac (ILS) injection of Ang II significantly extended the residence time of water in a dose-dependent manner. Ang II-dependent water uptake was inhibited by ICV pretreatment with an angiotensin II type-1 (AT(1)) receptor antagonist but not a type-2 (AT(2)) receptor antagonist. These results suggest that Ang II stimulates water-absorption behavior in the tree frog via an AT(1)-like but not AT(2)-like receptor. We then cloned and characterized cDNA of the tree frog AT(1) receptor from the brain. The tree frog AT(1) receptor cDNA encodes a 361 amino acid residue protein, which is 87% identical to the toad (Bufo marinus) AT(1) receptor and exhibits the functional characteristics of an Ang II receptor. AT(1) receptor mRNAs were found to be present in a number of tissues including brain (especially in the diencephalon), lung, large intestine, kidney and ventral pelvic skin. When tree frogs were exposed to dehydrating conditions, AT(1) receptor mRNA significantly increased in the diencephalon and the rhombencephalon. These data suggest that central Ang II may control water intake behavior via an AT(1) receptor on the diencephalon and rhombencephalon in anuran amphibians and may have implications for water consumption in vertebrates. Copyright 2010 Elsevier Inc. All rights reserved.

  5. Reassessment of the unique mode of binding between angiotensin II type 1 receptor and their blockers.

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    Shin-Ichiro Miura

    Full Text Available While the molecular structures of angiotensin II (Ang II type 1 (AT1 receptor blockers (ARBs are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT1 receptor, different positions of the AT1 receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT1 receptor, Tyr(113, Tyr(184, Lys(199, His(256 and Gln(257 using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT1 receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr(113 in the AT1 receptor and the hydroxyl group of olmesartan, between Lys(199 and carboxyl or tetrazole groups, and between His(256 or Gln(257 and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys(199, His(256 and Gln(257 of AT1 receptor. Lys(199 in the AT1 receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys(199. The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr(113. On the other hand, the n-butyl group of irbesartan may bind to Tyr(113. In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT1 receptor and for the formation of unique modes of binding.

  6. Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney.

    Science.gov (United States)

    Pinheiro, Sérgio Veloso Brant; Simões e Silva, Ana Cristina; Sampaio, Walkyria Oliveira; de Paula, Renata Dutra; Mendes, Elizabeth Pereira; Bontempo, Elizabete Dias; Pesquero, João Bosco; Walther, Thomas; Alenina, Natalia; Bader, Michael; Bleich, Markus; Santos, Robson Augusto Souza

    2004-10-01

    It has been described recently that the nonpeptide AVE 0991 (AVE) mimics the effects of angiotensin-(1-7) [Ang-(1-7)] in bovine endothelial cells. In this study, we tested the possibility that AVE is an agonist of the Ang-(1-7) receptor Mas, in vitro and in vivo. In water-loaded C57BL/6 mice, AVE (0.58 nmol/g body weight) produced a significant reduction in urinary volume (0.06+/-0.03 mL/60 min [n=9] versus 0.27+/-0.05 [n=9]; PAVE. As observed previously for Ang-(1-7), the antidiuretic effect of AVE after water load was blunted in Mas-knockout mice (0.37+/-0.10 mL/60 min [n=9] versus 0.27+/-0.03 mL/60 min [n=11] AVE-treated mice). In vitro receptor autoradiography in C57BL/6 mice showed that the specific binding of 125I-Ang-(1-7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of 125I-angiotensin II or 125I-angiotensin IV. Furthermore, AVE displaced the binding of 125I-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50=4.75x10(-8) mol/L) and of rhodamine-Ang-(1-7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT1) and AT2 antagonists. Contrasting with these data, the antidiuretic effect of AVE was totally blocked by AT2 antagonists and partially blocked (approximately 60%) by AT1 antagonists. The binding data, the results obtained in Mas-knockout mice and in Mas-transfected cells, show that AVE is a Mas receptor agonist. Our data also suggest the involvement of AT2/AT1-related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.

  7. Immunohistochemical detection of angiotensin AT 1 and AT 2 receptors in prostate cancer

    Science.gov (United States)

    Pawlikowski, Marek; Minias, Radosław; Zieliński, Krzysztof W.

    2011-01-01

    Introduction The human prostate gland contains all the compounds of the renin-angiotensin system (RAS), including AT1 and AT2 angiotensin receptors. The role of local RAS in the prostate pathology is recently discussed. The aim of the present study was the evaluation of AT1 and AT2 expressions in human prostate cancers. Material and methods The investigation was performed in 20 paraffin-embedded needle biopsy specimens from routine diagnostic prostate cancer biopsies. The specimens were stained with hematoxylin and eosin and immunostained with anti-AT1 and anti-AT2 antibodies. For visualization of primary antibodies, the streptavidin-biotin-peroxidase technique was applied. The expression of both receptor proteins was evaluated quantitatively using image analysis method. Results The positive immunostaining with both anti- AT1 and anti-AT2 antibodies can be found in stromal as well as epithelial structures. The results of quantitative evaluation showed the positive correlation between AT1 and AT2 expressions in neoplastic epithelium and overexpression of both AT1 and AT2 in neoplastic epithelium of Gleason grade 2, but not in cancerous structures of Gleason grades 3-5. Conclusions The data on AT1 and AT2 receptor expressions may suggest the involvement of RAS in prostate cancerogenesis. Moreover, the persistence of AT1 receptors in prostate cancer speaks in favor of attempts to use of AT1 receptor blockers (i.e. sartanes) and/or AT2 agonists in prostate cancer prophylaxis and/or treatment. PMID:24578905

  8. Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.

    Science.gov (United States)

    Magalhães, Giselle S; Rodrigues-Machado, Maria Glória; Motta-Santos, Daisy; Alenina, Natalia; Bader, Michael; Santos, Robson A; Barcelos, Lucíola S; Campagnole-Santos, Maria José

    2016-12-01

    The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma. Copyright © 2016 the American Physiological Society.

  9. Structure of the Human Angiotensin II Type 1 (AT1) Receptor Bound to Angiotensin II from Multiple Chemoselective Photoprobe Contacts Reveals a Unique Peptide Binding Mode*

    Science.gov (United States)

    Fillion, Dany; Cabana, Jérôme; Guillemette, Gaétan; Leduc, Richard; Lavigne, Pierre; Escher, Emanuel

    2013-01-01

    Breakthroughs in G protein-coupled receptor structure determination based on crystallography have been mainly obtained from receptors occupied in their transmembrane domain core by low molecular weight ligands, and we have only recently begun to elucidate how the extracellular surface of G protein-coupled receptors (GPCRs) allows for the binding of larger peptide molecules. In the present study, we used a unique chemoselective photoaffinity labeling strategy, the methionine proximity assay, to directly identify at physiological conditions a total of 38 discrete ligand/receptor contact residues that form the extracellular peptide-binding site of an activated GPCR, the angiotensin II type 1 receptor. This experimental data set was used in homology modeling to guide the positioning of the angiotensin II (AngII) peptide within several GPCR crystal structure templates. We found that the CXC chemokine receptor type 4 accommodated the results better than the other templates evaluated; ligand/receptor contact residues were spatially grouped into defined interaction clusters with AngII. In the resulting receptor structure, a β-hairpin fold in extracellular loop 2 in conjunction with two extracellular disulfide bridges appeared to open and shape the entrance of the ligand-binding site. The bound AngII adopted a somewhat vertical binding mode, allowing concomitant contacts across the extracellular surface and deep within the transmembrane domain core of the receptor. We propose that such a dualistic nature of GPCR interaction could be well suited for diffusible linear peptide ligands and a common feature of other peptidergic class A GPCRs. PMID:23386604

  10. Relationship between the bioavailability and molecular properties of angiotensin II receptor antagonists

    Directory of Open Access Journals (Sweden)

    Trbojević Jovana B.

    2016-01-01

    Full Text Available In the present study, we investigated the relationships between several molecular properties and bioavailability data for seven of the most commonly prescribed angiotensin II receptor antagonists (also known as angiotensin II receptor blockers (ARBs or sartans, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan. The molecular descriptors of ARBs are:, aqueous solubility (logS values, polar surface area (PSA, molecular weight (Mw, volume value (Vol, lipophilicity (logP values and the acidity descriptor (pKa1. The respective descriptors were calculated using four different software packages. The relevant bioavailability data were obtained from literature. Among calculated molecular descriptors, simple linear regression analysis showed the best correlation between bioavailability data and the lipophilicity descriptor, logP (R2 = 0.568. Multiple linear regression established good correlations between bioavailability and the lipophilicity descriptor, logP, using the molecular weight, Mw, or the acidity descriptor, pKa1, as an additional, independent variable (with R2 0.661 and 0.682, respectively. Finally, excluding candesartan from the calculations resulted in a very good correlation (R2 = 0.852 between the remaining ARB bioavailability and molecular descriptors MlogP and Mw as independent variables, determined by multiple linear regression. [Projekat Ministarstva nauke Republike Srbije, br. TR34031

  11. Involvement of the angiotensin II type 2 receptor in apoptosis during human fetal adrenal gland development.

    Science.gov (United States)

    Chamoux, E; Breault, L; Lehoux, J G; Gallo-Payet, N

    1999-12-01

    The aim of this study was to establish a link between the highly expressed angiotensin II (Ang II) type 2 receptor (AT2) in human fetal adrenal cells and the proposed apoptotic activity in the center of the gland. There was an important increase in apoptotic DNA fragmentation with age in adrenal glands of fetuses from 15-20 weeks gestation. Adrenal cells showing the characteristic apoptotic internucleosomal DNA fragmentation were localized in the central portion of the fetal zone. In cells cultured for 24 h, Ang II, via the AT2 receptor, induced DNA fragmentation and cleavage of the DNA repair enzyme, poly-(ADP-ribose) polymerase. Furthermore, characteristic membrane blebbing was observed specifically on cells of the fetal zone. Immunofluorescence studies demonstrated that stimulation with Ang II or CGP 42112 (an agonist of the AT2 receptor) strongly modified the actin network, now localized exclusively along the plasma membrane, with a predominance of labeling at the base of the bleb formation. This rearrangement of actin distribution was different in cells from the definitive zone, corroborating the observation that these cells express many more Ang II type 1 receptors (AT1) than AT2 receptors. Taken together, our data indicate that the AT2 receptor is involved in the apoptotic process observed in the human fetal adrenal gland and could participate in the morphological changes occurring after birth, leading to involution of the fetal zone.

  12. Stabilization of the angiotensin-(1-7) receptor Mas through interaction with PSD95.

    Science.gov (United States)

    Bian, Weihua; Sun, Licui; Yang, Longyan; Li, Ji-Feng; Hu, Jia; Zheng, Shuai; Guo, Ruihan; Feng, Duiping; Ma, Qian; Shi, Xiaocui; Xiong, Ying; Yang, Xiaomei; Song, Ran; Xu, Jianguo; Wang, Songlin; He, Junqi

    2013-08-01

    The functions and signalling mechanisms of the Ang-(1-7) [angiotensin-(1-7)] receptor Mas have been studied extensively. However, less attention has been paid to the intracellular regulation of Mas protein. In the present study, PSD95 (postsynaptic density 95), a novel binding protein of Mas receptor, was identified, and their association was characterized further. Mas specifically interacts with PDZ1-2, but not the PDZ3, domain of PSD95 via Mas-CT (Mas C-terminus), and the last four amino acids [ETVV (Glu-Thr-Val-Val)] of Mas-CT were determined to be essential for this interaction, as shown by GST pull-down, co-immunoprecipitation and confocal co-localization experiments. Gain-of-function and loss-of-function studies indicated that PSD95 enhanced Mas protein expression by increasing the stabilization of the receptor. Mas degradation was robustly inhibited by the proteasome inhibitor MG132 in time- and dose-dependent manners, and the expression of PSD95 impaired Mas ubiquitination, indicating that the PSD95-Mas association inhibits Mas receptor degradation via the ubiquitin-proteasome proteolytic pathway. These findings reveal a novel mechanism of Mas receptor regulation by which its expression is modulated at the post-translational level by ubiquitination, and clarify the role of PSD95, which binds directly to Mas, blocking the ubiquitination and subsequent degradation of the receptor via the ubiquitin-proteasome proteolytic pathway.

  13. Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor.

    Science.gov (United States)

    Steckelings, U Muscha; Kloet, Annette de; Sumners, Colin

    2017-09-01

    Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent to brain cardiovascular control centers is consistent with findings that stimulation of these receptors lowers BP, particularly during hypertension of neurogenic origin. Until recently brain AT2R had not been considered by many to play a role in the central control of BP. Demonstration of these powerful antihypertensive effects of brain AT2R opens the door to reconsideration of their role in BP regulation, and their consideration as a novel therapeutic avenue for resistant hypertension. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis.

    Science.gov (United States)

    Bruce, E; Shenoy, V; Rathinasabapathy, A; Espejo, A; Horowitz, A; Oswalt, A; Francis, J; Nair, A; Unger, T; Raizada, M K; Steckelings, U M; Sumners, C; Katovich, M J

    2015-05-01

    Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH. © 2014 The British Pharmacological Society.

  15. Direct Activation of Angiotensin II Type 2 Receptors Enhances Muscle Microvascular Perfusion, Oxygenation, and Insulin Delivery in Male Rats.

    Science.gov (United States)

    Yan, Fei; Yuan, Zhaoshun; Wang, Nasui; Carey, Robert M; Aylor, Kevin W; Chen, Li; Zhou, Xinmin; Liu, Zhenqi

    2018-02-01

    Angiotensin II receptors regulate muscle microvascular recruitment and the delivery of nutrients, oxygen, and insulin to muscle. Although angiotensin type 1 receptor antagonism increases muscle microvascular perfusion and insulin action, angiotensin type 2 receptor blockade markedly restricts muscle microvascular blood volume and decreases muscle delivery of insulin. To examine the effects of direct type 2 receptor stimulation using Compound 21 (C21) on microvascular perfusion, insulin delivery and action, and tissue oxygenation in muscle, overnight-fasted adult male rats were infused with C21 systemically. C21 potently increased microvascular blood volume without altering microvascular flow velocity or blood pressure, resulting in a net increase in microvascular blood flow in muscle. This was associated with a substantial increase in muscle interstitial oxygen saturation and insulin delivery into the skeletal and cardiac muscle. These effects were neutralized by coinfusion of the type 2 receptor antagonist or nitric oxide synthase inhibitor. Superimposing C21 infusion on insulin infusion increased insulin-mediated whole body glucose disposal by 50%. C21 significantly relaxed the preconstricted distal saphenous artery ex vivo. We have concluded that direct type 2 receptor stimulation markedly increases muscle microvascular perfusion through nitric oxide biosynthesis and enhances insulin delivery and action in muscle. These findings provide a physiologic mechanistic insight into type 2 receptor modulation of insulin action and suggest that type 2 receptor agonists might have therapeutic potential in the management of diabetes and its associated complications. Copyright © 2018 Endocrine Society.

  16. Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome

    NARCIS (Netherlands)

    Kröpelin, Tobias Felix; de Zeeuw, Dick; Holtkamp, Frank Arjan; Packham, David Kenneth; Heerspink, Hiddo J. L.

    Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study was to

  17. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats

    DEFF Research Database (Denmark)

    Bennion, Douglas M; Isenberg, Jacob D; Harmel, Allison T

    2017-01-01

    Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effe...

  18. Individualized prediction of the effect of angiotensin receptor blockade on renal and cardiovascular outcomes in patients with diabetic nephropathy.

    NARCIS (Netherlands)

    van der Sande, NGC; Dorresteijn, JAN; Visseren, FLJ; Dwyer, J.P.; Blankestijn, p; van der Graaf, Y; Heerspink, H. J Lambers

    2016-01-01

    Aims: To predict individualized treatment effects of angiotensin receptor blockers (ARBs) on cardiovascular and renal complications in order to help clinicians and patients assess the benefit of treatment (or adherence) and estimate remaining disease risk. Materials and methods: In patients with

  19. Effectiveness of Angiotensin II Receptor Antagonists in a Cohort of Dutch Patients With Type 2 Diabetes Mellitus (ZODIAC-14)

    NARCIS (Netherlands)

    van Hateren, Kornelis J. J.; Landman, Gijs W. D.; Groenier, Klaas H.; Bilo, Henk J. G.; Kleefstra, Nanne

    OBJECTIVE: There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure

  20. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence.

    Science.gov (United States)

    Polifka, Janine E

    2012-08-01

    Drugs that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are widely used to manage hypertension and heart failure. Adequate functioning of the RAS is essential for normal fetal kidney development. The potential for ACEIs and ARBs to impair fetal and neonatal renal function if taken after the first trimester of pregnancy has been well documented. Although these drugs were not found to be teratogenic in animals, until recently little was known about the teratogenic effects of ACEIs and ARBs in humans when exposure was limited to the first trimester of pregnancy. New evidence from epidemiologic studies indicates that there may be an elevated teratogenic risk when these drugs are taken during the first trimester of pregnancy. However, this elevated risk does not appear to be specific to ACEIs and ARBs, but is instead related to maternal factors and diseases that typically coexist with hypertension in pregnancy, such as diabetes, advanced maternal age, and obesity. Women who become pregnant while being treated with an ACEI or ARB should be advised to avoid exposure to these drugs during the second and third trimesters of pregnancy by switching to a different class of antihypertensive drugs between weeks 8 and 10 after conception. Copyright © 2012 Wiley Periodicals, Inc.

  1. Use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to reduce cardiovascular events in high-risk patients: Part 1.

    Science.gov (United States)

    Bommer, William J

    2008-01-01

    Cardiovascular disease is understood as a continuum; risk factors induce a pathophysiologic cascade that culminates in end-organ failure. The renin-angiotensin system (RAS) influences multiple aspects of the pathophysiology via hemodynamic and nonhemodynamic effects. Many long-term clinical trials provide overwhelming evidence of benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) across the cardiovascular continuum, including benefits regarding hypertension, myocardial infarction, stroke, renal disease, and heart failure. Trials also indicate additive or synergistic effects of combination therapy in renal disease and heart failure, a possibility supported by the basic biochemistry of the agents. Discussion of these trials is included in part 1 of this 2-part review. Part 2 of the review will discuss the extensive interaction of the RAS with the cellular and molecular pathophysiology of cardiovascular disease and the cross-continuum effects of ARBs and ACE inhibitors, which raise the possibility that RAS inhibition can offer protection in high-risk patients who do not have symptoms. The benefits of combined ACE inhibitor/ARB therapy in high-risk patients await confirmation; ongoing clinical research in this area will be discussed.

  2. Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Nielsen, Søren L; Akram, Kamran

    2009-01-01

    AIMS: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of th......AIMS: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A......-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment....... METHODS: The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases...

  3. Angiotensin-2-mediated Ca2+ signaling in the retinal pigment epithelium: role of angiotensin-receptor-associated-protein and TRPV2 channel.

    Directory of Open Access Journals (Sweden)

    Rene Barro-Soria

    Full Text Available Angiotensin II (AngII receptor (ATR is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap, and transient-receptor-potential channel-V2 (TRPV2. AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE cells by AngII results in biphasic increases in intracellular free Ca(2+inhibited by losartan. Xestospongin C (xest C and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca(2+response. RPE cells from Atrap(-/- mice showed smaller AngII-evoked Ca(2+peak (by 22% and loss of sustained Ca(2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD at 15 µM stimulates intracellular Ca(2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor reduced the cannabidiol-induced Ca(2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca(2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca(2+transients in the RPE by releasing Ca(2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca(2+elevation.

  4. Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

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    Wang, Xianwei, E-mail: XWang2@UAMS.edu; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L., E-mail: MehtaJL@UAMS.edu

    2012-03-15

    Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22{sup phox}, p47{sup phox}, p67{sup phox}, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H{sub 2}O{sub 2}. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac

  5. The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

    Directory of Open Access Journals (Sweden)

    Trbojević-Stanković Jasna B.

    2015-01-01

    Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

  6. Angiotensin II type 1 receptor (A1166C gene polymorphism and essential hypertension in Egyptian population

    Directory of Open Access Journals (Sweden)

    Marium M. Shamaa

    2016-09-01

    Full Text Available The pathogenesis of essential hypertension (EH is affected by genetic and environmental factors. Mutations in hypertension-related genes can affect blood pressure (BP via alteration of salt and water reabsorption by the nephron. The genes of the renin-angiotensin system (RAS have been extensively studied because of the well documented role of this system in the control of BP. It has been previously shown that Angiotensin II type 1 receptor (ATR1 gene polymorphism could be associated with increased risk of EH. So, in the current study, we evaluated the frequency of ATR1 (A1166C polymorphism in relation to EH in a group of Egyptian population. The study population included 83 hypertensive patients and 60 age and sex matched healthy control subjects. Restriction fragment length polymorphism – Polymerase chain reaction (RFLP – PCR was used for the analysis of A1166C polymorphism of ATR1 genes in peripheral blood samples of all patients and controls. The results revealed that there was a positive risk of developing EH when having the T allele whether in homozygous or heterozygous state. From this work, it was concluded that there was an association between ATR1 (A1166C gene polymorphism and the risk of developing EH.

  7. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2007-01-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  8. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2015-12-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  9. AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats.

    Science.gov (United States)

    Zhou, Jin; Pavel, Jaroslav; Macova, Miroslava; Yu, Zu-Xi; Imboden, Hans; Ge, Linna; Nishioku, Tsuyoshi; Dou, Jingtao; Delgiacco, Elizabeth; Saavedra, Juan M

    2006-05-01

    Blockade of angiotensin II AT1 receptors in cerebral microvessels protects against brain ischemia and inflammation. In this study, we tried to clarify the presence and regulation of the local renin-angiotensin system (RAS) in brain microvessels in hypertension. Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls were treated with an AT1 receptor antagonist (candesartan, 0.3 mg/kg per day) via subcutaneous osmotic minipumps for 4 weeks. The expression and localization of RAS components and the effect of AT1 receptor blockade were assessed by Affymetrix microarray, qRT-PCR, Western blots, immunohistochemistry and immunofluorescence. We found transcripts of most of RAS components in our microarray database, and confirmed their expression by qRT-PCR. Angiotensinogen (Aogen), angiotensin-converting enzyme (ACE) and AT1 receptors were localized to the endothelium. There was no evidence of AT2 receptor localization in the microvascular endothelium. In SHR, (pro)renin receptor mRNA and AT1 receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT2 receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT2 receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro)renin and AT1 receptors. Increased (pro)renin and AT1 receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT1 receptor blockade and increased AT2 receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.

  10. A 5'-upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the β-arrestin pathway.

    Science.gov (United States)

    Yosten, Gina L C; Liu, Jun; Ji, Hong; Sandberg, Kathryn; Speth, Robert; Samson, Willis K

    2016-03-15

    AUG sequences and short open reading frames are commonly present in the 5'-leader sequence of G protein-coupled receptor mRNAs. The presence of these upstream AUG sequences has been demonstrated to inhibit downstream receptor translation efficiency and, most recently, receptor signal transduction. A seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor has been shown to inhibit non-G protein-coupled signalling of angiotensin II, without altering the classical G protein-coupled pathway activated by the ligand. This finding may lead to the development of a new class of angiotensin receptor antagonists with activities biased for one, but not all, of the signalling cascades activated by angiotensin II, which could have therapeutic implications for the myriad hormones and neurotransmitters that signal through G protein-coupled receptors. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  11. A 5′‐upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the β‐arrestin pathway

    Science.gov (United States)

    Yosten, Gina L.C.; Liu, Jun; Ji, Hong; Sandberg, Kathryn; Speth, Robert

    2015-01-01

    Abstract AUG sequences and short open reading frames are commonly present in the 5′‐leader sequence of G protein‐coupled receptor mRNAs. The presence of these upstream AUG sequences has been demonstrated to inhibit downstream receptor translation efficiency and, most recently, receptor signal transduction. A seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor has been shown to inhibit non‐G protein‐coupled signalling of angiotensin II, without altering the classical G protein‐coupled pathway activated by the ligand. This finding may lead to the development of a new class of angiotensin receptor antagonists with activities biased for one, but not all, of the signalling cascades activated by angiotensin II, which could have therapeutic implications for the myriad hormones and neurotransmitters that signal through G protein‐coupled receptors. PMID:26333095

  12. Distinctions between non-peptide angiotensin II AT1-receptor antagonists

    Directory of Open Access Journals (Sweden)

    Georges Vauquelin

    2001-03-01

    Full Text Available A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct [3H]-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan causes parallel shifts of the angiotensin II (Ang II concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174, to almost complete (95% for candesartan reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan. Antagonist-bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or `rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor.

  13. Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity.

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J; Richard, Alexandra; Vandenberghe, Camille; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

    2015-06-01

    The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Addition of vitamin D reverses the decline in GFR following treatment with ACE inhibitors/angiotensin receptor blockers in patients with chronic kidney disease.

    Science.gov (United States)

    Soares, Abel Esteves; Maes, Michael; Godeny, Paula; Matsumoto, Andressa Keiko; Barbosa, Décio Sabbatini; da Silva, Taysa Antonia F; Souza, Flávio Henrique M O; Delfino, Vinicius Daher Alvares

    2017-12-15

    Vitamin D has anti-inflammatory, anti-fibrotic effect, and may block the intrarenal renin-angiotensin system. Adequate vitamin D levels in conjunction with the use of Angiotensin-converting Enzyme Inhibitors/Angiotensin Receptor Blockers may help to slow down chronic kidney disease progression. To study a possible beneficial effect of vitamin D supplementation in chronic kidney disease patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on chronic kidney disease progression we performed a clinical study involving vitamin D supplementation in patients with deficiency of this vitamin. This study was conducted in two chronic kidney disease clinics in the city of Londrina, Brazil, from October 2010 to December 2012. It was involved stage 3 and 4 chronic kidney disease (estimated glomerular filtration rate between 60 and 15mL/min/1.73m 2 ) patients with and without vitamin D deficiency. The patients ingested six-month cholecalciferol 50,000IU oral supplementation to chronic kidney disease patients with vitamin D deficiency. We hypothesize changes in estimated glomerular filtration rate over study period. Our data demonstrate reservation of estimated glomerular filtration with cholecalciferol supplementation to chronic kidney disease patients taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. The combination treatment of angiotensin converting enzyme inhibitors/angiotensin receptor blockers with cholecalciferol prevents the decline in estimated glomerular filtration in patients with chronic kidney disease following treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and may represent a valid approach to reduce renal disease progression in chronic kidney disease patients with vitamin D deficiency. This result needs confirmation in prospective controlled clinical trials. Copyright © 2017. Published by Elsevier Inc.

  15. Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet.

    Science.gov (United States)

    Noll, Christophe; Labbé, Sébastien M; Pinard, Sandra; Shum, Michael; Bilodeau, Lyne; Chouinard, Lucie; Phoenix, Serge; Lecomte, Roger; Carpentier, André C; Gallo-Payet, Nicole

    2016-01-01

    The role of the angiotensin type-2 receptor in adipose physiology remains controversial. The aim of the present study was to demonstrate whether genetic angiotensin type-2 receptor-deficiency prevents or worsens metabolic and adipose tissue morphometric changes observed following a 6-week high-fat/high-fructose diet with injection of a small dose of streptozotocin. We compared tissue uptake of nonesterified fatty acid and dietary fatty acid in wild-type and angiotensin type-2 receptor-deficient mice by using the radiotracer 14(R,S)-[(1) (8)F]-fluoro-6-thia-heptadecanoic acid in mice fed a standard or high-fat diet. Postprandial fatty acid uptake in the heart, liver, skeletal muscle, kidney and adipose tissue was increased in wild-type mice after a high-fat diet and in angiotensin type-2 receptor-deficient mice on both standard and high-fat diets. Compared to the wild-type mice, angiotensin type-2 receptor-deficient mice had a lower body weight, an increase in fasting blood glucose and a decrease in plasma insulin and leptin levels. Mice fed a high-fat diet exhibited increased adipocyte size that was prevented by angiotensin type-2 receptor-deficiency. Angiotensin type-2 receptor-deficiency abolished the early hypertrophic adipocyte remodeling induced by a high-fat diet. The small size of adipocytes in the angiotensin type-2 receptor-deficient mice reflects their inability to store lipids and explains the increase in fatty acid uptake in non-adipose tissues. In conclusion, a genetic deletion of the angiotensin type-2 receptor is associated with metabolic dysfunction of white adipose depots, and indicates that adipocyte remodeling occurs before the onset of insulin resistance in the high-fat fed mouse model.

  16. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST)

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Bath, Philip M W; Boysen, Gudrun

    2011-01-01

    significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian...... Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (renal failure was reported for 18 (2......BACKGROUND: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised...

  17. Antihypertensive efficacy and safety of the angiotensin receptor blocker azilsartan in elderly patients with hypertension.

    Science.gov (United States)

    Kamada, Tomohito; Hayashi, Mutsuharu; Fujiwara, Wakaya; Yoshikawa, Daiji; Mukaide, Daisuke; Sugishita, Yoshinori; Yoshinaga, Masataka; Itoh, Takehiro; Yokoi, Hiroatsu; Ishii, Junichi; Watanabe, Eiichi; Ozaki, Yukio; Izawa, Hideo

    2017-01-01

    The number of elderly patients with hypertension has been steadily increasing. However, there are limited data on the safety and efficacy of the new angiotensin type 1 receptor blocker (ARB) azilsartan in elderly patients with hypertension. We investigated the clinical efficacy and safety of azilsartan in this population. The study population comprised 56 ambulatory patients with essential hypertension. We evaluated the reduction in blood pressure and safety after 12 weeks of treatment with azilsartan in 29 hypertensive patients ≥65 years of age (aged group) in comparison with the findings in 27 patients elderly patients and may be safe. Therefore, azilsartan could be a valuable option for treating hypertension in elderly and non-elderly patients.

  18. Effect of angiotensin II receptor blockade on proximal tubular fluid reabsorption

    DEFF Research Database (Denmark)

    Leyssac, P P; Karlsen, F M; Holstein-Rathlou, N H

    1997-01-01

    convolution of halothane-anesthetized Sprague-Dawley rats. Four parameters that depend on the rate of proximal fluid reabsorption were measured: proximal intratubular pressure (Pprox), early and late proximal flow rate, and early distal NaCl concentration. Pprox decreased by 0.5 +/- 0.1 mmHg, late proximal...... flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load...... the early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption....

  19. Candesartan, an angiotensin II type 1 receptor antagonist, inhibits pathological retinal neovascularization by downregulating VEGF receptor-2 expression.

    Science.gov (United States)

    Nakamura, Shinsuke; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

    2012-06-15

    Several studies have examined the anti-angiogenic effects of angiotensin II type 1 (AT(1)) receptor antagonists; however, the mechanisms underlying these effects are currently unclear. In the present study, we examined the efficacy and the mechanism of candesartan, an AT(1) receptor antagonist, in suppressing pathological retinal neovascularization. We used an in vivo murine oxygen-induced retinopathy (OIR) model and also studied the in vitro proliferation and migration of human retinal microvascular endothelial cells (HRMECs) induced by vascular endothelial growth factor (VEGF)-A. The regulation of angiogenesis-associated genes such as hypoxia-inducible factor (HIF-1α), VEGF-A, VEGF receptor-1, and VEGF receptor-2 was evaluated with real-time RT-PCR in the OIR model. In the OIR model, candesartan suppressed the pathological neovascularization in a dose-dependent manner, but did not prevent the physiological angiogenesis. However, candesartan did not inhibit VEGF-A-induced proliferation or migration in HRMECs in the in vitro study. When administered interperitoneally in the OIR model, candesartan reduced the upregulation of VEGF receptor-2 in the retina, but had no effects in the other angiogenesis-related genes, such as HIF-1α, VEGF-A, and VEGF receptor-1. These findings indicate that candesartan inhibited the retinal pathological neovascularization, at least in part, by suppressing the expression of VEGF receptor-2, independent of VEGF signaling cascade. Therefore, candesartan may be a useful therapeutic target for the inhibition of retinal neovascularization that has a low risk of serious side effects. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. (Prorenin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

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    Anne-Mari Moilanen

    Full Text Available BACKGROUND: Activation of the renin-angiotensin-system (RAS plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (prorenin receptor ((PRR is not yet solved. We determined here the direct functional and structural effects of (PRR in the heart. METHODOLOGY/PRINCIPAL FINDINGS: (PRR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (PRR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01, fractional shortening (P<0.01, and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (PRR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (PRR gene overexpression was mediated by angiotensin II (Ang II, we infused an AT(1 receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (PRR overexpressing animals as well. Intramyocardial (PRR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (PRR gene delivery was Ang II-dependent. Finally, (PRR overexpression significantly increased direct protein-protein interaction between (PRR and promyelocytic zinc-finger protein. CONCLUSIONS/SIGNIFICANCE: These results indicate for the first time that (PRR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (PRR as a novel therapeutic target to optimize RAS blockade in failing hearts.

  1. ACE inhibition is superior to angiotensin receptor blockade for renography in renal artery stenosis

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    Karanikas, Georgios; Becherer, Alexander; Wiesner, Karoline; Dudczak, Robert; Kletter, Kurt [Department of Nuclear Medicine, University of Vienna (Austria)

    2002-03-01

    Angiotensin converting enzyme (ACE) inhibitors as well as angiotensin II receptor antagonists are able to prevent the vasoconstrictive effect of angiotensin II on the efferent renal vessels, which is believed to play an important role in renovascular hypertension. This effect is assumed to be essential for the demonstration of renovascular hypertension by captopril renography. In this study, renographic changes induced by captopril and the AT1 receptor antagonist valsartan were compared in patients with a high probability for renovascular hypertension. Twenty-five patients with 33 stenosed renal arteries (grade of stenosis >50%) and hypertension were studied. Captopril, valsartan and baseline renography were performed within 48 h using technetium-99m mercaptoacetyltriglycine. Blood pressure was monitored, plasma renin concentration before and after intervention was determined and urinary flow was estimated from the urinary output of the hydrated patients. Alterations in renographic curves after intervention were evaluated according to the Santa Fe consensus on ACE inhibitor renography. Captopril renography was positive, indicating renovascular hypertension, in 25 of the 33 stenosed vessels, whereas valsartan renography was positive in only ten. Blood pressure during captopril and valsartan renography was not different; reduction in blood pressure was the same after valsartan and captopril. Plasma renin concentration was comparable for valsartan and captopril studies, showing suppressed values after intervention in as many as 12 of the 25 patients. Urinary flow after valsartan was higher than after captopril (P<0.05). However, this difference could not explain the markedly higher sensitivity of captopril compared with valsartan in demonstrating renal artery stenosis. In 14 of the 25 patients, blood pressure response to revascularisation was monitored, showing a much better predictive value for captopril renography. It is concluded that captopril renography is much

  2. Effect of angiotensin II and its receptor antagonists on human corpus cavernous contractility and oxidative stress: modulation of nitric oxide mediated relaxation.

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    Ertemi, Hani; Mumtaz, Faiz H; Howie, Alexander J; Mikhailidis, Dimitri P; Thompson, Cecil S

    2011-06-01

    To our knowledge the interaction between angiotensin II and nitric oxide in the control of human corpus cavernous function has not been assessed previously. We determined the presence and role of angiotensin II and its receptors in human penile function. Corpus cavernous tissue was obtained from 35 patients undergoing gender reassignment surgery. Immunohistochemical analysis was done to determine angiotensin II peptide tissue distribution. Organ bath studies were done to determine the angiotensin II/nitric oxide interaction on corpus cavernous smooth muscle function. The role of oxidative stress in the angiotensin II response was also examined using the nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin. Angiotensin II was distributed in arteriolar endothelium, endothelium lining sinusoids and smooth muscle cells, and caused dose dependent contraction of human corpus cavernous smooth muscle strips that was inhibited by the angiotensin type 1 receptor antagonist losartan. Relaxation of corpus cavernous smooth muscle induced by the nitric oxide donor sodium nitroprusside or electrical field stimulation was potentiated by losartan. Apocynin decreased angiotensin II induced corpus cavernous contraction. Angiotensin II and nitric oxide interact to modulate human cavernous function since losartan potentiated sodium nitroprusside and electrical field stimulation mediated corpus cavernous smooth muscle relaxation. The angiotensin II response involves the production of superoxide and the development of oxidative stress. These findings support the role of angiotensin II in the regulation of human penile smooth muscle tone and suggest that angiotensin type 1 receptor inhibition may be a therapeutic approach to erectile dysfunction. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  3. The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

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    Hansen, Jakob Lerche; Aplin, Mark; Hansen, Jonas Tind

    2008-01-01

    The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin...

  4. Acute effects of angiotensin-converting enzyme inhibition versus angiotensin II receptor blockade on cardiac sympathetic activity in patients with heart failure.

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    Azevedo, Eduardo R; Mak, Susanna; Floras, John S; Parker, John D

    2017-10-01

    The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF. Copyright © 2017 the American Physiological Society.

  5. Molecular targeting therapy with angiotensin II receptor blocker for prostatic cancer

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    Hiroji Uemura

    2011-12-01

    Full Text Available Angiotensin II (Ang-II plays a key role as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis. Recently it has also been shown that this peptide is a cytokine, acting as a growth factor in cardiovascular and stromal cells. In addition, the physiological function of Ang-II seems to be similar in prostate cancer and stromal cells. It is widely assumed that Ang-II facilitates the growth of both cells, and its receptor blockers (ARBs have the potential to inhibit the growth of various cancer cells and tumors through the Ang-II receptor type 1 (AT1 receptor. The mechanism of cell growth inhibition by ARBs has been considered to be that of suppression of the signal transduction systems activated by growth factors or cytokines in prostate cancer cells, and suppression of angiogenesis. This review highlights the possible use of ARBs as novel agents for prostatic diseases including prostate cancer and benign hypertrophy, and covers related literature.

  6. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

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    Dimitrijevic, Ivan; Edvinsson, Marie-Louise; Chen, Qingwen

    2009-01-01

    pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...... in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P ...%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s). CONCLUSION: The results demonstrate, for the first time, upregulation of ETB and AT1...

  7. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers

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    Seyed Ali Sadjadi

    2009-07-01

    Full Text Available Seyed Ali Sadjadi1, James I McMillan1, Navin Jaipaul1, Patricia Blakely1, Su Su Hline21Section of Nephrology (111N, Jerry L Pettis Memorial Veterans Medical Center, Loma Linda, CA, USA; 2Divison of Nephrology, Loma Linda University Medical Center, Loma Linda, CA, USABackground and objectives: Angiotensin-converting enzyme inhibitors (ACEI and angiotensin receptor blockers (ARB are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.Design, settings, material, and measurements: Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables. Results: Hyperkalemia (>5 mEq/L was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher, was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001 in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001 in a model including adjustment for serum creatinine.Conclusions: Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of

  8. Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

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    Yuki Hamano

    2011-09-01

    Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

  9. Angiotensin II-AT1–receptor signaling is necessary for cyclooxygenase-2–dependent postnatal nephron generation

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    Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique

    2017-01-01

    Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2–dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2-/- mice was achieva......Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2–dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2-/- mice...... was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P...... development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2-/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L...

  10. Long-term use of angiotensin receptor blockers and the risk of cancer.

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    Laurent Azoulay

    Full Text Available The association between angiotensin receptor blockers (ARBs and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs and 95% confidence intervals (CIs of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years. When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03 or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively. This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

  11. Mechanical stress triggers cardiomyocyte autophagy through angiotensin II type 1 receptor-mediated p38MAP kinase independently of angiotensin II.

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    Li Lin

    Full Text Available Angiotensin II (Ang II type 1 (AT1 receptor is known to mediate a variety of physiological actions of Ang II including autophagy. However, the role of AT1 receptor in cardiomyocyte autophagy triggered by mechanical stress still remains elusive. The aim of this study was therefore to examine whether and how AT1 receptor participates in cardiomyocyte autophagy induced by mechanical stresses. A 48-hour mechanical stretch and a 4-week transverse aorta constriction (TAC were imposed to cultured cardiomyocytes of neonatal rats and adult male C57B/L6 mice, respectively, to induce cardiomyocyte hypertrophy prior to the assessment of cardiomyocyte autophagy using LC3b-II. Losartan, an AT1 receptor blocker, but not PD123319, the AT2 inhibitor, was found to significantly reduce mechanical stretch-induced LC3b-II upregulation. Moreover, inhibition of p38MAP kinase attenuated not only mechanical stretch-induced cardiomyocyte hypertrophy but also autophagy. To the contrary, inhibition of ERK and JNK suppressed cardiac hypertrophy but not autophagy. Intriguingly, mechanical stretch-induced autophagy was significantly inhibited by Losartan in the absence of Ang II. Taken together, our results indicate that mechanical stress triggers cardiomyocyte autophagy through AT1 receptor-mediated activation of p38MAP kinase independently of Ang II.

  12. Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

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    Henri Augusto Korkes

    2014-09-01

    Full Text Available Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor antagonists (ARAs are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

  13. Management of hypertension: Insights into prescribing behavior with focus on angiotensin receptor blockers

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    S Ramakrishnan

    2017-01-01

    Full Text Available Introduction: Angiotensin receptor blockers (ARBs are emerging as an attractive first choice antihypertensive as recommended by various guidelines. However, choice among the first-line antihypertensive classes and among ARBs differs between practicing physicians. Aims: This survey aimed to understand the usage preferences of ARBs and its place in for treating hypertension (HTN among physicians from various clinical settings in India. Methods: A cross-sectional survey was conducted with a prevalidated survey questionnaire consisting of 25 questions for HTN management. Practicing general physicians and cardiologists were approached for seeking their perception, opinions, and prescribing behavior. Results: Responses of 594 physicians and cardiologists were received. As opined by 90.1% of physicians, newly diagnosed HTN represented more than 10% of their overall patient load. As a monotherapy, 59.9% of the physicians preferred ARB as the first choice in newly diagnosed HTN patients, followed by calcium channel blocker (12.3% and angiotensin-converting-enzyme inhibitor (8.1%. Of all ARBs, telmisartan is preferred by 73% of physicians. Most physicians prefer telmisartan among all ARBs for 24 h blood pressure (BP control, including morning BP surge (76.4% and for prevention of cardiovascular morbidity and mortality (78.8% followed by olmesartan and losartan. Predominantly, majority of physicians (89.1% agreed for the beneficial role of telmisartan in preventing onset of microalbuminuria and nephropathy. Conclusion: Indian physicians prefer ARBs as the first choice in most hypertensive patients, which shows agreement with the guideline recommendations followed globally. Telmisartan has emerged as the most preferred ARB among all, for most of the HTN patients including those with comorbidities.

  14. Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas.

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    Morales, María Gabriela; Abrigo, Johanna; Acuña, María José; Santos, Robson A; Bader, Michael; Brandan, Enrique; Simon, Felipe; Olguin, Hugo; Cabrera, Daniel; Cabello-Verrugio, Claudio

    2016-04-01

    Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophyin vivousing unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy. © 2016. Published by The Company of Biologists Ltd.

  15. Sodium restriction potentiates the renoprotective effects of combined vitamin D receptor activation and angiotensin-converting enzyme inhibition in established proteinuric nephropathy

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    Mirkovic, Katarina; Frenay, Anne-Roos S; van den Born, Jacob; van Goor, Harry; Navis, Gerjan; de Borst, Martin H

    2015-01-01

    BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator

  16. Endogenous angiotensin II suppresses stretch-induced ANP secretion via AT1 receptor pathway.

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    Oh, Young-Bin; Gao, Shan; Shah, Amin; Kim, Jong Hun; Park, Woo Hyun; Kim, Suhn Hee

    2011-02-01

    Angiotensin II (Ang II) is released by stretch of cardiac myocytes and has paracrine and autocrine effects on cardiac myocytes and fibroblasts. However, the direct effect of Ang II on the secretion of atrial natriuretic peptide (ANP) is unclear. The aim of the present study is to test whether Ang II affects stretch-induced ANP secretion. The isolated perfused beating atria were used from control and two-kidney one-clip hypertensive (2K1C) rats. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5cmH(2)O to 7.5cmH(2)O. Atrial stretch by volume load caused increases in atrial contractility by 60% and in ANP secretion by 100%. Ang II suppressed stretch-induced ANP secretion and tended to increase atrial contractility whereas losartan stimulated stretch-induced ANP secretion. Neither PD123319 nor A779 had direct effect on stretch-induced ANP secretion. The suppressive effect of Ang II on stretch-induced ANP secretion was blocked by the pretreatment of losartan but not by the pretreatment of PD123319 or A779. In hypertrophied atria from 2K1C rats, stretch-induced ANP concentration attenuated and atrial contractility augmented. The response of stretch-induced ANP secretion to Ang II and losartan augmented. The expression of AT1 receptor protein and mRNA increased but AT2 and Mas receptor mRNA did not change in 2K1C rat atria. Therefore, we suggest that Ang II generated endogenously by atrial stretch suppresses stretch-induced ANP secretion through the AT1 receptor and alteration of Ang II effect in 2K1C rat may be due to upregulation of AT1 receptor. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Angiotensin type 2 receptors: blood pressure regulation and end organ damage.

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    Sumners, Colin; de Kloet, Annette D; Krause, Eric G; Unger, Thomas; Steckelings, Ulrike Muscha

    2015-04-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral. However, stimulation of AT2R locally within the brain or the kidney apparently elicits a systemic blood pressure lowering effect. A systemic effect of AT2R stimulation on blood pressure can also be achieved, when the prevailing effect of continuous background AT1R-stimulation is attenuated by low-dose AT1R blockade. Despite a lack of effect on blood pressure, AT2R stimulation still protects from hypertensive end-organ damage. Current data and evidence therefore suggest that AT2R agonists will not be suitable as future anti-hypertensive drugs, but that they may well be useful for end-organ protection in combination with established anti-hypertensives. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Role of blood cell-associated angiotensin II type 1 receptors in the cerebral microvascular response to ischemic stroke during angiotensin-induced hypertension.

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    Nagai, Mutsumi; Terao, Satoshi; Vital, Shantel A; Rodrigues, Stephen F; Yilmaz, Gokhan; Granger, D Neil

    2011-11-16

    Angiotensin II type 1 receptor (AT1R) blockers lower the incidence of ischemic stroke in hypertensive patients and attenuate brain inflammation and injury in animal models. Although AT1R on both blood cells (BC) and vascular endothelial cells (EC) can be activated by angiotensin II (Ang II) to elicit inflammation, little is known about the relative contributions of AT1R expressed on BC and EC to the brain injury responses to ischemia and reperfusion (I/R) in the setting of angiotensin-induced hypertension. The contributions of BC- and EC-associated AT1R to I/R-induced brain inflammation and injury were evaluated using wild type (WT), AT1aR-/-, and bone marrow chimera mice with either a BC+/EC+ (WT→WT) or BC-/EC+ (AT1aR-/-→WT) distribution of AT1aR. The adhesion of leukocytes and platelets in venules, blood brain barrier (BBB) permeability and infarct volume were monitored in postischemic brain of normotensive and Ang II-induced hypertensive mice. The inflammatory (blood cell adhesion) and injury (BBB permeability, infarct volume) responses were greatly exaggerated in the presence of Ang II-induced hypertension. The Ang II-enhanced responses were significantly blunted in AT1aR-/- mice. A similar level of protection was noted in AT1aR-/- →WT mice for BBB permeability and infarct volume, while less or no protection was evident for leukocyte and platelet adhesion, respectively. BC- and EC-associated AT1aR are both involved in the brain injury responses to ischemic stroke during Ang II-hypertension, with EC AT1aR contributing more to the blood cell recruitment response and BC AT1aR exerting a significant influence on the BBB disruption and tissue necrosis elicited by I/R.

  19. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.

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    Raimondi, Sara; Botteri, Edoardo; Munzone, Elisabetta; Cipolla, Carlo; Rotmensz, Nicole; DeCensi, Andrea; Gandini, Sara

    2016-07-01

    Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2) = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted. © 2016 UICC.

  20. Comparative effectiveness of angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers for major renal outcomes in patients with diabetes: A 15-year cohort study.

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    Hon-Yen Wu

    Full Text Available Angiotensin converting enzyme inhibitors (ACEIs and angiotensin II receptor blockers (ARBs are considered to have similar renoprotective effects; so far there has been no consensus about their priorities. This study aimed to compare ACEIs and ARBs for major renal outcomes and survival in a 15-year cohort of adults with diabetes.This study utilized Taiwan's medical and pharmacy claims data in the Longitudinal Cohort of Diabetes Patients. The primary outcome was long-term dialysis, and secondary outcomes were hospitalization for acute kidney injury, hospitalization for hyperkalemia, all-cause death, cardiovascular death, and non-cardiovascular death. Cox proportional hazards models were used to estimate the hazard ratios (HRs and 95% confidence intervals (CIs for outcomes comparing ACEIs with ARBs. We conducted subgroup analyses and interaction tests among patients with different age and comorbid diseases.A total of 34,043 patients received ACEIs and 23,772 patients received ARBs. No differences were found for primary or secondary outcomes in the main analyses. ACEIs showed significantly lower hazard than ARBs for long-term dialysis among patients with cardiovascular disease (HR 0.80, 95% CI 0.66-0.97, interaction P = 0.003 or chronic kidney disease (0.81, 0.71-0.93, interaction P = 0.001.Our analyses show similar effects of ACEIs and ARBs in patients with diabetes. However, ACEIs might provide additional renoprotective effects among patients who have cardiovascular disease or chronic kidney disease.

  1. Current topics in angiotensin II type 1 receptor research: Focus on inverse agonism, receptor dimerization and biased agonism.

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    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2017-09-01

    Although the octapeptide hormone angiotensin II (Ang II) regulates cardiovascular and renal homeostasis through the Ang II type 1 receptor (AT1R), overstimulation of AT1R causes various human diseases, such as hypertension and cardiac hypertrophy. Therefore, AT1R blockers (ARBs) have been widely used as therapeutic drugs for these diseases. Recent basic research and clinical studies have resulted in the discovery of interesting phenomena associated with AT1R function. For example, ligand-independent activation of AT1R by mechanical stress and agonistic autoantibodies, as well as via receptor mutations, has been shown to decrease the inverse agonistic efficacy of ARBs, though the molecular mechanisms of such phenomena had remained elusive until recently. Furthermore, although AT1R is believed to exist as a monomer, recent studies have demonstrated that AT1R can homodimerize and heterodimerize with other G-protein coupled receptors (GPCR), altering the receptor signaling properties. Therefore, formation of both AT1R homodimers and AT1R-GPCR heterodimer may be involved in the pathogenesis of human disease states, such as atherosclerosis and preeclampsia. Finally, biased AT1R ligands that can preferentially activate the β-arrestin-mediated signaling pathway have been discovered. Such β-arrestin-biased AT1R ligands may be better therapeutic drugs for cardiovascular diseases. New findings on AT1R described herein could provide a conceptual framework for application of ARBs in the treatment of diseases, as well as for novel drug development. Since AT1R is an extensively studied member of the GPCR superfamily encoded in the human genome, this review is relevant for understanding the functions of other members of this superfamily. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney.

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    Patel, Sanket N; Ali, Quaisar; Samuel, Preethi; Steckelings, Ulrike Muscha; Hussain, Tahir

    2017-10-01

    The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1-7) in OZR increased urine flow and urinary Na excretion, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1-7) stimulated NO which was blocked by either of the receptor antagonists. Dual labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive to the reducing β-mercaptoethanol, suggesting involvement of -SH groups in cross-linking. Collectively, the study reveals that AT2R and MasR are colocalized and functionally interdependent in terms of stimulating NO and promoting diuretic/natriuretic response. © 2017 American Heart Association, Inc.

  3. C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

    Science.gov (United States)

    Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

    2015-07-01

    Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.

  4. Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

    Science.gov (United States)

    Dolley-Hitze, T; Jouan, F; Martin, B; Mottier, S; Edeline, J; Moranne, O; Le Pogamp, P; Belaud-Rotureau, M-A; Patard, J-J; Rioux-Leclercq, N; Vigneau, C

    2010-11-23

    The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors. Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT-PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS). A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: PR: PR or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (PR and AT1-R were also found to be overexpressed in higher Fuhrman's grade (PR but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively). Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy.

  5. Reciprocal Roles of Angiotensin II and Angiotensin II Receptors Blockade (ARB in Regulating Cbfa1/RANKL via cAMP Signaling Pathway: Possible Mechanism for Hypertension-Related Osteoporosis and Antagonistic Effect of ARB on Hypertension-Related Osteoporosis

    Directory of Open Access Journals (Sweden)

    Ji-Yao Li

    2011-06-01

    Full Text Available Hypertension is a risk factor for osteoporosis. Animal and epidemiological studies demonstrate that high blood pressure is associated with increased calcium loss, elevated parathyroid hormone, and increased calcium movement from bone. However, the mechanism responsible for hypertension-related osteoporosis remains elusive. Recent epidemiological studies indicate the benefits of Angiotensin II Receptors Blockade (ARB on decreasing fracture risks. Since receptors for angiotensin II, the targets of ARB, are expressed in both osteoblasts and osteoclasts, we postulated that angiotensin II plays an important role in hypertension-related osteoporosis. Cbfa1 and RANKL, the important factors for maintaining bone homeostasis and key mediators in controlling osteoblast and osteoclast differentiation, are both regulated by cAMP-dependent signaling. Angiotensin II along with factors such as LDL, HDL, NO and homocysteine that are commonly altered both in hypertension and osteoporosis, can down-regulate the expression of Cbfa1 but up-regulate RANKL expression via the cAMP signaling pathway. We thus hypothesized that, by altering the ratio of Cbfa1/RANKL expression via the cAMP-dependent pathway, angiotensin II differently regulates osteoblast and osteoclast differentiation leading to enhanced bone resorption and reduced bone formation. Since ARB can antagonize the adverse effect of angiotensin II on bone by lowering cAMP levels and modifying other downstream targets, including LDL, HDL, NO and Cbfa1/RANKL, we propose the hypothesis that the antagonistic effects of ARB may also be exerted via cAMP signaling pathway.

  6. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy

    Science.gov (United States)

    Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A.; Leyton, Patricio A.; Cheng, Juan; Tainsh, Robert E. T.; Mayeur, Claire; Rhee, David K.; Wu, Mei. X.; Scherrer-Crosbie, Marielle; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.

    2016-01-01

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

  7. Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes.

    Science.gov (United States)

    Chandel, Nirupama; Ayasolla, Kamesh; Wen, Hongxiu; Lan, Xiqian; Haque, Shabirul; Saleem, Moin A; Malhotra, Ashwani; Singhal, Pravin C

    2017-02-01

    Vitamin D receptor (VDR) deficient status has been shown to be associated with the activation of renin angiotensin system (RAS). We hypothesized that lack of VDR would enhance p53 expression in podocytes through down regulation of SIRT1; the former would enhance the transcription of angiotensinogen (Agt) and angiotensinogen II type 1 receptor (AT1R) leading to the activation of RAS. Renal tissues of VDR mutant (M) mice displayed increased expression of p53, Agt, renin, and AT1R. In vitro studies, VDR knockout podocytes not only displayed up regulation p53 but also displayed enhanced expression of Agt, renin and AT1R. VDR deficient podocytes also displayed an increase in mRNA expression for p53, Agt, renin, and AT1R. Interestingly, renal tissues of VDR-M as well as VDR heterozygous (h) mice displayed attenuated expression of deacetylase SIRT1. Renal tissues of VDR-M mice showed acetylation of p53 at lysine (K) 382 residues inferring that enhanced p53 expression in renal tissues could be the result of ongoing acetylation, a consequence of SIRT1 deficient state. Notably, podocytes lacking SIRT1 not only showed acetylation of p53 at lysine (K) 382 residues but also displayed enhanced p53 expression. Either silencing of SIRT1/VDR or treatment with high glucose enhanced podocyte PPAR-y expression, whereas, immunoprecipitation (IP) of their lysates with anti-retinoid X receptor (RXR) antibody revealed presence of PPAR-y. It appears that either the deficit of SIRT1 has de-repressed expression of PPAR-y or enhanced podocyte expression of PPAR-y (in the absence of VDR) has contributed to the down regulation of SIRT1. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Royea, Jessika; Zhang, Luqing; Tong, Xin-Kang; Hamel, Edith

    2017-05-31

    The use of angiotensin receptor blockers (ARBs) correlates with reduced onset and progression of Alzheimer's disease (AD). The mechanism depicting how ARBs such as losartan restore cerebrovascular and cognitive deficits in AD is unknown. Here, we propose a mechanism underlying losartan's benefits by selectively blocking the effects of angiotensin IV (AngIV) at its receptor (AT4R) with divalinal in mice overexpressing the AD-related Swedish and Indiana mutations of the human amyloid precursor protein (APP mice) and WT mice. Young (3-month-old) mice were treated with losartan (∼10 mg/kg/d, 4 months), followed by intracerebroventricular administration of vehicle or divalinal in the final month of treatment. Spatial learning and memory were assessed using Morris water mazes at 3 and 4 months of losartan treatment. Cerebrovascular reactivity and whisker-evoked neurovascular coupling responses were measured at end point (∼7 months of age), together with biomarkers related to neuronal and vascular oxidative stress (superoxide dismutase-2), neuroinflammation (astroglial and microglial activation), neurogenesis (BrdU-labeled newborn cells), and amyloidosis [soluble amyloid-β (Aβ) species and Aβ plaque load]. Divalinal countered losartan's capacity to rescue spatial learning and memory and blocked losartan's benefits on dilatory function and baseline nitric oxide bioavailability. Divalinal reverted losartan's anti-inflammatory effects, but failed to modify losartan-mediated reductions in oxidative stress. Neither losartan nor divalinal affected arterial blood pressure or significantly altered the amyloid pathology in APP mice. Our findings identify activation of the AngIV/AT4R cascade as the underlying mechanism in losartan's benefits and a target that could restore Aβ-related cognitive and cerebrovascular deficits in AD.SIGNIFICANCE STATEMENT Antihypertensive medications that target the renin angiotensin system, such as angiotensin receptor blockers (ARBs), have

  9. Cardiac ACE2/angiotensin 1-7/Mas receptor axis is activated in thyroid hormone-induced cardiac hypertrophy.

    Science.gov (United States)

    Diniz, Gabriela P; Senger, Nathalia; Carneiro-Ramos, Marcela S; Santos, Robson A S; Barreto-Chaves, Maria Luiza M

    2016-08-01

    Thyroid hormone (TH) promotes marked effects on the cardiovascular system, including the development of cardiac hypertrophy. Some studies have demonstrated that the renin-angiotensin system (RAS) is a key mediator of the cardiac growth in response to elevated TH levels. Although some of the main RAS components are changed in cardiac tissue on hyperthyroid state, the potential modulation of the counter regulatory components of the RAS, such as angiotensin-converting enzyme type 2 (ACE2), angiotensin 1-7 (Ang 1-7) levels and Mas receptor induced by hyperthyroidism is unknown. The aim of this study was to investigate the effect of hyperthyroidism on cardiac Ang 1-7, ACE2 and Mas receptor levels. Hyperthyroidism was induced in Wistar rats by daily intraperitoneal injections of T4 for 14 days. Although plasma Ang 1-7 levels were unchanged by hyperthyroidism, cardiac Ang 1-7 levels were increased in TH-induced cardiac hypertrophy. ACE2 enzymatic activity was significantly increased in hearts from hyperthyroid animals, which may be contributing to the higher Ang 1-7 levels observed in the T4 group. Furthermore, elevated cardiac levels of Ang 1-7 levels were accompanied by increased Mas receptor protein levels. The counter-regulatory components of the RAS are activated in hyperthyroidism and may be contributing to modulate the cardiac hypertrophy in response to TH. © The Author(s), 2015.

  10. Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.

    Science.gov (United States)

    Hampl, V; Herget, J; Bíbová, J; Baňasová, A; Husková, Z; Vaňourková, Z; Jíchová, Š; Kujal, P; Vernerová, Z; Sadowski, J; Červenka, L

    2015-01-01

    The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT₁) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT₁receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT₁receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.

  11. Effect of chronic treatment with angiotensin receptor ligands on water-salt balance in Wistar and spontaneously hypertensive rats.

    Science.gov (United States)

    Pechlivanova, Daniela M; Stoynev, Alexander G

    2013-01-01

    The renin-angiotensin system plays a crucial role in the regulation of cardiovascular function and maintenance of water-electrolyte balance. The two major receptor types of the system, AT1 and AT2, have different, often opposite effects on these functions. To elucidate the impact of long-term treatment with selective angiotensin receptor antagonists and an agonist on water-salt balance in normotensive Wistar and spontaneously hypertensive rats (SHRs). 12-week-old male Wistar rats and SHRs were individually housed in metabolic cages and 24-h food and water intake and urine and electrolyte excretion were measured. Urinary sodium (UNa), potassium (UK) and chlorine (UCl) were determined by a flame photometer. Losartan, a selective AT1 receptor antagonist, was administered in the Wistar rats and SHRs at a dose of 10 mg/kg/day subcutaneously (sc). Wistar rats were also given the AT2 receptor antagonist, PD123319, subcutaneously at a dose of 10 mg/kg/ day. CGP 42112A, an AT2 receptor agonist, was administered intracerebroventricularly in Wistar rats at a dose of 12 microg/rat/day. The drugs were infused continuously for 14 days through osmotic minipumps. Losartan selectively increased sodium excretion in both rat strains and decreased weight gain in SHRs. PD123319 increased potassium excretion and decreased weight gain in Wistar rats. CGP 42112A increased food and water intake, urine output and UNa+ and UK+ excretion and decreased weight gain in normotensive Wistar rats. Chronic treatment with selective angiotensin receptor ligands modifies water-salt balance in rats through changes both in renal excretory function and ingestive behaviors.

  12. ANGIOTENSIN II RECEPTOR ANTAGONISTS AND ACE INHIBITORS: OPTIMIZATION OF CHOICE FOR TREATMENT OF CARDIOVASCULAR DISEASES

    Directory of Open Access Journals (Sweden)

    E. M. Khurs

    2010-01-01

    Full Text Available Aim. To evaluate the cardioprotective effects of ACE inhibitor, ramipril and angiotensin II receptor antagonist (ARA, valsartan at the cardiovascular continuum (CVC stages.Material and methods. 577 patients were examined. Patients with arterial hypertension (HT (n=283; group 1, with metabolic syndrome (n=137; group 2, with HT associated with ischemic heart disease (n=157; group 3 were randomized into treatment subgroups A (ramipril and B (valsartan. All patients had clinical examination, transthoracic echocardiography with remodeling indexes calculation, ambulatory blood pressure monitoring initially and after 6 months of therapy.Results. Valsartan had priority in prevention of early cardiac remodeling (reduction in left ventricular (LV hypertrophy and myocardial stress, improvement of functional heart parameters at early CVC stage (HT, metabolic syndrome. On the other hand ramipril had priority at advanced stage of CVC (reduction in systolic diameter-thickness ratio, LV hypertrophy, myocardial stress and myocardial stiffness. At the advance stage of CVC valsartan treatment also resulted in significant reduction in LV hypertrophy and myocardial stress, improvement in cardiac remodeling functional parameters but had no effect on LV diameter-thickness ratio.Conclusion. The ARA treatment is preferred at early CVC stage for better cardioprotection.

  13. Regression of experimental endometriotic implants in a rat model with the angiotensin II receptor blocker losartan.

    Science.gov (United States)

    Cakmak, Bulent; Cavusoglu, Turker; Ates, Utku; Meral, Ayfer; Nacar, Mehmet Can; Erbaş, Oytun

    2015-04-01

    Endometriosis is a common disease in women of reproductive age, and many different treatments have been developed, although none has provided a cure. In this study, the efficacy of losartan, an angiotensin II type 1 receptor blocker and an antiangiogenic and anti-inflammatory agent, on regression of experimental endometriotic implants in a rat model was investigated. Peritoneal endometriosis was surgically induced in 16 mature female Sprague-Dawley rats. The peritoneal endometriotic implant was confirmed after 28 days, and the animals were divided randomly into two groups. The control group (n = 8) was given 4 mL/day tap water by oral gavage, and the losartan group (n = 8) was given 20 mg/kg per day losartan p.o. We compared endometriotic implant size, extent and severity of adhesion, as well as plasma and peritoneal lavage fluid cytokine levels including vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-α, plasma inflammatory factor pentraxin-3 (PTX-3) and C-reactive protein (CRP) between the treatment groups. Mean surface endometriotic area, histological score of implants, adhesion formation, plasma VEGF, TNF, PTX-3 and CRP levels were significantly lower in the losartan group compared with control (P losartan group than in the control group (P 0.05). Losartan suppressed the implant surface area of experimental endometriosis in rats and reduced the levels of plasma VEGF, TNF-α, PTX-3 and CRP. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  14. Carotid intima-media thickness and anti-hypertensive treatment: Focus on angiotensin II receptor blockers.

    Science.gov (United States)

    Cuspidi, Cesare; Sala, Carla; Tadic, Marijana; Grassi, Guido; Mancia, Giuseppe

    2018-01-20

    Carotid intima-media thickness (CIMT), as assessed by ultrasonography, has been shown to be directly related to cardiovascular (CV) morbidity and mortality independently of conventional risk factors. Thus, CIMT has been proposed as a marker of CV risk and a surrogate end-point for therapeutic interventions. In the present article we will review available literature about CIMT clinical/prognostic significance in order to offer an updated comprehensive information on this topic. In particular, the anti-atherosclerotic effect of angiotensin II receptor blockers (ARBs) in the hypertensive setting will be addressed, based on findings provided by double blind, randomized, prospective studies comparing CIMT longitudinal changes. Our review, including 8 studies totaling 1154 hypertensive participants, shows that ARBs are as effective as the other classes of antihypertensive drugs in preventing/regressing subclinical carotid damage and that findings supporting their superiority in this field are limited and not univocal. Future studies aimed to clarify the therapeutic impact of ARBs on CIMT changes and their prognostic implications are warranted. Copyright © 2018. Published by Elsevier Ltd.

  15. Drug Interactions with Angiotensin Receptor Blockers: Role of Human Cytochromes P450.

    Science.gov (United States)

    Yang, Ruirui; Luo, Zhiqiang; Liu, Yang; Sun, Mohan; Zheng, Ling; Chen, Yingying; Li, Yanping; Wang, Hao; Chen, Lingzhu; Wu, Ming; Zhao, Huihui

    2016-01-01

    Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. However, ARBs may cause a low incidence of headache, upper respiratory infection, back pain, muscle cramps, fatigue, dizziness, and many other side effects. In some cases, such toxicity is associated with pharmacokinetic alterations. The cytochrome P450 (CYP) enzyme system plays an important role in a lot of clinically important pharmacokinetic drug interactions. To identify relevant studies on drug-drug and food-drug pharmacokinetic interactions with the ARBs, a literature search of Google Scholar was performed from January 1994 to June 2015, with the following keywords: 'losartan', 'valsartan,' 'candesartan,' 'irbesartan,' 'telmisartan,' 'eprosartan,' 'olmesartan,' and 'azilsartan', combined with the keyword 'pharmacokinetic interactions' and 'CYP'. Based on the literatures published, it has been demonstrated that pharmacokinetic interactions of losartan with other agents are mainly via CYP2C9- and CYP3A4-mediated, the role played by CYP enzyme system in the metabolism of valsartan, candesartan, irbesartan, and azilsartan appears modest, and cytochrome P450 system has no influence on the metabolism of telmisartan, eprosartan, olmesartan. Therefore, according to these pharmacokinetic findings, no dosage adjustment is recommended when eprosartan, telmisartan and olmesartan are combined with other pharmacological agents in patients with hypertension. This review summarize the available data on cytochrome P450 - related drug-drug interactions reported in the literature for the eight ARBs. Knowledge of the pharmacokinetic properties of the ARBs should allow the avoidance of the majority of drug interactions without compromising therapeutic benefits.

  16. Angiotensin-(1-7) recruits muscle microvasculature and enhances insulin's metabolic action via mas receptor.

    Science.gov (United States)

    Fu, Zhuo; Zhao, Lina; Aylor, Kevin W; Carey, Robert M; Barrett, Eugene J; Liu, Zhenqi

    2014-06-01

    Angiotensin-(1-7) [Ang-(1-7)], an endogenous ligand for the G protein-coupled receptor Mas, exerts both vasodilatory and insulin-sensitizing effects. In skeletal muscle, relaxation of precapillary arterioles recruits microvasculature and increases the endothelial surface area available for nutrient and hormone exchanges. To assess whether Ang-(1-7) recruits microvasculature and enhances insulin action in muscle, overnight-fasted adult rats received an intravenous infusion of Ang-(1-7) (0, 10, or 100 ng/kg per minute) for 150 minutes with or without a simultaneous infusion of the Mas inhibitor A-779 and a superimposition of a euglycemic insulin clamp (3 mU/kg per minute) from 30 to 150 minutes. Hind limb muscle microvascular blood volume, microvascular flow velocity, and microvascular blood flow were determined. Myographic changes in tension were measured on preconstricted distal saphenous artery. Ang-(1-7) dose-dependently relaxed the saphenous artery (Pmicrovasculature and enhances the metabolic action of insulin. These effects may contribute to the cardiovascular protective responses associated with Mas activation and explain the insulin-sensitizing action of Ang-(1-7).

  17. Angiotensin Receptor Blocker Losartan Inhibits Spontaneous Motility of Isolated Human Ureter.

    Science.gov (United States)

    Jankovic, Slobodan M; Stojadinovic, Dobrivoje; Stojadinovic, Miroslav; Jankovic, Snezana V; Djuric, Janko M; Stojic, Isidora; Kostic, Marina

    2016-12-01

    Ureteral motility is essential for elimination of intraluminal stones, and it may be adversely affected by cardiovascular drugs that a patient is taking chronically. The aim of our study was to test whether ACE inhibitors and an angiotensin receptor blocker may influence spontaneous contractions of isolated human ureter. Both phasic and tonic contractions of the isolated ureteral segments taken from 10 patients were measured as changes of the longitudinal tension or pressure recordings. Captopril, enalapril and losartan were separately added to the organ baths cumulatively. While enalapril (2.7 × 10 -7 -3.9 × 10 -4  M) and captopril (6.1 × 10 -7 -2.7 × 10 -3  M) did not affect either spontaneous activity or tone of isolated ureteral segments, losartan (2.9 × 10 -7 -4.2 × 10 -4  M) caused concentration-dependent inhibition of spontaneous contractions of the segments (50 % effective concentration (EC 50 ) = 13.46 ± 1.80 × 10 -6  M; F = 10.72, r = 0.79, p ureter.

  18. Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

    Directory of Open Access Journals (Sweden)

    Pieter Spincemaille

    2014-10-01

    Full Text Available The human pathology Wilson disease (WD is characterized by toxic copper (Cu accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp. The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.

  19. Candesartan, angiotensin II type 1 receptor blocker is able to relieve age-related cognitive impairment.

    Science.gov (United States)

    Trofimiuk, Emil; Wielgat, Przemysław; Braszko, Jan J

    2017-07-21

    Candesartan is one of the standard antihypertensive drug belonging to AT1R angiotensin receptor blockers (ARBs) group. Beneficial effects of this drug in the treatment of hypertension are well recognized. In this study we tested a hypothesis that candesartan could alleviate age-related memory decline. Aged and young rats have been treated with candesartan (0.1 mg kg-1) for 21 days and then underwent a battery of behavioral tests: for assessment of long-term memory (Passive avoidance test - PA), recognition memory (Object recognition test - OR), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM). Aged rats (2-years-old) displayed clear declining tendency in the retrieval of passive avoidance behavior showing thus increased forgetting. Prolonged administration of candesartan significantly (p candesartan significantly improved recognition memory (p candesartan potently abolishes some kinds of aging-induced memory impairments and cognitive declines in aged rats, but in some circumstances it may even could increase the damage of memory. It seems that the use of sartans in the treatment of hypertension for patients with associated cognitive impairment, or for people in risk groups for such disorders can be an interesting alternative. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  20. Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus.

    Science.gov (United States)

    Pena, Michelle J; Heinzel, Andreas; Rossing, Peter; Parving, Hans-Henrik; Dallmann, Guido; Rossing, Kasper; Andersen, Steen; Mayer, Bernd; Heerspink, Hiddo J L

    2016-07-05

    Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria. Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response. In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p diabetes mellitus.

  1. Properly timed exposure to central ANG II prevents behavioral sensitization and changes in angiotensin receptor expression.

    Science.gov (United States)

    Santollo, Jessica; Whalen, Philip E; Speth, Robert C; Clark, Stewart D; Daniels, Derek

    2014-12-15

    Previous studies show that the angiotensin type 1 receptor (AT1R) is susceptible to rapid desensitization, but that more chronic treatments that stimulate ANG II lead to sensitization of several responses. It is unclear, however, if the processes of desensitization and sensitization interact. To test for differences in AT1R expression associated with single or repeated injections of ANG II, we measured AT1R mRNA in nuclei that control fluid intake of rats given ANG II either in a single injection or divided into three injections spaced 20 min apart. Rats given a single injection of ANG II had more AT1R mRNA in the subfornical organ (SFO) and the periventricular tissue surrounding the anteroventral third ventricle (AV3V) than did controls. The effect was not observed, however, when the same cumulative dose of ANG II was divided into multiple injections. Behavioral tests found that single daily injections of ANG II sensitized the dipsogenic response to ANG II, but a daily regimen of four injections did not cause sensitization. Analysis of (125)I-Sar(1)-ANG II binding revealed a paradoxical decrease in binding in the caudal AV3V and dorsal median preoptic nucleus after 5 days of single daily injections of ANG II; however, this effect was absent in rats treated for 5 days with four daily ANG II injections. Taken together, these data suggest that a desensitizing treatment regimen prevents behavior- and receptor-level effects of repeated daily ANG II. Copyright © 2014 the American Physiological Society.

  2. The effects of angiotensin II receptor antagonist (candesartan on rat renal vascular resistance

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    Supatraviwat, J

    2004-05-01

    Full Text Available The present study aimed to investigate the action of angiotensin II (AII on renal perfusion pressure and renal vascular resistance using noncompetitive AT1-receptor antagonist (candesartan or CV 11974. Experiments were performed in isolated kidney of adult male Wistar rats. Kreb's Henseleit solution was perfused into the renal artery at the rate of 3.5 ml/min. This flow rate was designed in order to maintain renal perfusion pressure between 80-120 mm Hg. Dose-response relationship between perfusion flow rate and AII concentration were studied. Renal perfusion pressure in response to 1, 10 and 100 nM AII were increased from basal perfusion pressure of 94±8 mm Hg to 127±6, 157±12 and 190±16 mm Hg, respectively. Administration of perfusate containing 11.4 μM candesartan for 30 min had no effect on the basal perfusion pressure. However, this significantly reduced renal perfusion pressure in the presence of AII (1, 10 and 100 nM by 39%, 47% and 61%, (n=7, P<0.05 respectively. At the basal perfusion pressure, calculated renal vascular resistance was 27±2 mm Hg · min · ml-1. However, the vascular resistance were found to be 41±1, 45±2 and 47±2 mm Hg · min · ml-1 when 1, 10 and 100 nM AII were added. Moreover, this dose of candesartan also showed a significant decrease in renal vascular resistance at the corresponding doses of AII by 38%, 48% and 43%, (n=7, P<0.05 respectively. The higher dose of candesartan (22.7 μM completely inhibited the action of 1, 10 and 100 nM AII on renal vasoconstriction. These results may indicate that the action of AII on renal vascular resistance is via AT1-receptor, at least in rat isolated perfusion kidney.

  3. Effects of Antihypertensive Agents on Intestinal Contractility in the Spontaneously Hypertensive Rat: Angiotensin Receptor System Downregulation by Losartan.

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    Patten, Glen Stephen; Abeywardena, Mahinda Yapa

    2017-02-01

    Hypertension is an inflammatory condition controlled by the renin angiotensin system and is linked to kidney disease, diabetes mellitus, and recently to dysfunction of the gut. The aim of this study was to determine what effect antihypertensive drug treatments may have on intestinal function of the spontaneously hypertensive rat (SHR). In the first experiment, SHRs were treated with enalapril, hydralazine, or with no treatment as a control. In the second experiment, SHRs were treated with losartan or with no treatment as a control. All drug treatments led to significant lowering of blood pressure after 16 weeks. At termination, intact tissue sections of the ileum and colon were induced to contract ex vivo by KCl; electrical stimulation; and agonists carbachol, angiotensin II, and prostaglandin E2 (PGE2). There were no differences in ileal or colonic contractility due to hydralazine or enalapril compared with no-treatment SHR control. However, for the ileum, the losartan group responded significantly more to KCl and carbachol while responding less to angiotensin II, with no difference for PGE2 compared with the no-treatment SHR control. In contrast, the colon responded similarly to KCl, electrical stimulation, and PGE2 but responded significantly less to angiotensin II. These results demonstrate that the ileum responds differently (with KCl and carbachol as agonists) to the colon after losartan treatment, whereas there is a reduced contractile response in both the ileum and colon following losartan treatment. Although there are few well documented major contraindications for angiotensin receptor blockers, the modulation of gut contractility by losartan may have wider implications for bowel health. Copyright © 2017 by The Author(s).

  4. Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.

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    Luo, Jinghong; Chen, Xuanlan; Luo, Chufan; Lu, Guihua; Peng, Longyun; Gao, Xiuren; Zuo, Zhiyi

    2017-04-01

    Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects. © 2016 John Wiley & Sons Ltd.

  5. Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats.

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    Zhou, Jin; Ando, Hiromichi; Macova, Miroslava; Dou, Jingtao; Saavedra, Juan M

    2005-07-01

    Endothelial dysfunction and inflammation enhance vulnerability to hypertensive brain damage. To explore the participation of Angiotensin II (Ang II) in the mechanism of vulnerability to cerebral ischemia during hypertension, we examined the expression of inflammatory factors and the heat shock protein (HSP) response in cerebral microvessels from spontaneously hypertensive rats and their normotensive controls, Wistar Kyoto rats. We treated animals with vehicle or the Ang II AT(1) receptor antagonist candesartan, 0.3 mg/kg/day, via subcutaneously implanted osmotic minipumps for 4 weeks. Spontaneously hypertensive rats expressed higher Angiotensin II AT(1) receptor protein and mRNA than normotensive controls. Candesartan decreased the macrophage infiltration and reversed the enhanced tumor necrosis factor-alpha and interleukin-1beta mRNA and nuclear factor-kappaB in microvessels in hypertensive rats. The transcription of many HSP family genes, including HSP60, HSP70 and HSP90, and heat shock factor-1 was higher in hypertensive rats and was downregulated by AT(1) receptor blockade. Our results suggest a proinflammatory action of Ang II through AT(1) receptor stimulation in cerebral microvessels during hypertension, and very potent antiinflammatory effects of the Ang II AT(1) receptor antagonist. These compounds might be considered as potential therapeutic agents against ischemic and inflammatory diseases of the brain.

  6. IN SILICO EVALUATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST’S PLASMA PROTEIN BINDING USING COMPUTED MOLECULAR DESCRIPTORS

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    Jadranka Odović

    2014-03-01

    Full Text Available The discovery of new pharmacologically active substances and drugs modeling led to necessity of predicting drugs properties and its ADME data. Angiotensin II receptor antagonists are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system and today represent the most commonly prescribed anti-hypertensive drugs. The aim of this study was to compare different molecular properties of seven angiotensin II receptor antagonists / blockers (ARBs, (eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their plasma protein binding (PPB data. Several ARBs molecular descriptors were calculated using software package Molinspiration Depiction Software as well as Virtual Computational Chemistry Laboratory (electronic descriptor – PSA, constitutional parameter – Mw, geometric descriptor – Vol, lipophilicity descriptors - logP values, aqueous solubility data – logS. The correlations between all collected descriptors and plasma protein binding data obtained from relevant literature were established. In the simple linear regression poor correlations were obtained in relationships between PPB data and all calculated molecular descriptors. In the next stage of the study multiple linear regression (MLR was used for correlation of PPB data with two different descriptors as independent variables. The best correlation (R2=0.70 with P<0.05 was established between PPB data and molecular weight with addition of volume values as independent variables. The possible application of computed molecular descriptors in drugs protein binding evaluation can be of great importance in drug research.

  7. Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries

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    Hoa Ytterberg

    2001-03-01

    Full Text Available Enhanced responses to vasoconstriction induced by neuropeptide Y and α2-adrenoceptor agonists have been seen following pharmacological activation of the adenylyl cyclase (AC system. Since preliminary studies revealed only minor responses to angiotensin II (Ang II in human omental arteries, we have investigated whether enhanced activity of AC may unravel further functional Ang II receptors. Human omental arteries were obtained in conjunction with elective gut surgery. After dissection of the vessel, the endothelium was removed by 10 sec of Triton X-100 treatment. Ring segments (1—2 mm long were mounted on a myograph and studied. Ang II produced small contractions, 27±5% relative to the response elicited by 60 mM K+. However, enhanced Ang II (105±10%, p<0.001 responses were seen during AC activation by forskolin (0.1—1 µM. This enhanced contractile response to Ang II was not inhibited by the angiotensin II type 2 (AT2-receptor antagonist PD 123319 (0.1 µM, but was blocked in an insurmountable way by the angiotensin II type 1 (AT1-receptor antagonist candesartan (1 nM and in a surmountable manner by losartan (0.1 µM and irbesartan (0.1 µM. Pertussis toxin (a Gi-protein blocker and the protein kinase C inhibitor, RO31—8220 (0.01, 0.1 and 1 µM, markedly reduced this response, while the protein kinase A inhibitor, H89 (1, 10 µM, had no effect. RT-PCR provided evidence for the presence of mRNA for both AT1- and AT2-receptors. The results suggest that both a cAMP-dependent and a cAMP-independent mechanism are involved in the contractile responses to Ang II in human omental arteries and that both responses are mediated via the AT1-receptor.

  8. Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge

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    Andrew M Allen

    2001-03-01

    Full Text Available Microinjections of angiotensin II (Ang II into the rostral ventrolateral medulla (RVLM induce a sympathetically-mediated increase in blood pressure (BP, through an interaction with AT1-receptors. Under basal conditions in anaesthetised animals, microinjections of AT 1-receptor antagonists into the RVLM have little, or no effect on BP, suggesting that the angiotensin input to this nucleus is not tonically active. In contrast, microinjections of AT1-receptor antagonists into the RVLM of sodium-deplete rats and TGR(mRen227 rats, induce a depressor response through sympatho-inhibition. This indicates that when the renin-angiotensin system is activated, angiotensin can act in the RVLM to support sympathetic nerve discharge and BP. This study examined whether angiotensin inputs to the RVLM are activated in the spontaneously hypertensive rat — a pathophysiological model which displays increases in both brain angiotensin levels and sympathetic nerve activity. Bilateral microinjections of the AT 1-receptor antagonist candesartan cilexetil, (1 nmol in 100 nl, into the RVLM of the spontaneously hypertensive rat induced a significant decrease in lumbar sympathetic nerve discharge (-18±2% and BP (140±6 to 115±6 mmHg. In contrast, similar microinjections in the Wistar-Kyoto (WKY rat had no effect on BP or sympathetic nerve discharge. These results are interpreted to suggest that Ang II inputs to the RVLM are activated in the spontaneously hypertensive rat to maintain an elevated level of sympathetic nerve discharge, even in the face of increased BP.

  9. Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

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    Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

    2014-01-01

    To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

  10. Angiotensin II receptor blockers and risk of acute pancreatitis - a population based case-control study in Sweden.

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    Bexelius, Tomas S; Ljung, Rickard; Mattsson, Fredrik; Lu, Yunxia; Lindblad, Mats

    2017-03-07

    Acute pancreatitis is a potentially lethal disease, with a rising incidence in the Western world. Yet, no pharmacological prevention or specific treatment for acute pancreatitis exists. Also, the connection with severity of acute pancreatitis is unknown. Experimental and epidemiological research suggests a protective effect of angiotensin II receptor blockers. During 2006 to 2008, we performed a nationwide case-control study on Swedish residents aged 40-84 years. First-time cases with acute pancreatitis were identified in the National Patient Register and data on dispensed prescriptions was retrieved from the Prescribed Drug Register. Controls were randomly selected from the general population in Sweden frequency-matched on sex, age, and calendar year. To estimate relative risk of acute pancreatitis, by degree of severity, among users of angiotensin II receptor blockers, as compared to non-users, we used multivariable logistic regression analysis to calculate odds ratios (OR) with 95% confidence interval (CI). Among 6,161 cases of acute pancreatitis and 61,637 controls, current use of angiotensin II receptor blockers was followed by a decreased risk of acute pancreatitis, compared to non-users, adjusted OR 0 · 77 (95% CI 0 · 69-0 · 86). No protective association, but an increased risk was found for users of angiotensin-converting enzyme inhibitors (adjusted OR 1 · 11, 95% CI: 1 · 01-1 · 21), analysed for comparison reasons. There was a significant decreased risk associated with both severe acute pancreatitis, (OR 0 · 71 (0 · 59-0 · 85), and mild acute pancreatitis; adjusted OR 0 · 81 (0 · 70-0 · 94). This population-based case-control study indicates that use of angiotensin II receptor blockers might be associated with a lesser risk of acute pancreatitis, and that the protective association was significant among cases of both severe and mild acute pancreatitis.

  11. The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research.

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    Rodrigues Prestes, Thiago Ruiz; Rocha, Natalia Pessoa; Miranda, Aline Silva; Teixeira, Antônio Lúcio; Simoes-E-Silva, Ana Cristina

    2017-01-01

    The renin angiotensin system (RAS) plays an important role in inflammation and fibrosis. The classical axis of the RAS, formed by angiotensin converting en-zyme (ACE), angiotensin II (Ang II) and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signaling pathways related to tissue injury, inflammation and fibrosis. In sharp contrast, the RAS axis composed by angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor exerts opposite effects in relation to inflammatory response and tissue fibrosis. In this review, we have the aim to summarize recent findings on the anti-inflammatory and anti-fibrogenic role of ACE2/Ang-(1-7)/Mas axis in the context of basic research, experimental human dis-eases and clinical studies. Several studies showed that ACE2/Angiotensin-(1-7)/Mas axis reduces cytokine release and inhibits signaling pathways of tissue fibrosis in experimental models of human diseases including atherosclerosis, cerebral ischemia, obesity, chronic kidney disease, liver diseases and asthma. On the other hand, very few data was provided by clinical studies. Experimental studies clearly support the anti-inflammatory and anti-fibrotic effects of ACE2/ Ang-(1-7)/Mas axis. Clinical studies, especially phase III and IV trials, will be necessary to establish the therapeutic role of ACE2/Ang-(1-7)/Mas axis in controlling inflammation in different human diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. The influence of angiotensin-(1-7) Mas receptor agonist (AVE 0991) on mitochondrial proteome in kidneys of apoE knockout mice.

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    Suski, Maciej; Olszanecki, Rafał; Stachowicz, Aneta; Madej, Józef; Bujak-Giżycka, Beata; Okoń, Krzysztof; Korbut, Ryszard

    2013-12-01

    Excessive action of angiotensin II on mitochondria has been shown to play an important role in mitochondrial dysfunction, a common feature of atherogenesis and kidney injury. Angiotensin-(1-7)/Mas receptor axis constitutes a countermeasure to the detrimental effects of angiotensin II on AT1 receptors. The aim of the study was to assess the effects of angiotensin-(1-7) peptidomimetic AVE0991 on the kidney mitochondrial proteome in widely used animal model of atherosclerosis (apoE(-/-) mice). Proteins changed in apoE(-/-) mice belonged to the groups of antioxidant enzymes, apoptosis regulators, inflammatory factors and metabolic enzymes. Importantly, AVE0991 partially reversed atherosclerosis-related changes in apoE(-/-) mice. © 2013.

  13. The effect of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use on mortality in patients with chronic kidney disease: a meta-analysis of observational studies.

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    Qin, Yuchen; Chen, Tao; Chen, Qi; Lv, Jia Yi; Qi, Na; Wu, Cheng; He, Jia

    2016-05-01

    There has been much controversy over the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) on patients with renal dysfunction. The purpose of this study was to summarize the evidence regarding the effect of ACEIs/ARBs administration on mortality in patients with nondialysis-dependent chronic kidney disease (CKD) by using a meta-analytic approach. We searched the PubMed, Embase, and Web of Science databases for studies on the effect of ACEIs/ARBs administration on mortality in patients with nondialysis-dependent CKD published before March 2015. Summary effect estimates with 95% confidence intervals were derived using the random-effects model, no matter whether the heterogeneity between the included studies was of statistical significance or not. Subgroup analyses, sensitivity analyses, and publication bias tests were performed. Up to 25 March 2015, 10 cohort studies were included in this meta-analysis. The hazard risk of the association between ACEIs/ARBs administration and overall mortality was 0.83 (95% confidence interval 0.78-0.87) using a random-effects model with no heterogeneity (heterogeneity test I(2)  = 43.8%, p = 0.067) and publication bias (Egger's test, p = 0.763). The subgroup was divided according to estimated glomerular filtration rate, duration of follow-up, Newcastle-Ottawa Scale star, and proportion of patients with common complications including heart failure, diabetes mellitus, and hypertension. Improved survival outcomes were observed in all subgroups analysis. Sensitivity analysis proved that overall estimated effect was robust. This meta-analysis suggested that the use of ACEIs/ARBs in patients with nondialysis-dependent CKD was associated with improved survival. However, randomized studies are needed to confirm these findings and further establish causal relationship. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease.

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    Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

    2016-01-01

    Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (t(Na)), although 24-hour urinary Na excretion (U(Na)V) remained constant. Daily urinary angiotensinogen excretion (U(AGT)V, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r(2)=0.26) and t(Na) (r(2)=0.25) correlated with baseline 24-hour U(AGT)V. Changes in filtered Na load correlated with changes in nighttime systolic BP (r(2)=0.17), but not with changes in daytime systolic BP. The change in the t(Na) to filtered Na load ratio was influenced by the change in daytime U(Na)V (β=-0.67, F=16.8), rather than the change in nighttime U(Na)V. Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of U(AGT)V by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. © The Author(s) 2016.

  15. Gene polymorphism of endothelial NO-synthase, angiotensin-converting enzyme and receptors of angiotensin II type 1 in patients with coronary artery disease and type II diabetes

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    Yakovleva L.M.

    2013-12-01

    Full Text Available Purpose: to study the clinical manifestations of coronary artery disease (CAD in patients with diabetes mellitus (DM II type and the possible association of mutations in the genes of endothelial NO-synthase (eNOS, angiotensin-converting enzyme (ACE and receptor of angiotensin II type 1 (AT2R1 with the development of type II diabetes in these patients. Mate¬rials and methods. The study involved 318 patients with CAD, of whom 54 (17,0% patients had type II DM and 264 (83,0% patients -without diabetes. Study of allelic polymorphism of T-786S of eNOS gene promoter, insertion-deletion (I/D polymorphism of ACE gene and polymorphism A1166S of AT2R1 gene was performed by polymerase chain reaction. Results. In patients with CAD and DM type II such risk factors as hypertension, obesity, family history with early onset of cardiovascular disease were significantly more common; CAD manifestation occurs at a younger age, myocardial ischemia more often has silent nature. In the presence of type II DM, coronary artery lesions were of diffuse and multivessel character, other vascular pools are often involved in the atherosclerotic process. An independent as¬sociation of type II diabetes with hypertension, obesity, and CC genotype of eNOS gene T-786S polymorphism was identified in patients with CAD. Negative independent influence of ACE gene I/D polymorphism of D allele and AT2R1 gene A1166S polymorphism C allele on renal function in patients with CAD and type II DM was proved.

  16. Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis.

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    Fu-An Chen

    Full Text Available Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I, angiotensin receptor blocker (ARB, and calcium channel blocker (CCB are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive.We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF or arteriovenous graft (AVG creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications.Total 42244 patients were enrolled in this study, 37771 (89.4% used AVF, 4473 (10.6% used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR 0.586, 95% confidence interval (CI 0.557-0.616 for ACE-I use; HR 0.532, CI 0.508-0.556 for ARB use; HR 0.485, CI 0.470-0.501 for CCB use] and AVG (HR 0.557, CI 0.482-0.643 for ACE-I use, HR 0.536, CI 0.467-0.614 for ARB use, HR 0.482, CI 0.442-0.526 for CCB use.In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality.

  17. Effect of preoperative angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use on hemodynamic variables in pediatric patients undergoing cardiopulmonary bypass.

    Science.gov (United States)

    Ajuba-Iwuji, Chinwe C; Puttreddy, Sahitya; Maxwell, Bryan G; Bembea, Melania; Vricella, Luca; Heitmiller, Eugenie

    2014-10-01

    Some have suggested that children undergoing cardiac surgery who receive angiotensin-converting enzyme (ACE) inhibitors experience a greater degree of hypotension after anesthesia induction and in the immediate postcardiopulmonary bypass period than children who did not receive these drugs. Therefore, we examined the effect of ACE inhibitor/angiotensin II receptor blocker (ARB) therapy on intraoperative hemodynamics and vasopressor use in pediatric patients undergoing cardiac surgery. In a retrospective cohort study of patients younger than 18 years who underwent cardiopulmonary bypass between March 1, 2010, and April 1, 2011, we compared intraoperative hemodynamics and vasopressor use between patients who received preoperative ACE inhibitor/ARB therapy and those who did not. The primary outcome was vasoactive infusion score after cardiopulmonary bypass. The occurrence of hypotension did not differ significantly between the ACE inhibitor/ARB group and the control group during induction of anesthesia or at any time point after cardiopulmonary bypass. At 0, 30, 60, and 90 minutes after cessation of cardiopulmonary bypass, patients on ACE inhibitor/ARB therapy tended to have a higher vasoactive infusion score (7.1, 7.6, 9.4, and 11.3) than patients in the control group (6.3, 6.1, 6.0, and 6.7). Although this difference became more pronounced over time, it did not reach statistical significance. The use of preoperative ACE inhibitors and ARBs in pediatric patients undergoing cardiac surgery did not significantly increase the incidence of hypotension after induction of anesthesia and did not increase significantly the vasoconstrictor requirements upon weaning from cardiopulmonary bypass; however, additional prospective studies are needed. © The Author(s) 2014.

  18. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

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    John D Bisognano

    2007-11-01

    Full Text Available John D Bisognano1, Trent McLaughlin2, Craig S Roberts3, Simon SK Tang31Internal Medicine Department, Cardiology Division, the University of Rochester Medical Center, Rochester, NY, USA; 2NDC Health, Phoenix, Arizona, USA; 3Pfizer Inc, New York, NY, USAAbstract: This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs, angiotensin-converting enzyme (ACE inhibitors, and angiotensin receptor blockers (ARBs added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were –17.5/–8.8, –15.7/–6.3, and –13.0/–8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs.Keywords: hypertension, amlodipine besylate, lisinopril, valsartan, Joint National Committee (JNC 6 and 7

  19. The expression of angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats.

    Science.gov (United States)

    Lu, Jie; Jiang, Teng; Wu, Liang; Gao, Li; Wang, Yao; Zhou, Feng; Zhang, Shugang; Zhang, Yingdong

    2013-10-01

    There is now unequivocal evidence that the angiotensin-converting enzyme 2(ACE2)-Ang-(1-7)-Mas axis is a key component of the renin-angiotensin system (RAS) cascade, which is closely correlated with ischemic insult occurrence. Our previous studies demonstrated that the Ang-(1-7), was an active member of the brain RAS. However, the ACE2-Ang-(1-7)-Mas axis expression after cerebral ischemic injury are currently unclear. In the present study, we investigated the time course of ACE2-Ang-(1-7) and Mas receptor expression in the acute stage of cerebral ischemic stroke. The content of Ang-(1-7) in ischemic tissues and blood serum was measured by specific EIA kits. Real-time PCR and western blot were used to determine messenger RNA (mRNA) and protein levels of the ACE2 and Mas. The cerebral ischemic lesion resulted in a significant increase of regional cerebral and circulating Ang-(1-7) at 6-48 h compared with sham operation group following focal ischemic stroke (12h: 7.276±0.320 ng/ml vs. 2.466±0.410 ng/ml, serum; 1.024±0.056 ng/mg vs. 0.499±0.032, brain) (PMas expression were markedly enhanced compared to the control in the ischemic tissues (PMas immunopositive neurons were also seen stronger expression in the ischemic cortex (19.167±2.858 vs. 7.833±2.483) (PMas axis are upregulated after acute ischemic stroke and would play a pivotal role in the regulation of acute neuron injury in ischemic cerebrovascular diseases. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  20. Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.

    Science.gov (United States)

    Harikumar, Kaleeckal G; Augustine, Mary Lou; Lee, Leo T O; Chow, Billy K C; Miller, Laurence J

    2016-08-12

    Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these cross-class complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

    2009-01-01

    PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive...

  2. Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area

    Directory of Open Access Journals (Sweden)

    Antunes V.R.

    1998-01-01

    Full Text Available In this study we investigated the effects of the injection into the supraoptic nucleus (SON of non-peptide AT1- and AT2-angiotensin II (ANG II receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP receptor antagonist d(CH25-Tyr(Me-AVP, on water and 3% NaCl intake induced by the injection of ANG II into the medial septal area (MSA. The effects on water or 3% NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 ml over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65%, N = 10, P<0.01 and sodium intake (81%, N = 8, P<0.01 induced by the injection of ANG II (10 nmol into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45%, N = 9, P<0.01, ANG II-induced sodium intake was significantly increased (70%, N = 8, P<0.01 following injection of the V1-type vasopressin antagonist d(CH25-Tyr(Me-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses.

  3. Angiotensin II Type 1 and Type 2 Receptors Play Opposite Roles in Regulating the Barrier Function of Kidney Glomerular Capillary Wall

    OpenAIRE

    Suzuki, Koichi; HAN, Gi Dong; Miyauchi, Naoko; Hashimoto, Taeko; Nakatsue, Takeshi; FUJIOKA, Yumiko; Koike, Hiroko; Shimizu, Fujio; Kawachi, Hiroshi

    2007-01-01

    Although angiotensin II (Ang II) type 1 receptor antagonist ameliorates proteinuria, its pharmacological mechanism and the differential roles of Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R) are not well understood. We analyzed the effect of Ang II type 1 receptor antagonist on proteinuria caused by antibody against nephrin, a functional molecule of glomerular slit diaphragm and dysfunction of which is involved in the development of proteinuria in several glomerular diseases. We sh...

  4. Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.

    Directory of Open Access Journals (Sweden)

    Yasunori Iida

    Full Text Available BACKGROUND: Despite the importance of the renin-angiotensin (Ang system in abdominal aortic aneurysm (AAA pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. METHODOLOGY/PRINCIPAL FINDINGS: AAAs were induced using either 1 Ang II subcutaneous infusion (1000 ng/kg/min for 28 days in male ApoE(-/- mice, or 2 transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg, telmisartan (10 mg/kg, fluvastatin (40 mg/kg, bosentan (100 mg/kg, doxycycline (100 mg/kg or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE(-/- mice fed with standard chow and water alone (n = 15, and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14. Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. CONCLUSION/SIGNIFICANCE: Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

  5. Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis

    Science.gov (United States)

    Gundlach, Enken; Hoffmann, Michael Marcus; Prasse, Antje; Heinzelmann, Sonja; Ness, Thomas

    2016-01-01

    Purpose To study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients. Design Retrospective study. Methods Serum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis. Main Outcome Measure Our main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis. Results We measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis. Conclusions An elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients. PMID:26799486

  6. Angiotensin AT(2 receptor contributes towards gender bias in weight gain.

    Directory of Open Access Journals (Sweden)

    Preethi Samuel

    Full Text Available Obesity is a major disease condition, in turn leading to pathological changes collectively recognized as metabolic syndrome. Recently angiotensin receptor AT(2R has been associated negatively with body weight (BW gain in male mice. However, the gender differences in AT(2R and BW changes have not been studied. To understand the gender based role of AT(2R involving BW changes, we fed male and female wild type (WT and AT(2R knock out (AT(2KO mice with C57BL6 background with high fat diet (HFD for 16 weeks. The male AT(2KO had higher HFD calorie intake (WT: 1280±80; AT(2KO:1680±80 kcal but gained less BW compared with the WT (WT: 13; AT(2KO: 6 g. Contrary to the male animals, the female AT(2KO mice with equivalent caloric intake (WT: 1424±48; AT(2KO:1456±80 kcal gained significantly more BW than the WT mice (WT: 9 g; AT(2KO: 15 g. The male AT(2KO on HFD displayed lower plasma insulin level, less impaired glucose tolerance (GT, and higher plasma T3 compared with WT males on HFD; whereas the female AT(2KO mice on HFD showed elevated levels of plasma insulin, more impaired GT, lower plasma T3 and higher free fatty acid and hepatic triglycerides compared with WT females on HFD. Interestingly, compared with WT, AT(2KO female mice had significantly lower estrogen, which was further reduced by HFD. These results suggest that AT(2R in female mice via potentially regulating estrogen may have protective role against BW gain and impaired glucose tolerance and lipid metabolism.

  7. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.

    Science.gov (United States)

    Lapi, Francesco; Azoulay, Laurent; Yin, Hui; Nessim, Sharon J; Suissa, Samy

    2013-01-08

    To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. Retrospective cohort study using nested case-control analysis. General practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. A cohort of 487,372 users of antihypertensive drugs. Rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs. During a mean follow-up of 5.9 (SD 3.4) years, 2215 cases of acute kidney injury were identified (incidence rate 7/10,000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46). A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs.

  8. Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

    Directory of Open Access Journals (Sweden)

    Motoharu Hayashi

    Full Text Available A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1, tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1 and glucose transporter 4 (GLUT4 in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results

  9. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Sumners, C.; Wei Tang; Zelezna, B.; Raizada, M.K. (Univ. of Florida, Gainesville (United States))

    1991-09-01

    Both neurons and astrocytes contain specific receptors for angiotensin II (AII). The authors used selective ligands for the AT{sub 1} and AT{sub 2} types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of {sup 125}I-labeled AII ({sup 125}I-AII) specific binding with AT{sub 1} (DuP753) or AT{sub 2} {l brace}PD123177, CGP42112A, (Phe(p-NH{sub 2}){sup 6})AII{r brace} selective receptor ligands revealed a potency series of AII > DuP753 > > > CGP42112A > (Phe(p-NH{sub 2}){sup 6})AII > PD123177. These results suggest a predominance of the AT{sub 1} receptor subtype in neonatal astrocytes. {sup 125}I-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1 {mu} MPD123177, and the residual {sup 125}I-AII specific binding was eliminated by DuP753. The results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT{sub 1} receptors that are coupled to a stimulation of inositophospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT{sub 2} receptors that are coupled to a reduction in basal cGMP levels, but a smaller population of AT{sub 1} receptors is also present in these neurons.

  10. Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Lihua; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Yang, Yang [Department of General Surgery, Xingqiao Hospital, Third Military Medical University, Chongqing 400037 (China); Yang, Hua, E-mail: hwbyang@126.com [Department of General Surgery, Xingqiao Hospital, Third Military Medical University, Chongqing 400037 (China)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. Black-Right-Pointing-Pointer The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. Black-Right-Pointing-Pointer GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. Black-Right-Pointing-Pointer GATA-6 may play a critical role in apoptosis in response to the Ang II challenge. -- Abstract: Angiotensin II (Ang II) has been shown to play an important role in cell apoptosis. However, the mechanisms of Ang-II-induced apoptosis in intestinal epithelial cells are not fully understood. GATA-6 is a zinc finger transcription factor expressed in the colorectal epithelium, which directs cell proliferation, differentiation and apoptosis. In the present study we investigated the underlying mechanism of which GATA-6 affects Ang-II induced apoptosis in intestinal epithelial cells. The in vitro intestinal epithelial cell apoptosis model was established by co-culturing Caco-2 cells with Ang II. Pretreatment with Angiotensin type 2 (AT2) receptor antagonist, PD123319, significantly reduced the expression of Bax and prevented the Caco-2 cells apoptosis induced by Ang II. In addition, Ang II up-regulated the expression of GATA-6. Interestingly, GATA-6 short hairpin RNA prevented Ang II-induced intestinal epithelial cells apoptosis and reduced the expression of Bax, but not Bcl-2. Taken together, the present study suggests that Angiotensin II promotes apoptosis in intestinal epithelial cells through GATA-6 and the Bax pathway in an AT2 receptor-dependent manner.

  11. Intrarenal Mas and AT1 receptors play a role in mediating the excretory actions of renal interstitial angiotensin-(1-7) infusion in anaesthetized rats.

    Science.gov (United States)

    O'Neill, Julie; Healy, Vincent; Johns, Edward J

    2017-09-21

    What is the central question of this study? Dietary sodium manipulation alters the magnitude of angiotensin-(1-7) [Ang-(1-7)]-induced natriuresis. The present study sought to determine whether this was related to relative changes in the activity of intrarenal Mas and/or AT1 receptors. What is the main finding and its importance? Angiotensin-(1-7)-induced diuresis and natriuresis is mediated by intrarenal Mas receptors. However, intrarenal AT1 receptor blockade also had an inhibitory effect on Ang-(1-7)-induced natriuresis and diuresis. Thus, Ang-(1-7)-induced increases in sodium and water excretion are dependent upon functional Mas and AT1 receptors. We investigated whether angiotensin-(1-7) [Ang-(1-7)]-induced renal haemodynamic and excretory actions were solely dependent upon intrarenal Mas receptor activation or required functional angiotensin II type 1 (AT1 ) receptors. The renin-angiotensin system was enhanced in anaesthetized rats by prior manipulation of dietary sodium intake. Angiotensin-(1-7) and AT1 and Mas receptor antagonists were infused into the kidney at the corticomedullary border. Mas receptor expression was measured in the kidney. Mean arterial pressure, urine flow and fractional sodium excretion were 93 ± 4 mmHg, 46.1 ± 15.7 μl min(-1)  kg(-1) and 1.4 ± 0.3%, respectively, in the normal-sodium group and 91 ± 2 mmHg, 19.1 ± 3.3 μl min(-1)  kg(-1) and 0.7 ± 0.2%, respectively, in the low-sodium group. Angiotensin-(1-7) infusion had no effect on mean arterial pressure in rats receiving a normal-sodium diet but decreased it by 4 ± 5% in rats receiving a low-sodium diet (P Mas receptor inhibition after either losartan or A-779, respectively. Thus, AT1 receptor activation, as well as Mas receptor activation, plays an essential role in mediating Ang-(1-7)-induced natriuresis and diuresis. Whether this is because Ang-(1-7) partly antagonizes AT1 receptors or whether Ang-(1-7)-induced natriuresis is mediated through AT1

  12. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Edvinsson, Lars; Chen, Qingwen

    2009-01-01

    expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina...... pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...

  13. G protein-independent effects of the Angiotensin II type I receptor

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund

    2010-01-01

    Angiotensin II type 1 receptoren (AT1R) er en syv transmembranreceptor (7TMR) og et vigtigt terapeutisk target indenfor kardiovaskulær medicin. AT1R er gennem de seneste år blevet en model for det concept, at 7TMRer kan signalere via andre og mindre velbeskrevne signalveje end de G protein...... SII Angiotensin II (SII Ang II). På baggrund af massespektrometrianalyse fremlægger vi data som giver ny indsigt i Angotensin II’s (Ang II) signaltransduktion og som samtidig viser forskellen mellem fuld AT1R aktivering med Ang II og G protein uafhængig aktivering med SII Ang II. Resultaterne viser...

  14. Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor.

    Science.gov (United States)

    Zhang, Wei-Wei; Bai, Feng; Wang, Jin; Zheng, Rong-Hua; Yang, Li-Wang; James, Erskine A; Zhao, Zhi-Qing

    2017-01-01

    Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, preceptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, preceptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure.

  15. A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery.

    Science.gov (United States)

    Hollmann, Caryl; Fernandes, Nicole L; Biccard, Bruce M

    2018-01-29

    The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity. This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay. After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval

  16. Prescriptions for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and monitoring of serum creatinine and potassium in patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Pei-Tzu Wang

    2012-09-01

    Full Text Available Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs are commonly used in patients with chronic kidney disease (CKD. We studied the status of ACEI/ARB prescriptions and serum creatinine (Scr and potassium monitoring in CKD patients. A retrospective observational study was conducted on patients who had at least two sets of Scr data at outpatient visit. Estimated glomerular filtration rate (eGFR based on the second Scr value was calculated using the Modification of Diet in Renal Disease four-variable equation. CKD was defined and staged according to the National Kidney Foundation Disease Outcomes Quality Initiative Guideline. Patients with diabetes and/or hypertension with an eGFR over 60 mL/min/1.73 m2 and without proteinuria were defined as the CKD-at-risk group. The percentages and factors associated with ACEI/ARB prescription and Scr and potassium monitoring were calculated and analyzed by logistic regression. Among the 5714 subjects included, ACEIs/ARBs were prescribed to over 50% of patients in the CKD-at-risk group and in CKD stages 1–5. After adjusting for age, sex, potassium level, eGFR, and co-morbidities, the odds ratios for prescriptions of ACEIs/ARBs were 1.66 [95% confidence interval (CI 1.44–1.91, p < 0.001 and 2.80 (95% CI 2.12–3.70, p < 0.001 in CKD stage 3, and stages 4 and 5, respectively, compared with the reference group (eGFR≥60 mL/min/1.73 m2. During the year of ACEI/ARB treatment, Scr was monitored in 91.6% of ACEI/ARB-treated patients, while potassium was monitored in only 38.1%. Renal function status was the independent factor for monitoring of Scr and potassium. In conclusion, prescription of ACEIs/ARBs was common in all stages of CKD. Most patients underwent Scr monitoring, but potassium monitoring was less frequent, and this should be improved in clinical practice.

  17. Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice.

    Science.gov (United States)

    de Kloet, Annette D; Pitra, Soledad; Wang, Lei; Hiller, Helmut; Pioquinto, David J; Smith, Justin A; Sumners, Colin; Stern, Javier E; Krause, Eric G

    2016-08-01

    It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound 21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure.

  18. Short-term oral treatment with the angiotensin II receptor antagonist losartan does not improve coronary vasomotor function in asymptomatic type 2 diabetes patients

    DEFF Research Database (Denmark)

    Kjaer, Andreas; Kristoffersen, Ulrik Sloth; Tarnow, Lise

    2009-01-01

    BACKGROUND: We have previously found that acute intravenous infusion of an ACE inhibitor normalized the reduced coronary vasomotor function in type 2 diabetes. The aim of the present study was to extend this investigation to an angiotensin II receptor blocker (ARB) administered orally in normoten...... with an ARB did not normalize coronary vasomotor function in type 2 diabetes patients without cardiovascular disease.......BACKGROUND: We have previously found that acute intravenous infusion of an ACE inhibitor normalized the reduced coronary vasomotor function in type 2 diabetes. The aim of the present study was to extend this investigation to an angiotensin II receptor blocker (ARB) administered orally...

  19. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Directory of Open Access Journals (Sweden)

    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  20. Preparation and Biological Activity of the Monoclonal Antibody against the Second Extracellular Loop of the Angiotensin II Type 1 Receptor

    Directory of Open Access Journals (Sweden)

    Mingming Wei

    2016-01-01

    Full Text Available The current study was to prepare a mouse-derived antibody against the angiotensin II type 1 receptor (AT1-mAb based on monoclonal antibody technology, to provide a foundation for research on AT1-AA-positive diseases. Balb/C mice were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII. Then, mouse spleen lymphocytes were fused with myeloma cells and monoclonal hybridomas that secreted AT1-mAb were generated and cultured, after which those in logarithmic-phase were injected into the abdominal cavity of mice to retrieve the ascites. Highly purified AT1-mAb was isolated from mouse ascites after injection with 1 × 107 hybridomas. A greater amount of AT1-mAb was purified from mouse ascites compared to the cell supernatant of hybridomas. AT1-mAb purified from mouse ascites constricted the thoracic aorta of mice and increased the beat frequency of neonatal rat myocardial cells via the AT1R, identical to the effects of AT1-AA extracted from patients’ sera. Murine blood pressure increased after intravenous injection of AT1-mAb via the tail vein. High purity and good biological activity of AT1-mAb can be obtained from mouse ascites after intraperitoneal injection of monoclonal hybridomas that secrete AT1-mAb. These data provide a simple tool for studying AT1-AA-positive diseases.

  1. Use of angiotensin II receptor blockers in children- a review of ...

    African Journals Online (AJOL)

    Background: The incidence of hypertension in the pediatric population has been increasing. Childhood blood pressure is predictive of adult BP. The renin angiotensin aldosterone system pathway is important in the mediation of pediatric hypertension. New therapies approved for adults are often used off label in children ...

  2. Fibroblast growth factor 23 modifies the pharmacological effects of angiotensin receptor blockade in experimental renal fibrosis

    NARCIS (Netherlands)

    de Jong, Maarten A.; Mirkovic, Katarina; Mencke, Rik; Hoenderop, Joost G.; Bindels, Rene J.; Vervloet, Marc G.; Hillebrands, Jan-Luuk; van den Born, Jacob; Navis, Gerjan; de Borst, Martin H.

    Background. Blockade of the renin-angiotensin-aldosterone system (RAAS) retards progression of chronic kidney disease. Yet, in many patients, the renoprotective effect is incomplete. A high circulating level of the phosphaturic hormone fibroblast growth factor 23 is associated with an impaired

  3. New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptors

    NARCIS (Netherlands)

    B. Tom (Beril)

    2003-01-01

    textabstractThe beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of

  4. Protective Effects of Angiotensin II AT1 Receptors Blockade against Brain Injury in Experimental Model of Stroke in Rat

    Directory of Open Access Journals (Sweden)

    Hamdollah Panahpour

    2014-06-01

    Full Text Available Background & objectives: Ischemic stroke remains the third leading cause of invalidism and death in industrialized countries. It is suggested that renin–angiotensin system (RAS may contribute in stroke related pathogenic mechanisms and involve in the ischemic brain damage. This study designed to investigate the role of angiotensin II (Ang II in conjunction with AT1 receptors in treatment of the brain injuries following transient focal cerebral ischemia in rats.   Methods: Forty eight male Sprague-Dawley rats were studied in four groups. Sham group, ischemic control group and two ischemic groups that received candesartan (0.1mg/kg, or 0.5mg/kg at the beginning of reperfusion period. Transient focal cerebral ischemia was induced by 60 minutes occlusion of the middle cerebral artery, followed by 24 hours reperfusion. At the end of the reperfusion period, neurological deficit score (NDS was performed. Total cortical and striatal infarct volumes were determined using triphenyltetrazolium chloride (TTC staining technique.   Results: Animals in sham operated group had normal motor function and no ischemic lesions were observed in cortical or striatal regions. Occurring ischemia in ischemic control group that received vehicle produced considerable infarction in cortex (253±15mm3 and striatum (92±7mm3, as well as these animals had sever impaired motor dysfunctions. Blocking of AT1 receptors with candesartan (0.1mg/kg or 0.5mg/kg improved neurological outcome and significantly lowered cortical and striatal infarct volumes relative to ischemic control group.   Conclusion: The findings of the present study indicated that stimulation of AT1 receptors by Ang II involved in ischemia/reperfusion injuries and blocking of AT1 receptors can decrease ischemic brain injury and improve neurological outcome.

  5. Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats.

    Science.gov (United States)

    Dai, Shu-Yan; Peng, Wei; Zhang, Yu-Ping; Li, Jian-Dong; Shen, Ying; Sun, Xiao-Fei

    2015-03-08

    Recent studies demonstrate that there are sex differences in the expression of angiotensin receptor type 2 (AT2-R) in the kidney and that AT2-R plays an enhanced role in regulating blood pressure (BP) in females. Also, brain AT2-R activation has been reported to negatively modulate BP and sympathetic outflow. The present study investigated whether the central blockade of endogenous AT2-R augments deoxycorticosterone acetate (DOCA)/salt-induced hypertension in both male and female rats. All rats were subcutaneously infused with DOCA combined with 1% NaCl solution as the sole drinking fluid. BP and heart rate (HR) were recorded by telemetric transmitters. To determine the effect of central AT2-R on DOCA/salt-induced hypertension, male and female rats were intracerebroventricularly (icv) infused with AT2-R antagonist, PD123,319, during DOCA/salt treatment. Subsequently, the paraventricular nucleus (PVN) of the hypothalamus, a key cardiovascular regulatory region of the brain, was analyzed by quantitative real-time PCR and Western blot. DOCA/salt treatment elicited a greater increase in BP in male rats than that in females. Icv infusions of the AT2-R antagonist significantly augmented DOCA/salt pressor effects in females. However, this same treatment had no enhanced effect on DOCA/salt-induced increase in the BP in males. Real-time PCR and Western blot analysis of the female brain revealed that DOCA/salt treatment enhanced the mRNA and protein expression for both antihypertensive components including AT2-R, angiotensin-converting enzyme (ACE)-2, and interleukin (IL)-10 and hypertensive components including angiotensin receptor type 1 (AT1-R), ACE-1, tumor necrosis factor (TNF)-α, and IL-1β, but decreased mRNA expression of renin in the PVN. The central blockade of AT2-R reversed the changes in mRNA and protein expressions of ACE-2, IL-10, and renin, further increased the expressions of TNF-α and IL-1β, and kept higher the expressions of AT1-R, ACE-1, and AT2-R

  6. Mechanical stretch stimulates protein kinase B/Akt phosphorylation in epidermal cells via angiotensin II type 1 receptor and epidermal growth factor receptor.

    Science.gov (United States)

    Kippenberger, Stefan; Loitsch, Stefan; Guschel, Maike; Müller, Jutta; Knies, Yvonne; Kaufmann, Roland; Bernd, August

    2005-01-28

    Mechanical stress is known to modulate fundamental events such as cell life and death. Mechanical stretch in particular has been identified as a positive regulator of proliferation in skin keratinocytes and other cell systems. In the present study it was investigated whether antiapoptotic signaling is also stimulated by mechanical stretch. It was demonstrated that mechanical stretch rapidly induced the phosphorylation of the proto-oncogene protein kinase B (PKB)/Akt at both phosphorylation sites (serine 473/threonine 308) in different epithelial cells (HaCaT, A-431, and human embryonic kidney-293). Blocking of phosphoinositide 3-OH kinase by selective inhibitors (LY-294002 and wortmannin) abrogated the stretch-induced PKB/Akt phosphorylation. Furthermore mechanical stretch stimulated phosphorylation of epidermal growth factor receptor (EGFR) and the formation of EGFR membrane clusters. Functional blocking of EGFR phosphorylation by either selective inhibitors (AG1478 and PD168393) or dominant-negative expression suppressed stretch-induced PKB/Akt phosphorylation. Finally, the angiotensin II type 1 receptor (AT1-R) was shown to induce positive transactivation of EGFR in response to cell stretch. These findings define a novel signaling pathway of mechanical stretch, namely the activation of PKB/Akt by transactivation of EGFR via angiotensin II type 1 receptor. Evidence is provided that stretch-induced activation of PKB/Akt protects cells against induced apoptosis.

  7. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

    Directory of Open Access Journals (Sweden)

    Lee Robert E

    2006-01-01

    Full Text Available Abstract Background There have been indications that common Angiotensin Receptor Blockers (ARBs may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone and the Parathyroid Hormone (PTH. Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma, which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b, which recruits monocytes to the site of inflammatory immune challenge. Results Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol and Losartan (Ki≈70 nmol may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol, while Losartan (Ki≈3 nmol, Irbesartan (Ki≈6 nmol, Olmesartan and Valsartan (Ki≈12 nmol also seem likely to have significant PPAR modulatory activity. Olmesartan andIrbesartan (Ki≈9 nmol additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1 has been presented. Conclusion Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the

  8. Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress

    Science.gov (United States)

    Sánchez-Lemus, Enrique; Honda, Masaru; Saavedra, Juan M.

    2012-01-01

    Centrally acting Angiotensin II AT1 receptor blockers (ARBs) protect from stress-induced disorders and decrease anxiety in a model of inflammatory stress, the systemic injection of bacterial endotoxin lipopolysaccharide (LPS). In order to better understand the anxiolytic effect of ARBs, we treated rats with LPS (50 µg/kg) with or without three days of pretreatment with the ARB candesartan (1 mg/kg/day), and studied cortical benzodiazepine (BZ) and corticotrophin-releasing factor (CRF) receptors. We compared the cortical BZ and CRF receptors expression pattern induced by LPS with that produced in restraint stress. Inflammation stress produced a generalized increase in cortical BZ1 receptors and reduced mRNA expression of the GABAA receptor γ2 subunit in cingulate cortex; changes were prevented by candesartan pretreatment. Moreover, restraint stress produced similar increases in cortical BZ1 receptor binding, and candesartan prevented these changes. Treatment with candesartan alone increased cortical BZ1 binding, and decreased γ2 subunit mRNA expression in the cingulate cortex. Conversely, we did not find changes in CRF1 receptor expression in any of the cortical areas studied, either after inflammation or restraint stress. Cortical CRF2 receptor binding was undetectable, but CRF2 mRNA expression was decreased by inflammation stress, a change prevented by candesartan. We conclude that stress promotes rapid and widespread changes in cortical BZ1 receptor expression; and that the stress-induced BZ1 receptor expression is under the control of AT1 receptor activity. The results suggest that the anti-anxiety effect of ARBs may be associated with their capacity to regulate stress-induced alterations in cortical BZ1 receptors. PMID:22503782

  9. Selective C1 Lesioning Slightly Decreases Angiotensin II Type I Receptor Expression in the Rat Rostral Ventrolateral Medulla (RVLM).

    Science.gov (United States)

    Bourassa, Erick A; Stedenfeld, Kristen A; Sved, Alan F; Speth, Robert C

    2015-10-01

    Cardiovascular homeostasis is regulated in large part by the rostral ventrolateral medulla (RVLM) in mammals. Projections from the RVLM to the intermediolateral column of the thoracolumbar spinal cord innervate preganglionic neurons of the sympathetic nervous system causing elevation of blood pressure and heart rate. A large proportion, but not all, of the neurons in the RVLM contain the enzymes necessary for the production of epinephrine and are identified as the C1 cell group. Angiotensin II (Ang II) activates the RVLM acting upon AT1 receptors. To assess the proportion of AT1 receptors that are located on C1 neurons in the rat RVLM this study employed an antibody to dopamine-beta-hydroxylase conjugated to saporin, to selectively destroy C1 neurons in the RVLM. Expression of tyrosine hydroxylase immunoreactive neurons in the RVLM was reduced by 57 % in the toxin injected RVLM compared to the contralateral RVLM. In contrast, densitometric analysis of autoradiographic images of (125)I-sarcosine(1), isoleucine(8) Ang II binding to AT1 receptors of the injected side RVLM revealed a small (10 %) reduction in AT1-receptor expression compared to the contralateral RVLM. These results suggest that the majority of AT1 receptors in the rat RVLM are located on non-C1 neurons or glia.

  10. NF-κB and CREB are required for angiotensin II type 1 receptor upregulation in neurons.

    Directory of Open Access Journals (Sweden)

    Karla K V Haack

    Full Text Available Nuclear factor kappa B (NF-κB and the Ets like gene-1 (Elk-1 are two transcription factors that have been previously established to contribute to the Angiotensin II mediated upregulation of Angiotensin II type 1 receptor (AT1R in neurons. The cAMP response element binding protein (CREB is another transcription factor that has also been implicated in AT1R gene transcription. The goal of the current study was to determine if NF-κB and CREB association was required for AT1R upregulation. We hypothesized that the transcription of the AT1R gene occurs via an orchestration of transcription factor interactions including NF-κB, CREB, and Elk-1. The synergistic role of CREB and NFκB in promoting AT1R gene expression was determined using siRNA-mediated silencing of CREB. Electrophorectic Mobility Shift Assay studies employing CREB and NF-κB demonstrated increased protein - DNA binding as a result of Ang II stimulation which was blunted by siRNA silencing of CREB. Upstream inhibition of p38 mitogen activated protein kinase (p38 MAPK with SB203580 or inhibition of the calmodulin kinase (CAMK pathway using KN-62 blunted changes in CREB and NF-κB expression. These findings suggest that Ang II may activate multiple signaling pathways involving p38 MAPK leading to the activation of NF-κB and CREB, which feed back to upregulate the AT1R gene. This study provides insight into the molecular mechanisms involving multiple transcription factor activation in a coordinated fashion which may be partially responsible for sympathoexcitation in clinical conditions associated with increased activation of the renin angiotensin system.

  11. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.

    Science.gov (United States)

    Chen, Kui; Mehta, Jawahar L; Li, Dayuan; Joseph, Lija; Joseph, Jacob

    2004-12-10

    Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II-induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor beta (TGF-beta) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-beta1 receptors including endoglin, and the role of Ang II type 1 (AT1) and type 2 (AT2) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-beta receptors I and II expression. This effect was AT1 receptor mediated, because AT1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II-induced endoglin expression, whereas the AT2 receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II-induced endoglin expression. Ang II-induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II-induced cardiac remodeling.

  12. Mechanism for blockade of angiotensin subtype 1 receptors to lower plasma glucose in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Chan, P; Liu, I-M; Tzeng, T-F; Yang, T-L; Cheng, J-T

    2007-01-01

    We investigated the mechanism(s) by which valsartan, a selective antagonist of angiotensin subtype 1 (AT(1)) receptor, decreased plasma glucose in streptozotocin (STZ)-induced diabetic rats. The plasma glucose concentration was assessed by the glucose oxidase method. The concentration of beta-endorphin in plasma or medium incubating adrenal medulla was measured using an enzyme-linked immunosorbent assay. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis, while the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis. A single intravenous injection of valsartan dose-dependently increased plasma beta-endorphin-like immunoreactivity (BER) in parallel with the lowering of plasma glucose concentration in STZ-induced diabetic rats. Naloxone and naloxonazine inhibited the plasma glucose-lowering action of valsartan at doses sufficient to block opioid micro-receptors. In contrast to its action in wild-type diabetic mice, valsartan failed to modify plasma glucose in opioid micro-receptor knockout diabetic mice. Bilateral adrenalectomy in STZ-induced diabetic rats eliminated both the plasma glucose-lowering action and the plasma BER-elevating action of valsartan. In the isolated adrenal medulla of STZ-induced diabetic rats, angiotensin II (Ang II) or valsartan did not affect spontaneous BER secretion. Activation of cholinergic receptors by 1.0 micromol/l acetylcholine (ACh) enhanced BER secretion from the isolated adrenal medulla of STZ-induced diabetic rats, but not in the presence of 1.0 nmol/l Ang II, while valsartan reversed this inhibition by Ang II in a concentration-dependent manner. Treatment of STZ-induced diabetic rats with valsartan (0.2 mg/kg) three times daily for 3 days resulted in an increase in gene expression of GLUT4 in soleus muscle and impeded the

  13. The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-07-15

    The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT1) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Angiotensin Mediated Oxidative Stress and Neuroprotective Potential of Antioxidants and AT1 Receptor Blockers.

    Science.gov (United States)

    Prusty, Shakti Ketan; Sahu, Pratap Kumar; Subudhi, Bharat Bhusan

    2017-01-01

    Oxidative stress in brain underlies the major neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Peripherally, Angiotensin-II is a major effector of inflammation. Identification of its capacity to access brain during hypertension, as well as location of central renin angiotensin system have led to its recognition as the major effector of oxidative stress in brain. Clinical uses of antioxidants to antagonize this oxidative stress have mostly failed. In this scenario, AT1 blockers have been investigated to prevent neurodegeneration. Although it has shown promise, clinical efficacy is limited to few drugs including telmisartan mainly due to the poor brain availability of others. In this review we aim to analyze the potential of antioxidants to reduce oxidative stress in brain. We have given critical analysis of the approaches for re-purposing of AT1 blockers against oxidative stress induced neurodegeneration. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Depletion of endothelial or smooth muscle cell-specific angiotensin II type 1a receptors does not influence aortic aneurysms or atherosclerosis in LDL receptor deficient mice.

    Directory of Open Access Journals (Sweden)

    Debra L Rateri

    Full Text Available Whole body genetic deletion of AT1a receptors in mice uniformly reduces hypercholesterolemia and angiotensin II-(AngII induced atherosclerosis and abdominal aortic aneurysms (AAAs. However, the role of AT1a receptor stimulation of principal cell types resident in the arterial wall remains undefined. Therefore, the aim of this study was to determine whether deletion of AT1a receptors in either endothelial cells or smooth muscle cells influences the development of atherosclerosis and AAAs.AT1a receptor floxed mice were developed in an LDL receptor -/- background. To generate endothelial or smooth muscle cell specific deficiency, AT1a receptor floxed mice were bred with mice expressing Cre under the control of either Tie2 or SM22, respectively. Groups of males and females were fed a saturated fat-enriched diet for 3 months to determine effects on atherosclerosis. Deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effect on the size of atherosclerotic lesions. We also determined the effect of cell-specific AT1a receptor deficiency on atherosclerosis and AAAs using male mice fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min. Again, deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effects on either AngII-induced atherosclerotic lesions or AAAs.Although previous studies have demonstrated whole body AT1a receptor deficiency diminishes atherosclerosis and AAAs, depletion of AT1a receptors in either endothelial or smooth muscle cells did not affect either of these vascular pathologies.

  16. Angiotensin II receptor blockade does not protect against progressive loss of residual renal function in hemodialysis patients: A randomized controlled trial (SAFIR study)

    DEFF Research Database (Denmark)

    Kjærgaard, Krista Dybtved; Peters, Christian Daugaard; Jespersen, Bente

    centers and randomized to placebo or the angiotensin II receptor blocker irbesartan 300 mg daily. Target systolic blood pressure (BP) was 140 mmHg. Outcomes were GFR measured as the mean of creatinine and urea renal clearance, urine volume and time to anuria. Results: Of the 82 patients randomized...

  17. initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    Hellemons, Merel E; Persson, Frederik; Bakker, Stephan J L

    2011-01-01

    We aimed to investigate the individual impact of initial responses in urinary albumin excretion (UAE) and systolic blood pressure (SBP) to angiotensin II receptor blocker (ARB) treatment on long-term renal outcome in patients with type 2 diabetes and microalbuminuria....

  18. The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers

    DEFF Research Database (Denmark)

    Smink, P A; Miao, Y; Eijkemans, M J C

    2014-01-01

    Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The ...... of single markers to establish drug efficacy....

  19. Differential clinical profile of candesartan compared to other angiotensin receptor blockers

    OpenAIRE

    Cernes R; Mashavi M; Zimlichman R

    2011-01-01

    Relu Cernes1,2, Margarita Mashavi1,3, Reuven Zimlichman1,31The Brunner Institute for Cardiovascular Research, Wolfson Medical Center and Tel Aviv University, Tel Aviv, Israel; 2Department of Nephrology, Wolfson Medical Center, Holon, Israel; 3Department of Medicine, Wolfson Medical Center, Holon, IsraelAbstract: The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis...

  20. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure

    OpenAIRE

    Li, Huiping; Weatherford, Eric T.; Davis, Deborah R.; Keen, Henry L.; Grobe, Justin L.; Daugherty, Alan; Cassis, Lisa A.; Allen, Andrew M.; Sigmund, Curt D.

    2011-01-01

    All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to ge...

  1. Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension.

    Science.gov (United States)

    Chen, Daian; Stegbauer, Johannes; Sparks, Matthew A; Kohan, Donald; Griffiths, Robert; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

    2016-06-01

    The main actions of the renin-angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT1Rs). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the collecting duct in both principal and intercalated cells. Principal cells play the major role in sodium and water reabsorption. Although aldosterone is considered to be the dominant regulator of sodium reabsorption by principal cells, recent studies suggest a role for direct actions of AT1R. To specifically examine the contributions of AT1AR in principal cells to BP regulation and the development of hypertension in vivo, we generated inbred 129/SvEv mice with deletion of AT1AR from principal cells (PCKO). At baseline, we found that BPs measured by radiotelemetry were similar between PCKOs and controls. During 1-week of low-salt diet (hypertension, there was a modest but significant attenuation of hypertension in PCKOs (163±6 mm Hg) compared with controls (178±2 mm Hg; Phypertension and epithelial sodium channel activation. © 2016 American Heart Association, Inc.

  2. Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan.

    Science.gov (United States)

    Hayashi, Kaori; Sasamura, Hiroyuki; Azegami, Tatsuhiko; Itoh, Hiroshi

    2012-01-01

    Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased. These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

  3. Effect of angiotensin II receptor blockers, candesartan, on osteoprotegerin level in hypertensive patients: Link between bone and RAAS.

    Science.gov (United States)

    Oz, H; Gavish, D; Hass, A; Shargorodsky, M

    2015-09-01

    The renin-angiotensin-aldosterone system (RAAS) has recently been considered as a possible link between bone and vascular disease. The present study was designed to determine the effect of the angiotensin II receptor blocker candesartan on circulating osteoprotegerin (OPG) in hypertensive patients with multiple cardiovascular risk factors. A total of 69 hypertensive patients were randomized to two groups: Group 1 included patients treated with oral candesartan in doses of 16 mg to 32 mg per day in addition to routine standard of care (routine care + ARB), and Group 2 included patients who received routine standard of care other than ARBs or ACEIs, with no change to their treatment (routine care). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin, homeostasis model assessment-insulin resistance (HOMA-IR) and OPG. Baseline OPG levels did not differ significantly by treatment group. Post-treatment serum OPG levels were marginally lower in Group1 compared with Group 2; however, this decrease did not reach statistical significance (p = 0.077). In the present study, treatment with the ARB candesartan had no significant effect on circulating OPG levels in hypertensive patients with multiple cardiovascular risk factors. To the best of our knowledge, the present study is the first to estimate an effect of candesartan on bone remodeling marker such as OPG. © The Author(s) 2015.

  4. Cardioprotective effect of fimasartan, a new angiotensin receptor blocker, in a porcine model of acute myocardial infarction.

    Science.gov (United States)

    Sim, Doo Sun; Jeong, Myung Ho; Song, Ho Chun; Kim, Jahae; Chong, Ari; Bom, Hee Seung; Jeong, In Seok; Oh, Sang Gi; Kim, Jong Min; Park, Dae Sung; Kim, Jung Ha; Lim, Kyung Seob; Kim, Min Suk; Ryu, Shi Hyun; Kim, Hyun Kuk; Kim, Sung Soo; Jang, Su Young; Cho, Jae Yeong; Jeong, Hae Chang; Lee, Ki Hong; Park, Keun Ho; Yoon, Nam Sik; Yoon, Hyun Ju; Kim, Kye Hun; Hong, Young Joon; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kang, Jung Chaee

    2015-01-01

    Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

  5. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    Science.gov (United States)

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  6. Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan.

    Science.gov (United States)

    Miura, Shin-ichiro; Okabe, Atsutoshi; Matsuo, Yoshino; Karnik, Sadashiva S; Saku, Keijiro

    2013-02-01

    The angiotensin II type 1 (AT(1)) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT(1) receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT(1) receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT(1) receptor (Tyr(113), Lys(199) and Gln(257)), the hydrogen bonding between the oxadiazole of azilsartan-Gln(257) is stronger than that between the tetrazole of candesartan-Gln(257), according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan-Gln(257) interaction and that azilsartan had a stronger interaction with Gln(257) than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT(1) receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP-lowering efficacy compared with candesartan and other ARBs.

  7. NMDA Receptor Plasticity in the Hypothalamic Paraventricular Nucleus Contributes to the Elevated Blood Pressure Produced by Angiotensin II.

    Science.gov (United States)

    Glass, Michael J; Wang, Gang; Coleman, Christal G; Chan, June; Ogorodnik, Evgeny; Van Kempen, Tracey A; Milner, Teresa A; Butler, Scott D; Young, Colin N; Davisson, Robin L; Iadecola, Costantino; Pickel, Virginia M

    2015-07-01

    Hypertension induced by angiotensin II (Ang II) is associated with glutamate-dependent dysregulation of the hypothalamic paraventricular nucleus (PVN). Many forms of glutamate-dependent plasticity are mediated by NMDA receptor GluN1 subunit expression and the distribution of functional receptor to the plasma membrane of dendrites. Here, we use a combined ultrastructural and functional analysis to examine the relationship between PVN NMDA receptors and the blood pressure increase induced by chronic infusion of a low dose of Ang II. We report that the increase in blood pressure produced by a 2 week administration of a subpressor dose of Ang II results in an elevation in plasma membrane GluN1 in dendrites of PVN neurons in adult male mice. The functional implications of these observations are further demonstrated by the finding that GluN1 deletion in PVN neurons attenuated the Ang II-induced increases in blood pressure. These results indicate that NMDA receptor plasticity in PVN neurons significantly contributes to the elevated blood pressure mediated by Ang II. Copyright © 2015 the authors 0270-6474/15/359558-10$15.00/0.

  8. Neonatal handling reduces angiotensin II receptor density in the medial preoptic area and paraventricular nucleus but not in arcuate nucleus and locus coeruleus of female rats.

    Science.gov (United States)

    Gomes, Cármen Marilei; Donadio, Márcio Vinícius Fagundes; Franskoviaki, Inélia; Anselmo-Franci, Janete A; Franci, Celso Rodrigues; Lucion, Aldo Bolten; Sanvitto, Gilberto Luiz

    2006-01-05

    Neonatal handling alters the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonads axis (HPG) in adult animals, and angiotensin II (Ang II) modulates the functions in these axes. We tested whether neonatal handling could change the density of Ang II receptors in some central areas in female rats. Results showed decreased density of the Ang II receptors in the medial preoptic area (MPOA) and hypothalamic paraventricular nucleus (PVN) of the neonatal handled group.

  9. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system

    NARCIS (Netherlands)

    Roks, AJM; van Geel, PP; Pinto, YM; Buikema, H; Henning, RH; de Zeeuw, D; van Gilst, WH

    The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to

  10. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system

    NARCIS (Netherlands)

    Roks, A. J.; van Geel, P. P.; Pinto, Y. M.; Buikema, H.; Henning, R. H.; de Zeeuw, D.; van Gilst, W. H.

    1999-01-01

    The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to

  11. Therapeutic Effect of Losartan, an Angiotensin II Type 1 Receptor Antagonist, on CCl₄-Induced Skeletal Muscle Injury.

    Science.gov (United States)

    Hwang, Ok-Kyung; Park, Jin-Kyu; Lee, Eun-Joo; Lee, Eun-Mi; Kim, Ah-Young; Jeong, Kyu-Shik

    2016-02-08

    TGF-β1 is known to inhibit muscle regeneration after muscle injury. However, it is unknown if high systemic levels of TGF-β can affect the muscle regeneration process. In the present study, we demonstrated the effect of a CCl₄ intra-peritoneal injection and losartan (an angiotensin II type 1 receptor antagonist) on skeletal muscle (gastrocnemius muscle) injury and regeneration. Male C57BL/6 mice were grouped randomly as follows: control (n = 7), CCl₄-treatment group (n = 7), and CCl₄ + losartan treatment group (n = 7). After CCl₄ treatment for a 16-week period, the animals were sacrificed and analyzed. The expression of dystrophin significantly decreased in the muscle tissues of the control group, as compared with that of the CCl₄ + losartan group (p losartan group (p losartan group compared to the corresponding levels in the control group (p losartan promotes muscle repair from injury via blockade of TGF-β1 signaling.

  12. Effect of Angiotensin receptor blockers on flow-mediated vasodilation: a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Chen, Jian-Dong; Liu, Ming; Chen, Xiao-hu; Yang, Zhi-Jian

    2015-01-01

    In a meta-analysis, we investigated the effects of angiotensin receptor blockers (ARBs) in comparison to placebo or other classes of antihypertensive drugs on endothelial function, which was measured by brachial flow-mediated vasodilation (FMD). We searched for randomized controlled trials that compared ARBs with placebo or other classes of antihypertensive drugs in improving FMD. A random-effect model was used to compute pooled estimates. In 13 trials (n = 529), ARBs were more efficacious in improving brachial FMD than placebo [pooled weighted mean change difference (WMD) 1.34%, 95% CI, 0.93-1.75%, pclasses of drugs (p ≥ 0.072). This meta-analysis shows that ARBs improve brachial FMD, a marker of endothelial function, and that they are superior to placebo and CCBs. There was no significant difference in the effect on brachial FMD between ARBs and the other antihypertensive drugs. © 2015 S. Karger AG, Basel.

  13. Dosage of angiotensin-II receptor blockers in heart failure patients following changes in Danish drug reimbursement policies

    DEFF Research Database (Denmark)

    Selmer, Christian; Lamberts, Morten; Kristensen, Søren Lund

    2014-01-01

    PURPOSE: National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up-titrated...... to optimal or suboptimal ARB dosage. METHODS: A historical cohort study was performed including HF patients with at least one prescription of ARB in the months of May-Jul 2010 (baseline). Patients were considered up-titrated at doses 100, 16 or 160 mg for losartan, valsartan and candesartan, respectively....... Individual-level linkage of nationwide registries of hospitalization and drug dispensing in Denmark was used to describe patterns of ARB prescriptions and estimate dosage before and after November 2010. Logistic regression models were used to assess the probability for being up-titrated in the period...

  14. An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model.

    Science.gov (United States)

    Kobayashi, Ryu; Wakui, Hiromichi; Azushima, Kengo; Uneda, Kazushi; Haku, Sona; Ohki, Kohji; Haruhara, Kotaro; Kinguchi, Sho; Matsuda, Miyuki; Ohsawa, Masato; Toya, Yoshiyuki; Nishiyama, Akira; Yamashita, Akio; Tanabe, Katsuyuki; Maeshima, Yohei; Umemura, Satoshi; Tamura, Kouichi

    2017-05-01

    Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  15. Angiotensin receptor blocker as adjunctive therapy for rhythm control in atrial fibrillation: results of the irbesartan-amiodarone trial.

    Science.gov (United States)

    Madrid, Antonio H; Escobar, Carlos; Rebollo, José María G; Marín, Irene; Bernal, Enrique; Nannini, Sebastián; Limón, Lilianna; Peng, Jian; Moro, Concepción

    2003-09-01

    Atrial fibrillation (AF) is a common arrhythmia associated with increased risk of stroke and mortality. The early appearance of electrical remodeling is followed by structural remodeling of the atrial tissue. Direct current cardioversion of persistent AF is the most effective treatment for the restoration of sinus rhythm, but it is hampered by a high percentage of recurrences. Recurrences may be the consequence of both electrical and structural remodeling. A study on the use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent AF showed that this angiotensin II receptor blocker combined with amiodarone prolonged sinus rhythm after cardioversion. Irbesartan may have antifibrotic effects due not only to the ability to diminish the synthesis of collagen type I molecules but also to its capacity to stimulate the degradation of collagen type I fibers, as has been demonstrated with losartan, another angiotensin II receptor blocker. This suggests that efforts to reduce the structural changes that occur during AF may be more useful in preventing recurrences than efforts designed to minimize the electrical changes alone. The AFFIRM trial compared two approaches to the treatment of AF: cardioversion with antiarrhythmic drugs to maintain sinus rhythm and the use of rate-controlling drugs. The results show that management of AF with the rhythm-control strategy offers no survival advantage over the rate-control strategy. However, non-antiarrhythmic drugs to prevent recurrences, like irbesartan, were not controlled and amiodarone was used in a low percentage of the patients. The treatment strategies proposed in both AFFIRM and RACE, in our opinion, may not be the optimal. The modern clinical approach to AF involves an early intervention to restore sinus rhythm, therefore preventing atrial remodeling. The pretreatment of patients with AF who undergo electrical cardioversion is very important and will be the subject for continuous improvement.

  16. Impact of cell type and epitope tagging on heterologous expression of G protein-coupled receptor: a systematic study on angiotensin type II receptor.

    Directory of Open Access Journals (Sweden)

    Lili Jiang

    Full Text Available Despite heterologous expression of epitope-tagged GPCR is widely adopted for functional characterization, there is lacking of systematic analysis of the impact of expression host and epitope tag on GPCR expression. Angiotensin type II (AT2 receptor displays agonist-dependent and -independent activities, coupling to a spectrum of signaling molecules. However, consensus has not been reached on the subcellular distributions, signaling cascades and receptor-mediated actions. To examine the contributions of host cell and epitope tag on receptor expression and activity, epitope-tagged AT2 receptor variants were transiently or stably expressed in HEK293, CHO-K1 and PC12 cells. The epitope-tagged AT2 receptor variants were detected both on the cell membrane and in the perinuclear region. In transiently transfected HEK293 cells, Myc-AT2 existed predominantly as monomer. Additionally, a ladder of ubiquitinated AT2 receptor proteins was detected. By contrast, stably expressed epitope-tagged AT2 receptor variants existed as both monomer and high molecular weight complexes, and the latter was enriched in cell surface. Glycosylation promoted cell surface expression of Myc-AT2 but had no effect on AT2-GFP in HEK293 cells. In cells that stably expressed Myc-AT2, serum starvation induced apoptosis in CHO-K1 cells but not in HEK293 or PC12 cells. Instead, HEK293 and PC12 cells stably expressing Myc-AT2 exhibited partial cell cycle arrest with cells accumulating at G1 and S phases, respectively. Taken together, these results suggest that expression levels, subcellular distributions and ligand-independent constitutive activities of AT2 receptor were cell type-dependent while posttranslational processing of nascent AT2 receptor protein was modulated by epitope tag and mode of expression.

  17. Impact of cell type and epitope tagging on heterologous expression of G protein-coupled receptor: a systematic study on angiotensin type II receptor.

    Science.gov (United States)

    Jiang, Lili; Teng, Gladys M K; Chan, Elaine Y M; Au, Shannon W N; Wise, Helen; Lee, Susanna S T; Cheung, Wing-Tai

    2012-01-01

    Despite heterologous expression of epitope-tagged GPCR is widely adopted for functional characterization, there is lacking of systematic analysis of the impact of expression host and epitope tag on GPCR expression. Angiotensin type II (AT2) receptor displays agonist-dependent and -independent activities, coupling to a spectrum of signaling molecules. However, consensus has not been reached on the subcellular distributions, signaling cascades and receptor-mediated actions. To examine the contributions of host cell and epitope tag on receptor expression and activity, epitope-tagged AT2 receptor variants were transiently or stably expressed in HEK293, CHO-K1 and PC12 cells. The epitope-tagged AT2 receptor variants were detected both on the cell membrane and in the perinuclear region. In transiently transfected HEK293 cells, Myc-AT2 existed predominantly as monomer. Additionally, a ladder of ubiquitinated AT2 receptor proteins was detected. By contrast, stably expressed epitope-tagged AT2 receptor variants existed as both monomer and high molecular weight complexes, and the latter was enriched in cell surface. Glycosylation promoted cell surface expression of Myc-AT2 but had no effect on AT2-GFP in HEK293 cells. In cells that stably expressed Myc-AT2, serum starvation induced apoptosis in CHO-K1 cells but not in HEK293 or PC12 cells. Instead, HEK293 and PC12 cells stably expressing Myc-AT2 exhibited partial cell cycle arrest with cells accumulating at G1 and S phases, respectively. Taken together, these results suggest that expression levels, subcellular distributions and ligand-independent constitutive activities of AT2 receptor were cell type-dependent while posttranslational processing of nascent AT2 receptor protein was modulated by epitope tag and mode of expression.

  18. Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan

    Directory of Open Access Journals (Sweden)

    Georges Vauquelin

    2001-03-01

    Full Text Available To explain the insurmountable/long-lasting binding of biphenyltetrazole-containing AT1-receptor antagonists such as candesartan, to the human angiotensin II type 1-receptor, a model is proposed in which the basic amino acids Lys199 and Arg 167 of the receptor interact respectively with the carboxylate and the tetrazole group of the antagonists. To validate this model, we have investigated the impact of substitution of Lys199 by Ala or Gln and of Arg167 by Ala on the binding properties of [3H]candesartan and on competition binding by candesartan, EXP3174, irbesartan, losartan, angiotensin II (Ang II and [Sar1-Ile8]angiotensin. Our results indicate that both amino acids play an important role in the AT1-receptor ligand binding. Whereas the negative charge of Lys 199 is involved in an ionic bond with the end-standing carboxylate group of the peptide ligands, its polarity also contributes to the non-peptide antagonist binding. Substitution of Arg167 by Ala completely abolished [3H]Ang II, as well as [3H] candesartan, binding. Whereas these results are in line with the proposed model, it cannot be excluded that both amino acid residues are important for the structural integrity of the AT1-receptor with respect to its ligand binding properties.

  19. Angiotensin-(1-7) Is an Endogenous Ligand for the G Protein-Coupled Receptor Mas

    National Research Council Canada - National Science Library

    Robson A. S. Santos; Ana C. Simoes e Silva; Christine Maric; Denise M. R. Silva; Raquel Pillar Machado; Insa de Buhr; Silvia Heringer-Walther; Sergio Veloso B. Pinheiro; Myriam Teresa Lopes; Michael Bader; Elizabeth P. Mendes; Virgina Soares Lemos; Maria Jose Campagnole-Santos; Heinz-Peter Schultheiss; Robert Speth; Thomas Walther

    2003-01-01

    ...) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys...

  20. Beneficial Effects of the Activation of the Angiotensin-(1–7) Mas Receptor in a Murine Model of Adriamycin-Induced Nephropathy

    Science.gov (United States)

    Silveira, Kátia Daniela; Barroso, Lívia Corrêa; Vieira, Angélica Thomáz; Cisalpino, Daniel; Lima, Cristiano Xavier; Bader, Michael; Arantes, Rosa Maria Esteves; dos Santos, Robson Augusto Souza

    2013-01-01

    Angiotensin-(1–7) [Ang-(1–7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas+/+) and Mas knockout (Mas−/−) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas+/+, but not in Mas−/− mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1–7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies. PMID:23762470

  1. Beneficial effects of the activation of the angiotensin-(1-7) MAS receptor in a murine model of adriamycin-induced nephropathy.

    Science.gov (United States)

    Silveira, Kátia Daniela; Barroso, Lívia Corrêa; Vieira, Angélica Thomáz; Cisalpino, Daniel; Lima, Cristiano Xavier; Bader, Michael; Arantes, Rosa Maria Esteves; Dos Santos, Robson Augusto Souza; Simões-E-Silva, Ana Cristina; Teixeira, Mauro Martins

    2013-01-01

    Angiotensin-(1-7) [Ang-(1-7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+) ) and Mas knockout (Mas (-/-)) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+) , but not in Mas (-/-) mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.

  2. Losartan suppresses the kainate-induced changes of angiotensin AT1 receptor expression in a model of comorbid hypertension and epilepsy.

    Science.gov (United States)

    Atanasova, Dimitrinka; Tchekalarova, Jana; Ivanova, Natasha; Nenchovska, Zlatina; Pavlova, Ekaterina; Atanassova, Nina; Lazarov, Nikolai

    2017-12-06

    Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT1 receptor) in limbic structures, as well as the effect of the AT1 receptor antagonist losartan in a model of comorbid hypertension and epilepsy. The expression of AT1 receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT1 receptor expression in epileptic rats that were treated for a period of 4weeks after status epilepticus. The naive and epileptic SHRs were characterized by stronger protein expression of AT1 receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT1 immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT1 receptor expression in SHRs compared to Wistar rats. Our results confirm the important role of AT1 receptor in epilepsy and suggest that the AT1receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy. Copyright © 2017. Published by Elsevier Inc.

  3. Intracellular angiotensin II elicits Ca2+ increases in A7r5 vascular smooth muscle cells

    NARCIS (Netherlands)

    Filipeanu, CM; Brailoiu, E; Kok, JW; Henning, RH; De Zeeuw, D; Nelemans, SA

    2001-01-01

    Recent studies show that angiotensin II can act within the cell, possibly via intracellular receptors pharmacologically different from typical plasma membrane angiotensin II receptors. The signal transduction of intracellular angiotensin LI is unclear. Therefore. we investigated the effects of

  4. Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta.

    Science.gov (United States)

    Mishra, Jay S; Hankins, Gary D; Kumar, Sathish

    2016-10-01

    Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT2R) induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. AT2R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT2R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT2R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT2R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT2R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFβ signaling with specific inhibitors abolished dihydrotestosterone-induced AT2R downregulation. Androgens downregulate AT2R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT2R expression, implicating androgens' contributing role to gender differences in vascular AT2R expression. © The Author(s) 2016.

  5. Abilities of candesartan and other AT1 receptor blockers to impair angiotensin II-induced AT1 receptor activation after wash-out

    Science.gov (United States)

    Kiya, Yoshihiro; Miura, Shin-ichiro; Matsuo, Yoshino; Karnik, Sadashiva S; Saku, Keijiro

    2013-01-01

    Angiotensin II (Ang II) binds to Ang II type 1 (AT1) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT1 receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT1 receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln257 in the AT1 receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs. PMID:21824992

  6. Abilities of candesartan and other AT(1) receptor blockers to impair angiotensin II-induced AT(1) receptor activation after wash-out.

    Science.gov (United States)

    Kiya, Yoshihiro; Miura, Shin-ichiro; Matsuo, Yoshino; Karnik, Sadashiva S; Saku, Keijiro

    2012-03-01

    Angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT(1) receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT(1) receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln(257) in the AT(1) receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs.

  7. Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats.

    Science.gov (United States)

    Montez, Priscilla; Vázquez-Medina, José Pablo; Rodríguez, Rubén; Thorwald, Max A; Viscarra, José A; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2012-12-01

    Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity.

  8. Analysis of Transmembrane Domains 1 and 4 of the Human Angiotensin II AT1 Receptor by Cysteine-scanning Mutagenesis*

    Science.gov (United States)

    Yan, Liping; Holleran, Brian J.; Lavigne, Pierre; Escher, Emanuel; Guillemette, Gaétan; Leduc, Richard

    2010-01-01

    The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the AT1 receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. Here, we investigated the role of the first and fourth transmembrane domains (TMDs) in the formation of the binding pocket of the human AT1 receptor using the substituted-cysteine accessibility method. Each residue within the Phe-28(1.32)–Ile-53(1.57) fragment of TMD1 and Leu-143(4.40)–Phe-170(4.67) fragment of TMD4 was mutated, one at a time, to a cysteine. The resulting mutant receptors were expressed in COS-7 cells, which were subsequently treated with the charged sulfhydryl-specific alkylating agent methanethiosulfonate ethylammonium (MTSEA). This treatment led to a significant reduction in the binding affinity of TMD1 mutants M30C(1.34)-AT1 and T33C(1.37)-AT1 and TMD4 mutant V169C(4.66)-AT1. Although this reduction in binding of the TMD1 mutants was maintained when examined in a constitutively active receptor (N111G-AT1) background, we found that V169C(4.66)-AT1 remained unaffected when treated with MTSEA compared with untreated in this context. Moreover, the complete loss of binding observed for R167C(4.64)-AT1 was restored upon treatment with MTSEA. Our results suggest that the extracellular portion of TMD1, particularly residues Met-30(1.34) and Thr-33(1.37), as well as residues Arg-167(4.64) and Val-169(4.66) at the junction of TMD4 and the second extracellular loop, are important binding determinants within the AT1 receptor binding pocket but that these TMDs undergo very little movement, if at all, during the activation process. PMID:19940150

  9. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure.

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    Andrea Kuenzli

    Full Text Available BACKGROUND: There is insufficient evidence whether the benefit of adding angiotensin II receptor blockers (ARBs to angiotensin-converting enzyme (ACE inhibitors outweighs the increased risk of adverse effects in patients with heart failure. METHODOLOGY/PRINCIPAL FINDINGS: Two independent reviewers searched and abstracted randomized controlled trials of ARBs and ACE inhibitors compared to ACE inhibitor therapy alone in patients with heart failure reporting mortality and hospitalizations having a follow-up of at least 6 months identified by a systematic literature search. Eight trials including a total of 18,061 patients fulfilled our inclusion criteria. There was no difference between patients treated with combination therapy and ACE inhibitor therapy alone for overall mortality, hospitalization for any reason, fatal or nonfatal MI. Combination therapy was, however, associated with fewer hospital admissions for heart failure (RR 0.81, 95%CI 0.72-0.91, although there was significant heterogeneity across trials (p-value for heterogeneity = 0.04; I(2 = 57% [95%CI 0-83%]. Patients treated with combination therapy had a higher risk of worsening renal function and symptomatic hypotension, and their trial medications were more often permanently discontinued. Lack of individual patient data precluded the analysis of time-to-event data and identification of subgroups which potentially benefit more from combination therapy such as younger patients with preserved renal function and thus at lower risk to experience worsening renal function or hyperkalemia. CONCLUSIONS/SIGNIFICANCE: Combination therapy with ARBs and ACE inhibitors reduces admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but does not reduce overall mortality or all-cause hospitalization and is associated with more adverse events. Thus, based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved

  10. Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice.

    Science.gov (United States)

    Chung, Sarah; Jeong, Jin Young; Chang, Yoon Kyung; Choi, Dae Eun; Na, Ki Ryang; Lim, Beom Jin; Lee, Kang Wook

    2016-03-01

    There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor β (TGF-β) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-β in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

  11. Angiotensin II Type 2 Receptor Agonist Experts Sustained Neuroprotective Effects In Aged Rats

    DEFF Research Database (Denmark)

    Sumners, Colin; Isenberg, Jacob; Harmel, Allison

    2016-01-01

    in preclinical studies, effects that likely involve neurotropic actions. However, these beneficial actions of C21 have not been demonstrated to occur beyond 1 week post stroke. The objective of this study was to determine if systemic administration of C21 would exert sustained neuroprotective effects in aged...... rats. DESIGN AND METHOD: Aged adult male Sprague Dawley rats (18-20 months) underwent ischemic stroke by monofilament middle cerebral artery occlusion (MCAO) and were randomly divided into two groups that received intraperitoneal (IP) injections of either 0.9% NaCl or 0.03 mg/kg C21 at reperfusion (90...... adhesive. Infarct volume tended to be non-significantly decreased by C21 treatment at 21d post-stroke. CONCLUSIONS: These findings indicate that targeting the renin-angiotensin system, by stimulation of AT2Rs with C21, improves neurological function in aged rats with stroke over a sustained period of 21...

  12. Angiotensin II type 2 receptor is critical for the development of human fetal pancreatic progenitor cells into islet-like cell clusters and their potential for transplantation.

    Science.gov (United States)

    Leung, Kwan Keung; Liang, Juan; Ma, Man Ting; Leung, Po Sing

    2012-03-01

    Local renin-angiotensin systems (RASs) regulate the differentiation of tissue progenitors. However, it is not known whether such systems can regulate the development of pancreatic progenitor cells (PPCs). To address this issue, we characterized the expression profile of major RAS components in human fetal PPC preparations and examined their effects on the differentiation of PPCs into functional islet-like cell clusters (ICCs). We found that expression of RAS components was highly regulated throughout PPC differentiation and that locally generated angiotensin II (Ang II) maintained PPC growth and differentiation via Ang II type 1 and type 2 (AT(1) and AT(2)) receptors. In addition, we observed colocalization of AT(2) receptors with critical β-cell phenotype markers in PPCs/ICCs, as well as AT(2) receptor upregulation during differentiation, suggesting that these receptors may regulate β-cell development. In fact, we found that AT(2) , but not AT(1) , receptor was a key mediator of Ang II-induced upregulation of transcription factors important in β-cell development. Furthermore, lentivirus-mediated knockdown of AT(2) receptor suppressed the expression of these transcription factors in ICCs. Transplantation of AT(2) receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT(2) receptors are indispensable during ICC maturation in vivo. These data strongly indicate that a local RAS is involved in governing the functional maturation of pancreatic progenitors toward the endocrine lineage. Copyright © 2011 AlphaMed Press.

  13. Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system.

    Science.gov (United States)

    de Kloet, Annette D; Wang, Lei; Ludin, Jacob A; Smith, Justin A; Pioquinto, David J; Hiller, Helmut; Steckelings, U Muscha; Scheuer, Deborah A; Sumners, Colin; Krause, Eric G

    2016-03-01

    Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses.

  14. [Effects of long term therapy with angiotensin converting enzyme inhibitor quinapril, antagonist of receptors to angiotensin II valsartan, and combination of quinapril and valsartan in patients with moderate chronic heart failure. Main results of the SADKO-CHF study].

    Science.gov (United States)

    Skvortsov, A A; Nasonova, S N; Sychev, A V; Orlova, Ia A; Baklanova, N A; Masenko, V P; Mareev, V Iu; Belenkov, Iu N

    2006-01-01

    To compare effects of therapy with angiotensin converting enzyme inhibitor quinapril (Q), angiotensin II receptor antagonist valsartan (V), and their combination in patients with stable moderate chronic heart failure (CHF). Patients (n=80) with NYHA class II-III CHF due to ischemic heart disease, dilated cardiomyopathy or decompensated hypertensive heart and ejection fraction ECG monitoring with measurements of parameters of heart rate variability (HRV), and determination of neurohormones in peripheral blood. Examinations and measurements were made at baseline, in 3 and 6 months. Six months therapy with Q, V and their combination resulted in improvement of clinical and functional state of patients. More pronounced augmentation of exercise tolerance and lowering of CHF functional class were observed in group Q. Combined use of Q and V had no significant advantages over monotherapy with Q and V when effect on parameters of left ventricular remodeling were concerned. Therapy with Q was associated with "escape" of blockade of aldosterone synthesis and "reactivation" of angiotensin II formation after 6 months. The use of V and combination of V+Q allowed to achieve more stable but incomplete control of aldosterone activity. The use of Q appears to be the preferential regimen to influence activity of sympathoadrenal system and parameters of 24 hour HRV compared with V and Q+V. Long term therapy with V does not improve main parameters of 24 hour HRV.

  15. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

    Directory of Open Access Journals (Sweden)

    Antoine eHuart

    2015-02-01

    Full Text Available Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease. Currently, inhibitors of the renin angiotensin system (RAS remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra with that of an angiotensin type 1 receptor antagonist (AT1a in the unilateral ureteral obstruction (UUO model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

  16. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

    Science.gov (United States)

    Huart, Antoine; Klein, Julie; Gonzalez, Julien; Buffin-Meyer, Bénédicte; Neau, Eric; Delage, Christine; Calise, Denis; Ribes, David; Schanstra, Joost P.; Bascands, Jean-Loup

    2015-01-01

    Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID:25698969

  17. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory

    DEFF Research Database (Denmark)

    Jing, Fei; Mogi, Masaki; Sakata, Akiko

    2012-01-01

    evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT(2) receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B(2) receptor antagonist. Administration of C21 dose dependently...

  18. Evidence that the angiotensin at 2-receptor agonist compound 21 is also a low affinity thromboxane TXA2-receptor antagonist

    DEFF Research Database (Denmark)

    Fredgart, M.; Leurgans, T.; Stenelo, M.

    2015-01-01

    AT2-receptor specificity, arteries were pre-incubated with the AT2-receptor antagonist PD123319 (10muM), or mesenteric arteries from AT2-receptor knock-out (AT2R-/y) mice were used. An inhibitory effect of C21 (100nM - 10muM) on U46619 (0,3muM) induced platelet aggregation was examined in whole human...

  19. Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6

    Science.gov (United States)

    Ohkura, Sei-ichiro; Takashima, Shin-ichiro; Yoshioka, Kazuaki; Okamoto, Yasuo; Inagaki, Yutaka; Sugimoto, Naotoshi; Kitano, Teppei; Takamura, Masayuki; Wada, Takashi; Kaneko, Shuichi; Takuwa, Yoh

    2017-01-01

    Background: Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are involved in myocardial remodeling. The lysophospholipid mediator sphigosine-1-phosphate (S1P) regulates functions of cardiovascular cells through multiple receptors including S1PR1–S1PR3. S1PR1 but not other S1P receptors was upregulated in angiotensin II-induced hypertrophic hearts. Therefore, we investigated a role of S1PR1 in fibroblasts for cardiac remodeling by employing transgenic mice that overexpressed S1PR1 under the control of α-smooth muscle actin promoter. In S1PR1-transgenic mouse heart, fibroblasts and/or myofibroblasts were hyperplastic, and those cells as well as vascular smooth muscle cells overexpressed S1PR1. Transgenic mice developed bi-ventricular hypertrophy by 12-week-old and diffuse interstitial fibrosis by 24-week-old without hemodynamic stress. Cardiac remodeling in transgenic mice was associated with greater ERK phosphorylation, upregulation of fetal genes, and systolic dysfunction. Transgenic mouse heart showed increased mRNA expression of angiotensin-converting enzyme and interleukin-6 (IL-6). Isolated fibroblasts from transgenic mice exhibited enhanced generation of angiotensin II, which in turn stimulated IL-6 release. Either an AT1 blocker or angiotensin-converting enzyme inhibitor prevented development of cardiac hypertrophy and fibrosis, systolic dysfunction and increased IL-6 expression in transgenic mice. Finally, administration of anti-IL-6 antibody abolished an increase in tyrosine phosphorylation of STAT3, a major signaling molecule downstream of IL-6, in the transgenic mouse heart and prevented development of cardiac hypertrophy in transgenic mice. These results demonstrate a promoting role of S1PR1 in cardiac fibroblasts for cardiac remodeling, in which angiotensin II—AT1 and IL-6 are involved. PMID:28771545

  20. A polymorphism in the angiotensin II type 1 receptor gene has different effects on the risk of diabetic nephropathy in men and women

    DEFF Research Database (Denmark)

    Möllsten, Anna; Vionnet, Nathalie; Forsblom, Carol

    2011-01-01

    to AER≥200 μg/min or ≥300 mg/l (n=1546), and patients with renal replacement therapy were also included in this group. The controls had >15 years diabetes duration, AER ...-control study investigated the association of the rs5186 polymorphism, in the angiotensin II type 1 receptor gene (AGTR1), with diabetic nephropathy. The study included 3561 patients with type 1 diabetes from Denmark, Finland, France and Sweden. Microalbuminuria was defined as albumin excretion rate (AER) ≥20...

  1. Use of angiotensin II receptor blockers alone and in combination with other drugs: a large clinical experience trial

    Directory of Open Access Journals (Sweden)

    Matthew R Weir

    2001-03-01

    Full Text Available Angiotensin II (Ang II receptor blockers are the newest class of antihypertensive drugs to be developed. No large-scale clinical trials have been performed to evaluate their efficacy alone, or in combination with other drugs. A large-scale, eight week, open-label, non-placebo-controlled, single-arm trial evaluated the efficacy, tolerability and dose-response of candesartan cilexetil, 16—32 mg once-daily, either as monotherapy or as part of combination therapy, in a diverse hypertensive population in actual practice settings. 6465 patients with high blood pressure, of whom 52% were female and 16% African American, with a mean age of 58 years, were included. 5446 patients had essential hypertension and 1014 patients had isolated systolic hypertension. In order to be included in this study, patients had either untreated or uncontrolled hypertension (systolic blood pressure (SBP 140—179 mmHg and/or diastolic blood pressure (DBP 90—109 mmHg inclusive at baseline, despite a variety of other antihypertensive drugs. Of the 5156 patients with essential hypertension and at least one post baseline efficacy measurement, the mean pretreatment blood pressure (BP was 156/97 mmHg. Candesartan cilexetil monotherapy reduced mean SBP/DBP by 18.0/12.2 mmHg. Similarly, in the 964 patients with isolated systolic hypertension and at least one post baseline efficacy measurement, candesartan cilexetil monotherapy reduced SBP/DBP from 158/81 by 16.5/4.5 mmHg. Candesartan cilexetil was similarly effective when employed as add-on therapy. When added to baseline antihypertensive medication in 51% of the patients with essential hypertension not achieving BP control, additional reduction in BP was achieved regardless of the background therapy, including diuretics (17.8/11.7 mmHg calcium antagonists (16.6/11.2 mmHg, beta-blockers (16.5/10.4 mmHg, angiotensin-converting enzyme inhibitors (ACE-I (15.3/10.0 mmHg, and alpha blockers (16.4/10.4 mmHg. Likewise, when

  2. Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice

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    Troyer Deryl

    2010-02-01

    Full Text Available Abstract Background Pancreatic cancer is one of the most aggressive human malignancies, with a very poor prognosis. To evaluate the effect of angiotensin II (Ang II type 2 receptor (AT2 expression in the host's body on the growth of pancreatic carcinoma, we have investigated the growth of mouse pancreatic ductal carcinoma grafts in syngeneic wild type and AT2 receptor-deficient (AT2-KO mice. Methods The role of AT2 receptor-signaling in stromal cells on the growth of murine pancreatic carcinoma cells (PAN02 was studied using various in vitro and in vivo assays. In vivo cell proliferation, apoptosis, and vasculature in tumors were monitored by Ki-67 immunostaining, TUNEL assay, and von Willebrand factor immunostaining, respectively. In the co-culture study, cell proliferation was measured by MTT cell viability assay. All the data were analyzed using t-test and data were treated as significant when p Results Our results show that the growth of subcutaneously transplanted syngeneic xenografts of PAN02 cells, mouse pancreatic ductal carcinoma cells derived from the C57/BL6 strain, was significantly faster in AT2-KO mice compared to control wild type mice. Immunohistochemical analysis of tumor tissue revealed significantly more Ki-67 positive cells in xenografts grown in AT2-KO mice than in wild type mice. The index of apoptosis is slightly higher in wild type mice than in AT2-KO mice as evaluated by TUNEL assay. Tumor vasculature number was significantly higher in AT2-KO mice than in wild type mice. In vitro co-culture studies revealed that the growth of PAN02 cells was significantly decreased when grown with AT2 receptor gene transfected wild type and AT2-KO mouse-derived fibroblasts. Faster tumor growth in AT2-KO mice may be associated with higher VEGF production in stromal cells. Conclusions These results suggest that Ang II regulates the growth of pancreatic carcinoma cells through modulating functions of host stromal cells; Moreover, Ang II AT2

  3. Direct angiotensin II type 2 receptor stimulation ameliorates insulin resistance in type 2 diabetes mice with PPARγ activation.

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    Kousei Ohshima

    Full Text Available OBJECTIVES: The role of angiotensin II type 2 (AT(2 receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2 receptor stimulation by compound 21 (C21 might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM with PPARγ activation, mainly focusing on adipose tissue. METHODS: T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPARγ antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined. RESULTS: Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPARγ pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-α concentration; however, these effects were attenuated by PPARγ blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPARγ DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored β cell damage in diabetic pancreatic tissue. CONCLUSION: The present study demonstrated that direct AT(2 receptor stimulation by C21 accompanied with PPARγ activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic β cells.

  4. The Role of Apelin on the Alleviative Effect of Angiotensin Receptor Blocker in Unilateral Ureteral Obstruction-Induced Renal Fibrosis

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    Masashi Nishida

    2012-03-01

    Full Text Available Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1. The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO model. Results: We obtained the following results: (1 At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS in the UUO kidney were increased compared to those in the nonobstructed kidney. (2 AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3 Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4 Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

  5. Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

    Science.gov (United States)

    Carter, D A; Guo, H; Connelly, A A; Bassi, J K; Fong, A Y; Allen, A M; McDougall, S J

    2018-02-01

    Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT 1A R) in the NTS. AT 1A R-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT 1A R-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT 1A R-GFP mice to make targeted whole cell recordings from AT 1A R-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT 1A R-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT 1A R-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT 1A R-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT 1A R-expressing viscerosensory neurons terminate on AT 1A R-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT 1A R-expressing NTS neurons.

  6. Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors.

    Science.gov (United States)

    Lazartigues, Eric; Sinnayah, Puspha; Augoyard, Ginette; Gharib, Claude; Johnson, Alan Kim; Davisson, Robin L

    2008-11-01

    To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT(1A)) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT(1A)] with brain-restricted overexpression of AT(1A) receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT(1A) compared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT(1A). Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in NSE-AT(1A) mice compared with wild types. Fos immunohistochemistry, used to assess neuronal activation, demonstrated sodium depletion-enhanced activity in the anteroventral third ventricle region of the brain in NSE-AT(1A) mice compared with control animals. The results show that brain-selective overexpression of AT(1A) receptors results in enhanced salt appetite and altered water intake. This model provides a new tool for studying the mechanisms of brain AT(1A)-dependent water and salt consumption.

  7. The role of the angiotensin AT2 receptor on the diurnal variations of nociception and motor coordination in rats.

    Science.gov (United States)

    Pechlivanova, D M; Markova, P P; Popov, D; Stoynev, A G

    2013-01-01

    Phasic pain demonstrates significant diurnal variation in rats. Angiotensin II modulates pain transmission and the diurnal variation in nociception in several rodent pain models. The participation of AT2 receptors in the diurnal regulation of nociception is not yet elucidated. In the present study we investigated the effects of selective peptide AT2 agonist CGP 42112A and the nonpeptide AT2 receptor antagonist PD 123319 on the nociception, motor coordination and arterial blood pressure. Male Wistar 12 weeks old rats were used. CGP 42112A was injected at single doses of 1 and 5 μg/rat intracerebroventricularly (ICV) and infused chronically ICV at a dose of 12 μg/rat/day during 14 days by osmotic minipumps. PD123319 was injected at single doses of 1 and 5 μg/rat, ICV and chronically subcutaneously at a dose of 10 mg/kg/day/14 days. Nociception was assessed by an analgesimeter, arterial blood pressure (ABP) was measured by tail cuff method, and motor coordination by Rota-rod method. Single doses of CGP 42112A (1 and 5 μg/rat) provoked a short lasting antinociception. Unlike acute injection, chronic CGP 42112A infusion increased nociception at the beginning and the end of light phase thus attenuating the diurnal variations observed in the controls. Moreover, it produced an increase of ABP and improved motor coordination. Both acute (1 μg/rat) and chronic PD 123319 treatment resulted in a decrease of pain threshold and chronic treatment attenuated its diurnal fluctuation. Our data support a role for Ang II type 2 receptors in the control of diurnal variations of nociception in rats. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis.

    Science.gov (United States)

    Young, Colin N; Morgan, Donald A; Butler, Scott D; Rahmouni, Kamal; Gurley, Susan B; Coffman, Thomas M; Mark, Allyn L; Davisson, Robin L

    2015-04-01

    Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the subfornical organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis. Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation. Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin-induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT. These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.

  9. Reduced anxiety-like behavior in transgenic rats with chronically overproduction of angiotensin-(1-7): Role of the Mas receptor.

    Science.gov (United States)

    Kangussu, Lucas M; Almeida-Santos, Ana Flávia; Moreira, Fabrício A; Fontes, Marco A P; Santos, Robson A S; Aguiar, Daniele C; Campagnole-Santos, Maria José

    2017-07-28

    Angiotensin-(1-7) [Ang-(1-7)], a counterregulatory peptide of the renin-angiotensin system (RAS), exerts its cardiovascular and renal functions through the G-protein-coupled receptor Mas. More recently, Ang-(1-7) has also been implicated in the control of emotional states related to fear and anxiety. Here, we tested the hypothesis that transgenic rats overexpressesing Ang-(1-7) (TGR) show reduced anxiety-like behavior in two distinct animals models, the Elevated Plus Maze (EPM) and Vogel Conflict Test (VCT). Sprague-Dawley rats (SDs) were used as controls. In addition, we also verified whether this phenotype depend on activation of the Mas receptor. In line with our hypothesis, TGR rats showed an increase in the percentage of time and entries in the open arms of the EPM. There was also an increase in the number of punished licks in VCT. These phenotypes were reversed by ICV injection of the Mas receptor antagonist, A779, but not by the AT2 and MrgD receptor antagonist, PD123319. These results suggest that chronic elevation of Ang-(1-7) levels results in a phenotype characterized by reduced anxiety-like behavior, possibly due to higher activation of the Mas receptor. Therefore, facilitation of the Ang-(1-7)/Mas receptor signaling may be further investigated as an additional strategy for the treatment of anxiety-related disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Increased expression of endothelin ET(B) and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Ekelund, Ulf; Edvinsson, Marie-Louise

    2009-01-01

    of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 microm) were surgically removed......Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression...... group. There were no significant differences in AT(2) and ET(A) receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ET(B) and AT(1) receptors are increased in patients with suspected but ruled out ACS. These receptor changes could be important...

  11. Induction of multiple ovulation via modulation of angiotensin II receptors in in vitro ovarian follicle culture models.

    Science.gov (United States)

    Kim, Yong Jin; Kim, Yoon Young; Kang, Byeong-Cheol; Kim, Moon Suk; Ko, In Kap; Liu, Hung Ching; Rosenwaks, Zev; Ku, Seung-Yup

    2017-11-01

    In vitro culture of ovarian follicles is a promising bioengineering technique for retrieving fertilizable oocytes from preserved ovarian tissues of cancer survivors. However, current in vitro follicle culture techniques are labour-intensive and of low efficiency, as only single follicle culture (SFC) has been possible to date. The present study investigated the feasibility of multifollicular cluster culture (MFCC) system using angiotensin II receptor (ATII-Rc) analogues. Ovarian pre-antral follicles isolated from 2-week-old C57BL6 mice were cultured with ATII-Rc agonist or antagonist and their maturation outcomes were compared with control group. When single follicles were cultured, the ovulation and maturation rates were similar in all three groups. When three-follicle clusters were cultured, up to three follicles were ovulated in the ATII-Rc agonist group while none or one follicle ovulated in control or antagonist groups (p cultured droplets) (p vitro mature oocyte retrieval via ATII-Rc modulation. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Sunitinib Combined with Angiotensin-2 Type-1 Receptor Antagonists Induces More Necrosis: A Murine Xenograft Model of Renal Cell Carcinoma

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    Grégory Verhoest

    2014-01-01

    Full Text Available Background. Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. Material and Methods. 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO, the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. Results. All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P=0.06. Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P=0.038. Central microvascular density decreased (P=0.0038 as well as circulating VEGF (P=0.003. There was no significant variation in proliferation or apoptosis markers. Conclusion. The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.

  13. ANGIOTENSIN-(1-7) RECRUITS MUSCLE MICROVASCULATURE AND ENHANCES INSULIN’S METABOLIC ACTION VIA MAS RECEPTOR

    Science.gov (United States)

    Fu, Zhuo; Zhao, Lina; Aylor, Kevin W.; Carey, Robert M.; Barrett, Eugene J.; Liu, Zhenqi

    2014-01-01

    Angiotensin (Ang)-(1-7), an endogenous ligand for the G protein-coupled receptor Mas, exerts both vasodilatory and insulin sensitizing effects. In skeletal muscle relaxation of pre-capillary arterioles recruits microvasculature and increases the endothelial surface area available for nutrient and hormone exchanges. To assess whether Ang-(1-7) recruits microvasculature and enhances insulin action in muscle, overnight-fasted adult rats received an intravenous infusion of Ang-(1-7) (0, 10 or 100 ng/kg/min) for 150 min with or without a simultaneous infusion of the Mas inhibitor A-779 and a superimposition of a euglycemic insulin clamp (3 mU/kg/min) from 30 to 150 min. Hindlimb muscle microvascular blood volume (MBV), microvascular flow velocity (MFV) and microvascular blood flow (MBF) were determined. Myographic changes in tension were measured on pre-constricted distal saphenous artery. Ang-(1-7) dose-dependently relaxed the saphenous artery (pmicrovasculature and enhances insulin’s metabolic action. These effects may contribute to the cardiovascular protective responses associated with Mas activation and explain Ang-(1-7)’s insulin sensitizing action. PMID:24711523

  14. The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension

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    Ji Hyun Kim

    2011-06-01

    Full Text Available BackgroundHypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension.MethodsWe used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan.ResultsIn the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels.ConclusionShort-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.

  15. Effectiveness of angiotensin II receptor antagonists in a cohort of Dutch patients with type 2 diabetes mellitus (ZODIAC-14).

    Science.gov (United States)

    van Hateren, Kornelis J J; Landman, Gijs W D; Groenier, Klaas H; Bilo, Henk J G; Kleefstra, Nanne

    2015-04-01

    There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure (SBP) and the albumin-creatinine ratio after 1 year in a large cohort of patients with type 2 diabetes mellitus. In 2007, 24 940 primary care patients with type 2 diabetes mellitus participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study, a prospective observational cohort study. Patients were included in the current study if they were prescribed an ARB in 2007 and if 1-year follow-up data were available. The final study population comprised 3610 patients. Multivariate mixed-model analyses were performed to estimate effects of the various ARBs on SBP and albuminuria. Stratified subgroup analyses were performed according to baseline hypertension and albuminuria. SBP decreased in all groups, the largest decrease being observed in the group receiving telmisartan. No significant or relevant changes over time were observed among groups for SBP and albuminuria. In the subgroup (n=1225) of normotensive patients, telmisartan was associated with a larger decrease in SBP after 1 year compared to other ARBs, without different effects on the albumin-creatinine ratio. We observed no differences in effects on SBP and the albumin-creatinine ratio among differing ARBs in patients with type 2 diabetes mellitus. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  16. Effect of Diuretic or Calcium-Channel Blocker Plus Angiotensin-Receptor Blocker on Diastolic Function in Hypertensive Patients.

    Science.gov (United States)

    Toh, Norihisa; Ishii, Katsuhisa; Kihara, Hajime; Iwakura, Katsuomi; Watanabe, Hiroyuki; Yoshikawa, Junichi; Ito, Hiroshi

    2016-01-01

    Hypertension increases the risk of left ventricular (LV) diastolic dysfunction, and anti-hypertensive therapy may improve LV relaxation. The aim of this study was to investigate whether combining an angiotensin-receptor blocker (ARB) with either hydrochlorothiazide (HCTZ) or a calcium-channel blocker (CCB) improves LV relaxation in patients with hypertension and diastolic dysfunction. Hypertensive patients who had not achieved their target blood pressure with at least 4 weeks of ARB therapy were randomly assigned to receive either a fixed-dose combination of losartan and HCTZ (losartan/HCTZ; n=110) or a combination of amlodipine and a typical ARB dosage (CCB/ARB; n=121) and followed for 24 weeks. The primary endpoint was change in early diastolic mitral annular velocity (e', cm/s). Systolic blood pressure decreased in both groups after switch to the combination therapies. E' velocity increased both in the losartan/HCTZ (0.52 cm/s) and in the CCB/ARB (0.59 cm/s) groups. The mean (95% CI) treatment difference was -0.02 (-0.37 to 0.34) cm/s, indicating that improvement in LV relaxation was similar between the groups. The ratio of early mitral inflow velocity to e' velocity and left atrial volume index were significantly decreased in the losartan/HCTZ group. The combination of losartan and HCTZ is as effective as amlodipine plus ARB in improving LV relaxation in hypertensive patients.

  17. Switch strategies in the management of hypertension: a cost minimisation analysis of angiotensin receptor blocker based regimen.

    Science.gov (United States)

    Belsey, J D

    2008-02-01

    Budgetary pressures within health care systems have led many health care providers to consider the switching of patients on long term anti hypertensive medication to agents with the lowest acquisition price. The long term success of this strategy hinges on price differentials remaining stable, an assumption that may not be valid in drug classes where patent expiry times vary. The treatment of hypertension using angiotensin receptor blockers (ARBs) represents just such a case. The present study, therefore, modelled the 5-year cost consequences of treatment based on losartan, candesartan, valsartan and irbesartan, based on expected patent expiry dates. A Markov model was constructed, applying dose-specific blood-pressure lowering and costs to a cohort of uncontrolled mild-moderate hypertensive patients and assessing the anticipated cost of treatment over a 5 year period. A probabilistic approach was adopted to account for between-patient and between-treatment differences. For both undiscounted and discounted models, a losartan-based regimen represents the least costly option of the four agents tested. Median (IQR) discounted expenditure per patient for each agent was: losartan: pound 506 ( pound 441- pound 650), candesartan: pound 610 ( pound 542- pound 766), valsartan: pound 809 ( pound 796- pound 1078), irbesartan pound 696 ( pound 694- pound 934). Switching hypertensive patients taking ARBs to the agent with the lowest current acquisition cost may yield only transient budgetary savings. Once patent expiry is taken into account, this model suggests that maintaining or switching patients to losartan would yield considerably greater savings over 5 years.

  18. TO STUDY THE EFFECT OF ANGIOTENSIN RECEPTOR BLOCKERS ON DIABETIC RETINOPATHY

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    Chakravarthy K

    2017-05-01

    Full Text Available BACKGROUND Diabetic Retinopathy (DR is the most common microvascular complication of Diabetes Mellitus (DM and is the leading cause of blindness in working age adults of patients with type 1 and 2 DM. Large observational and randomised studies shown that optimal blood glucose and blood pressure control halt or regress the disease and limit the risk of progression to the proliferative stage and visual loss. Recently, evidence has also emerged that Renin-Angiotensin System (RAS inhibitors may electively prevent or delay progression of retinopathy by acting on local RAS. Thus, metabolic and blood pressure control by RAS inhibition is to prevent or limit the onset of retinopathy and its progression towards visual-threatening stages. The aim of the study is to categorise and analyse grading of DR who are on currently ACE and ARBs unchanged for at least 2 years. MATERIALS AND METHODS 178 patients with type 1 and 2 DM of both genders on ARBs and ACEI unchanged for at least 2 years are divided into two groups as follows- 1. ARB group, which includesa 28 patients on losartan (50 mg. b 32 patients on losartan (50 mg + hydrochlorothiazide (12.5 mg. c 28 patients on telmisartan (40 mg. d 32 patients on telmisartan (40 mg + hydrochlorothiazide (12.5 mg. 2. ACE inhibitor group includesa 30 patients on enalapril (5 mg. b 28 patients on ramipril (2.5 mg + hydrochlorothiazide (12.5 mg. Retinopathy grading assessed by indirect ophthalmoscope and comparison of retinopathy grading between ARBs and ACEI groups have done. Two-tailed Chi-square test, GraphPad Prism Software used for statistical calculations. RESULTS Losartan and telmisartan (ARB group showed significant protection from diabetic retinopathy than enalapril and ramipril (ACEI group (p<0.05. CONCLUSION ARBs help in preventing the progression of DR and vision loss in those belonging to mild and moderate nonproliferative diabetic retinopathy patients.

  19. The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond.

    Science.gov (United States)

    Kario, Kazuomi

    2018-01-27

    Sacubitril/valsartan (LCZ696) is a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of neprilysin and the angiotensin (AT 1 ) receptor. A recent clinical trial PRARDIGM-HF demonstrated that this drug is superior to angiotensin-converting enzyme (ACE) inhibitors for improving the prognosis in the patients with heart failure, and this has resulted in the drug being included in clinical practice guidelines for the management of heart failure with reduced ejection fraction (EF). In addition, sacubitril/valsartan has been developed for the management of hypertension, because it has unique anti-aging properties. However, the clinical evidence of mechanism has not been well validated. A recent mechanistic study PARAMETER demonstrated that sacubitril/valsartan (LCZ696) is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Considering these results, sacubitril/valsartan may be an attractive therapeutic agent to treat the elderly with age-related hypertension phenotypes, such as drug-uncontrolled (resistant) hypertension characterized as systolic (central) hypertension (structural hypertension) and/or nocturnal hypertension (salt-sensitive hypertension). These are the high-risk hypertension phenotypes which are prone to develop heart failure with preserved EF and chronic kidney disease. Sacubitril/valsartan may be effective to suppress the age-related continuum from hypertension to heart failure, and it could be clinically useful not only for secondary prevention, but also as primary prevention of heart failure in uncontrolled elderly hypertensive patients.

  20. A Novel Cellular Model to Study Angiotensin II AT2 Receptor Function in Breast Cancer Cells

    OpenAIRE

    Sylvie Rodrigues-Ferreira; Marina Morel; Rosana I Reis; Françoise Cormier; Véronique Baud; Costa-Neto, Claudio M.; Clara Nahmias

    2012-01-01

    Recent studies have highlighted the AT1 receptor as a potential therapeutic target in breast cancer, while the role of the AT2 subtype in this disease has remained largely neglected. The present study describes the generation and characterization of a new cellular model of human invasive breast cancer cells (D3H2LN-AT2) stably expressing high levels of Flag-tagged human AT2 receptor (Flag-hAT2). These cells exhibit high-affinity binding sites for AngII, and total binding can be displaced by t...

  1. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Stranahan, Alexis M; Krause, Eric G; de Kloet, Annette D; Stern, Javier E

    2016-02-01

    ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. Copyright © 2016 the American Physiological Society.

  2. Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta

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    Jay S Mishra

    2016-10-01

    Full Text Available Introduction: Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT2R induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. Methods: AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. Results: AT2R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT2R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT2R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT2R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT2R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFβ signaling with specific inhibitors abolished dihydrotestosterone-induced AT2R downregulation. Conclusion: Androgens downregulate AT2R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT2R expression, implicating androgens’ contributing role to gender differences in vascular AT2R expression.

  3. Effect of angiotensin II type 2 receptor-interacting protein on adipose tissue function via modulation of macrophage polarization.

    Directory of Open Access Journals (Sweden)

    Fei Jing

    Full Text Available We demonstrated that angiotensin II type 2 (AT2 receptor-interacting protein (ATIP 1 ameliorates inflammation-mediated vascular remodeling independent of the AT2 receptor, leading us to explore the possibility of whether ATIP1 could exert anti-inflammatory effects and play a role in other pathophysiological conditions. We examined the possible anti-inflammatory effects of ATIP1 in adipose tissue associated with amelioration of insulin resistance. In mice fed a high-cholesterol diet, adipose tissue macrophage (ATM infiltration and M1-to-M2 ratio were decreased in ATIP1 transgenic mice (ATIP1-Tg compared with wild-type mice (WT, with decreased expression of inflammatory cytokines such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in white adipose tissue (WAT, but an increase in interleukin-10, an anti-inflammatory cytokine. Moreover, 2-[(3H]deoxy-d-glucose (2-[(3H]DG uptake was significantly increased in ATIP1-Tg compared with WT. Next, we examined the roles of ATIP1 in BM-derived hematopoietic cells, employing chimeric mice produced by BM transplantation into irradiated type 2 diabetic mice with obesity, KKAy, as recipients. ATM infiltration and M1-to-M2 ratio were decreased in ATIP1 chimera (ATIP1-tg as BM donor, with improvement of insulin-mediated 2-[(3H]DG uptake and amelioration of inflammation in WAT. Moreover, serum adiponectin concentration in ATIP1 chimera was significantly higher than that in WT chimera (WT as BM donor and KKAy chimera (KKAy as BM donor. These results indicate that ATIP1 could exert anti-inflammatory effects in adipose tissue via macrophage polarization associated with improvement of insulin resistance, and ATIP1 in hematopoietic cells may contribute to these beneficial effects on adipose tissue functions in type 2 diabetes.

  4. A PROSPECTIVE STUDY OF EFFECT OF TELMISARTAN (ANGIOTENSIN II RECEPTOR BLOCKER ON METABOLIC PARAMETERS IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

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    Somesekhar

    2016-04-01

    Full Text Available BACKGROUND The metabolic syndrome is currently a major worldwide epidemic. It strongly associates with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases, which are major pathologies contributing to mortality and morbidity worldwide. The effect of PPAR-y on metabolic syndrome is significant it is critical regulator of adipogenesis the gain in PPAR-y is resulted in obesity but loss of PPAR–y by mutation is associated with loss of weight and insulin resistance. Telmisartan is an orally active, long-acting, non-peptide angiotensin type 1 (ATI receptor blocker. In addition to this, it has been identified as partial agonist/selective modulator of the nuclear hormone receptor PPAR-y. MATERIAL AND METHOD This is a prospective, randomised and open labelled 16 weeks study conducted in the Dept. of General Medicine, Konaseema Institute of Medical Science, Amalapuram. Present study is designed to study the effect of telmisartan on various metabolic parameters in hypertensive patients who fulfilled the criteria of metabolic syndrome. RESULT There was statistically significant change in all parameters most important was lipid profile; LDL concentration was decreased from 139.2 mg/dL to 120.2 mg/dL. Baseline triglyceride concentration was 161.0 mg/dL which was changed 152.8 mg/dL Total cholesterol was decreased from 203.2 to 193.8 mg/dL. CONCLUSION In our study, we have also found that use of telmisartan is associated with decrease in lipid concentration in addition to its effect on blood pressure regulation. But a long term study with high dose required of this drug is required because safety profile of this drug is better than thiazolidinedione. Financial part of this study is our limitation.

  5. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    Energy Technology Data Exchange (ETDEWEB)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Li, Xiao-Dong [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Hong, Mo-Na [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Chen, Qi-Zhi [Shanghai Institute of Hypertension, Shanghai (China); Han, Wei-Qing, E-mail: whan020@gmail.com [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Gao, Ping-Jin, E-mail: gaopingjin@sibs.ac.cn [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China)

    2016-04-29

    Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

  6. Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Hashimoto, Seiji; Briggs, Josie

    2003-01-01

    In the present experiments we examined the renovascular constrictor effects of ANG II in the chronic and complete absence of A1 adenosine receptors (A1AR) using mice with targeted deletion of the A1AR gene. Glomerular filtration rate (GFR) was not different between A1AR +/+ and A1AR -/- mice unde...

  7. POSSIBILITY OF ANGIOTENSIN RECEPTOR BLOCKERS IN OPTIMIZING OF ANTIHYPERTENSIVE PHARMACOTHERAPY IN PATIENTS AFTER STROK

    Directory of Open Access Journals (Sweden)

    Z M. Sizova

    2013-01-01

    Full Text Available Current possibilities of AT1 receptor blockers (ARBs, such as candesartan, for optimization of antihypertensive therapy in stroke patients are presented in the article. ARBs are original drugs that effect to the delicate balance of pressor and depressor neurohormonal systems. They also have cerebroprotective action and are the drugs of choice for primary and secondary prevention of stroke in hypertensive patients

  8. Effects of the angiotensin-(1-7) receptor Mas on cell proliferation and on the population of doublecortin positive cells within the dentate gyrus and the piriform cortex.

    Science.gov (United States)

    Freund, M; Walther, T; von Bohlen Und Halbach, O

    2014-02-01

    Aside from the well-known biologically active angiotensin II, other biologically active angiotensins have been discovered, including angiotensin IV and angiotensin-(1-7). Some years ago, we and others discovered that the Mas proto-oncogene encodes a G protein-coupled receptor being essential for angiotensin-(1-7) signaling. Mas is not only expressed in the periphery but also within the brain, e.g. in the dentate gyrus (DG) and the piriform cortex (PC). Since the DG is capable of adult neurogenesis, we examined the impact of a deletion of Mas upon adult neurogenesis. Deletion of Mas did not alter cell proliferation in the adult DG (as monitored with phosphohistone H3) and did not alter cell death (as monitored with activated Caspase 3). However, Mas deficiency resulted in an increase in the number of doublecortin (DCX) positive cells, indicating that lack of Mas increases the number of this cell population. Concerning the PC, it is discussed whether adult neurogenesis occurs under physiological conditions in this area. We could demonstrate that Mas deficiency has an impact on cell division and on the population of DCX-positive cells within the PC. Since Mas is not expressed before birth within the brain, our data may suggest that adult hippocampal neurogenesis and neurogenesis occurring during prenatal development share several common mechanisms, but are, at least in part, differentially regulated. Moreover, since deficiency for Mas increases the numbers of DCX-positive young neurons, blockage of Mas might be beneficial in stimulating neurogenesis in adults. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

  9. Genetic Association Study of Angiotensin II Receptor Types 1 (A168G) and 2 (T1247G and A5235G) Polymorphisms in Breast Carcinoma among Brazilian Women.

    Science.gov (United States)

    Molina Wolgien, Maria Del Carmen Garcia; Guerreiro da Silva, Ismael Dale Cotrim; Pinto Nazário, Afonso Celso; Nakaie, Clovis Riuche; Correa-Noronha, Silvana Aparecida Alves; Ribeiro de Noronha, Samuel Marcos; Facina, Gil

    2014-07-01

    Many types of cancer are associated with polymorphisms of the renin-angiotensin system. Our aim was to assess possible association between single-nucleotide polymorphisms (SNPs) of the angiotensin II receptor types 1 (A168G), and 2 (T1247G and A5235G) with breast cancer. 242 participating subjects were genotyped and allocated to case or control groups. Genotype distribution (in %) was: for AGTR1 (A168G): AA, AG, GG = 61, 30, 09 for cases, and 69, 25, 06 for controls (p = 0.55); for AGTR2 (T1247G): TT, TG, GG = 84, 12, 04 for cases, and 81, 17, 02 for controls (p = 0.45); for AGTR2 (A5235G): AA, AG, GG = 32, 67, 01 for cases, and 53, 28, 19 for controls (p II type 2 receptor had an 11-fold higher risk of breast cancer than GG carriers. Many types of cancer have been associated with polymorphisms of the renin-angiotensin system. For SNP A5235G, the GG genotype seems to be protective against breast cancer. The other 2 SNPs showed no association. However, SNPs T1247G and A5235G were associated with at least 1 clinical variable, with G being a predictor of better outcome. The use of SNPs A5235G and T1247G (the latter to a lesser degree) as genetic markers should be considered.

  10. Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2/Mas receptor axis.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-05-23

    The local and systemic renin angiotensin system (RAS) influences the skeletal system micro-structure and metabolism. Studies suggested angiotensin 1-7 (Ang(1-7)) as the beneficial RAS molecule via Mas receptor activation. This study examines the function of Ang(1-7) in bone micro-architecture and metabolism in an ovariectomized (OVX) rodent model of osteoporosis. OVX rats showed structural and bone metabolic degeneration in parallel with suppressed expressions of the angiotensin converting enzyme-2 (ACE-2)/Ang(1-7)/Mas components. The infusion of Ang(1-7) markedly alleviated the altered bone metabolism and significantly enhanced both trabecular (metaphyseal) and cortical (metaphyseal-diaphyseal) morphometry. Urinary and bones minerals were also improved in OVX rats by Ang(1-7). The infusion of the heptapeptide enhanced ACE-2/Mas receptor expressions, while down-regulated AngII, ACE, and AngII type-1 receptor (AT1R) in OVX animals. Moreover, Ang(1-7) markedly improved osteoprotegerin (OPG) and lowered receptor activator NF-κB ligand (RANKL) expressions. The defensive properties of Ang(1-7) on bone metabolism, structure and minerals were considerably eradicated after blockage of Mas receptor with A-779. Ang(1-7)-induced up-regulated ACE-2/Ang(1-7)/Mas cascade and OPG expressions were abolished and the expressions of ACE/AngII/AT1R and RANKL were provoked by A-779. These findings shows for the first time the novel valuable therapeutic role of Ang(1-7) on bone health and metabolism through the ACE-2/Mas cascade.

  11. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

    2009-01-01

    immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: Ten patients with GCA and 10 control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included. METHODS: Immunohistochemistry, using anti-AT(1) and anti......-AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia......, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control...

  12. Biased signaling of the angiotensin II type 1 receptor can be mediated through distinct mechanisms

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Hansen, Jonas Tind; Sanni, Samra Joke

    2010-01-01

    molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit ß-arrestins. Since uncoupling of G proteins by increased ability...... to recruit ß-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms....

  13. Reversible Fetal Renal Impairment following Angiotensin Receptor Blocking Treatment during Third Trimester of Pregnancy: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Tal Saar

    2016-01-01

    Full Text Available Background. Late pregnancy usage of angiotensin converting enzyme inhibitors (ACE-I and angiotensin II receptor blockers (ARB may cause severe oligohydramnios due to fetal renal impairment. Affected neonates will often suffer from fatal, renal, and respiratory failure. Case. A 39-year-old multigravida admitted due to anhydramnios secondary to valsartan (ARB exposure at 30 weeks’ gestation. Following secession of treatment amniotic fluid volume returned to normal. Delivery was induced at 34 weeks’ gestation following premature rupture of membranes and maternal fever. During the two-year follow-up, no signs of renal insufficiency were noted. Conclusions. This description of reversible fetal renal damage due to ARB intake during pregnancy is the first to show no adverse renal function in a two-year follow-up period. This case may help clinicians counsel patients with pregnancies complicated by exposure to these drugs.

  14. An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Masaya Koshizaka

    2012-01-01

    Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

  15. Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice

    DEFF Research Database (Denmark)

    Schwengel, Katja; Namsolleck, Pawel; Lucht, Kristin

    2016-01-01

    /BL6J or AT2R-knockout mice (AT2-KO) underwent MCAO for 30 min followed by reperfusion. Starting 45 min after MCAO, mice were treated once daily for 4 days with either vehicle or C21 (0.03 mg/kg ip). Neurological deficits were scored daily. Infarct volumes were measured 96 h post-stroke by MRI. C21......This study investigated the effect of post-stroke, direct AT2-receptor (AT2R) stimulation with the non-peptide AT2R-agonist compound 21 (C21) on infarct size, survival and neurological outcome after middle cerebral artery occlusion (MCAO) in mice and looked for potential underlying mechanisms. C57...... significantly improved survival after MCAO when compared to vehicle-treated mice. C21 treatment had no impact on infarct size, but significantly attenuated neurological deficits. Expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) (receptor for BDNF) and growth...

  16. Redistribution of NMDA Receptors in Estrogen-Receptor-β-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure.

    Science.gov (United States)

    Marques-Lopes, Jose; Tesfaye, Ephrath; Israilov, Sigal; Van Kempen, Tracey A; Wang, Gang; Glass, Michael J; Pickel, Virginia M; Iadecola, Costantino; Waters, Elizabeth M; Milner, Teresa A

    2017-01-01

    Hypertension in male and aging female rodents is associated with glutamate-dependent plasticity in the hypothalamus, but existing models have failed to capture distinct transitional menopausal phases that could have a significant impact on the synaptic plasticity and emergent hypertension. In rodents, accelerated ovarian failure (AOF) induced by systemic injection of 4-vinylcyclohexane diepoxide mimics the estrogen fluctuations seen in human menopause including the perimenopause transition (peri-AOF) and postmenopause (post-AOF). Thus, we used the mouse AOF model to determine the impact of slow-pressor angiotensin II (AngII) administration on blood pressure and on the subcellular distribution of obligatory N-methyl-D-aspartate (NMDA) receptor GluN1 subunits in the paraventricular hypothalamic nucleus (PVN), a key estrogen-responsive cardiovascular regulatory area. Estrogen-sensitive neuronal profiles were identified in mice expressing enhanced green fluorescent protein under the promoter for estrogen receptor (ER) β, a major ER in the PVN. Slow-pressor AngII increased arterial blood pressure in mice at peri- and post-AOF time points. In control oil-injected (nonhypertensive) mice, AngII decreased the total number of GluN1 in ERβ-containing PVN dendrites. In contrast, AngII resulted in a reapportionment of GluN1 from the cytoplasm to the plasma membrane of ERβ-containing PVN dendrites in peri-AOF mice. Moreover, in post-AOF mice, AngII increased total GluN1, dendritic size and radical production in ERβ-containing neurons. These results indicate that unique patterns of hypothalamic glutamate receptor plasticity and dendritic structure accompany the elevated blood pressure in peri- and post-AOF time points. Our findings suggest the possibility that distinct neurobiological processes are associated with the increased blood pressure during perimenopausal and postmenopausal periods. © 2016 S. Karger AG, Basel.

  17. Increased expression of endothelin ET(B) and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Ekelund, Ulf; Edvinsson, Lars

    2009-01-01

    in an abdominal biopsy from 12 patients suspicious of ACS (susp ACS), admitted to the medical telemetry unit for chest pain. The vessels were analyzed for their receptor protein expression by quantitative immunohistochemistry using specific antibodies directed against ET(A), ET(B), AT(1), and AT(2) receptors......Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression...... of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 microm) were surgically removed...

  18. Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.

    Science.gov (United States)

    Hong, Kwangseok; Li, Min; Nourian, Zahra; Meininger, Gerald A; Hill, Michael A

    2017-12-01

    Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by GPCRs (G protein-coupled receptors), including the AT 1 R (angiotensin II type 1 receptor). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether RGS (regulators of G protein signaling) proteins in vascular smooth muscle cells are colocalized with the AT 1 R when activated by mechanical stress or angiotensin II and whether this modulates AT 1 R-mediated vasoconstriction. To determine whether activation of the AT 1 R recruits RGS5, an in situ proximity ligation assay was performed in primary cultures of cremaster muscle arteriolar vascular smooth muscle cells treated with angiotensin II or hypotonic solution in the absence or presence of candesartan (an AT 1 R blocker). Proximity ligation assay results revealed a concentration-dependent increase in trafficking/translocation of RGS5 toward the activated AT 1 R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to angiotensin II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to downregulation of AT 1 R-mediated signaling. Further, translocation of RGS5 was impaired in vascular smooth muscle cells of spontaneously hypertensive rats. This is consistent with dysregulated (RGS5-mediated) AT 1 R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in spontaneously hypertensive rats compared with controls. Collectively, these findings suggest that AT 1 R activation results in translocation of RGS5 toward the plasma membrane, limiting AT 1 R-mediated vasoconstriction through its role in G q/11 protein-dependent signaling. © 2017 American Heart Association, Inc.

  19. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yogi, Alvaro; Callera, Glaucia E. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Mecawi, André S. [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Batalhão, Marcelo E.; Carnio, Evelin C. [Department of General and Specialized Nursing, College of Nursing of Ribeirão Preto, USP, São Paulo (Brazil); Antunes-Rodrigues, José [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Queiroz, Regina H. [Department of Clinical, Toxicological and Food Science Analysis, Faculty of Pharmaceutical Sciences, USP, São Paulo (Brazil); Touyz, Rhian M. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Tirapelli, Carlos R., E-mail: crtirapelli@eerp.usp.br [Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP (Brazil)

    2012-11-01

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT{sub 1} receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT{sub 1}-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT{sub 1} receptor activation.

  20. Angiotensin II type 1 receptors and systemic hemodynamic and renal responses to stress and altered blood volume in conscious rabbits

    Directory of Open Access Journals (Sweden)

    Tony B. Xu

    2011-07-01

    Full Text Available We examined how systemic blockade of type 1 angiotensin (AT1- receptors affects reflex control of the circulation and the kidney. In conscious rabbits, the effects of candesartan on responses of systemic and renal hemodynamics and renal excretory function to acute hypoxia, mild hemorrhage and plasma volume expansion were tested. Candesartan reduced resting mean arterial pressure (MAP, -8 ± 2% without significantly altering cardiac output (CO, increased renal blood flow (RBF, +38 ± 9% and reduced renal vascular resistance (RVR, -32 ± 6%. Glomerular filtration rate (GFR was not significantly altered but sodium excretion (UNa+V increased four-fold. After vehicle treatment, hypoxia (10% inspired O2 for 30 min did not significantly alter MAP or CO, but reduced HR (-17 ± 6%, increased RVR (+33 ± 16% and reduced GFR (-46 ± 16% and UNa+V (-41 ± 17%. Candesartan did not significantly alter these responses. After vehicle treatment, plasma volume expansion increased CO (+35 ± 7%, reduced total peripheral resistance (TPR, -26 ± 5%, increased RBF (+62 ± 23% and reduced RVR (-32 ± 9%, but did not significantly alter MAP or HR. It also increased UNa+V (803 ± 184% yet reduced GFR (-47 ± 9%. Candesartan did not significantly alter these responses. After vehicle treatment, mild hemorrhage did not significantly alter MAP but increased HR (+16 ± 3%, reduced CO (-16 ± 4% and RBF (-18 ± 6%, increased TPR (+18 ± 4% and tended to increase RVR (+18 ± 9%, P = 0.1, but had little effect on GFR or UNa+V. But after candesartan treatment MAP fell during hemorrhage (-19 ± 1%, while neither TPR nor RVR increased, and GFR (-64 ± 18% and UNa+V (-83 ± 10% fell. AT1-receptor activation supports MAP and GFR during hypovolemia. But AT1-receptors appear to play little role in the renal vasoconstriction, hypofiltration and antinatriuresis accompanying hypoxia, or the systemic and renal vasodilatation and natriuresis accompanying plasma volume expansion.

  1. The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines.

    Science.gov (United States)

    Pawlik, M W; Kwiecien, S; Ptak-Belowska, A; Pajdo, R; Olszanecki, R; Suski, M; Madej, J; Targosz, A; Konturek, S J; Korbut, R; Brzozowski, T

    2016-02-01

    The inhibition of angiotensin-converting enzyme (ACE) or the blockade of angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of acetic-acid-induced gastric ulcers with or without the blockade of Mas receptors by A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and losartan, respectively, the inhibition of ACE by lisinopril, the NO/cNOS inhibition by L-NAME and inhibition of prostaglandin/COX system by indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after ulcer induction, the area of these ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at ulcer margin and gastric oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive nitric oxide synthase (cNOS), superoxide dismutase (SOD), and pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) and plasma level of both cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the luminal content of NO significantly reduced the area of gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at ulcer margin. Similar GMBF changes and significant reduction the area of gastric ulcer was

  2. Live Cell Imaging and 3D Analysis of Angiotensin Receptor Type 1a Trafficking in Transfected Human Embryonic Kidney Cells Using Confocal Microscopy.

    Science.gov (United States)

    Kadam, Parnika; McAllister, Ryan; Urbach, Jeffrey S; Sandberg, Kathryn; Mueller, Susette C

    2017-03-27

    Live-cell imaging is used to simultaneously capture time-lapse images of angiotensin type 1a receptors (AT1aR) and intracellular compartments in transfected human embryonic kidney-293 (HEK) cells following stimulation with angiotensin II (Ang II). HEK cells are transiently transfected with plasmid DNA containing AT1aR tagged with enhanced green fluorescent protein (EGFP). Lysosomes are identified with a red fluorescent dye. Live-cell images are captured on a laser scanning confocal microscope after Ang II stimulation and analyzed by software in three dimensions (3D, voxels) over time. Live-cell imaging enables investigations into receptor trafficking and avoids confounds associated with fixation, and in particular, the loss or artefactual displacement of EGFP-tagged membrane receptors. Thus, as individual cells are tracked through time, the subcellular localization of receptors can be imaged and measured. Images must be acquired sufficiently rapidly to capture rapid vesicle movement. Yet, at faster imaging speeds, the number of photons collected is reduced. Compromises must also be made in the selection of imaging parameters like voxel size in order to gain imaging speed. Significant applications of live-cell imaging are to study protein trafficking, migration, proliferation, cell cycle, apoptosis, autophagy and protein-protein interaction and dynamics, to name but a few.

  3. The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

    Science.gov (United States)

    Irani, Roxanna A; Zhang, Yujin; Blackwell, Sean C; Zhou, Cissy Chenyi; Ramin, Susan M; Kellems, Rodney E; Xia, Yang

    2009-11-23

    Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

  4. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

    Science.gov (United States)

    Chia, N; Fulcher, J; Keech, A

    2016-06-01

    Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition. © 2016 Royal Australasian College of Physicians.

  5. Association of Angiotensin-Converting Enzyme Intron 16 Insertion/Deletion and Angiotensin II Type 1 Receptor A1166C Gene Polymorphisms with Preeclampsia in South East of Iran

    Directory of Open Access Journals (Sweden)

    Saeedeh Salimi

    2011-01-01

    Full Text Available Some evidence suggests that a variety of genetic factors contributed in pathogenesis of the preeclampsia. The aim of this study was to assess the association between the angiotensin-converting enzyme (ACE I/D and angiotensin II type1 receptor A1166C polymorphisms with preeclampsia. This study was performed in 125 preeclamptic pregnant women and 132 controls. The I/D Polymorphism of the ACE gene was assessed by polymerase chain reaction and the A1166C Polymorphism of the AT1R gene was determined by restriction fragment length polymorphism. The genotype and allele frequencies of I/D polymorphism differed between two groups. The risk of preeclampsia was 3.2-fold in pregnant women with D allele (OR, 3.2 [95% CI, 1.1 to 3.8]; P=0.01. The distribution of the AT1R gene A1166C polymorphism was similar in affected and control groups. Our results supported that presence of the I/D polymorphism of ACE gene is a marker for the increased risk of preeclampsia.

  6. Angiotensin II, a neuropeptide at the frontier between endocrinology and neuroscience: Is there a link between the angiotensin II type 2 receptor (AT2R and Alzheimer’s disease?

    Directory of Open Access Journals (Sweden)

    Nicole eGallo-Payet

    2011-08-01

    Full Text Available Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer’s disease. Angiotensin II (Ang II is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type-1 receptor (AT1R and the type-2 receptor (AT2R. Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of Alzheimer’s disease (AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by nonpeptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in Alzheimer’s disease and other neurological cognitive disorders.

  7. Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome.

    Science.gov (United States)

    Felix Kröpelin, Tobias; de Zeeuw, Dick; Holtkamp, Frank Arjan; Packham, David Kenneth; L Heerspink, Hiddo J

    2016-09-01

    Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study was to assess individual albuminuria fluctuations after the initial ARB response and to determine whether taking individual albuminuria fluctuations into account improves renal outcome prediction. Patients with diabetes and nephropathy treated with losartan or irbesartan in the RENAAL and IDNT trials were included. Patients with >30% reduction in albuminuria 3 months after ARB initiation were stratified by the subsequent change in albuminuria until Month 12 in enhanced responders (>50% albuminuria reduction), sustained responders (between 20 and 50% reduction), and response escapers (albuminuria exposure until Month 3 was compared with the exposure over the first 12 months using receiver operating characteristics (ROC) curves. Following ARB initiation, 388 (36.3%) patients showed an >30% reduction in albuminuria. Among these patients, the albuminuria level further decreased in 174 (44.8%), remained stable in 123 (31.7%), and increased in 91 (23.5%) patients. Similar albuminuria fluctuations were observed in patients with albuminuria reduction. Renal risk prediction improved when using the albuminuria exposure during the first 12 months versus the initial Month 3 change [ROC difference: 0.78 (95% CI 0.75-0.82) versus 0.68 (0.64-0.72); P albuminuria variability is observed. Hence, incorporating multiple albuminuria measurements over time in risk algorithms may be more appropriate to monitor treatment effects and quantify renal risk. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  8. Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey; Moss, M Elizabeth; Jaffe, Iris Z; Jackson, William F; Dorrance, Anne M

    2017-12-01

    The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia. © 2017 American Heart Association, Inc.

  9. Angiotensin II AT1 receptors mediate neuronal sensitization and sustained blood pressure response induced by a single injection of amphetamine.

    Science.gov (United States)

    Marchese, N A; Paz, M C; Caeiro, X; Dadam, F M; Baiardi, G; Perez, M F; Bregonzio, C

    2017-01-06

    A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT1 receptors (AT1-R) activation, is involved in these responses. However, amphetamine-induced alterations can be extended to extra-striatal areas involved in blood pressure control and their physiological outcomes. Our aim for the present study was to analyze the possible role for AT1-R in these events using a two-injection protocol and to further characterize the proposed AT1-R antagonism protocol. Central effect of orally administered AT1-R blocker (Candesartan, 3mg/kg p.o.×5days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT1-R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5mg/kg i.p. - day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5mg/kg i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood pressure response. AT1-R blockade decreased LC neurons' spontaneous firing rate. Moreover, sensitized c-Fos immunoreactivity in TH+neurons was found in LC and NTS; and both responses were blunted by the AT1-R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT1-R blockade. Our results extend AT1-R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    Science.gov (United States)

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.

  11. Effect of Compound 21, a Selective Angiotensin II Type 2 Receptor Agonist, in a Murine Xenograft Model of Dupuytren Disease.

    Science.gov (United States)

    Chisholm, Jessica; Gareau, Alison J; Byun, Stephanie; Paletz, Justin L; Tang, David; Williams, Jason; LeVatte, Terry; Bezuhly, Michael

    2017-11-01

    Although surgical excision and intralesional collagenase injection are mainstays in Dupuytren disease treatment, no effective medical therapy exists for recurrent disease. Compound 21, a selective agonist of the angiotensin II type 2 receptor, has been shown to protect against fibrosis in models of myocardial infarction and stroke. The authors investigated the potential use of compound 21 in the treatment of Dupuytren disease. Human dermal fibroblasts were treated in vitro with compound 21 and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration by means of scratch assay, and profibrotic gene transcription by means of quantitative reverse transcription polymerase chain reaction. Compound 21 effects in vivo were assessed using a xenograft model. Dupuytren disease cord specimens from patients undergoing open partial fasciectomy were divided into two segments. Segments were implanted under the dorsal skin of nude mouse pairs. Beginning on day 5, one mouse from each pair received daily intraperitoneal injections of compound 21 (10 μg/kg/day), and the other received vehicle. On day 10, segments were explanted and submitted for immunohistochemistry. Human dermal fibroblasts treated with compound 21 displayed decreased migration and decreased gene expression of connective tissue growth factor, fibroblast specific protein-1, transforming growth factor-β1, Smad3, and Smad4. Dupuytren disease segments from compound 21-treated mice demonstrated significantly reduced alpha-smooth muscle actin and Ki67 staining, with increased density of CD31 staining vessels. Compound 21 significantly decreases expression of profibrotic genes and decreases myofibroblast proliferation as indicated by reduced Ki67 and alpha-smooth muscle actin expression. These findings support compound 21 as a potential novel treatment modality for Dupuytren disease.

  12. Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Eiichiro Yamamoto

    Full Text Available The combination therapy of an angiotensin receptor blocker (ARB with a calcium channel blocker (CCB or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP were divided into 6 groups, and they were orally administered (1 vehicle, (2 olmesartan, an ARB, (3 azelnidipine, a CCB, (4 hydrochlorothiazide, a diuretic, (5 olmesartan combined with azelnidipine, or (6 olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

  13. Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response.

    Directory of Open Access Journals (Sweden)

    Bart F J Heijnen

    Full Text Available Transient activation of the renin-angiotensin system (RAS induces irreversible renal damage causing sustained elevation in blood pressure (BP in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C. Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day or hydralazine (100 mg/kg/day treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1 cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.

  14. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.

    Directory of Open Access Journals (Sweden)

    Douglas M Bennion

    Full Text Available Activation of the angiotensin II type 2 receptor (AT2R by administration of Compound 21 (C21, a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

  15. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.

    Science.gov (United States)

    Bennion, Douglas M; Isenberg, Jacob D; Harmel, Allison T; DeMars, Kelly; Dang, Alex N; Jones, Chad H; Pignataro, Megan E; Graham, Justin T; Steckelings, U Muscha; Alexander, Jon C; Febo, Marcelo; Krause, Eric G; de Kloet, Annette D; Candelario-Jalil, Eduardo; Sumners, Colin

    2017-01-01

    Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

  16. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  17. Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

    Science.gov (United States)

    Kakuta, Hirotoshi; Kurosaki, Eiji; Niimi, Tatsuya; Gato, Katsuhiko; Kawasaki, Yuko; Suwa, Akira; Honbou, Kazuya; Yamaguchi, Tomohiko; Okumura, Hiroyuki; Sanagi, Masanao; Tomura, Yuichi; Orita, Masaya; Yonemoto, Takako; Masuzaki, Hiroaki

    2014-04-01

    A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.

  18. Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells.

    Science.gov (United States)

    Leung, Joseph C K; Chan, Loretta Y Y; Saleem, M A; Mathieson, P W; Tang, Sydney C W; Lai, Kar Neng

    2015-07-01

    Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN.

  19. The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model.

    Science.gov (United States)

    Dorri Mashhadi, Fahimeh; Zavvar Reza, Javad; Jamhiri, Mohabbat; Hafizi, Zeinab; Zare Mehrjardi, Fatemeh; Safari, Fatemeh

    2017-03-01

    This study investigated the effect of resveratrol on serum and cardiac levels of angiotensin II and transcription of its main receptors following pressure overload induced-hypertrophy. Rats were divided into untreated (Hyp) and resveratrol treated hypertrophied groups (H + R). Intact animals served as the control (Ctl). Cardiac hypertrophy was induced by abdominal aortic banding. Blood pressure (BP) was recorded via left carotid artery cannula. Fibrosis was confirmed by Masson trichrome staining. Angiotensin II level was measured using an ELIZA test. Gene expression was assessed by a real time PCR (RT-PCR) technique. We observed that in the H + R group BP and heart weight/body weight were decreased significantly (p < 0.001, p < 0.05, respectively vs Hyp). The cardiac levels of angiotensin II and AT1a mRNA were increased in the Hyp group (p < 0.01 vs Ctl). In the H + R group the AT1a mRNA level was decreased significantly (p < 0.05 vs Hyp). It could be concluded that resveratrol protects the heart against hypertrophy progression in part by affecting cardiac AT1a transcription.

  20. Comparative Effects of Direct Renin Inhibitor and Angiotensin Receptor Blocker on Albuminuria in Hypertensive Patients with Type 2 Diabetes. A Randomized Controlled Trial.

    Science.gov (United States)

    Uzu, Takashi; Araki, Shin-Ichi; Kashiwagi, Atsunori; Haneda, Masakazu; Koya, Daisuke; Yokoyama, Hiroki; Kida, Yasuo; Ikebuchi, Motoyoshi; Nakamura, Takaaki; Nishimura, Masataka; Takahara, Noriko; Obata, Toshiyuki; Omichi, Nobuyuki; Sakamoto, Katsuhiko; Shingu, Ryosuke; Taki, Hideki; Nagai, Yoshio; Tokuda, Hiroaki; Kitada, Munehiro; Misawa, Miwa; Nishiyama, Akira; Kobori, Hiroyuki; Maegawa, Hiroshi

    2016-01-01

    In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to albuminuria. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

  1. Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2 knockout mice

    Directory of Open Access Journals (Sweden)

    Halfyard Sarah J

    2008-10-01

    Full Text Available Abstract Background In this study we used radiotelemetry to measure hemodynamic variables and locomotor activity in conscious unrestrained male Protease-Activated Receptor 2 (PAR-2 knockout mice in order to provide a detailed assessment of their blood pressure phenotype. In addition we tested for an influence of PAR-2 on salt-sensitivity (8% versus 0.5% NaCl diet, 2.5 weeks and angiotensin II-induced hypertension (1 μg Ile5-angiotensin II/kg/min versus 0.25 μl/h saline, 2 weeks. Results Systolic arterial pressures of PAR-2 -/- (129 ± 1 mmHg, n = 21, P P Conclusion The data indicated gene knockout of PAR-2 was associated with a modest change in blood pressure phenotype. PAR-2 -/- mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increased diastolic arterial pressure, no increased blood pressure responses to high salt diet and a subtle difference in the time course of the blood pressure responses to angiotensin II infusion.

  2. Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial.

    Science.gov (United States)

    Solomon, Scott D; Rizkala, Adel R; Gong, Jianjian; Wang, Wenyan; Anand, Inder S; Ge, Junbo; Lam, Carolyn S P; Maggioni, Aldo P; Martinez, Felipe; Packer, Milton; Pfeffer, Marc A; Pieske, Burkert; Redfield, Margaret M; Rouleau, Jean L; Van Veldhuisen, Dirk J; Zannad, Faiez; Zile, Michael R; Desai, Akshay S; Shi, Victor C; Lefkowitz, Martin P; McMurray, John J V

    2017-07-01

    The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction ≥45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus

    Energy Technology Data Exchange (ETDEWEB)

    Pendergrass, Karl D.; Gwathmey, TanYa M. [The Hypertension and Vascular Research Center, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States); Michalek, Ryan D.; Grayson, Jason M. [Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States); Chappell, Mark C., E-mail: mchappel@wfubmc.edu [The Hypertension and Vascular Research Center, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States)

    2009-06-26

    We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1 nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 was present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.

  4. Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

    DEFF Research Database (Denmark)

    Patel, Sanket N; Ali, Quaisar; Samuel, Preethi

    2017-01-01

    which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1-7) in OZR increased urine flow and urinary Na excretion, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated...... renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1-7) stimulated NO which was blocked by either of the receptor antagonists. Dual labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also...

  5. Hypertension: Renin-Angiotensin-Aldosterone System Alterations

    NARCIS (Netherlands)

    L. te Riet (Luuk); J.H.M. Esch, van (Joep); A.J.M. Roks (Anton); A.H. van den Meiracker (Anton); A.H.J. Danser (Jan)

    2015-01-01

    textabstractBlockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly

  6. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003)

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Murray, Gordon; Boysen, Gudrun Margrethe

    2010-01-01

    Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large trials. AIMS......, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland. STUDY OUTCOMES: There are two co-primary effect variables: • Functional status at 6-months, measured by the modified Rankin Scale, and • vascular death, myocardial infarction or stroke during the first 6-months. Secondary outcome...

  7. Assignment of the human angiotensin II type 2 receptor gene (AGTR2) to chromosome Xq22-q23 by fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Chassagne, C.; Meloche, S. [Hotel-Dieu de Montreal, Quebec (Canada); Beatty, B.G. [Hospital for Sick Children, Toronto, Ontario (Canada)

    1995-01-20

    Angiotensin II (AII), the biologically active effector of the renin-angiotensin system, is a major regulator of blood pressure and electrolyte balance and a growth factor for diverse cell types. AII exerts its physiological effects by interacting with two pharmacologically distinct subtypes of receptors, designated AT{sub 1}, and AT{sub 2}. Most of the known responses to AII are mediated by the AT{sub 1} subtype, whereas the function of the AT{sub 2} receptor remains largely unknown. AT{sub 2} receptor expression is abundant in particular tissues such as adrenal medulla, specific brain regions, uterine myometrium, and ovarian granuloma cells. This specific localization in adult coupled to the demonstration that some actions of AII such as secretion of luteinizing hormone and prolactine, dilation of brain arterioles, or drinking response in rats can be inhibited in vitro by an AT{sub 2} receptor antagonist suggests that the AT{sub 2} subtype may play a role in neuronal and reproductive function. In addition, a growing amount of evidence indicates that the AT{sub 2} receptor may play a most important role in processes involving cellular growth and differentiation. It is abundantly and widely expressed in the mesenchymal tissues of the developing fetus and in the immature brain and is up-regulated in the heart and in vascular smooth muscle cells in the first days following birth. Moreover, AT{sub 2} receptor expression is enhanced in the adult in wound healing, in the neointima of injured vessels, and in pheochromocytoma. 12 refs., 1 fig.

  8. Angiotensin converting enzyme 2 and atherosclerosis.

    Science.gov (United States)

    Wang, Yutang; Tikellis, Chris; Thomas, Merlin C; Golledge, Jonathan

    2013-01-01

    Angiotensin converting enzyme 2 (ACE2) is a homolog of angiotensin converting enzyme (ACE) which generates angiotensin II from angiotensin I. ACE, its product angiotensin II and the downstream angiotensin type I receptor are important components of the renin-angiotensin system (RAS). Angiotensin II, the most important component of the RAS, promotes the development of atherosclerosis. The identification of ACE2 in 2000 opened a new chapter of research on the regulation of the RAS. ACE2 degrades pro-atherosclerotic angiotensin II and generates anti-atherosclerotic angiotensin 1-7. In this review, we explored the importance of ACE2 in protecting experimental animals from developing atherosclerosis and its involvement in human atherosclerosis. We also examined the published evidence assessing the importance of ACE2 in different cell types relevant to atherosclerosis and putative underlying cellular and molecular mechanisms linking ACE2 with protection from atherosclerosis. ACE2 shifts the balance from angiotensin II to angiotensin 1-7 inhibiting the progression of atherosclerosis in animal models. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Lack of an association between angiotensin receptor blocker based therapy and increased risk of cancer: evidence from large observational studies.

    Science.gov (United States)

    Yang, Yuan; Zhang, Fan; Skrip, Laura; Lei, Han; Luo, Suxin; Lu, Kai; Hu, Dayi

    2015-01-01

    A previous meta-analysis of randomized controlled studies that were not designed to investigate cancer as a primary outcome suggested that ARB-based therapy is associated with increased risk of cancer; however, results of recent observational studies considering the association have been contradictory. This study sought to evaluate the association between angiotensin receptor blocker (ARB)-based therapy and risk of cancer by conducting a meta-analysis of observational studies. Relevant articles published before February 2014 were identified by searching PubMed and the Cochrane Library. Pooled relative risks (RRs) were determined using a random effects model and were used to assess the strength of association between use of ARB-based therapy and risk of cancer. Six retrospective cohort studies involving a total of 3,827,109 participants and four case-control studies involving a total of 193,029 cases were included. The present study found that ARB-based therapy was not significantly associated with an increased risk of cancer (RR = 0.87, 95%CI: [0.75, 1.01]). However, an analysis including only cohort studies suggested a significantly decreased risk of cancer among individuals with any history of ARB use as compared to those with no history of ARB use (RR = 0.80, 95%CI: [0.55, 0.95]); no significant association was found between ARB use and risk of cancer when the case-control studies were separately considered (RR = 1.03, 95%CI: [0.93, 1.13]). Subgroup analyses showed that use of ARB-based therapy was associated with decreased risk of lung cancer (RR = 0.81, 95%CI: [0.69, 0.94]); however, no significant associations were found with the other cancer sites investigated. Furthermore, no association was observed upon adjustment by type of ARB drug. No publication bias was detected. Overall, ARB-based therapy was not associated with increased risk of cancer. However, its use may be related to decreased incidence of lung cancer; this finding should be considered

  10. The angiotensin II type 1 receptor blocker losartan attenuates bioprosthetic valve leaflet calcification in a rabbit intravascular implant model.

    Science.gov (United States)

    Shin, Hong Ju; Kim, Dae-Hyun; Park, Han Ki; Park, Young Hwan

    2016-12-01

    There is evidence that angiotensin II type I receptor blocker (ARB) could reduce structural valve deterioration. However, the anticalcification effect on the bioprosthetic heart valve (BHV) has not been investigated. Thus, we investigated the effects of losartan (an ARB) on calcification of implanted bovine pericardial tissue in a rabbit intravascular implant model. A total of 16 male New Zealand White rabbits (20 weeks old, 2.98-3.34 kg) were used in this study. Commercially available BHV leaflet of bovine pericardium was trimmed to the shape of a 3-mm triangle and implanted to both external jugular veins of the rabbit. The ARB group (n = 8) was given 25 mg/kg of powdered losartan daily until 6 weeks after surgery by direct administration in the buccal pouch of the animals. The control group (n = 8) was given 5 ml of normal saline by the same method. After 6 weeks, quantitative calcium determination, histological evaluation and western blot analysis of interleukin-6 (IL-6), osteopontin and bone morphogenetic protein 2 (BMP-2) were performed to investigate the mechanisms of the anticalcification effect of losartan. No deaths or complications such as infection or haematoma were recorded during the experiment. All animals were euthanized on the planned date. The calcium measurement level in the ARB group (2.28 ± 0.65 mg/g) was significantly lower than that in the control group (3.68 ± 1.00 mg/g) (P = 0.0092). Immunohistochemistry analyses revealed that BMP-2-positive reactions were significantly attenuated in the ARB group. Western blot analysis showed that losartan suppressed the expression of IL-6, osteopontin and BMP-2. Our results indicate that losartan significantly attenuates postimplant degenerative calcification of a bovine pericardial bioprosthesis in a rabbit intravascular implant model. Further studies are required to assess the effects of ARBs on BHV tissue in orthotopic implantations using a large animal model. © The Author 2016. Published by Oxford

  11. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    Energy Technology Data Exchange (ETDEWEB)

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

  12. Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure.

    Science.gov (United States)

    Carstens, Nadia; van der Merwe, Lize; Revera, Miriam; Heradien, Marshall; Goosen, Althea; Brink, Paul A; Moolman-Smook, Johanna C

    2011-09-01

    Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin-angiotensin-aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT(1)R). However, Ang II binding to Ang II type 2 receptors (AT(2)R) also has hypertrophy-modulating effects. We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT(2)R gene (AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate. We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ~0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates (p = 0.020). This study therefore confirms a hypertrophy-modulating effect for AT(2)R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM.

  13. Effect of Combination of Angiotensin-Converting Enzyme Inhibitors and Vitamin D Receptor Activators on Cardiac Oxidative Stress in Diabetic Rats.

    Science.gov (United States)

    Ali, Tarek Mohamed; Mehanna, Osama Mahmoud; Elsaid, Amgad Gaber; Askary, Ahmad El

    2016-08-01

    The principle mediator of diabetic myocardial injury is oxidative stress. The aim was to compare the effect of monotherapy with enalapril, angiotensin-converting enzyme inhibitor and paricalcitol (vitamin D receptor activator), to the combined therapy with both drugs on the cardiac oxidant-antioxidant balance in the type 2 diabetic rats. A total of 50 male Sprague-Dawley rats were divided into 5 groups, namely the normal control and diabetic, vehicle, enalapril, paricalcitol and paricalcitol and enalapril-treated groups. Enalapril was given at a dose of (25mg/L) in drinking water once daily and paricalcitol was given intraperitoneally (0.8μg/kg/3 × week) for 3 months. Glycemic status, cardiac oxidant-antioxidant parameters and histologic examination were determined. Paricalcitol and combined treatment significantly (P model assessment-insulin resistance, cardiac malondialdehyde and nitric oxide. Moreover, they significantly (P < 0.01) increased the levels of insulin and c-peptide compared to diabetic control rats. Combined treatment significantly (P < 0.01) raised the level of glutathione, glutathione S-transferase and catalase more than monotherapy. The combination of angiotensin-converting enzyme inhibitors and vitamin D receptor activators has a superior effect on reducing cardiac oxidative stress by raising antioxidant activity than monotherapy in diabetic rats. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  14. The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action.

    Science.gov (United States)

    Kim, Hyoung Kyu; Youm, Jae Boum; Lee, Sung Ryul; Lim, Se Eun; Lee, Sun-Young; Ko, Tae Hee; Long, Le Thanh; Nilius, Bernd; Won, Du Nam; Noh, Jung-Hyun; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Han, Jin

    2012-12-01

    Telmisartan is an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma agonist that modulates the renin-angiotensin-aldosterone system. It is used primarily to manage hypertension, diabetic nephropathy, and congestive heart failure. Recent studies have reported that myocardial infarction (MI) has occurred in telmisartan-treated patients. The purpose of the study was to investigate the specific conditions and underlying mechanisms that may result in telmisartan-induced MI. We evaluated the effect of telmisartan on whole hearts, cardiomyocytes, and cardiac sarcolemmal ion channels. Hearts of 8-week-old male Sprague-Dawley rats were perfused with 3, 10, 30, or 100 μM telmisartan or losartan or with normal Tyrode's solution (control) for 3 h. We found that telmisartan induced myocardial infarction, with an infarct size of 21 % of the total at 30 μM (P action potential duration, and subsequent Ca(2+) overload. Above 30 μM, telmisartan may potentially cause cardiac cell death and MI.

  15. Patterns of use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers among patients with acute myocardial infarction in China from 2001 to 2011: China PEACE-Retrospective AMI Study.

    Science.gov (United States)

    Liu, Jiamin; Masoudi, Frederick A; Spertus, John A; Wang, Qing; Murugiah, Karthik; Spatz, Erica S; Li, Jing; Li, Xi; Ross, Joseph S; Krumholz, Harlan M; Jiang, Lixin

    2015-02-23

    Chinese and U.S. guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) for all patients with acute myocardial infarction (AMI) in the absence of contraindications as either a Class I or Class IIa recommendation. Little is known about the use and trends of ACEI/ARB therapy in China over the past decade. Using nationally representative data from the China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction (China PEACE-Retrospective AMI Study), we assessed use of ACEI/ARB therapy in 2001, 2006, and 2011, overall and across geographic regions and strata of estimated mortality risk, and predictors of ACEI/ARB therapy, among patients with Class I indication by Chinese guidelines. The weighted rate of ACEI/ARB therapy increased from 62.0% in 2001 to 71.4% in 2006, decreasing to 67.6% in 2011. Use was low across all 5 geographic regions. By strata of estimated mortality risk, in 2001, rates of therapy increased with increasing risk; however, by 2011, this reversed and those at higher risk were less likely to be treated (70.7% in lowest-risk quintile vs. 63.5% in the highest-risk quintile; P<0.001). One third of Chinese AMI patients with Class I indications do not receive ACEI/ARB therapy during hospitalization, with little improvement in rates over time. Patients at higher mortality risk in 2011 were less likely to be treated, highlighting important opportunities to optimize the use of this cost-effective therapy. ClinicalTrials.gov. Unique identifier: NCT01624883. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  16. High intraluminal pressure via H2O2 upregulates arteriolar constrictions to angiotensin II by increasing the functional availability of AT1 receptors

    Science.gov (United States)

    Bagi, Zsolt; Erdei, Nora; Koller, Akos

    2008-01-01

    Previously, we found that high intraluminal pressure leads to production of reactive oxygen species (ROS) and also upregulates several components of the renin-angiotensin system in the wall of small arteries. We hypothesized that acute exposure of arterioles to high intraluminal pressure in vitro via increasing ROS production enhances the functional availability of type 1 angiotensin II (Ang II) receptors (AT1 receptors), resulting in sustained constrictions. In arterioles (∼180 μm) isolated from rat skeletal muscle, Ang II elicited dose-dependent constrictions, which decreased significantly by the second application [maximum (max.): from 59% ± 4% to 26% ± 5% at 10−8 M; P < 0.05] in the presence of 80 mmHg of intraluminal pressure. In contrast, if the arterioles were exposed to high intraluminal pressure (160 mmHg for 30 min), Ang II-induced constrictions remained substantial on the second application (max.: 51% ± 3% at 10−8 M). In the presence of Tiron and polyethylene glycol (PEG)-catalase, known to reduce the level of superoxide anion and hydrogen peroxide (H2O2), second applications of Ang II evoked similarly reduced constrictions, even after high-pressure exposure (29% ± 4% at 10−8 M). Furthermore, when arterioles were exposed to H2O2 (for 30 min, 10−7 M, at normal 80 mmHg pressure), Ang II-induced constrictions remained substantial on second applications (59% ± 5% at 10−8 M). These findings suggest that high pressure, likely via inducing H2O2 production, increases the functional availability of AT1 receptors and thus enhances Ang II-induced arteriolar constrictions. We propose that in hypertension–regardless of etiology–high intraluminal pressure, via oxidative stress, enhances the functional availability of AT1 receptors augmenting Ang II-induced constrictions. PMID:18567710

  17. Angiotensin-(1-7 Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β via Mas Receptor Activation

    Directory of Open Access Journals (Sweden)

    Johanna Ábrigo

    2016-11-01

    Full Text Available Background: Transforming growth factor type beta 1 (TGF-β1 produces skeletal muscle atrophy. Angiotensin-(1-7 (Ang-(1-7, through the Mas receptor, prevents the skeletal muscle atrophy induced by sepsis, immobilization, or angiotensin II (Ang-II. However, the effect of Ang-(1-7 on muscle wasting induced by TGF-β1 is unknown. Aim: To evaluate whether Ang-(1-7/Mas receptor axis could prevent the skeletal muscle atrophy induced by TGF-β1. Methods: This study assessed the atrophic effect of TGF-β1 in C2C12 myotubes and mice in absence or presence of Ang-(1-7, and the receptor participation using A779, an antagonist of the Mas receptor. The levels of myosin heavy chain (MHC, polyubiquitination, and MuRF-1 were detected by western blot. Myotube diameter was also evaluated. In vivo analysis included the muscle strength, fibre diameter, MHC and MuRF-1 levels by western blot, and ROS levels by DCF probe detection. Results: The results showed that Ang-(1-7 prevented the increase in MuRF-1 and polyubiquitined protein levels, the decrease of MHC levels, the myotubes/fibre diameter diminution, and the increased production of reactive oxygen species (ROS induced by TGF-β1. Utilizing A779 inhibited the anti-atrophic effect of Ang-(1-7. Conclusion: The preventive effect of Ang-(1-7 on skeletal muscle atrophy induced by TGF-β1 is produced through inhibition of ROS production and proteasomal degradation of MHC.

  18. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    R blockade. Despite a lack of effect on blood pressure, AT2R stimulation still protects from hypertensive end-organ damage. Current data and evidence therefore suggest that AT2R agonists will not be suitable as future anti-hypertensive drugs, but that they may well be useful for end-organ protection...... in combination with established anti-hypertensives....

  19. Activation of the cell membrane angiotensin AT2 receptors in human leiomyosarcoma cells induces differentiation and apoptosis by a PPARγ - dependent mechanism.

    Science.gov (United States)

    LÜtzen, U; Zhao, Y; Lucht, K; Zuhayra, M; Hedderich, J; Cascorbi, I; Culman, J

    2017-01-01

    Angiotensin II (Ang II), the main effector peptide of the renin-angiotensin system (RAS), acting on AT1 and AT2 receptors participates in the regulation of proliferation, differentiation and apoptosis in tumour cells. The peroxisome-proliferator activated receptor γ (PPARγ) and its ligands exert anti-tumour effects in various human cancer cell lines. The present study investigates the effects initiated by AT1- and AT2 receptor stimulation in SK-UT-1 cells, a human leiomyosarcoma cell line, and clarifies the role of the PPARγ in the AT2 receptor-induced differentiation and apoptosis.Selective stimulation of AT1- and AT2 receptors was achieved by incubation of the cells with Ang II (10-6 M) in the presence of the selective AT2 receptor antagonist, PD 123177 (10-6 M) and the AT1 receptor antagonist, losartan (10-5 M), respectively, the selective PPARγ antagonist, GW 9662, was used at concentration 10-6 M. The expression of smooth muscle cell differentiation markers, SM22α and calponin, was analysed at RNA- and protein levels using RT PCR and Western blot, which was also used to quantify Bcl-2-, Bax- and cleaved caspase-3 proteins. The translocation of the AT2-receptor interacting protein 1 (ATIP1) to the nuclei was studied by Western blot and immunofluorescence staining. The mitochondrial status and the metabolic activity in response to AT1- and AT2 receptor activation were assessed by the quantification of 99mTc - sestamibi and 2´-deoxy-2´-[18F]fluoro-D-glucose uptake.AT1 receptor stimulation did not exert any profound effects in quiescent SK-UT-1 cells. The effects induced by Ang II acting on AT2 receptors were time-dependent. A short, 3 - 6 h lasting stimulation promotes differentiation, i.e increases in the mRNA- and protein levels of SM22α and calponin, whereas a sustained stimulation for 48 h activates the intrinsic apoptotic pathway, as evidenced by reduced cell numbers, down-regulation of the anti-apoptotic Bcl-2 protein and increased levels of the Bax

  20. Emerging Role of Angiotensin Type 2 Receptor (AT2R)/Akt/NO Pathway in Vascular Smooth Muscle Cell in the Hyperthyroidism

    Science.gov (United States)

    Carrillo-Sepúlveda, Maria Alícia; Ceravolo, Graziela S.; Furstenau, Cristina R.; Monteiro, Priscilla de Souza; Bruno-Fortes, Zuleica; Carvalho, Maria Helena; Laurindo, Francisco R.; Tostes, Rita C.; Webb, R. Clinton; Barreto-Chaves, Maria Luiza M.

    2013-01-01

    Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium. PMID:23637941

  1. Angiotensin II receptor type 2 activation is required for cutaneous sensory hyperinnervation and hypersensitivity in a rat hind paw model of inflammatory pain.

    Science.gov (United States)

    Chakrabarty, Anuradha; Liao, Zhaohui; Smith, Peter G

    2013-10-01

    Many pain syndromes are associated with abnormal proliferation of peripheral sensory fibers. We showed previously that angiotensin II, acting through its type 2 receptor (AT2), stimulates axon outgrowth by cultured dorsal root ganglion neurons. In this study, we assessed whether AT2 mediates nociceptor hyperinnervation in the rodent hind paw model of inflammatory pain. Plantar injection of complete Freund's adjuvant (CFA), but not saline, produced marked thermal and mechanical hypersensitivity through 7 days. This was accompanied by proliferation of dermal and epidermal PGP9.5-immunoreactive (ir) and calcitonin gene-related peptide-immunoreactive (CGRP-ir) axons, and dermal axons immunoreactive for GFRα2 but not tyrosine hydroxylase or neurofilament H. Continuous infusion of the AT2 antagonist PD123319 beginning with CFA injection completely prevented hyperinnervation as well as hypersensitivity over a 7-day period. A single PD123319 injection 7 days after CFA also reversed thermal hypersensitivity and partially reversed mechanical hypersensitivity 3 hours later, without affecting cutaneous innervation. Angiotensin II-synthesizing proteins renin and angiotensinogen were largely absent after saline but abundant in T cells and macrophages in CFA-injected paws with or without PD123319. Thus, emigrant cells at the site of inflammation apparently establish a renin-angiotensin system, and AT2 activation elicits nociceptor sprouting and heightened thermal and mechanical sensitivity. Short-term AT2 activation is a potent contributor to thermal hypersensitivity, whereas long-term effects (such as hyperinnervation) also contribute to mechanical hypersensitivity. Pharmacologic blockade of AT2 signaling represents a potential therapeutic strategy aimed at biologic mechanisms underlying chronic inflammatory pain. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

  2. Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1 receptor blockade.

    Directory of Open Access Journals (Sweden)

    Els Moltzer

    Full Text Available Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang II type 1 (AT(1 receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R and 4-fold (homozygous Fibulin-4(R/R reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT(1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic

  3. Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor β1 in the Rat Heart

    DEFF Research Database (Denmark)

    Lauer, Dilyara; Slavic, Svetlana; Sommerfeld, Manuela

    2014-01-01

    Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying mech...

  4. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

    Directory of Open Access Journals (Sweden)

    Tahereh Safari

    2015-01-01

    Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

  5. Diuretics enhance effects of increased dose of candesartan on ambulatory blood pressure reduction in Japanese patients with uncontrolled hypertension treated with medium-dose angiotensin II receptor blockers.

    Science.gov (United States)

    Sakima, Atsushi; Kita, Toshihiro; Nakada, Seigo; Yokota, Naoto; Tamaki, Noboru; Etoh, Takuma; Shimokubo, Toru; Kitamura, Kazuo; Takishita, Shuichi; Ohya, Yusuke

    2014-01-01

    Abstract Although blockade of the renin-angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly (pdiuretics than those without (p=0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect.

  6. Study of signal transduction mechanism of angiotensin 2 receptor by means of site-directed mutagenesis; Bui totsuzen hen'iho wo mochiita anjiotenshin 2 reseputa no joho dentatsu kiko no kaimei

    Energy Technology Data Exchange (ETDEWEB)

    Yamano, Yoshiaki [Tottori University, Tottori (Japan). Faculty of Agriculture

    1998-12-16

    The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. In order to clarify the signaling mechanism mediated by angiotensin 2 receptor, Gq-protein binding amino acid residues of this receptor were clarified by site-directed mutagenesis study. Amino acid residues in the carboxyl tail region were changed by alanines, individually. These mutated receptors were expressed stably in CHO cells, and GTP effect and second messenger molecules were determined, and three residues (Y 312, F313 and L 314) in this region were determined to be concerned for the binding of Gq protein. The other signaling systems, Gi, MAP kinase, JAK-STAT mediated, were reported to be concerned for this receptor. Novel drags for high blood pressure therapy would be explored by clarifying these signaling mechanisms. (author)

  7. Upregulation of ERK1/2-eNOS via AT2 receptors decreases the contractile response to angiotensin II in resistance mesenteric arteries from obese rats.

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    Graziela N Hagihara

    Full Text Available It has been clearly established that mitogen-activated protein kinases (MAPKS are important mediators of angiotensin II (Ang II signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese and non-obese Wistar rats (control were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2 restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats.

  8. Upregulation of ERK1/2-eNOS via AT2 receptors decreases the contractile response to angiotensin II in resistance mesenteric arteries from obese rats.

    Science.gov (United States)

    Hagihara, Graziela N; Lobato, Nubia S; Filgueira, Fernando P; Akamine, Eliana H; Aragão, Danielle S; Casarini, Dulce E; Carvalho, Maria Helena C; Fortes, Zuleica B

    2014-01-01

    It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats.

  9. Detection of Nitric Oxide Induced by Angiotensin II Receptor Type 1 Using Soluble Guanylate Cyclase beta1 Subunit Fused to a Yellow Fluorescent Protein, Venus.

    Science.gov (United States)

    Tsuji, Yuichi; Ozawa, Kentaro; Komatsubara, Akira T; Zhao, Jing; Nishi, Mayumi; Yoshizumi, Masanori

    2017-01-01

    Nitric oxide (NO) is an important gaseous molecule involved in many physiological and pathophysiological processes, including the regulation of G protein-coupled receptors (GPCRs). Here, we report the development of a high-affinity method to detect NO using soluble guanylate cyclase beta1 subunit fused to Venus, a variant of yellow fluorescent protein (sGC-Venus). We measured the fluorescence intensity of sGC-Venus with and without an NO donor using purified probes. At 560 nm emission, the fluorescence intensity of sGC-Venus at 405 nm excitation was increased by approximately 2.5-fold by the NO donor, but the fluorescence intensities of sGC-Venus excited by other wavelengths showed much less of an increase or no significant increase. To measure NO in living cells, the fluorescence intensity of sGC-Venus at 405 nm excitation was normalized to that at 488 nm excitation because it showed no significant difference with or without the NO donor. In HEK293 cells overexpressing the angiotensin II receptor type 1 (AT1 receptor), the production of NO induced by activation of the AT1 receptor was detected using sGC-Venus. These data indicate that sGC-Venus will be a useful tool for visualizing intracellular NO in living cells and that NO might be a common tool to regulate GPCRs.

  10. Is there a difference between an angiotensin-converting enzyme ...

    African Journals Online (AJOL)

    Modulation of the RAS by the two most widely used inhibitors of the system, i.e. angiotensin-converting enzyme (ACE) inhibitors and angiotensin-specific receptor blockers (ARBs) plays a crucial role in the primary and secondary prevention of cardiovascular events. These drugs both target angiotensin II, but in different.

  11. Staphylococcal nuclease domain containing-1 (SND1 promotes migration and invasion via angiotensin II type 1 receptor (AT1R and TGFβ signaling

    Directory of Open Access Journals (Sweden)

    Prasanna K. Santhekadur

    2014-01-01

    Full Text Available Staphylococcal nuclease domain containing-1 (SND1 is overexpressed in human hepatocellular carcinoma (HCC patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGFβ signaling pathway, promoting epithelial–mesenchymal transition (EMT and migration and invasion by human HCC cells. A positive correlation was observed between SND1 and AT1R expression levels in human HCC patients. Small molecule inhibitors of SND1, alone or in combination with AT1R blockers, might be an effective therapeutic strategy for late-stage aggressive HCC.

  12. Renin angiotensin system blockade reduces urinary levels of soluble urokinase plasminogen activator receptor (suPAR) in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, Frederik; Theilade, Simone; Eugen-Olsen, Jesper

    2016-01-01

    Soluble urokinase plasminogen activator receptor (suPAR) is associated with faster decline in kidney function and the pathogenesis of diabetic nephropathy. However, little is known about the impact of treatment on plasma and urinary levels of suPAR. We aimed to investigate the impact of renin...... angiotensin system (RAS) single and dual blockade on suPAR levels in patients with type 2 diabetes and albuminuria. We conducted a post-hoc analysis of a randomized controlled crossover trial. Urine and plasma samples were analyzed for suPAR levels. The placebo period was considered reference and all.......1) and urine levels were 4.0 ng/mL (1.1). None of the treatments had significant effects on plasma levels of suPAR compared to placebo. Compared to placebo, irbesartan and combination treatment decreased urinary levels of suPAR significantly (-1.3 ng/mL), while aliskiren did not. In patients with type 2...

  13. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise

    2015-01-01

    during hypoglycaemia. METHODS: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular...... parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. RESULTS: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration...... of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan...

  14. The impact of the 'Better Care Better Value' prescribing policy on the utilisation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for treating hypertension in the UK primary care setting: longitudinal quasi-experimental design.

    Science.gov (United States)

    Baker, Amanj; Chen, Li-Chia; Elliott, Rachel A; Godman, Brian

    2015-09-10

    In April/2009, the UK National Health Service initiated four Better Care Better Value (BCBV) prescribing indicators, one of which encouraged the prescribing of cheaper angiotensin-converting enzyme inhibitors (ACEIs) instead of expensive angiotensin receptor blockers (ARBs), with 80 % ACEIs/20 % ARBs as a proposed, and achievable target. The policy was intended to save costs without affecting patient outcomes. However, little is known about the actual impact of the BCBV indicator on ACEIs/ARBs utilisation and cost-savings. Therefore, this study aimed to evaluate the impact of BCBV policy on ACEIs/ARBs utilisation and cost-savings, including exploration of regional variations of the policy's impact. This cross-sectional study used data from the UK Clinical Practice Research Datalink. Segmented time-series analysis was applied to monthly ACEIs prescription proportion, adjusted number of ACEIs/ARBs prescriptions and costs. Overall, the proportion of ACEIs prescription decreased during the study period from 71.2% in April/2006 to 70.7% in March/2012, with a small but a statistically significant pre-policy reduction in its monthly trend of 0.02% (p < 0.001). Instantly after its initiation, the policy was associated with a sudden reduction in the proportion of ACEIs prescription; however, it resulted in a statistically significant increase in the post-policy monthly trend of ACEIs prescription proportion of 0.013% (p < 0.001), resulting in an overall post-policy slope of -0.007%. Despite this post-policy induced increment, the policy failed to achieve the 80% target, which resulted in missing a potential cost-saving opportunity. The pre-policy trend of the adjusted number of ACEIs/ARBs prescriptions was increasing; however, their trends declined after the policy implementation. The policy affected neither total ACEIs/ARBs cost nor individual ACEIs or ARBs costs. ACEIs/ARBs utilisation was not affected by the BCBV policy. The small increase in post-policy ACEIs

  15. Health outcomes and economic consequences of using angiotensin-converting enzyme inhibitors in comparison with angiotensin receptor blockers in the treatment of arterial hypertension in the contemporary Polish setting.

    Science.gov (United States)

    Wrona, Witold; Budka, Katarzyna; Filipiak, Krzysztof J; Niewada, Maciej; Wojtyniak, Bogdan; Zdrojewski, Tomasz

    2016-01-01

    Arterial hypertension (AH) represents a public health problem in Poland, firstly due to the huge, still growing population of patients (10.45 million patients based on NATPOL 2011 and PolSenior Surveys), and secondly because of the substantial cost of reimbursement from the National Health Fund (NHF). The most commonly used drugs in the treatment of AH include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), the latter being associated with significantly higher unit reimbursement cost. Recent meta-analyses of randomised, controlled trials indicate that there is no medical reason to favour ARBs over ACEIs in AH treatment. To assess the clinical benefit of using ACEIs instead of ARBs and to calculate the potential savings for the payer and patients associated with changing the treatment paradigm to preferential use of ACEIs. The assessment of clinical consequences includes differences between ACEIs and ARBs in terms of average life expectancy and quality-adjusted life years (QALYs) gained. The impact of these drugs on general mortality was estimated based on the meta-analysis carried out by van Vark et al. in 2012. Patients' health-related quality of life was adjusted with Polish population utility norms derived for the EQ-5D-3L questionnaire and additionally for ACEI-induced cough-related utility decrease. Potential savings for the payer on a yearly basis were calculated for a hypothetical cohort of patients who are currently treated with ARBs and might be switched to ACEIs. The number of patients treated with ARBs and ACEIs was estimated based on NHF and IMS Health data. ACEIs were associated with a statistically significant 10% reduction in all-cause mortality, which results in extra life gained of 0.354 years (4.2 months) or an additional 0.201 QALY (2.4 months). Potential annual savings could amount to 112.0 million PLN (25.7 million EUR) and 10.5 million PLN (2.4 million EUR) for the public payer (NHF) and patients

  16. Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.

    Science.gov (United States)

    Liu, Youxia; Ma, Xinxin; Zheng, Jie; Jia, Junya; Yan, Tiekun

    2017-06-30

    The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue. We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed. Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups. This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk

  17. Candesartan prevents resiniferatoxin-induced sensory small-fiber neuropathy in mice by promoting angiotensin II-mediated AT2 receptor stimulation.

    Science.gov (United States)

    Bessaguet, Flavien; Danigo, Aurore; Magy, Laurent; Sturtz, Franck; Desmoulière, Alexis; Demiot, Claire

    2017-11-01

    Sensory defects associated with small-fiber neuropathy (SFN) can lead to profound disabilities. The relationship between the sensory nervous system and modulation of the renin-angiotensin system (RAS) has been described and focused on pain and neurodegeneration in several animal models. We have recently developed an experimental model of functional sensory neuropathy showing thermal hypoalgesia and neuropeptide depletion without nerve fiber degeneration. Here, we aimed to determine whether the modulation of angiotensin II (Ang II) activity could prevent sensory neuropathy induced by RTX. Control and RTX mice received ramipril, an Ang II converting enzyme (ACE) inhibitor, (0.5 mg/kg/day) or candesartan, an Ang II type 1 receptor (AT1R) blocker (0.5 mg/kg/day), one day before vehicle or RTX administration, and each day for the next seven days. Ramipril did not have a beneficial effect in RTX mice, whereas candesartan prevented thermal hypoalgesia and reduced neuropeptide depletion in intraepidermal nerve fibers and dorsal root ganglion neurons. The preventive effect of candesartan was not observed in mice deficient for the Ang II type 2 receptor (AT2R) and was counteracted in wild type mice by EMA200, an AT2R antagonist (3 mg/kg/day). Thus, candesartan may promote AT2R activation by blocking AT1R and increasing Ang II production and enhance its mechanisms of neuroprotection in our RTX model. Our finding that candesartan prevents nociception deficits and neuropeptide depletion encourages the evaluation of its therapeutic potential in patients presenting SFN, particularly those who experience chemotherapy-induced SFN. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production.

    Directory of Open Access Journals (Sweden)

    Priscila R De Batista

    Full Text Available Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day and SHRs treated with losartan (15 mg/kg·day, the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day, as well as cultured vascular smooth muscle cells (VSMC from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1 reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2 increased the potentiation of phenylephrine contraction after endothelium removal; and 3 abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(PH oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

  19. Synthesis, anti-hypertensive effect of a novel angiotensin II AT1 receptor antagonist and its anti-tumor activity in prostate cancer.

    Science.gov (United States)

    Da, Y-J; Yuan, W-D; Zhu, L-F; Chen, Z-L

    2012-12-01

    Since the first non-peptide Ang II receptor antagonist was originally reported, it has become the most common target in the development of new treatments for hypertension. In recent years, all components of the classical RAS have been reported in the prostate, these results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer. In this study, a new compound 2-(4-((2-propyl-5-nitro-1H-benzo[d]imidazol-1-yl) methyl)-1H-indol-1-yl) benzoic acid was synthesized and evaluated as a novel angiotensin II AT1 receptor antagonist by radioligand binding assays, anti-hypertensive assays in vivo and oral acute toxicity test. MTT assays and tests in nude mice were used to demonstrate its anti-tumor activity. This new compound showed high affinity to AT1 receptor and anti-hypertensive activity in spontaneously hypertensive rats and renal hypertensive rats. Moreover, in human prostate cancer cells and in athymic nude mice bearing human prostate cancer cells, we observed this new compound had an efficient antiproliferative activity in vitro and anti-tumor activity in vivo. The preliminary pharmacological characteristics with oral acute toxicity test suggested that this new compound can be considered as a candidate for both anti-hypertensive and anti-tumor drug. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Early changes of hypothalamic angiotensin II receptors expression in gestational protein-restricted offspring: effect on water intake, blood pressure and renal sodium handling.

    Science.gov (United States)

    de Lima, Marcelo Cardoso; Scabora, José Eduardo; Lopes, Agnes; Mesquita, Flávia Fernandes; Torres, Daniele; Boer, Patrícia Aline; Gontijo, José Antonio Rocha

    2013-09-01

    The current study examines changes in the postnatal hypothalamic angiotensin receptors by maternal protein restriction (LP), and its impact on in uteri programming of hypertension in adult life. The data show that LP male pup body weight was significantly reduced when compared to that of control (NP) pups. Also, immunoblotting analysis demonstrated a significantly decreased expression of type 1 AngII receptors (AT1R) in the entire hypothalamic tissue extract of LP rats at 12 days of age compared to age-matched NP offspring. Conversely, the expression of the type 2 AngII (AT2R) receptors in 12-day- and 16-week-old LP hypothalamus was significantly increased. The current data show the influence of central AngII administration on water consumption in a concentration-dependent fashion, but also demonstrate that the water intake response to AngII was strikingly attenuated in 16-week-old LP. These results may be related to decreased brain arginine vasopressin (AVP) expression appearing in maternal protein-restricted offspring. The present investigation shows an early decrease in fractional urinary sodium excretion in maternal protein-restricted offspring. The decreased fractional sodium excretion was accompanied by a fall in proximal sodium excretion and occurred despite unchanged creatinine clearance. These effects were associated with a significant enhancement in arterial blood pressure in the LP group, but the precise mechanism of these phenomena remains unknown.

  1. Phylogenetic Diversity of Sponge-Associated Fungi from the Caribbean and the Pacific of Panama and Their In Vitro Effect on Angiotensin and Endothelin Receptors.

    Science.gov (United States)

    Bolaños, Jessica; De León, Luis Fernando; Ochoa, Edgardo; Darias, José; Raja, Huzefa A; Shearer, Carol A; Miller, Andrew N; Vanderheyden, Patrick; Porras-Alfaro, Andrea; Caballero-George, Catherina

    2015-10-01

    Fungi occupy an important ecological niche in the marine environment, and marine fungi possess an immense biotechnological potential. This study documents the fungal diversity associated with 39 species of sponges and determines their potential to produce secondary metabolites capable of interacting with mammalian G-protein-coupled receptors involved in blood pressure regulation. Total genomic DNA was extracted from 563 representative fungal strains obtained from marine sponges collected by SCUBA from the Caribbean and the Pacific regions of Panama. A total of 194 operational taxonomic units were found with 58% represented by singletons based on the internal transcribed spacer (ITS) and partial large subunit (LSU) rDNA regions. Marine sponges were highly dominated by Ascomycota fungi (95.6%) and represented by two major classes, Sordariomycetes and Dothideomycetes. Rarefaction curves showed no saturation, indicating that further efforts are needed to reveal the entire diversity at this site. Several unique clades were found during phylogenetic analysis with the highest diversity of unique clades in the order Pleosporales. From the 65 cultures tested to determine their in vitro effect on angiotensin and endothelin receptors, the extracts of Fusarium sp. and Phoma sp. blocked the activation of these receptors by more than 50% of the control and seven others inhibited between 30 and 45%. Our results indicate that marine sponges from Panama are a "hot spot" of fungal diversity as well as a rich resource for capturing, cataloguing, and assessing the pharmacological potential of substances present in previously undiscovered fungi associated with marine sponges.

  2. The Second Transmembrane Domain of the Human Type 1 Angiotensin II Receptor Participates in the Formation of the Ligand Binding Pocket and Undergoes Integral Pivoting Movement during the Process of Receptor Activation*

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J.; Martin, Stéphane S.; Lavigne, Pierre; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan

    2009-01-01

    The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the angiotensin II type-1 (AT1) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. In order to identify those residues in the second transmembrane domain (TMD2) that contribute to the formation of the binding pocket of the AT1 receptor, we used the substituted cysteine accessibility method. All of the residues within the Leu-70 to Trp-94 region were mutated one at a time to a cysteine, and, after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of D74C-AT1, L81C-AT1, A85C-AT1, T88C-AT1, and A89C-AT1 mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT1 receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD2 reporter cysteines engineered in a constitutively active N111G-AT1 receptor background. Indeed, mutant D74C-N111G-AT1 became insensitive to MTSEA, whereas mutant L81C-N111G-AT1 lost some sensitivity and mutant V86C-N111G-AT1 became sensitive to MTSEA. Our results suggest that constitutive activation of the AT1 receptor causes TMD2 to pivot, bringing the top of TMD2 closer to the binding pocket and pushing the bottom of TMD2 away from the binding pocket. PMID:19276075

  3. An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT1 Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies

    Science.gov (United States)

    Agelis, George; Roumelioti, Panagiota; Resvani, Amalia; Durdagi, Serdar; Androutsou, Maria-Eleni; Kelaidonis, Konstantinos; Vlahakos, Demetrios; Mavromoustakos, Thomas; Matsoukas, John

    2010-09-01

    A new 1,5 disubstituted imidazole AT1 Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity ( V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT1 receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.

  4. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism.

    Directory of Open Access Journals (Sweden)

    Alan Daugherty

    Full Text Available AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs, although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.Male AT2 receptor wild type (AT2 +/y and deficient (AT2 -/y mice in an LDL receptor -/- background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min. AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day and AngII were co-infused into male LDL receptor -/- mice that were either AT2 +/y or -/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.AT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism.

  5. Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations.

    Science.gov (United States)

    Cabana, Jérôme; Holleran, Brian; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan; Lavigne, Pierre

    2015-06-19

    Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. The angiotensin-II type 1 (AT1) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the Gq/11 protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT1 receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore the conformational landscape sampled by the WT-AT1 receptor, the N111G-AT1 receptor (constitutively active and biased for the Gq/11 pathway), and the D74N-AT1 receptor (biased for the β-arrestin1 and -2 pathways) in their apo-forms and in complex with AngII. The molecular dynamics simulations of the AngII-WT-AT1, N111G-AT1, and AngII-N111G-AT1 receptors revealed specific structural rearrangements compared with the initial and ground state of the receptor. Simulations of the D74N-AT1 receptor revealed that the mutation stabilizes the receptor in the initial ground state. The presence of AngII further stabilized the ground state of the D74N-AT1 receptor. The biased agonist [Sar(1),Ile(8)]AngII also showed a preference for the ground state of the WT-AT1 receptor compared with AngII. These results suggest that activation of the Gq/11 pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease.

    Science.gov (United States)

    Fröhlich, Hanna; Nelges, Christoph; Täger, Tobias; Schwenger, Vedat; Cebola, Rita; Schnorbach, Johannes; Goode, Kevin M; Kazmi, Syed; Katus, Hugo A; Cleland, John G F; Clark, Andrew L; Frankenstein, Lutz

    2016-08-01

    Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become cornerstones of therapy for chronic heart failure (CHF). Guidelines advise high target doses for ACEIs/ARBs, but fear of worsening renal function may limit dose titration in patients with concomitant chronic kidney disease (CKD). In this retrospective observational study, we identified 722 consecutive patients with systolic CHF, stable CKD stage III/IV (estimated glomerular filtration rate [eGFR] 15-60 mL min(-1) 1.73 m(-2)) and chronic ACEI/ARB treatment from the outpatient heart failure clinics at the Universities of Hull, UK, and Heidelberg, Germany. Change of renal function, worsening CHF, and hyperkalemia at 12-month follow-up were analyzed as a function of both baseline ACEI/ARB dose and dose change from baseline. ΔeGFR was not related to baseline dose of ACEI/ARB (P = .58), or to relative (P = .18) or absolute change of ACEI/ARB dose (P = .21) during follow-up. Expressing change of renal function as a categorical variable (improved/stable/decreased) as well as subgroup analyses with respect to age, sex, New York Heart Association functional class, left ventricular ejection fraction, diabetes, concomitant aldosterone antagonists, CKD stage, hypertension, ACEI vs ARB, and congestion status yielded similar results. There was no association of dose/dose change with incidence of either worsening CHF or hyperkalemia. In patients with systolic CHF and stable CKD stage III/IV, neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function. Conversely, down-titration was not associated with improvement in eGFR. Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Src is required for mechanical stretch-induced cardiomyocyte hypertrophy through angiotensin II type 1 receptor-dependent β-arrestin2 pathways.

    Directory of Open Access Journals (Sweden)

    Shijun Wang

    Full Text Available Angiotensin II (AngII type 1 receptor (AT1-R can be activated by mechanical stress (MS without the involvement of AngII during the development of cardiomyocyte hypertrophy, in which G protein-independent pathways are critically involved. Although β-arrestin2-biased signaling has been speculated, little is known about how AT1-R/β-arrestin2 leads to ERK1/2 activation. Here, we present a novel mechanism by which Src kinase mediates AT1-R/β-arrestin2-dependent ERK1/2 phosphorylation in response to MS. Differing from stimulation by AngII, MS-triggered ERK1/2 phosphorylation is neither suppressed by overexpression of RGS4 (the negative regulator of the G-protein coupling signal nor by inhibition of Gαq downstream protein kinase C (PKC with GF109203X. The release of inositol 1,4,5-triphosphate (IP3 is increased by AngII but not by MS. These results collectively suggest that MS-induced ERK1/2 activation through AT1-R might be independent of G-protein coupling. Moreover, either knockdown of β-arrestin2 or overexpression of a dominant negative mutant of β-arrestin2 prevents MS-induced activation of ERK1/2. We further identifies a relationship between Src, a non-receptor tyrosine kinase and β-arrestin2 using analyses of co-immunoprecipitation and immunofluorescence after MS stimulation. Furthermore, MS-, but not AngII-induced ERK1/2 phosphorylation is attenuated by Src inhibition, which also significantly improves pressure overload-induced cardiac hypertrophy and dysfunction in mice lacking AngII. Finally, MS-induced Src activation and hypertrophic response are abolished by candesartan but not by valsartan whereas AngII-induced responses can be abrogated by both blockers. Our results suggest that Src plays a critical role in MS-induced cardiomyocyte hypertrophy through β-arrestin2-associated angiotensin II type 1 receptor signaling.

  8. Valsartan ameliorates the constitutive adipokine expression pattern in mature adipocytes: a role for inverse agonism of the angiotensin II type 1 receptor in obesity.

    Science.gov (United States)

    Hasan, Arif U; Ohmori, Koji; Hashimoto, Takeshi; Kamitori, Kazuyo; Yamaguchi, Fuminori; Ishihara, Yasuhiro; Ishihara, Naoko; Noma, Takahisa; Tokuda, Masaaki; Kohno, Masakazu

    2014-07-01

    Angiotensin (Ang) II receptor blockers (ARBs) alleviate obesity-related insulin resistance, which suggests an important role for the Ang II type 1 receptor (AT1R) in the regulation of adipocytokines. Therefore, we treated mature 3T3-L1 adipocytes with 50 μmol l(-1) of valsartan, a selective AT1R blocker without direct agonism to peroxisome proliferator-activated receptor (PPAR)-γ. In the absence of effective concentrations of Ang II, unstimulated mature adipocytes expressed and secreted high levels of interleukin (IL)-6. This constitutive proinflammatory activity was attenuated by the suppression of extracellular signal-regulated kinase phosphorylation by valsartan but was unaffected by the Ang II type 2 receptor blocker PD123319. COS7 cells co-transfected with AT1R and IL-6, which expressed NF-κB but lacked PPAR-γ, showed no constitutive but substantial ligand-dependent IL-6 reporter activity, which was counteracted by valsartan. Valsartan preserved cytosolic IκB-α and subsequently reduced nuclear NF-κB1 protein expression in mature adipocytes. Interestingly, valsartan did not increase PPAR-γ messenger RNA expression per se but enhanced the transcriptional activity of PPAR-γ in mature adipocytes; this enhancement was accompanied by upregulation of the PPAR coactivator (PGC)-1α. Moreover, T0090907, a PPAR-γ inhibitor, increased IL-6 expression, and this increase was attenuated by valsartan. Indeed, addition of valsartan without direct PPAR-γ agonism increased adiponectin production in mature adipocytes. Together, the findings indicate that valsartan blocks the constitutive AT1R activity involving the NF-κB pathway that limits PPAR-γ activity in mature adipocytes. Thus, inverse agonism of AT1R attenuates the spontaneous proinflammatory response and enhances the constitutive insulin-sensitizing activities of mature adipocytes, which may underlie the beneficial metabolic impacts of ARBs.

  9. Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Schneider, Mikael

    2007-01-01

    The angiotensin II (AngII) type 1 receptor (AT(1)R) is a seven-transmembrane receptor well established to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) by discrete G protein-dependent and beta-arrestin2-dependent pathways. The biological importance of this, however, remains obs...... obscure. Application of the modified analogue [Sar(1), Ile(4), Ile(8)]-AngII ([SII] AngII) allowed us to dissect the two pathways of ERK1/2 activation in native cardiac myocytes. Although cytosol-retained, the beta-arrestin2-bound pool of ERK1/2 represents an active signalling component...... that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the beta-arrestin2-dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to G(q)-activated ERK1/2, and in keeping with its failure to translocate to the nucleus......, the beta-arrestin2-scaffolded pool of ERK1/2 does not phosphorylate the transcription factor Elk-1, induces no increased transcription of the immediate-early gene c-Fos, and does not entail myocyte hypertrophy. These results clearly demonstrate the biological significance of differential signalling...

  10. Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

    Science.gov (United States)

    Kikuchi, Kiyoshi; Tancharoen, Salunya; Ito, Takashi; Morimoto-Yamashita, Yoko; Miura, Naoki; Kawahara, Ko-ichi; Maruyama, Ikuro; Murai, Yoshinaka; Tanaka, Eiichiro

    2013-01-01

    Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. PMID:24065095

  11. Stimulation of the Angiotensin II AT2 Receptor is Anti-inflammatory in Human Lipopolysaccharide-Activated Monocytic Cells

    DEFF Research Database (Denmark)

    Menk, Mario; Graw, Jan Adriaan; von Haefen, Clarissa

    2015-01-01

    Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses...... in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-α (TNFα), and IL-1β were analyzed on both the transcriptional...... and the translational level over course of time. Treatment with C21 attenuated the expression of TNFα, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine...

  12. Angiotensin AT2 receptor agonist stimulates high stretch induced- ANP secretion via PI3K/NO/sGC/PKG/pathway.

    Science.gov (United States)

    Gao, Shan; Park, Byung Mun; Cha, Seung Ah; Park, Woo Hyun; Park, Byung Hyun; Kim, Suhn Hee

    2013-09-01

    Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1μM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1μM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Protective effects of the angiotensin type 1 receptor antagonist losartan in infection-induced and arthritis-associated alveolar bone loss.

    Science.gov (United States)

    Queiroz-Junior, C M; Silveira, K D; de Oliveira, C R; Moura, A P; Madeira, M F M; Soriani, F M; Ferreira, A J; Fukada, S Y; Teixeira, M M; Souza, D G; da Silva, T A

    2015-12-01

    The angiotensin type 1 (AT1) receptor has been implicated in the pathogenesis of inflammatory bone disorders. This study aimed to investigate the effect of an AT1 receptor antagonist in infection-induced and arthritis-associated alveolar bone loss in mice. Mice were subjected to Aggregatibacter actinomycetemcomitans oral infection or antigen-induced arthritis and treated daily with 10 mg/kg of the prototype AT1 antagonist, losartan. Treatment was conducted for 30 d in the infectious condition and for 17 d and 11 d in the preventive or therapeutic regimens in the arthritic model, respectively. The mice were then killed, and the maxillae, serum and knee joints were collected for histomorphometric and immunoenzymatic assays. In vitro osteoclast assays were performed using RAW 264.7 cells stimulated with A. actinomycetemcomitans lipopolysacharide (LPS). Arthritis and A. actinomycetemcomitans infection triggered significant alveolar bone loss in mice and increased the levels of myeloperoxidase and of TRAP(+) osteoclasts in periodontal tissues. Losartan abolished such a phenotype, as well as the arthritis joint inflammation. Both arthritis and A. actinomycetemcomitans conditions were associated with the release of tumor necrosis factor alpha (TNF-α), interferon-gamma, interleukin-17 and chemokine (C-X-C motif) ligand 1 and an increased RANKL/osteoprotegerin ratio in periodontal tissues, but such expression decreased after losartan treatment, except for TNF-α. The therapeutic approach was as beneficial as the preventive one. In vitro, losartan prevented LPS-induced osteoclast differentiation and activity. The blockade of AT1 receptor exerts anti-inflammatory and anti-osteoclastic effects, thus protecting periodontal tissues in distinct pathophysiological conditions of alveolar bone loss. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Differential expression of angiotensin II type 1 and type 2 receptors at the maternal-fetal interface: potential roles in early placental development.

    Science.gov (United States)

    Tower, C L; Lui, S; Charlesworth, N R; Smith, S D; Aplin, J D; Jones, R L

    2010-12-01

    Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal-fetal interface and explore the effects on cytotrophoblast turnover. Low levels of AGTR2 mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal-fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs.

  15. Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice.

    Science.gov (United States)

    Villapol, Sonia; Yaszemski, Alexandra K; Logan, Trevor T; Sánchez-Lemus, Enrique; Saavedra, Juan M; Symes, Aviva J

    2012-12-01

    Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT₁R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFβ1 while increasing expression of TGFβ3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT₁R-blocking and PPARγ activation properties may have therapeutic value in treating TBI.

  16. Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice

    Science.gov (United States)

    Villapol, Sonia; Yaszemski, Alexandra K; Logan, Trevor T; Sánchez-Lemus, Enrique; Saavedra, Juan M; Symes, Aviva J

    2012-01-01

    Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT1R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFβ1 while increasing expression of TGFβ3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT1R-blocking and PPARγ activation properties may have therapeutic value in treating TBI. PMID:22892395

  17. The Protective Arm of the Renin Angiotensin System (RAS)

    DEFF Research Database (Denmark)

    The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...... Mas, and the enzyme ACE 2, which exert significant beneficial, health-promoting actions by counterbalancing the well-known harmful arm of the RAS with its classical angiotensin AT1 receptor. This innovative concept of the protective arm of the RAS, examined in this reference, represents...

  18. Effect of AVE 0991 angiotensin-(1-7) receptor agonist treatment on elemental and biomolecular content and distribution in atherosclerotic plaques of apoE-knockout mice

    Science.gov (United States)

    Kowalska, J.; Gajda, M.; Jawień, J.; Kwiatek, W. M.; Appel, K.; Dumas, P.

    2013-12-01

    Gene-targeted apolipoprotein E-knockout (apoE-KO) mice display early and highly progressive vascular lesions containing lipid deposits and they became a reliable animal model to study atherosclerosis. The aim of the present study was to investigate the effect of AVE 0991 angiotensin-(1-7) receptor agonist on the distribution of selected pro- and anti- inflammatory elements as well as biomolecules in atherosclerotic plaques of apoE-knockout mice. Synchrotron radiation-based X-ray fluorescence (micro-XRF) and Fourier Transform Infrared (micro-FTIR) microspectroscopies were applied. Two-month-old apoE-KO mice were fed for following four months diet supplemented with AVE 0991 (0.58 μmol/kg b.w. per day). Histological sections of ascending aortas were analyzed spectroscopically. The distribution of P, Ca, Fe and Zn were found to correspond with histological structure of the lesion. Significantly lower contents of P, Ca, Zn and significantly higher content of Fe were observed in animals treated with AVE 0991. Biomolecular analysis showed lower lipids saturation level and lower lipid to protein ratio in AVE 0991 treated group. Protein secondary structure was studied according to the composition of amide I band (1660 cm-1) and it demonstrated higher proportion of β-sheet structure as compared to α-helix in both studied groups.

  19. Treatment of primary chronic glomerulonephritis with Rehmannia glutinosa acteosides in combination with the angiotensin receptor blocker irbesartan: a randomized controlled trial.

    Science.gov (United States)

    Qiu, HongYu; Fu, Ping; Fan, WenXing; Zuo, Chuan; Feng, Ping; Shi, Peng; Cao, Lina; Liu, Fang; Zhou, Li; Chen, Feng; Zhong, Hui; Gou, ZhongPing; Liang, YaPing; Shi, Mei

    2014-01-01

    This study aims to assess the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis. A total of 479 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules, bid; and irbesartan, one 150-mg tablet, qd) or the control group (irbesartan, one 150-mg tablet, qd). The primary outcome was 24-h urinary protein. Secondary outcome measures included blood pressure, estimated glomerular filtration rate, erythrocyturia, serum alanine aminotransferase, aspartate transaminase and electrolytes. After 8 weeks of treatment, the treatment group showed a mean reduction in 24-h proteinuria of 36.42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27.97% in the control group (P = 0.0278).Adverse drug reactions occurred at a similarly low rate in the treatment group (0.4%) and control group (1.2%, P = 0.3724). In the treatment of chronic glomerulonephritis, the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone. Copyright © 2013 John Wiley & Sons, Ltd.

  20. Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study).

    Science.gov (United States)

    Adachi, Sen; Miura, Shin-Ichiro; Shiga, Yuhei; Arimura, Tadaaki; Kuwano, Takashi; Kitajima, Ken; Ike, Amane; Sugihara, Makoto; Iwata, Atsushi; Nishikawa, Hiroaki; Morito, Natsumi; Saku, Keijiro

    2016-10-01

    We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD.

  1. Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Satoshi Umemura

    2013-07-01

    Full Text Available An altered ambulatory blood pressure (BP and heart rate (HR profile is related to chronic kidney disease (CKD and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18 or the benazepril add-on group (n = 18. Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

  2. Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

    Science.gov (United States)

    Ohsawa, Masato; Tamura, Kouichi; Kanaoka, Tomohiko; Wakui, Hiromichi; Maeda, Akinobu; Dejima, Toru; Azushima, Kengo; Uneda, Kazushi; Kobayashi, Ryu; Tsurumi-Ikeya, Yuko; Toya, Yoshiyuki; Fujikawa, Tetsuya; Umemura, Satoshi

    2013-01-01

    An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles. PMID:23887656

  3. Development and characterization of colloidal soft nano-carriers for transdermal delivery and bioavailability enhancement of an angiotensin II receptor blocker.

    Science.gov (United States)

    Hathout, Rania M; Elshafeey, Ahmed H

    2012-10-01

    The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (σ) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex-vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65μgcm(-2)h(-1). Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Angiotensin II type 1 receptor (AT-1R) expression correlates with VEGF-A and VEGF-D expression in invasive ductal breast cancer.

    Science.gov (United States)

    Jethon, Aleksandra; Pula, Bartosz; Piotrowska, Aleksandra; Wojnar, Andrzej; Rys, Janusz; Dziegiel, Piotr; Podhorska-Okolow, Marzena

    2012-10-01

    Recent studies point to the involvement of angiotensin II (Ang II) receptor type 1 (AT-1R) on processes of metastasing, stimulation of invasiveness and angiogenesis in tumours. In this study, the correlation between intensity of AT-1R expression and expression of lymph- and angiogenesis markers in invasive ductal breast cancers (IDC) was examined. Immunohistochemical studies (IHC) were performed on archival material of 102 IDC cases. Only 28 (27.5%) cases manifested low AT-1R expression while 74 (72.5%) cases demonstrated a moderate or pronounced AT-1R expression. Expression intensity of AT-1R was found to correlate with expressions of VEGF-A (r = 0.26; p = 0.008) and VEGF-D (r = 0.24; p = 0.015). Out of the examined markers of angiogenesis and lymphangiogenesis only the pronounced expression of VEGF-C was found to correlate with patient poor clinical outcome (p = 0.009). The positive correlation between AT-1R and VEGF-A and VEGF-D could point to stimulatory action of Ang II on their expression what might result in augmented lymph- and angiogenesis in IDC.

  5. Angiotensin-(1-7) attenuated long-term hypoxia-stimulated cardiomyocyte apoptosis by inhibiting HIF-1α nuclear translocation via Mas receptor regulation.

    Science.gov (United States)

    Chang, Ruey-Lin; Lin, Jing-Wei; Kuo, Wei-Wen; Hsieh, Dennis Jine-Yuan; Yeh, Yu-Lan; Shen, Chia-Yao; Day, Cecilia-Hsuan; Ho, Tsung-Jung; Viswanadha, Vijaya Padma; Huang, Chih-Yang

    2016-02-01

    Extreme hypoxia often leads to myocardial apoptosis and causes heart failure. Angiotensin-(1-7)Ang-(1-7) is well known for its cardio-protective effects. However, the effects of Ang-(1-7) on long-term hypoxia (LTH)-induced apoptosis remain unknown. In this study, we found that Ang-(1-7) reduced myocardial apoptosis caused by hypoxia through the Mas receptor. Activation of the Ang-(1-7)/Mas axis down-regulated the hypoxia pro-apoptotic signaling cascade by decreasing the protein levels of hypoxia-inducible factor 1α (HIF-1α) and insulin-like growth factor binding protein-3 (IGFBP3). Moreover, the Ang-(1-7)/Mas axis further inhibited HIF-1α nuclear translocation. On the other hand, Ang-(1-7) activated the IGF1R/PI3K/Akt signaling pathways, which mediate cell survival. However, the above effects were abolished by A779 treatment or silencing of Mas expression. Taken together, our findings indicate that the Ang-(1-7)/Mas axis protects cardiomyocytes from LTH-stimulated apoptosis. The protective effect of Ang-(1-7) is associated with the inhibition of HIF-1α nuclear translocation and the induction of IGF1R and Akt phosphorylation.

  6. Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury.

    Science.gov (United States)

    Fouda, Abdelrahman Y; Pillai, Bindu; Dhandapani, Krishnan M; Ergul, Adviye; Fagan, Susan C

    2017-03-15

    We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)-10. Wistar rats were subjected to 3h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03mg/kg)±IL-10 neutralizing antibody (0.1mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. C21 provides direct neuroprotection as well as indirect protection through IL-10. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT1 and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii

    Science.gov (United States)

    Cheng, Wen-Han; Lu, Pei-Jung; Hsiao, Michael; Hsiao, Chun-Hui; Ho, Wen-Yu; Cheng, Pei-Wen; Lin, Chia-Te; Hong, Ling-Zong; Tseng, Ching-Jiunn

    2012-01-01

    BACKGROUND AND PURPOSE The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin-mediated blood pressure regulation, at the NTS. EXPERIMENTAL APPROACH Depressor responses to renin microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of the endothelial nitric oxide synthase (eNOS)-specific inhibitor, N(5)-(-iminoethyl)-L-ornithine, Akt inhibitor IV and LY294002, a PI3K inhibitor and GP antagonist-2A [Gq inhibitor]. Lisinopril (angiotensin converting enzyme inhibitor), losartan, valsartan (angiotensin AT1 receptor antagonists), D-Ala7-Ang-(1-7) (angiotensin-(1-7) receptor antagonist) were used to study the involvement of RAS on renin-induced depressor effects. KEY RESULTS Microinjection of renin into the NTS produced a prominent depressor effect and increased NO production. Pretreatment with Gq-PI3K-Akt-eNOS pathway-specific inhibitors significantly attenuated the depressor response evoked by renin. Immunoblotting and immunohistochemical studies further showed that inhibition of PI3K significantly blocked renin-induced eNOS-Ser117 and Akt-Ser473 phosphorylation in situ. In addition, pre-treatment of the NTS with RAS inhibitors attenuated the vasodepressor effects evoked by renin. Microinjection of renin also increased Ras activation in the NTS. CONCLUSIONS AND IMPLICATIONS Taken together, these results suggest renin modulated blood pressure at the NTS by AT1 and Mas receptor-mediated activation of Gq and Ras to evoke PI3K-Akt-eNOS signalling. PMID:22224457

  8. Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase.

    Science.gov (United States)

    Cozzoli, Anna; Liantonio, Antonella; Conte, Elena; Cannone, Maria; Massari, Ada Maria; Giustino, Arcangela; Scaramuzzi, Antonia; Pierno, Sabata; Mantuano, Paola; Capogrosso, Roberta Francesca; Camerino, Giulia Maria; De Luca, Annamaria

    2014-10-01

    Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers. Copyright © 2014 the American Physiological Society.

  9. Genetic polymorphisms of angiotensin-2 type 1 receptor and angiotensinogen and risk of renal dysfunction and coronary heart disease in type 2 diabetes mellitus

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    Hu Frank B

    2009-03-01

    Full Text Available Abstract Background Increased activation of the renin-angiotensin system (RAS may be important in promoting coronary heart disease (CHD and renal dysfunction, but limited data are available on associations between angiotensin type 1 receptor (AGT1R and angiotensinogen (AGT genotypes in type 2 diabetes. Methods Study participants were diabetics from the Health Professionals Follow-Up Study (HPFS and the Nurses' Health Study (NHS. We analyzed single nucleotide polymorphisms (SNPs associated with cardiovascular pathophysiology (including AGT1R T573C, AGT1R A1166C, and AGT M235T and presence of renal dysfunction (eGFR2 or history of CHD. Results The AGT1R 1166 C-allele was associated with eGFR2 (multivariable OR 1.63 [1.01, 2.65] in the HPFS men (n = 733 and in the combined dataset (n = 1566 (OR 1.42 [1.02, 1.98]. The AGT1R 1166 C-allele was also associated with CHD in men (OR 1.57 [1.10, 2.24]. In NHS women (n = 833, AGT 235T-allele was associated with CHD (OR 1.72 [1.20, 2.47]. Removal of hypertension from the fully adjusted models did not influence results, suggesting that the associations may not be mediated by hypertension. There were significant interactions between sex and AGT1R 1166 C-allele (p = 0.008 and AGT M235T (p = 0.03 in models for CHD. No significant associations were seen between AGT1R T573 C-allele and renal dysfunction or CHD. Conclusion Polymorphisms in AGT1R and AGT genes are associated with renal dysfunction and CHD in type 2 diabetes and further support the important role of the RAS in these complications. Sex may modify associations between AGT1R 1166 C-allele and AGT 235T and CHD in type 2 diabetes.

  10. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Castoldi, Giovanna; di Gioia, Cira Rt; Bombardi, Camila

    2014-01-01

    Aim of the study was to evaluate the effect of compound 21 (C21), selective AT2 receptor agonist, in diabetic nephropathy and the potential additive effect of C21, when associated to losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The ...

  11. Activation of liver X receptor-alpha reduces activation of the renal and cardiac renin-angiotensin-aldosterone system

    NARCIS (Netherlands)

    Kuipers, Irma; van der Harst, Pim; Kuipers, Folkert; van Genne, Linda; Goris, Maaike; Lehtonen, Jukka Y.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; de Boer, Rudolf A.

    Liver X receptor (LXR)-alpha is a pivotal player in reverse cholesterol metabolism. Recently, LXR-alpha was implicated as an immediate regulator of renin expression in a cAMP-responsive manner. To determine whether long-term LXR-alpha activation affects activation of the renal and cardiac

  12. Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system

    DEFF Research Database (Denmark)

    de Kloet, Annette D; Wang, Lei; Ludin, Jacob A

    2016-01-01

    ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent...

  13. Angiotensin II Reduces Cardiac AdipoR1 Expression through AT1 Receptor/ROS/ERK1/2/c-Myc Pathway

    Science.gov (United States)

    Lei, Hong; Wang, Cheng; Wu, Li-Peng; Wang, Jin-Yu; Fu, Feng-Ying; Zhu, Wei-Guo; Wu, Li-Ling

    2013-01-01

    Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII. PMID

  14. Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

  15. Effects of withdrawing vs continuing renin-angiotensin blockers on incidence of acute kidney injury in patients with renal insufficiency undergoing cardiac catheterization: Results from the Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker and Contrast Induced Nephropathy in Patients Receiving Cardiac Catheterization (CAPTAIN) trial.

    Science.gov (United States)

    Bainey, Kevin R; Rahim, Sherali; Etherington, Krystal; Rokoss, Michael L; Natarajan, Madhu K; Velianou, James L; Brons, Sonya; Mehta, Shamir R

    2015-07-01

    It is unclear if holding angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prior to coronary angiography reduces contrast-induced acute kidney injury (AKI). We undertook a randomized trial to investigate the effect of holding ACEI/ARB therapy prior to coronary angiography on the incidence of AKI. We randomly assigned 208 patients with moderate renal insufficiency (creatinine ≥ 1.7mg/dL within 3 months and/or documented creatinine ≥ 1.5mg/dL within 1 week before cardiac catheterization) to hold ACEI/ARB ≥24 hours preprocedure or continue ACEI/ARB. The primary outcome was the incidence of AKI defined as an absolute rise in serum creatinine of ≥0.5mg/dL from baseline and/or a relative rise in serum creatinine of ≥25% compared with baseline measured at 48 to 96 hours postcardiac catheterization. All patients were taking an ACEI (72.1%) or ARB (27.9%) prior to randomization. At 48 to 96 hours, the primary outcome occurred in 18.4% of patients who continued ACEI/ARB compared with 10.9% of the patients who held ACEI/ARB (hazard ratio 0.59, 95% CI 0.30-1.19, P = .16). In a prespecified secondary outcome, there was a lower rise in mean serum creatinine after the procedure in patients who held ACEI/ARB (0.3 ± 0.5 vs 0.1 ± 0.3mg/dL, P = .03). The clinical composite of death, myocardial infarction, ischemic stroke, congestive heart failure, rehospitalization for cardiovascular cause, or need for dialysis preprocedure occurred in 3.9% who continued ACEI/ARB compared with 0% who held the ACEI/ARB (hazard ratio 0.11, 95% CI 0.01-2.96, P = .06). In this pilot study of patients with moderate renal insufficiency undergoing cardiac catheterization, with-holding ACEI/ARB resulted in a non-significant reduction in contrast-induced AKI and a significant reduction in post-procedural rise of creatinine. This low cost intervention could be considered when referring a patient for cardiac catheterization. Copyright © 2015 Elsevier Inc. All

  16. Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

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    Garrido-Gil Pablo

    2012-02-01

    Full Text Available Abstract Background Several recent studies have shown that angiotensin type 1 receptor (AT1 antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ. PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. Methods We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. Results We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co

  17. TNF receptor-associated factor 6 (TRAF6) mediates the angiotensin-induced non-canonical TGF-β pathway activation of c-kit+ cardiac stem cells

    Science.gov (United States)

    Cao, Qing; Wang, Yuqiang; Huang, Liya; Wang, Fei; Chen, Shuyan

    2015-01-01

    Cardiac stem cells (CSCs) can differentiate into cardiac muscle-like cells upon stimulation by angiotensin II (Ang II). TNF receptor-associated factor 6 (TRAF6) has been shown to promote JNK- and p38-induced myogenic differentiation and mediate Smad-independent activation of TGF-β. However, the detailed mechanisms underlying the activation of these signaling pathways are not entirely known. Herein, we hypothesized that Ang II could promote the differentiation of CSCs into cardiac muscle-like cells by non-canonical TGF-β/TRAF6 signaling pathway, and sought to test the hypothesis. C-kit+ CSCs were isolated from neonatal Sprague Dawley (SD) rats, and their c-kit status was confirmed with immunofluorescence staining. A TGF-β type I receptor inhibitor (SB431542) was used to inhibit SMAD2/3 phosphorylation. The small interfering RNA (siRNA)-mediated knockdown of TRAF6 was used to investigate the role of TRAF6 in TGF-β signaling. Rescue of TRAF6 siRNA transfected cells with a 3’UTR-deleted siRNA insensitive construct was performed to rule out any off-target effects of the siRNA. TRAF6 dominant-negative (TRAF6DN) vector was constructed and used to infect c-kit+ CSCs. Our results showed that the increase in JNK and p38 activation by Ang-II was blocked by siRNA. After transfection by TRAF6-siRNA or Ad-TRAF6, the cardiac specific markers and Wnt signaling proteins were tested by Western blotting. Physical interactions between TRAF6 and TGF-β receptors were studied by co-immunoprecipitation. Forced expression of TRAF6 enhanced the expression of cTnT and Cx-43 but inhibited the expression of Wnt3a.Our data suggested that TRAF6 mediated Ang II-induced differential responses in c-kit+ CSCs via the non-canonical TGF-β signaling pathway. PMID:26807171

  18. Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis

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    Colin N. Young

    2015-04-01

    Conclusions: These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.

  19. C allele of angiotensin II type 1 receptor gene A1166C polymorphism affects plasma adiponectin concentrations in healthy young Japanese women.

    Science.gov (United States)

    Miyanaga, Katsuko; Fukuo, Keisuke; Akasaka, Hiroshi; Katsuya, Tomohiro; Fukada, Rumi; Rakugi, Hiromi; Kazumi, Tsutomu

    2009-10-01

    Angiotensin II and its type 1 receptor (AT1R) are both expressed in the adipose tissue and involved in the genesis of atherosclerosis as well as hypertension. However, the influence of the AT1R gene A1166C polymorphism on atherosclerosis risk factors and on the development of early atherosclerosis is not clear. We evaluated 416 healthy young women to investigate the effects of this genotype on atherosclerosis risk factors and on carotid intima-media thickness as a validated marker of early atherosclerosis. After adjusting for confounding factors including body mass index, homeostasis model assessment of insulin resistance and plasma high-density lipoprotein (HDL)-cholesterol levels, plasma adiponectin concentrations were significantly lower in carriers of the C allele compared with non-carriers. Moreover, multiple logistic regression analysis showed that the C allele was the strongest and most independent determinant of lower plasma adiponectin concentrations. It is noted that the participants with the lowest quartile of plasma adiponectin concentrations had thicker levels of carotid intima-media thickness, lower plasma HDL-cholesterol and lipoprotein lipase levels, as well as higher trunk fat mass compared with the highest quartile. In addition, a weak but significant positive correlation was observed between percentages of fat in the diet and plasma adiponectin concentrations in non-carriers of the C allele. In conclusion, AT1R A1166C was associated with plasma adiponectin concentrations and influenced the correlations between dietary fat intake and plasma concentrations of adiponectin. These findings may help to identify vulnerable populations that are susceptible to the development of atherosclerosis and require early dietary recommendations for young women.

  20. Sodium restriction potentiates the renoprotective effects of combined vitamin D receptor activation and angiotensin-converting enzyme inhibition in established proteinuric nephropathy.

    Science.gov (United States)

    Mirkovic, Katarina; Frenay, Anne-Roos S; van den Born, Jacob; van Goor, Harry; Navis, Gerjan; de Borst, Martin H

    2017-08-01

    Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake. Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment. Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes. The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.

  1. Regression of glomerular and tubulointerstitial injuries by dietary salt reduction with combination therapy of angiotensin II receptor blocker and calcium channel blocker in Dahl salt-sensitive rats.

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    Kazi Rafiq

    Full Text Available A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB plus calcium channel blocker (CCB reverses renal tissue injury in Dahl salt-sensitive (DSS hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl, NS + an ARB (olmesartan, 10 mg/kg/day, NS + a CCB (azelnidipine, 3 mg/kg/day, NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day. Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

  2. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

    Science.gov (United States)

    Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant; Cunningham, J Thomas

    2015-03-01

    Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH. Copyright © 2015 the American Physiological Society.

  3. Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain.

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    Cao, Xian; Peterson, Jeffrey R; Wang, Gang; Anrather, Josef; Young, Colin N; Guruju, Mallikarjuna R; Burmeister, Melissa A; Iadecola, Costantino; Davisson, Robin L

    2012-04-01

    Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E(2) (PGE(2)) and its receptor EP(1) (EP(1)R) have emerged as key players in angiotensin II (Ang II)-dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE(2,) that is, COX-1 or COX-2, and its site(s) of action are not known. The subfornical organ (SFO) is a key forebrain region that mediates systemic Ang II-dependent HTN via reactive oxygen species (ROS). We tested the hypothesis that cross-talk between PGE(2)/EP(1)R and ROS signaling in the SFO is required for Ang II HTN. Radiotelemetric assessment of blood pressure revealed that HTN induced by infusion of systemic "slow-pressor" doses of Ang II was abolished in mice with null mutations in EP(1)R or COX-1 but not COX-2. Slow-pressor Ang II-evoked HTN and ROS formation in the SFO were prevented when the EP(1)R antagonist SC-51089 was infused directly into brains of wild-type mice, and Ang-II-induced ROS production was blunted in cells dissociated from SFO of EP(1)R(-/-) and COX-1(-/-) but not COX-2(-/-) mice. In addition, slow-pressor Ang II infusion caused a ≈3-fold increase in PGE(2) levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP(1)R selectively in the SFO of EP(1)R-null mice was sufficient to rescue slow-pressor Ang II-elicited HTN and ROS formation in the SFO of this model. Thus, COX 1-derived PGE(2) signaling through EP(1)R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang II and suggests that EP(1)R in the SFO may provide a novel target for antihypertensive therapy.

  4. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

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    Nishida Yayoi

    2012-05-01

    Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

  5. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus control cardiovascular reactivity and anxiety-like behavior in male mice.

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    Wang, Lei; Hiller, Helmut; Smith, Justin A; de Kloet, Annette D; Krause, Eric G

    2016-09-01

    This study tested the hypothesis that deletion of angiotensin type 1a receptors (AT1a) from the paraventricular nucleus of hypothalamus (PVN) attenuates anxiety-like behavior, hypothalamic-pituitary-adrenal (HPA) axis activity, and cardiovascular reactivity. We used the Cre/LoxP system to generate male mice with AT1a specifically deleted from the PVN. Deletion of the AT1a from the PVN reduced anxiety-like behavior as indicated by increased time spent in the open arms of the elevated plus maze. In contrast, PVN AT1a deletion had no effect on HPA axis activation subsequent to an acute restraint challenge but did reduce hypothalamic mRNA expression for corticotropin-releasing hormone (CRH). To determine whether PVN AT1a deletion inhibits cardiovascular reactivity, we measured systolic blood pressure, heart rate, and heart rate variability (HRV) using telemetry and found that PVN AT1a deletion attenuated restraint-induced elevations in systolic blood pressure and elicited changes in HRV indicative of reduced sympathetic nervous activity. Consistent with the decreased HRV, PVN AT1a deletion also decreased adrenal weight, suggestive of decreased adrenal sympathetic outflow. Interestingly, the altered stress responsivity of mice with AT1a deleted from the PVN was associated with decreased hypothalamic microglia and proinflammatory cytokine expression. Collectively, these results suggest that deletion of AT1a from the PVN attenuates anxiety, CRH gene transcription, and cardiovascular reactivity and reduced brain inflammation may contribute to these effects. Copyright © 2016 the American Physiological Society.

  6. Angiotensin II receptor blockers suppress the release of stromal cell-derived factor-1α from infarcted myocardium in patients with acute myocardial infarction.

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    Yoshizaki, Toru; Uematsu, Manabu; Obata, Jun-Ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Nakamura, Kazuto; Kugiyama, Kiyotaka

    2018-04-01

    Although angiotensin II receptor blockers (ARBs) have been shown to have anti-inflammatory effects on infarcted myocardium in experimental models, little is known in humans. Stromal cell-derived factor-1α (SDF-1α), a pro-inflammatory chemokine, is released from infarcted tissue in patients with acute myocardial infarction (AMI). This study examined whether ARBs suppress SDF-1α production in the infarcted lesion in patients with AMI. SDF-1α levels were measured by enzyme-linked immunosorbent assays in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in 50 patients with an anterior AMI. Measurement of SDF-1α levels and left ventriculography were repeated at discharge and 6 months after AMI. Patients were divided into 2 groups according to treatment with ARBs, which were administered at the discretion of the attending physician after admission. The AIV-AO gradient of SDF-1α, reflecting SDF-1α release from the infarcted myocardial region, decreased between the time of discharge and 6 months after AMI in patients taking an ARB. In contrast, the SDF-1α transcardiac gradient did not change in patients not taking an ARB. Among the clinical parameters tested, only the use of ARBs was significantly associated with percent changes in the SDF-1α transcardiac gradient from the time of discharge to 6 months after AMI in a linear regression analysis (r=-0.31, p=0.03). The SDF-1α transcardiac gradient 6 months after AMI was inversely correlated with the percent change in left ventricular (LV) ejection fraction (r=-0.52, pinfarcted myocardial region, which was associated with improvement in LV dysfunction and adverse remodeling in AMI survivors. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  7. Association of angiotensin II type 1 receptor gene A1166C polymorphism with the presence of diabetes mellitus and metabolic syndrome in patients with documented coronary artery disease.

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    Assali, Akram; Ghayour-Mobarhan, Majid; Sahebkar, Amirhossein; Hassani, Mitra; Kasaian, Jamal; Tatari, Farnoosh; Moohebati, Mohsen; Paydar, Roghayeh; Oladi, Mohammadreza; Esmaeili, Habib A; Tavallaie, Shima; Tehrani, Shahireh Omidvar; Ferns, Gordon A A; Behravan, Javad

    2011-06-01

    There are relatively limited data available on the genetic susceptibility to diabetes mellitus and metabolic syndrome in the Iranian population. We have therefore investigated the association between the angiotensin II type I receptor gene polymorphism (AT(1)R/A1166C) and the presence of diabetes mellitus and metabolic syndrome in a well defined group of patients. Patients with angiographically defined coronary artery disease (CAD) (n=309) were evaluated for the presence of AT(1)R/A1166C polymorphism. These patients were classified into subgroups with (n=164, M/F: 109/55) and without (n=145, M/F: 84/61) diabetes mellitus. The AT(1)R polymorphism was assessed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based method. There was a higher frequency of polymorphic genotypes (AC+CC) in the diabetic compared with the non-diabetic group (p=0.01). When determined for each gender separately, this difference remained significant in the males (p=0.04) but not in females (p=0.09). With regard to the allele frequencies, the C allele was significantly higher and the A allele frequency was lower in the diabetic group (p=0.01). This remained significant after gender segregation for males (p=0.01) but not females. In the binary logistic regression analysis, only serum fasting glucose was found as the independent predictor for the presence of diabetes in the CAD patients (β=1.16, pdefinition of metabolic syndrome used apart from a significantly lower frequency of C allele in male subjects with metabolic syndrome defined by the NCEP ATP III criteria (p=0.04). The AT(1)R/A1166C polymorphism may be associated with the presence of diabetes mellitus in male subjects with documented CAD. Copyright © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  8. Significance of initial blood pressure and comorbidity for the efficacy of a fixed combination of an angiotensin receptor blocker and hydrochlorothiazide in clinical practice

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    Roland E Schmieder

    2009-11-01

    Full Text Available Roland E Schmieder1, Markus Schwertfeger2, Peter Bramlage31Department of Nephrology and Hypertension, University Hospital of Erlangen; Germany; 2Sanofi-Aventis Deutschland GmbH, Berlin, Germany; 3Institute of Cardiovascular Pharmacology and Epidemiology, Mahlow, GermanyBackground: Two-thirds of all patients with arterial hypertension need drug combinations to achieve blood pressure (BP goals. Fixed combinations have high efficacy and result in high patient compliance. 300 mg irbesartan plus 25 mg hydrochlorothiazide (HCTZ has been investigated only in clinical trials but not in daily practice.Methods: A multicenter, noninterventional, noncontrolled observational study with 8123 patients seen by 1604 physicians in daily practice. BP reduction (office measurements, co-morbid disease and tolerability were documented over a 6-month observational period.Results: At mean baseline BP of 161 ± 15/94 ± 10 mmHg, administering of fixed combination resulted in a substantial BP reduction averaging 28 ± 15/14 ± 10 mmHg (P < 0.001. Decrease of systolic BP ran parallel with increasing systolic baseline BP (Spearman’s Rho –0.731; P < 0.0001; diastolic BP vs diastolic baseline BP Rho 0.740; P < 0.0001, independent from patient characteristics (age, obesity, diabetes or nephropathy but enhanced with short history of hypertension (P < 0.0001 vs long history, prior beta blockers (P = 0.001 vs prior angiotensin receptor blockers [ARBs], prior calcium channel blockers (P = 0.046 vs prior ARBs and no prior medication (P = 0.012 vs prior ARBs. High compliance (>98% and low incidence of adverse events (0.66% were documented.Conclusions: The fixed combination of 300 mg irbesartan with 25 mg HCTZ was efficacious and tolerable in an unselected patient population in primary care.Keywords: hypertension, combination therapy, obesity, irbesartan, noninterventional study, diuretics

  9. Classical Renin-Angiotensin System in Kidney Physiology

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    Sparks, Matthew A.; Crowley, Steven D.; Gurley, Susan B.; Mirotsou, Maria; Coffman, Thomas M.

    2014-01-01

    The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiote