WorldWideScience

Sample records for angiotensin ii receptor

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

    African Journals Online (AJOL)

    Ehab

    2012-06-18

    Jun 18, 2012 ... The effect of serum angiotensin II and angiotensin II type 1 receptor gene polymorphism on pediatric lupus nephritis. INTRODUCTION. Renin angiotensin system (RAS) has been considered one of the probable pathophysiologic mechanisms involved in SLE progression. However, the contribution of the ...

  2. Angiotensin II receptors in amphibian kidney

    International Nuclear Information System (INIS)

    Tchernitchin, S.M.; Galli, S.M.; Raizada, M.

    1986-01-01

    The localization of Angiotensin II (Ang II) receptors in the Amphibia kidney was investigated by radioautography and binding studies. 125 I-Ang II was injected into the dorsal aorta of anesthetized toads, Calyptocephalella caudiverbera. The kidney excised 2 and 10 min after injection show intense labeling in the glomeruli and a lesser amount in the tubules. Ang II labeling was found in the proximal, distal and collecting tubules. The thin connecting segment (diluting segment) also shows a distinct labeling. Afferent and efferent arterioles and interstitial connective tissue do not show radioautographic granules above the background level. Ang II binding studies of glomerular and tubular membranes show that the binding of 125 I-Ang II is higher in the glomerular than in the tubular membranes with a Kd of 1.9 x 10 -9 M and 1.0 x 10 -9 M respectively. Their results show that angiotensin II receptors in the amphibian nephron are present in the glomeruli and tubular segments, supporting the hypothesis of the intrarenal action of Ang II in this group of vertebrates

  3. Intracellular angiotensin II inhibits heterologous receptor stimulated Ca2+ entry

    NARCIS (Netherlands)

    Filipeanu, CM; Brailoiu, E; Henning, RH; Deelman, LE; de Zeeuw, D; Nelemans, SA

    2001-01-01

    Recent studies show that angiotensin II (AngII) can act from within the cell, possibly via intracellular receptors pharmacologically different from typical plasma membrane AngII receptors. The role of this intracellular AngII (AngII(i)) is unclear. Besides direct effects of AngII(i) on cellular

  4. 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...

  5. 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

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

    Indian Academy of Sciences (India)

    2014-12-26

    Dec 26, 2014 ... RESEARCH ARTICLE. 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 PATNAIK1,5, PALLABI PATI1, SURENDRA N. SWAIN2, MANOJ K.

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

    Indian Academy of Sciences (India)

    This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, ...

  8. 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

    probing with analogues of angiotensin II. These studies also provide clues about the conformational changes that underlie different functional outcomes. In this review, we evaluate current knowledge of the molecular determinants of AT(1) receptor activation, which may distinguish G protein...... of molecular mechanisms that govern disparate signalling events....

  9. Downregulation of angiotensin II type 1 receptors during sepsis.

    Science.gov (United States)

    Bucher, M; Ittner, K P; Hobbhahn, J; Taeger, K; Kurtz, A

    2001-08-01

    Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.

  10. 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

  11. 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...

  12. 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

  13. Autoradiographic localization of angiotensin II receptors in rat brain

    International Nuclear Information System (INIS)

    Mendelsohn, F.A.O.; Quirion, R.; Saavedra, J.M.; Aguilera, G.; Catt, K.J.

    1984-01-01

    The 125 I-labeled agonist analog [1-sarcosine]-angiotensin II ([Sar 1 ]AII) bound with high specificity and affinity (K/sub a/ = 2 x 10 9 M -1 ) to a single class of receptor sites in rat brain. This ligand was used to analyze the distribution of AII receptors in rat brain by in vitro autoradiography followed by computerized densitometry and color coding. A very high density of AII receptors was found in the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, nucleus of the tractus solitarius, and area postrema. A high concentration of receptors was found in the suprachiasmatic nucleus of the hypothalamus, lateral olfactory tracts, nuclei of the accessory and lateral olfactory tracts, triangular septal nucleus, subthalamic nucleus, locus coeruleus, and inferior olivary nuclei. Moderate receptor concentrations were found in the organum vasculosum of the lamina terminalis, median preoptic nucleus, medial habenular nucleus, lateral septum, ventroposterior thalamic nucleus, median eminence, medial geniculate nucleus, superior colliculus, subiculum, pre- and parasubiculum, and spinal trigeminal tract. Low concentrations of sites were seen in caudate-putamen, nucleus accumbens, amygdala, and gray matter of the spinal cord. These studies have demonstrated that AII receptors are distributed in a highly characteristic anatomical pattern in the brain. The high concentrations of AII receptors at numerous physiologically relevant sites are consistent with the emerging evidence for multiple roles of AII as a neuropeptide in the central nervous system. 75 references, 2 figures

  14. 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...... 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....

  15. An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong

    2010-01-01

    in the cytoplasmic parts of TM2, TM3, and TM6 to form an activation switch that is common to all family A 7TM receptors. We tested this hypothesis in the rat Angiotensin II (Ang II) type 1a (AT1a) receptor. The receptor has important roles in the cardiovascular system, but has also frequently been applied as a model...

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

    African Journals Online (AJOL)

    Abstract. Background: Genetic variability in the genes of different components of renin-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 ...

  17. Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

    OpenAIRE

    Krause, Eric; Shepherd, Andrew; Mickle, Aaron; Copits, Bryan; Karlsson, Pall; Kadunganattil, Suraj; Golden, Judith; Tadinada, Satya; Mack, Madison; Haroutounian, Simon; De Kloet, Annette; Samineni, Vijay; Valtcheva, Manouela; Mcilvried, Lisa; Sheahan, Tayler

    2017-01-01

    Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-...

  18. Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor

    Directory of Open Access Journals (Sweden)

    Veronika Y. Sysoeva

    2017-12-01

    Full Text Available Obesity is often associated with high systemic and local activity of renin-angiotensin system (RAS. Mesenchymal stem cells of adipose tissue are the main source of adipocytes. The aim of this study was to clarify how local RAS could control adipose differentiation of human adipose tissue derived mesenchymal stem cells (ADSCs. We examined the distribution of angiotensin receptor expressing cells in human adipose tissue and found that type 1 and type 2 receptors are co-expressed in its stromal compartment, which is known to contain mesenchymal stem cells. To study the expression of receptors specifically in ADSCs we have isolated them from adipose tissue. Up to 99% of cultured ADSCs expressed angiotensin II (AngII receptor type 1 (AT1. Using the analysis of Ca2+ mobilization in single cells we found that only 5.2 ± 2.7% of ADSCs specifically respond to serial Ang II applications via AT1 receptor and expressed this receptor constantly. This AT1const ADSCs subpopulation exhibited increased adipose competency, which was triggered by endogenous AngII. Inhibitory and expression analyses showed that AT1const ADSCs highly co-express AngII type 2 receptor (AT2, which was responsible for increased adipose competency of this ADSC subpopulation.

  19. Replacement of angiotensin-converting enzyme inhibitors by angiotensin-II-receptor antagonists in hypertensive patients with type II diabetes mellitus: metabolic and hemodynamic consequences

    NARCIS (Netherlands)

    van der Meulen, J.; Cleophas, T. J.; Zwinderman, A. H.

    1999-01-01

    The main pharmacodynamic difference between angiotensin-converting enzyme-inhibitors (ACE-i) and angiotensin-II-receptor antagonists (AII-r) is that ACE-i increase levels of bradykinin, which, in addition to vasodilation, may cause a decrease in insulin resistance. Hypertensive patients with

  20. Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury.

    Science.gov (United States)

    Li, Tuoyi; Yu, Bing; Liu, Zhixin; Li, Jingyuan; Ma, Mingliang; Wang, Yingbao; Zhu, Mingjiang; Yin, Huiyong; Wang, Xiaofeng; Fu, Yi; Yu, Fang; Wang, Xian; Fang, Xiaohong; Sun, Jinpeng; Kong, Wei

    2018-01-02

    Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg 167 and Cys 289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

  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...... peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA. DESIGN: Experimental retrospective...... with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls. CONCLUSIONS: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA. FINANCIAL...

  2. Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction.

    Science.gov (United States)

    Ehanire, Tosan; Ren, Licheng; Bond, Jennifer; Medina, Manuel; Li, George; Bashirov, Latif; Chen, Lei; Kokosis, George; Ibrahim, Mohamed; Selim, Angelica; Blobe, Gerard C; Levinson, Howard

    2015-03-01

    Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility is key to mitigating HSc. Angiotensin II (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors angiotensin type 1 receptor (AT1 receptor) and angiotensin type 2 receptor (AT2 receptor) and analyzed for AT1 receptor expression using Western blot. In vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1 receptor, AT2 receptor, p38, Jun N-terminal kinase (JNK), MEK, and activin receptor-like kinase 5 (ALK5) antagonism. Excisional wounds were created on AT1 receptor KO and wild-type (WT) mice treated with AngII ± losartan and ALK5 and JNK inhibitors SB-431542 and SP-600125, respectively. Granulation tissue contraction was quantified, and wounds were analyzed by immunohistochemistry. AT1 receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1 receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In vivo experiments determined that absence of AT1 receptor and chemical AT1 receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII promotes granulation tissue contraction through AT1 receptor and downstream canonical transforming growth factor (TGF)-β signaling pathway, ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions. AT1 receptor expression is increased in scar tissue compared to unwounded tissue

  3. Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism

    International Nuclear Information System (INIS)

    Wilkes, B.M.

    1987-01-01

    Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml. At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus. Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl 2 , a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively

  4. Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome.

    Science.gov (United States)

    Qin, Xian-Yun; Zhang, Yun-Long; Chi, Ya-Fei; Yan, Bo; Zeng, Xiang-Jun; Li, Hui-Hua; Liu, Ying

    2018-01-01

    Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases. © 2018 The Author(s). Published by S. Karger AG, Basel.

  5. 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

    BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hem...... 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....... 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...

  6. 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.

  7. Angiotensin II promotes development of the renal microcirculation through AT1 receptors

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Marcussen, Niels; Pedersen, Michael

    2010-01-01

    Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantified...... CD31(+) postglomerular microvessels, performed quantitative PCR analysis of vascular growth factor expression, and measured renal blood flow by magnetic resonance. Treating rats with the angiotensin II type 1 receptor antagonist candesartan for 2 weeks after birth reduced the total length, volume......, and surface area of capillaries in both the cortex and the medulla and inhibited the organization of vasa recta bundles. In addition, angiotensin II type 1 antagonism inhibited the transcription of angiogenic growth factors vascular endothelial growth factor, angiopoietin-1, angiopoietin-2...

  8. Angiotensin II type 1a receptor-deficient mice develop angiotensin II-induced oxidative stress and DNA damage without blood pressure increase.

    Science.gov (United States)

    Zimnol, Anna; Amann, Kerstin; Mandel, Philipp; Hartmann, Christina; Schupp, Nicole

    2017-12-01

    Hypertensive patients have an increased risk of developing kidney cancer. We have shown in vivo that besides elevating blood pressure, angiotensin II causes DNA damage dose dependently. Here, the role of blood pressure in the formation of DNA damage is studied. Mice lacking one of the two murine angiotensin II type 1 receptor (AT1R) subtypes, AT1aR, were equipped with osmotic minipumps, delivering angiotensin II during 28 days. Parameters of oxidative stress and DNA damage of kidneys and hearts of AT1aR-knockout mice were compared with wild-type (C57BL/6) mice receiving angiotensin II, and additionally, with wild-type mice treated with candesartan, an antagonist of both AT1R subtypes. In wild-type mice, angiotensin II induced hypertension, reduced kidney function, and led to a significant formation of reactive oxygen species (ROS). Furthermore, genomic damage was markedly increased in this group. All these responses to angiotensin II could be attenuated by concurrent administration of candesartan. In AT1aR-deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected. However, angiotensin II still led to an increase of ROS in kidneys and hearts of these animals. Additionally, genomic damage in the form of double-strand breaks was significantly induced in kidneys of AT1aR-deficient mice. Our results show that angiotensin II induced ROS production and DNA damage even without the presence of AT1aR and independently of blood pressure changes. Copyright © 2017 the American Physiological Society.

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

    DEFF Research Database (Denmark)

    Tarnow, L; Cambien, Francois; Rossing, P

    1996-01-01

    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...... with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility...

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

    NARCIS (Netherlands)

    Hoffmann, S.; Krause, T.; van Geel, P. P.; Willenbrock, R.; Pagel, I.; Pinto, Y. M.; Buikema, H.; van Gilst, W. H.; 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 AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  11. Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade.

    Directory of Open Access Journals (Sweden)

    Kana Tsukuda

    Full Text Available Browning of white adipose tissue (WAT has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named 'beige' or 'brite' adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R and type 2 receptor (AT2R. However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT compared to wild-type (WT mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders.

  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. Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes

    DEFF Research Database (Denmark)

    Jeppesen, Pia Lindgren; Christensen, Gitte Lund; Schneider, Mikael

    2011-01-01

    Background and purpose: The Angiotensin II type 1 receptor (AT(1) R) is a key regulator of blood pressure and cardiac contractility and is profoundly involved in development of cardiac disease. Since several microRNAs (miRNAs) have been implicated in cardiac disease, we asked whether miRNAs might...

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

    African Journals Online (AJOL)

    H. El-banawy

    2015-01-05

    Jan 5, 2015 ... Abstract Background: Genetic variability in the genes of different components of renin-angioten- sin 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 ...

  15. Distinct angiotensin II receptor in primary cultures of glial cells from rat brain

    International Nuclear Information System (INIS)

    Raizada, M.K.; Phillips, M.I.; Crews, F.T.; Sumners, C.

    1987-01-01

    Angiotensin II (Ang-II) has profound effects on the brain. Receptors for Ang-II have been demonstrated on neurons, but no relationship between glial cells and Agn-II has been established. Glial cells (from the hypothalamus and brain stem of 1-day-old rat brains) in primary culture have been used to demonstrate the presence of specific Ang-II receptors. Binding of 125 I-Ang-II to glial cultures was rapid, reversible, saturable, and specific for Ang-II. The rank order of potency of 125 I-Ang-II binding was determined. Scatchard analysis revealed a homogeneous population of high-affinity binding sites with a B/sub max/ of 110 fmol/mg of protein. Light-microscopic autoradiography of 125 I-Ang-II binding supported the kinetic data, documenting specific Ang-II receptors on the glial cells. Ang-II stimulated a dose-dependent hydrolysis of phosphatidylinositols in glial cells, an effect mediated by Ang-II receptors. However, Ang-II failed to influence [ 3 H] norepinephrine uptake, and catecholamines failed to regulate Ang-II receptors, effects that occur in neurons. These observations demonstrate the presence of specific Ang-II receptors on the glial cells in primary cultures derived from normotensive rat brain. The receptors are kinetically similar to, but functionally distinct from, the neuronal Ang-II receptors

  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. 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

  18. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    Science.gov (United States)

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question.

  19. The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

    DEFF Research Database (Denmark)

    Chow, Bryna S M; Koulis, Christine; Krishnaswamy, Pooja

    2016-01-01

    AIMS/HYPOTHESIS: Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT1R) subtype. However, its actions via the angiotensin II type 2 receptor (AT2R) subtype...... are still poorly understood. This study is the first to investigate the role of the novel selective AT2R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). METHODS: Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate...

  20. 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.

  1. Perivascular Adipose Tissue Angiotensin II Type 1 Receptor Promotes Vascular Inflammation and Aneurysm Formation.

    Science.gov (United States)

    Sakaue, Tomoki; Suzuki, Jun; Hamaguchi, Mika; Suehiro, Chika; Tanino, Akiko; Nagao, Tomoaki; Uetani, Teruyoshi; Aono, Jun; Nakaoka, Hirotomo; Kurata, Mie; Sakaue, Tomohisa; Okura, Takafumi; Yasugi, Takumi; Izutani, Hironori; Higaki, Jitsuo; Ikeda, Shuntaro

    2017-10-01

    Perivascular adipose tissue exhibits characteristics of active local inflammation, which contributes to the development of atherosclerotic disease as a complication of obesity/metabolic syndrome. However, the precise role of perivascular adipose tissue in the progression of abdominal aortic aneurysm remains unclear. To test the hypothesis that genetic deletion of angiotensin II type 1a (AT 1a ) receptor in perivascular visceral adipose tissue (VAT) can attenuate aortic aneurysm formation in apolipoprotein E-deficient (ApoE -/- ) mice, we performed adipose tissue transplantation experiments by using an angiotensin II-induced aneurysm murine model, in which we transplanted VAT from ApoE -/- or ApoE -/- AT 1a -/- donor mice onto the abdominal aorta of ApoE -/- recipient mice. Compared with ApoE -/- VAT transplantation, ApoE -/- AT 1a -/- VAT transplantation markedly attenuated aortic aneurysm formation, macrophage infiltration, and gelatinolytic activity in the abdominal aorta. AT 1a receptor activation led to the polarization of macrophages in perivascular VAT toward the proinflammatory phenotype. Moreover, osteopontin expression and gelatinolytic activity were considerably lower in ApoE -/- AT 1a -/- perivascular VAT than in ApoE -/- perivascular VAT, and angiotensin II-induced osteopontin secretion from adipocytes was eliminated after deletion of AT 1a receptor in adipocytes. Notably, induction of macrophage migration by conditioned medium from angiotensin II-stimulated wild-type adipocytes was suppressed by treatment with an osteopontin-neutralizing antibody, and ApoE -/- OPN -/- VAT transplantation more potently attenuated aortic aneurysm formation than ApoE -/- VAT transplantation. Our findings indicate a previously unrecognized effect of AT 1a receptor in perivascular VAT on the pathogenesis of abdominal aortic aneurysm. © 2017 American Heart Association, Inc.

  2. 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...

  3. 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.

  4. Effects of angiotensin converting enzyme inhibitor and angiotensin II antagonist receptor on neointima hyperplasia after vascular balloon injury

    International Nuclear Information System (INIS)

    Wang Yeling; Zhao Lihua

    2004-01-01

    Objective: To study the effects of angiotensin converting enzyme inhibitor (captopril) and angiotensin II antagonist receptor (valsartan) on neointima hyperplasia after vascular balloon injury. Methods: Thirty-six rabbit models were randomly divided into three groups: injuried group, captopril group and valsartan group. Captopril (2 mg·kg -1 ·d -1 po) and valsartan (10 mg·kg -1 ·d -1 po) were given to twelve rabbits respectively from 1 day before the right carotidarteries were injuried by 2.0 mm ballon cathether to 14 days after injury in captopil group and valsartan group. The medicine was not administered in the injuried group. The tissue plasminogen activator (tPA), plaminogen activor inhibitor-1 (PAI-1) antigen level and plasma endothelin (ET) levels were measured before injury, and 7, 14 days after vascular injury. The pathomorphoiogical examination were carried out 14 days after angioplasty. Results: The levels of plasma PAI-1 and ET in captopril group and valsartan group were significantly lower than those in the injuried group (P<0.05). The intimal thickness and extent of lumen stenosis in captopril and valsartan groups were significantly lower than those in the injuried group (P<0.05). Conclusion: Captopril and valsartan can inhibit neointima hyperplasia after vascular ballon injury. (authors)

  5. 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

    OBJECTIVE: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2R). The selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exhibit neuroprotection and improve stroke outcomes...... 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...... min), 24 h, and 48 h after stroke. Infarct size was assessed by magnetic resonance imaging at 21 days post MCAO. Animals received blinded neurological exams at 4 h, 24 h, 72 h, 7d, 14d, and 21d post-MCAO. RESULTS: Systemic treatment with C21 after stroke significantly improved neurological function...

  6. No significant effect of angiotensin II receptor blockade on intermediate cardiovascular end points in hemodialysis patients

    DEFF Research Database (Denmark)

    Peters, Christian D; Kjaergaard, Krista D; Jensen, Jens D

    2014-01-01

    points such as central aortic blood pressure, carotid-femoral pulse wave velocity, left ventricular mass index, N-terminal brain natriuretic prohormone, heart rate variability, and plasma catecholamines were not significantly affected by irbesartan treatment. Changes in systolic blood pressure during......Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis......, and residual renal function. Brachial blood pressure decreased significantly in both groups, but there was no significant difference between placebo and irbesartan. Use of additional antihypertensive medication, ultrafiltration volume, and dialysis dosage were not different. Intermediate cardiovascular end...

  7. 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 β-arrestins. Since uncoupling of G proteins by increased ability......Seven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or β-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given...... 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...

  8. 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......Seven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or ß-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given...... 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 ß-arrestins without activation of G proteins. However, the underlying...

  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. Escherichia coli lipopolysaccharide impairs the calcium signaling pathway in mesangial cells: role of angiotensin II receptors.

    Science.gov (United States)

    Maquigussa, Edgar; Arnoni, Carine P; Cristovam, Priscila C; de Oliveira, Andrea S; Higa, Elisa M S; Boim, Mirian A

    2010-06-01

    Sepsis causes impaired vascular reactivity, hypotension and acute renal failure. The ability of the Escherichia coli endotoxin (lipopolysaccharide [LPS]) to impair agonist-induced contractility in mesangial cells, which contributes to LPS-induced renal dysfunction, was evaluated. Agonist-induced intracellular calcium ([Ca(2+)]i) mobilization was analyzed using angiotensin II (AngII). The effect of LPS on the levels of the renin-angiotensin system (RAS) components and the roles of vasodilatation-inducing molecules including AT2 receptor (AT2R) and nitric oxide (NO) in the cell reactivity were also evaluated. Confluent human mesangial cells (HMCs) were stimulated with LPS (0111-B4, 100 microg/mL). AngII-induced [Ca(2+)]i mobilization was measured by fluorometric analysis using Fura-2AM in the absence and presence of an AT2R antagonist (PD123319). The mRNA and protein levels for angiotensinogen, renin, angiotensin-converting enzyme, AT1R and AT2R were analyzed by realtime reverse transcriptase-polymerase chain reaction and Western blot, respectively. NO production was measured by the chemiluminescence method in the culture media after 24, 48 and 72 h of LPS incubation. After 24 h, LPS-stimulated HMCs displayed lower basal [Ca(2+)]i and an impaired response to AngII-induced rise in [Ca(2+)]i. LPS significantly increased AT2R levels, but did not cause significant alterations of RAS components. PD123319 restored both basal and AngII-induced [Ca(2+)]i peak, suggesting an involvement of AT2R in these responses. The expected increase in NO production was significant only after 72 h of LPS incubation and it was unaffected by PD123319. Results showed that LPS reduced the reactivity of HMCs to AngII and suggest that the vasodilatation induced by AT2R is a potential mediator of this response through a pathway independent of NO.

  11. 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.

  12. 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.

  13. 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...... 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue....

  14. 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......, 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...... patients. This was a result of increased AT(1) receptor immunostaining of both vascular smooth muscle cells and infiltrating inflammatory cells. Only faint immunostaining was seen for AT(2) receptors, primarily in the endothelial cells, and to a lesser extent on the smooth muscle cells. Immunostaining...

  15. Role of vascular smooth muscle PPARγ in regulating AT1 receptor signaling and angiotensin II-dependent hypertension.

    Directory of Open Access Journals (Sweden)

    Maria Alicia Carrillo-Sepulveda

    Full Text Available Peroxisome proliferator activated receptor γ (PPARγ has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARγ mutation in mice (S-P467L leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2 was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day, for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0 ± 10.2 vs 129.1 ± 3.0 mmHg, p<0.05. Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2 ± 6.9 mmHg to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0 ± 3.9 mmHg mice, such that there was no difference in the losartan-induced depressor response between groups (-13.53 ± 1.39 in S-P467L vs -16.16 ± 3

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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...... group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline...

  18. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    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...

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

    DEFF Research Database (Denmark)

    Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique

    2017-01-01

    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...

  20. 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

    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......% and -62% in the clipped and contralateral kidney, respectively; and - 50% after water restriction; p...

  1. Effect of dietary fiber on the level of free angiotensin II receptor blocker in vitro.

    Science.gov (United States)

    Iwazaki, Ayano; Takahashi, Kazuhiro; Tamezane, Yui; Tanaka, Kenta; Nakagawa, Minami; Imai, Kimie; Nakanishi, Kunio

    2014-01-01

    The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber.

  2. Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

    DEFF Research Database (Denmark)

    Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B

    2002-01-01

    and inositol phosphate turnover assays in COS-7 cells transiently transfected with the wild-type and mutant forms of the receptor. Mutant receptors bore modifications in the extracellular region: T88H, Y92H, G1961, G196W, and D278E. Compound L-162,313 displaced [125I]-Sar1,Leu8-AngII from the mutants G196I...... and G196W with IC50 values similar to that of the wild-type. The affinity was, however, slightly affected by the D278E mutation and more significantly by the T88H and Y92H mutations. In inositol phosphate turnover assays, the ability of L-162,313 to trigger the activation cascade was compared...... with that of angiotensin II. These assays showed that the G196W mutant reached a relative maximum activation exceeding that of the wild-type receptor; the efficacy was slightly reduced in the G1961 mutant and further reduced in the T88H, Y92H, and D278E mutants. Our data suggest that residues of the extracellular domain...

  3. The mechanisms behind decreased internalization of angiotensin II type 1 receptor.

    Science.gov (United States)

    Bian, Jingwei; Zhang, Suli; Yi, Ming; Yue, Mingming; Liu, Huirong

    2018-02-06

    The internalization of angiotensin II type 1 receptor (AT 1 R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT 1 R, such as hypertension. However, the mechanism behind reduced AT 1 R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT 1 R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P 2 ), which can increase the consumption of PtdIns (4,5) P 2 . (2) AT 1 R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-β-arrestin complex conformation. (3) The abnormal formation of vesicles or AT 1 R heterodimers with fewer endocytic receptors results in less AT 1 R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT 1 R recycling. In addition, lower expression of AT 1 R-associated protein (ATRAP) or higher expression of AT 1 R-associated protein 1 (ARAP1) can reduce receptor internalization. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. 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.

  5. 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.

  6. Inactivation of the EP3 receptor attenuates the Angiotensin II pressor response via decreasing arterial contractility

    Science.gov (United States)

    Chen, Lihong; Miao, Yifei; Zhang, Yahua; Dou, Dou; Liu, Limei; Tian, Xiaoyu; Yang, Guangrui; Pu, Dan; Zhang, Xiaoyan; Kang, Jihong; Gao, Yuansheng; Wang, Shiqiang; Breyer, Matthew D.; Wang, Nanping; Zhu, Yi; Huang, Yu; Breyer, Richard M; Guan, Youfei

    2012-01-01

    Objective The present studies aimed at elucidating the role of prostaglandin E2 (PGE2) receptor subtype 3 (EP3) in regulating blood pressure. Methods and Results Mice bearing a genetic disruption of the EP3 gene (EP3−/−) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3−/− mice, while the reduction of BP induced by PGE2 was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (AngII) was attenuated in EP3−/− mice. AngII–induced vasoconstriction in mesenteric arteries decreased in EP3−/− group. In mesenteric arteries from wild type mice, AngII–induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished AngII-induced phosphorylation of MLC20 and MYPT1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells (VSMCs), AngII induced intracellular Ca2+ increase was potentiated by EP3 agonist sulprostone, while inhibited by DG-041. Conclusions Activation of the EP3 receptor raises baseline blood pressure and contributes to AngII-dependent hypertension at least partially via enhancing Ca2+ sensitivity and intracellular calcium concentration in VSMCs. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension. PMID:23065824

  7. 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.

  8. 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.

  9. Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

    Science.gov (United States)

    Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

    2009-12-15

    Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

  10. 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

  11. Corticosteroids decrease glomerular angiotensin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Douglas, J.G.

    1987-03-01

    Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular /sup 125/I ANG II receptor density of 33 and 45%, respectively. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.

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

    Science.gov (United States)

    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.

  13. 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.

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

    International Nuclear Information System (INIS)

    Sun, Lihua; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Yang, Yang; Yang, Hua

    2012-01-01

    Highlights: ► Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. ► The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. ► GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. ► 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.

  15. Influence of the angiotensin II AT1 receptor antagonist irbesartan on ischemia/reperfusion injury in the dog heart

    NARCIS (Netherlands)

    Preckel, B.; Schlack, W.; Gonzàlez, M.; Obal, D.; Barthel, H.; Thämer, V.

    2000-01-01

    The aim of the present study was to investigate whether the non-peptide angiotensin II type 1 (AT1) receptor antagonist irbesartan (SR 47436, BMS 186295, 2-n-butyl-3 [2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro [4,4]non-1-en-4-one) has myocardial protective effects during regional

  16. 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

  17. 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.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

    Science.gov (United States)

    Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

    2014-09-01

    This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

  2. Angiotensin II type 2 receptor-interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathway.

    Science.gov (United States)

    Ping, Huang; Guo, Liang; Xi, Jie; Wang, Donghui

    2017-06-01

    Local migration and long-distance metastasis is the main reason for higher mortality of ovarian cancer. Microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein is associated with tumor initiation and progression and exerts anti-tumor effects. High mobility group AT-hook 2 is overexpressed in majority of metastatic carcinomas, which contributes to carcinomas metastasis through Snail-induced epithelial-to-mesenchymal transition signal pathway. The purpose of this study was to investigate the signal pathway of microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein-mediated anti-tumor effects. Our data observed that ovarian carcinoma cells exhibited lower expression of angiotensin II type 2 receptor-interacting protein 3a and higher expression of high mobility group AT-hook 2 compared to normal ovarian cells. Restoration of angiotensin II type 2 receptor-interacting protein 3a expression in ovarian carcinoma cells inhibited high mobility group AT-hook 2 expression and exhibited anti-proliferative effects. In addition, angiotensin II type 2 receptor-interacting protein 3a treatment suppressed the phosphorylation of epithelial-to-mesenchymal transition and extracellular signal-regulated kinase in ovarian carcinoma cells. We also observed that angiotensin II type 2 receptor-interacting protein 3a restoration downregulated expression of Snail, E-Cadherin, N-Cadherin, and Vimentin in ovarian carcinoma cells, whereas angiotensin II type 2 receptor-interacting protein 3a knockdown enhanced the phosphorylation of extracellular signal-regulated kinase and epithelial-to-mesenchymal transition. In vivo assay indicated that angiotensin II type 2 receptor-interacting protein 3a inhibited ovarian tumor growth and elevated survival of tumor-bearing immunodeficient mice. Tumor histological analysis indicated that Snail, E-Cadherin, N-Cadherin, and Vimentin expression levels were downregulated via decreasing

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction.

    Science.gov (United States)

    Tower, Clare; Chappell, Sally; Acharya, Meera; Crane, Richard; Szolin, Stephanie; Symonds, Lyneth; Chevins, Helen; Kalsheker, Noor; Baker, Philip; Morgan, Linda

    2006-02-01

    Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); PG (OR, 0.21 (0.08-0.55); P 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor. 2006 Wiley-Liss, Inc.

  5. Role of angiotensin II and endothelin-1 receptors in aging-related functional changes in rat cardiovascular system.

    Science.gov (United States)

    Ishihata, Akira; Katano, Yumi

    2006-05-01

    Angiotensin II (AII) and endothelin-1 (ET-1) are regarded as key players in the age-related changes in cardiovascular function. They are known to be involved in the pathogenesis of cardiac fibrosis and coronary vascular atherosclerosis. AII- and ET-induced vasoconstriction was augmented in coronary arteries of Langendorff-perfused heart from aged rats. In papillary muscles, ET-1-induced positive inotropic effect (PIE) was diminished by aging. On the other hand, both ET-1 and AII caused greater vasoconstriction in aged rat coronary arteries compared to those in the young rat. To further elucidate the mechanism of these age-dependent changes in cardiovascular effects of ET-1 and AII, we examined the expression of AII and ET-1 receptors in young (2-month-old) and aged (24-month-old) rats. Total RNA was isolated from left ventricles. For determination of the gene expression of AT(1) receptor and ET(A)/ET(B) receptor mRNA, competitive RT-PCR and Northern blot analysis were performed, respectively. [(125)I]ET-1 receptor assay was carried out in left ventricular membrane fraction. AT(1)-receptor, ET(A)-, and ET(B)-receptor mRNA were upregulated in the left ventricles of senescent rats compared with young ones. The affinity of ET-1-receptor was not changed, but receptor density was significantly increased in aged rats. Although the precise mechanism for the upregulation of AT(1) receptor and ET-1 receptor in the aged rat heart has not been clarified yet, these findings suggest that the activation of the renin-angiotensin system as well as ET receptor may be important for the physiological changes in aged hearts.

  6. Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation.

    Science.gov (United States)

    Isobe, Aki; Takeda, Takashi; Sakata, Masahiro; Miyake, Asako; Yamamoto, Toshiya; Minekawa, Ryoko; Nishimoto, Fumihito; Oskamoto, Yoko; Walker, Cheryl Lyn; Kimura, Tadashi

    2008-02-01

    Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure. In this study, we investigated the potential role of Ang II (1-1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT-PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II. Ang II induced ELT-3 leiomyoma cell proliferation (P estradiol-induced cell proliferation (P < 0.01). AT(1)R, but not AT(2)R, plays a role in Ang II-induced ELT-3 cell proliferation. These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells.

  7. Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

    Science.gov (United States)

    Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2017-08-01

    We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

  8. 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.

  9. Change of expression of renal alpha1-adrenergic receptor and angiotensin II receptor subtypes with aging in rats.

    Science.gov (United States)

    Li, Yan-Fang; Cao, Xiao-Jing; Bai, Xue-Yuan; Lin, Shu-Peng; Shi, Shu-Tian

    2010-04-01

    It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (page and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (prenal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.

  10. 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.

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  12. Angiotensin II type 2 receptor stimulation increases the rate of NG108-15 cell migration via actin depolymerization.

    Science.gov (United States)

    Kilian, Peter; Campbell, Shirley; Bilodeau, Lyne; Guimond, Marie-Odile; Roberge, Claude; Gallo-Payet, Nicole; Payet, Marcel Daniel

    2008-06-01

    Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108-15 cell migration. This effect was antagonized by PD123319, a selective AT2 receptor antagonist, but not by DUP753, a selective AT1 receptor antagonist, and was mimicked by the specific AT2 receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT2 receptor, guanylyl cyclase/cyclic GMP or p42/p44 mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108-15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT2 receptor increases the migration speed of NG108-15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT2 receptor action, in the context of cellular migration.

  13. Effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II-induced facilitation of sympathetic neurotransmission in the rat mesenteric artery

    NARCIS (Netherlands)

    Balt, J. C.; Mathy, M. J.; Nap, A.; Pfaffendorf, M.; van Zwieten, P. A.

    2001-01-01

    SUMMARY: The effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II (Ang II)-induced facilitation of noradrenergic neurotransmission was investigated in the isolated rat mesenteric artery under isometric conditions. Electrical field stimulation (2, 4, and 8

  14. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

    2011-01-01

    connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate...... phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does...

  15. Angiotensin II disrupts inhibitory avoidance memory retrieval.

    Science.gov (United States)

    Bonini, Juliana S; Bevilaqua, Lia R; Zinn, Carolina G; Kerr, Daniel S; Medina, Jorge H; Izquierdo, Iván; Cammarota, Martín

    2006-08-01

    The brain renin-angiotensin system (RAS) is involved in learning and memory, but the actual role of angiotensin II (A(II)) and its metabolites in this process has been difficult to comprehend. This has been so mainly due to procedural issues, especially the use of multi-trial learning paradigms and the utilization of pre-training intracerebroventricular infusion of RAS-acting compounds. Here, we specifically analyzed the action of A(II) in aversive memory retrieval using a hippocampal-dependent, one-trial, step-down inhibitory avoidance task (IA) in combination with stereotaxically localized intrahippocampal infusion of drugs. Rats bilaterally implanted with infusion cannulae aimed to the CA1 region of the dorsal hippocampus were trained in IA and tested for memory retention 24 h later. We found that when given into CA1 15 min before IA memory retention test, A(II), but not angiotensin IV or angiotensin(1-7) induced a dose-dependent and reversible amnesia without altering locomotor activity, exploratory behavior or anxiety state. The effect of A(II) was blocked in a dose-dependent manner by the A(II)-type 2 receptor (AT(2)) antagonist PD123319 but not by the A(II)-type 1 receptor (AT(1)) antagonist losartan. By themselves, neither PD123319 nor losartan had any effect on memory expression. Our data indicate that intra-CA1 A(II) hinders retrieval of avoidance memory through a process that involves activation of AT(2) receptors.

  16. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.

    Science.gov (United States)

    Hisamichi, Mikako; Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Ichikawa, Daisuke; Natsuki, Takayuki; Hoshino, Seiko; Kimura, Kenjiro; Shibagaki, Yugo

    2017-01-01

    The aim of this study was to investigate the in vivo role of angiotensin II type 1a (AT1a) receptor in renal damage as a result of hypertension by using transgenic mice with AT1a receptor gene disruption. Transgenic mice that express human liver-type fatty acid binding protein (L-FABP) with or without disruption of the AT1a receptor gene (L-FABP +/- AT1a -/- , and L-FABP +/- AT1a +/+ , respectively) were used with urinary L-FABP as an indicator of tubulointerstitial damage. Those female mice were administered subcutaneously deoxycorticosterone acetate (DOCA)-salt tablets plus drinking water that contained 1% saline for 28 d after uninephrectomy. In L-FABP +/- AT1a +/+ mice that received DOCA-salt treatment, hypertension was induced and slight expansion of glomerular area, glomerular sclerosis, and tubulointerstitial damage were observed. In L-FABP +/- AT1a -/- mice that received DOCA-salt treatment, hypertension was similarly induced and the degree of glomerular damage was significantly more severe than in L-FABP +/- AT1a +/+ -DOCA mice. Urinary L-FABP levels were significantly higher in L-FABP +/- AT1a -/- -DOCA mice compared with those in L-FABP +/- AT1a +/+ -DOCA mice. Hydralazine treatment significantly attenuated renal damage that was found in L-FABP +/- AT1a -/- -DOCA mice along with a reduction in blood pressure. In summary, activation of the AT1a receptor may contribute to maintenance of the glomerular structure against hypertensive renal damage.-Hisamichi, M., Kamijo-Ikemori, A., Sugaya, T., Ichikawa, D., Natsuki, T., Hoshino, S., Kimura, K., Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension. © The Author(s).

  17. 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...

  18. Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Nana Pei

    Full Text Available Increased expression of angiotensin II type 2 receptor (AT2R induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2, 2 cytokine genes (IL6 and IL8 and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7 in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

  19. 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.

  20. Angiotensin II and taste sensitivity

    Directory of Open Access Journals (Sweden)

    Noriatsu Shigemura, DDS, PhD

    2015-05-01

    Full Text Available The sense of taste plays a major role in evaluating the quality of food components in the oral cavity. Sweet, salty, umami, sour and bitter taste are generally accepted as five basic taste qualities. Among them, salty taste is attractive to animals and influences sodium intake. Angiotensin II (ANG II and aldosterone (ALDO, which is stimulated by ANG II are key hormones that regulate sodium homeostasis and water balance. At the peripheral gustatory organs, it has been reported that ALDO increases the amiloride-sensitivity of the rat gustatory neural responses to NaCl in a time course of several hours. A recent study demonstrated that ANG II suppresses amiloride-sensitivity of the mouse gustatory and behavioral responses to NaCl via its receptor AT1 within an hour. Moreover, ANG II enhances sweet taste sensitivity without affecting umami, sour and bitter tastes. These results suggest that the reciprocal and sequential regulatory mechanisms by ANG II (as an acute suppressor together with ALDO (as a slow enhancer on the salt taste sensitivity may exist in peripheral taste organs, contribute to salt intake, and play an important role in sodium homeostasis. Furthermore, the linkage between salty and sweet taste modulations via the ANG II signaling may optimize sodium and calorie intakes.

  1. ACE inhibitor and angiotensin II type 1 receptor antagonist therapies in elderly patients with diabetes mellitus: are they underutilized?

    Science.gov (United States)

    Pappoe, Lamioko Shika; Winkelmayer, Wolfgang C

    2010-02-01

    Diabetes mellitus is highly prevalent in older adults in the industrialized world. These patients are at high risk of complications from diabetes, including diabetic kidney disease. ACE inhibitors and their newer cousins, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are powerful medications for the prevention of progression of diabetic renal disease. Unfortunately, among the elderly, these medications have been underutilized. The reasons for this include physician concerns regarding patient age and limited life expectancy and potential complications of ACE inhibitor or ARB use, specifically an increase in creatinine levels and hyperkalaemia. As discussed in this article, there have been several studies that show that the effects of inhibition of the renin-angiotensin system can be beneficial for the treatment of cardiovascular disease and renal disease among elderly patients with diabetes and that the potential risks mentioned above are no greater in this group than in the general population. For these reasons, several professional societies recommend that elderly patients with diabetes and hypertension (systolic blood pressure >or=140 mmHg or diastolic blood pressure >or=90 mmHg) be treated with an ACE inhibitor or ARB (as is recommended for younger diabetics). Use of ACE inhibitors or ARBs is also recommended for those with cardiovascular disease or those who are at risk of cardiovascular disease. Furthermore, in the management of diabetic kidney disease in elderly patients, treatment with ACE inhibitors or ARBs is also recommended to reduce the risk or slow the progression of nephropathy. Renal function and potassium levels should be monitored within the first 12 weeks of initiation of these medications, with each dose increase, and on a yearly basis thereafter. This article summarizes the current guidelines on the use of ACE inhibitors and ARBs in older adults with diabetes, reviews the evidence for their use in the elderly

  2. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    International Nuclear Information System (INIS)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li; Li, Xiao-Dong; Hong, Mo-Na; Chen, Qi-Zhi; Han, Wei-Qing; Gao, Ping-Jin

    2016-01-01

    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.

  3. 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.

  4. ANGIOTENSIN II AND MYOCARDIAL INFARCTION

    Directory of Open Access Journals (Sweden)

    O. P. Shevchenko

    2008-01-01

    Full Text Available The role of angiotensin II in pathogenesis of cardiovascular diseases is discussed. Angiotensin II participates in development of acute myocardial infarction (MI in patients with atherosclerosis. It contributes to inflammation of vessel intimae, oxidative stress, cells apoptosis, matrix remodeling, has pro-thrombosis action, promotes MI expansion and post-MI remodeling. Angiotensin converting enzyme (ACE inhibitors reduce mortality and improve prognosis of patients with acute MI. In patients with ischemic heart disease including patients after MI ACE inhibitors reduce mortality, risk of repeated MI as well as improve quality of life.

  5. Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice.

    Science.gov (United States)

    Yamamoto, Rie; Akazawa, Hiroshi; Ito, Kaoru; Toko, Haruhiro; Sano, Masanori; Yasuda, Noritaka; Qin, Yingjie; Kudo, Yoko; Sugaya, Takeshi; Chien, Kenneth R; Komuro, Issei

    2007-12-01

    Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbidity in patients of heart failure. The aim of this study was to elucidate the role of the AT1 receptor in disease progression in muscle LIM protein (MLP)-deficient mice, which are susceptible to heart failure because of defective function of mechanosensors in cardiomyocytes. Hearts from MLP knockout (MLPKO) mice and MLP-AT1a receptor double knockout (DKO) mice were analyzed. MLPKO hearts showed marked chamber dilatation with cardiac fibrosis and reactivation of the fetal gene program. All of these changes were significantly milder in the DKO hearts. Impaired left ventricular (LV) contractility and filling were alleviated in DKO hearts. However, the impaired relaxation and downregulated expression of sarcoplasmic reticulum calcium-ATPase 2 were unchanged in DKO hearts. The AT1a receptor is involved in progression of LV remodeling and deterioration of cardiac function in the hearts of MLPKO mice. These results suggest that blockade of the receptor is effective in preventing progression of heart failure in dilated cardiomyopathy.

  6. Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats

    NARCIS (Netherlands)

    Wagenaar, Gerry T M; Sengers, Rozemarijn M A; Laghmani, El Houari; Chen, Xueyu; Lindeboom, Melissa P H A; Roks, Anton J M; Folkerts, Gert; Walther, Frans J

    2014-01-01

    Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2

  7. 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...

  8. 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

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function...... 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...

  9. Circulating angiotensin type II receptor: Possible marker for antibody mediated rejection after renal transplantation?

    Science.gov (United States)

    Kimball, Pamela M; Gupta, Gaurav; McDougan, Felecia

    2017-10-01

    Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR1yr [Gp3]. AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes. Copyright © 2017. Published by Elsevier Inc.

  10. 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....... 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....... 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...

  11. 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...

  12. 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.

  13. 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.

  14. NADPH oxidase 1 deficiency alters caveolin phosphorylation and angiotensin II-receptor localization in vascular smooth muscle.

    Science.gov (United States)

    Basset, Olivier; Deffert, Christine; Foti, Michelangelo; Bedard, Karen; Jaquet, Vincent; Ogier-Denis, Eric; Krause, Karl-Heinz

    2009-10-01

    The superoxide-generating NADPH oxidase NOX1 is thought to be involved in signaling by the angiotensin II-receptor AT1R. However, underlying signaling steps are poorly understood. In this study, we investigated the effect of AngII on aortic smooth muscle from wild-type and NOX1-deficient mice. NOX1-deficient cells showed decreased basal ROS generation and did not produce ROS in response to AngII. Unexpectedly, AngII-dependent Ca(2+) signaling was markedly decreased in NOX1-deficient cells. Immunostaining demonstrated that AT1R was localized on the plasma membrane in wild-type, but intracellularly in NOX1-deficient cells. Immunohistochemistry and immunoblotting showed a decreased expression of AT1R in the aorta of NOX1-deficient mice. To investigate the basis of the abnormal AT1R targeting, we studied caveolin expression and phosphorylation. The amounts of total caveolin and of caveolae were not different in NOX1-deficient mice, but a marked decrease occurred in the phosphorylated form of caveolin. Exogenous H(2)O(2) or transfection of a NOX1 plasmid restored AngII responses in NOX1-deficient cells. Based on these findings, we propose that NOX1-derived reactive oxygen species regulate cell-surface expression of AT1R through mechanisms including caveolin phosphorylation. The lack cell-surface AT1R expression in smooth muscle could be involved in the decreased blood pressure in NOX1-deficient mice.

  15. 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...... afhængige. Skæve agonister, som blokerer G protein signaleringen mens de samtidig aktiverer de G protein uafhængige signaleringsveje er blevet brugt til at beskrive de to hovedgrene i AT1R signaleringen i cellemodelsystemer. Vi påviser at denne farmakologiske differentiering af de to signalveje er relevant...... i primære kardiomyocytter og hele hjerter og endvidere at skæve agonister kan adskille skadelig hypertrofisk vækst fra ønskelig fornyelse af hjertemuskelceller. Deruover har fokus i denne PhD afhandling været på at beskrive de G protein uafhængige effekter af AT1R aktivering vha. den skæve agonist...

  16. A different role of angiotensin II type 1a receptor in the development and hypertrophy of plantaris muscle in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-Ichi; Ogawa, Masahito; Watanabe, Ryo; Isobe, Mitsuaki

    2016-02-01

    The role of angiotensin II type 1 (AT1) receptors in muscle development and hypertrophy remains unclear. This study was designed to reveal the effects that a loss of AT1 receptors has on skeletal muscle development and hypertrophy in mice. Eight-week-old male AT1a receptor knockout (AT1a(-/-)) mice were used for this experiment. The plantaris muscle to body weight ratio, muscle fiber cross-sectional area, and number of muscle fibers of AT1a(-/-) mice was significantly greater than wild type (WT) mice in the non-intervention condition. Next, the functional overload (OL) model was used to induce plantaris muscle hypertrophy by surgically removing the two triceps muscles consisting of the calf, soleus, and gastrocnemius muscles in mice. After 14 days of OL intervention, the plantaris muscle weight, the amount of fiber, and the fiber area increased. However, the magnitude of the increment of plantaris weight was not different between the two strains. Agtr1a mRNA expression did not change after OL in WT muscle. Actually, the Agt mRNA expression level of WT-OL was lower than WT-Control (C) muscle. An atrophy-related gene, atrogin-1 mRNA expression levels of AT1a(-/-)-C, WT-OL, and AT1a(-/-)-OL muscle were lower than that of WT-C muscle. Our findings suggest that AT1 receptor contributes to plantaris muscle development via atrogin-1 in mice.

  17. 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 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.

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

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund

    2010-01-01

    involveret i regulering af genekspression. Alligevel observerer vi at SII Ang II markant potentierer Isoproterenol og den β-adrenerge receptors evne til at inducere transkription, hvilket kan tyde på at G protein uafhængig signalering har en modulatorisk rolle i regulering af genekspression. Studierne der...... uafhængig signalering ikke har en selvstændig inducerende men måske en modulatorisk rolle i regulering af gentranskription....

  19. 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 R(2) increase from 0.10 to 0.70; p R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response. A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus.

  20. Intracellular Angiotensin II and cell growth of vascular smooth muscle cells

    NARCIS (Netherlands)

    Filipeanu, CM; Henning, RH; de Zeeuw, D; Nelemans, A

    1 We recently demonstrated that intracellular application of Angiotensin II (Angiotensin IIintr) induces rat aorta contraction independent of plasma membrane Angiotensin II receptors. In this study we investigated the effects of Angiotensin IIintr on cell growth in A7r5 smooth muscle cells. 2

  1. Role of angiotensin II type 1 receptor antagonists in the treatment of hypertension in patients aged >or=65 years.

    Science.gov (United States)

    Gradman, Alan H

    2009-01-01

    Systolic blood pressure (SBP) increases with age, and hypertension affects approximately two-thirds of adults in the US aged >60 years. Blood pressure (BP) increases as a consequence of age-related structural changes in large arteries, which lead to loss of elasticity and reduced vascular compliance. Increased pulse wave velocity augments SBP, resulting in a high prevalence of isolated systolic hypertension. Because age itself elevates cardiovascular risk, effective treatment of hypertension in an older (aged >or=65 years) patient population prevents many more events per 1000 patients treated than treatment of younger hypertensive patients. Recommendations for treating hypertension are similar in older patients compared with the general population. The Seventh Report of the Joint National Committee on Detection, Prevention, Evaluation, and Treatment of High Blood Pressure recommends target BP goals of hypertension, and treatment goals to include patients with coronary artery disease, other types of vascular disease and heart failure. Randomized clinical trials have demonstrated the efficacy of calcium channel antagonists (calcium channel blockers [CCBs]), low-dose diuretics, ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) in reducing the risk of stroke and other adverse cardiovascular outcomes in older patients; beta-adrenoceptor antagonists are less effective in terms of endpoint reduction. The majority of older patients require two or more drugs to achieve BP goals. Despite active treatment, half of these patients do not achieve target BP, in part because of the reluctance of physicians to intensify treatment, a phenomenon referred to as 'clinical inertia'. ARBs are effective antihypertensive agents in older patients and have been shown to reduce cardiovascular endpoints in patients with hypertension, diabetic nephropathy, cerebrovascular disease and heart failure. ARBs produce additive BP reduction when

  2. Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension.

    Science.gov (United States)

    Banday, Anees A; Lokhandwala, Mustafa F

    2011-03-01

    Oxidative stress modulates angiotensin (Ang) II type 1 receptor (AT(1)R) expression and function. Ang II activates renal Na(+)/H(+) exchanger 3 (NHE3) to increase sodium reabsorption, but the mechanisms are still elusive. In addition, the upregulation of AT(1)R during oxidative stress could promote sodium retention and lead to an increase in blood pressure. Herein, we investigated the mechanism of Ang II-mediated, AT(1)R-dependent renal NHE3 regulation and effect of oxidative stress on AT(1)R signaling and development of hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mmol/L of l-buthionine-sulfoximine, an oxidant, with and without 1 mmol/L of Tempol, an antioxidant, for 3 weeks. l-Buthionine-sulfoximine-treated rats exhibited oxidative stress and high blood pressure. Incubation of renal proximal tubules with Ang II caused significantly higher NHE3 activation in l-buthionine-sulfoximine-treated rats compared with control. The activation of NHE3 was sensitive to AT(1)R blocker and inhibitors of phospholipase C, tyrosine kinase, janus kinase 2 (Jak2), Ca(2+)-dependent calmodulin (CaM), and Ca(2+) chelator. Also, incubation of proximal tubules with Ang II caused Jak2-dependent CaM phosphorylation, which led to Jak2-CaM complex formation and increased Jak2-CaM interaction with NHE3. The activation of these signaling molecules was exaggerated in l-buthionine-sulfoximine-treated rats, whereas Tempol normalized the AT(1)R signaling. In conclusion, Ang II activates renal proximal tubular NHE3 through novel pathways that involve phospholipase C and an increase in intracellular Ca(2+), Jak2, and CaM. In addition, oxidative stress exaggerates Ang II signaling, which leads to overstimulation of renal NHE3 and contributes to an increase in blood pressure.

  3. 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.

  4. 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

  5. Clathrin-dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to COX-2 protein expression in rat aortic vascular smooth muscle cells.

    Science.gov (United States)

    Morinelli, Thomas A; Walker, Linda P; Velez, Juan Carlos Q; Ullian, Michael E

    2015-02-05

    The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT1A receptor activation. Certain effects initiated by AT1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by β-arrestin-dependent receptor internalization and NF-κB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT1A receptor mediates NF-κB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2׳s effects on AT1 receptor/GFP internalization in HEK-293 cells and p65 NF-κB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT1A receptor (44.7% ± 3.1% Control vs. 13.2% ± 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-κB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFα signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through β-arrestin mediated internalization of G protein-coupled receptors, such as AT1A receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. 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 ...

  7. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

    Directory of Open Access Journals (Sweden)

    Pang XF

    2015-11-01

    Full Text Available Xue-Fen Pang,1 Li-Hui Zhang,2 Feng Bai,1 Ning-Ping Wang,3 Ron E Garner,3 Robert J McKallip,4 Zhi-Qing Zhao1,3 1Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Cardiology, Shanxi Academy of Medical Sciences and Shanxi Dayi Hospital, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Department of Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA; 4Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA Abstract: Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II receptors and angiotensin-converting enzyme 2 (ACE2. Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1 receptor was reduced, and the Ang II type 2 (AT2 receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02% vs in the Ang II group (0.7±0.03%, P<0.05. These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was

  8. 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 (AT 1 ) 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.

  9. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

    Directory of Open Access Journals (Sweden)

    Menk M

    2018-05-01

    Full Text Available Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2 receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21 might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9, a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9, and a control group that received mechanical ventilation only (control, n=9. Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6

  10. 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.

  11. 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...

  12. [Effect of tanshinone II A on angiotensin receptor in hypertrophic myocardium of rats with pressure over-loading].

    Science.gov (United States)

    Li, Yong-Sheng; Wang, Zhao-Hua; Wang, Jin

    2008-07-01

    To explore the molecular biological mechanism of tanshinone II A (TSN) in preventing hypertensive left ventricular hypertrophy (HLVH) through studying the effects of TSN on angiotensin receptor (ATR) expression and free calcium ion ([Ca2+]i) in rats with hypertrophic myocardium caused by abdominal aorta constriction. SD rats were established into HLVH model by abdominal aorta constriction operation, they were randomly divided into the model group, the three treated groups treated respectively with intra peritoneal injection of low dose TSN (10 mg/kg) and high dose TSN (20 mg/kg) and gastrogavage of Valsartan (10 mg/kg) once a day 4 weeks after modeling. Besides, 8 sham-operated SD rats were set up as the control group. Eight weeks later, rats' caudal arterial pressure was measured, and their hearts were taken for measuring the left ventricular mass index (LVMI) and myocardial fiber diameter (MFD) by HE stain of the pathological section. Moreover, the mRNA and protein expressions of AT1 and AT2 receptors in the left ventricular tissue were detected by RT-PCR and Western blot, and [Ca2+]i concentration was determined with laser-scanning confocal microscope. (1) The elevated blood pressure in the TSN treated groups, either high or low dose, remained unchanged, significantly higher than that in the control group and the Valsartan treated group (P 0.05). (5) The elevated (Ca2+]i concentration in hypertrophic myocardium after modeling was significantly lowered after treatment in the three treated groups (P TSN treated group was more significant than that in the Valsartan treated group (P TSN on myocardial hypertrophy is blood pressure independent, its mechanism is possibly related with the inhibition on AT1R gene expression and the blocking of free calcium ion influx in cardiac muscle cells. AT2 receptor may participate the effect of Valsartan in lowering blood pressure and reversing myocardial hypertrophy.

  13. Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium.

    Science.gov (United States)

    Terenzi, Riccardo; Manetti, Mirko; Rosa, Irene; Romano, Eloisa; Galluccio, Felice; Guiducci, Serena; Ibba-Manneschi, Lidia; Matucci-Cerinic, Marco

    2017-10-16

    Despite increasing evidence suggesting that angiotensin II type 2 receptor (AT2R) may regulate tissue inflammation, no study has yet analyzed its possible implication in rheumatoid arthritis (RA) synovitis. In this study, we investigated the expression and function of AT2R in synovial tissue and cultured fibroblast-like synoviocytes (FLS) from RA patients. AT2R expression was strongly increased in RA compared with osteoarthritis (OA) synovium, as well as in in cultured RA-FLS respect to OA-FLS and healthy FLS. Treatment with pro-inflammatory cytokines was able not only to boost AT2R expression in RA-FLS and OA-FLS, but also to induce its de novo expression in healthy FLS. The stimulation of AT2R with the specific agonist CGP42112A significantly reduced gene expression of interleukin (IL)-1β and IL-6 and activation of NF-κB in RA-FLS, while opposite effects were elicited by AT2R small interfering RNA. Moreover, AT2R agonism efficiently decreased RA-FLS proliferation and migration either at baseline or under pro-inflammatory cytokine challenge. In conclusion, AT2R is strongly expressed in key effector cells of rheumatoid synovitis, namely RA-FLS, and the activation of AT2R with a specific agonist may effectively dampen their pro-inflammatory and aggressive behavior. AT2R agonism might represent a novel therapeutic strategy for patients with RA.

  14. Two selective HPTLC methods for determination of some angiotensin II receptor antagonists in tablets and biological fluids.

    Science.gov (United States)

    Salah, Gamal A; Abd El-Wadood, Hanaa M; Khairy, Mohamed; Khorshed, Ahmed A

    2017-07-01

    Two simple, selective, precise and highly sensitive high-performance thin-layer chromatography (HPTLC) methods have been developed and validated for analysis of five angiotensin II receptor antagonists, namely losartan, irbesartan valsartan, candesartan and olmesartan, which are widely used in clinical practice. HPTLC of the drugs was performed on pre-coated silica gel HPTLC plates 60 F 254 by development using a mobile phase composed of chloroform-acetone-glacial acetic acid (7.8:1.5:0.7m v/v/v), which was suitable for all of the studied drugs. The first method depended on utilizing reflectance/fluorescence mode for detection while the second method depended on using 2,3,5,6-tetrachloro-1,4-benzoquinone as spraying reagent for the first time to form orange spots scanned at 460 nm. A good linear relationship was obtained over the concentration ranges of 1.2-60 and 360-3000 ng/band while detection and quantification limits were in the ranges of 0.07-0.43, 45.2-140.49 and 0.21-1.29, 137.05-425.74 ng/band for reflectance/fluorescence and reflectance/absorbance methods respectively. The developed methods were applied successfully for their determination in tablets and spiked human plasma for reflectance/fluorescence method with good accuracy and precision, and so can be applied in the pharmacokinetic and bioavailability studies. Copyright © 2016 John Wiley & Sons, Ltd.

  15. 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.

  16. Blockade of AT1 type receptors for angiotensin II prevents cardiac microvascular fibrosis induced by chronic stress in Sprague-Dawley rats.

    Science.gov (United States)

    Firoozmand, Lília Taddeo; Sanches, Andrea; Damaceno-Rodrigues, Nilsa Regina; Perez, Juliana Dinéia; Aragão, Danielle Sanches; Rosa, Rodolfo Mattar; Marcondes, Fernanda Klein; Casarini, Dulce Elena; Caldini, Elia Garcia; Cunha, Tatiana Sousa

    2018-04-20

    To test the effects of chronic-stress on the cardiovascular system, the model of chronic mild unpredictable stress (CMS) has been widely used. The CMS protocol consists of the random, intermittent, and unpredictable exposure of laboratory animals to a variety of stressors, during 3 consecutive weeks. In this study, we tested the hypothesis that exposure to the CMS protocol leads to left ventricle microcirculatory remodeling that can be attenuated by angiotensin II receptor blockade. Male Sprague-Dawley rats were randomly assigned into four groups: Control, Stress, Control + losartan, and Stress + losartan (N = 6, each group, losartan: 20 mg/kg/day). The rats were euthanized 15 days after CMS exposure, and blood samples and left ventricle were collected. Rats submitted to CMS presented increased glycemia, corticosterone, noradrenaline and adrenaline concentration, and losartan reduced the concentration of the circulating amines. Cardiac angiotensin II, measured by high-performance liquid chromatography (HPLC), was significantly increased in the CMS group, and losartan treatment reduced it, while angiotensin 1-7 was significantly higher in the CMS losartan-treated group as compared with CMS. Histological analysis, verified by transmission electron microscopy, showed that rats exposed to CMS presented increased perivascular collagen and losartan effectively prevented the development of this process. Hence, CMS induced a state of microvascular disease, with increased perivascular collagen deposition, that may be the trigger for further development of cardiovascular disease. In this case, CMS fibrosis is associated with increased production of catecholamines and with a disruption of renin-angiotensin system balance, which can be prevented by angiotensin II receptor blockade.

  17. Angiotensin II stimulates renin in inner medullary collecting duct cells via protein kinase C and independent of epithelial sodium channel and mineralocorticoid receptor activity.

    Science.gov (United States)

    Gonzalez, Alexis A; Liu, Liu; Lara, Lucienne S; Seth, Dale M; Navar, L Gabriel; Prieto, Minolfa C

    2011-03-01

    Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of systolic blood pressure. In primary cultures of inner medullary CD cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (Ang II type 1 receptor antagonist) prevented this effect. Aldosterone (10(-10) to 10(-7) mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II-treated cells. However, inhibition of protein kinase C with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, protein kinase C activation with phorbol 12-myristate 13-acetate increased renin expression to the same extent as Ang II. These data indicate that an Ang II type 1 receptor-mediated increase in CD renin is induced directly by Ang II via the protein kinase C pathway and that this regulation is independent of mineralocorticoid receptor activation or epithelial sodium channel activity.

  18. Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation

    DEFF Research Database (Denmark)

    Hezel, M.; Peleli, Maria; Liu, M.

    2016-01-01

    . Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate...... that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve...... glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10–15 mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased...

  19. 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.

  20. Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guinea pigs.

    Science.gov (United States)

    Valdés, Gloria; Schneider, Daniela; Corthorn, Jenny; Ortíz, Rita; Acuña, Stephanie; Padilla, Oslando

    2014-06-04

    The opposing renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are upregulated in pregnancy and localize in the utero-placental unit. To test their participation as counter-regulators, circulating angiotensin II (AII) was exogenously elevated and the bradykinin B2 receptor (B2R) was antagonized in pregnant guinea-pigs. We hypothesized that disrupting the RAS/KKS balance during the period of maximal trophoblast invasion and placental development would provoke increased blood pressure, defective trophoblast invasion and a preeclampsia-like syndrome. Pregnant guinea-pigs received subcutaneous infusions of AII (200 μg/kg/day), the B2R antagonist Bradyzide (BDZ; 62.5 microg/kg/day), or both (AII + BDZ) from gestational day 20 to 34. Non-pregnant cycling animals were included in a control group (C NP) or received AII + BDZ (AII + BDZ NP) during 14 days. Systolic blood pressure was determined during cycle in C NP, and on the last day of infusion, and 6 and 26 days thereafter in the remaining groups. Twenty six days after the infusions blood and urine were extracted, fetuses, placentas and kidneys were weighed, and trophoblast invasion of spiral arteries was defined in the utero-placental units by immunocytochemistry. Systolic blood pressure transiently rose in a subgroup of the pregnant females while receiving AII + BDZ infusion, but not in AII + BDZ NP. Plasma creatinine was higher in AII- and BDZ-treated dams, but no proteinuria or hyperuricemia were observed. Kidney weight increased in AII + BDZ-treated pregnant and non-pregnant females. Aborted and dead fetuses were increased in dams that received AII and AII + BDZ. The fetal/placental weight ratio was reduced in litters of AII + BDZ-treated mothers. All groups that received interventions during pregnancy showed reduced replacement of endothelial cells by extravillous trophoblasts in lateral and myometrial spiral arteries. The acute effects on fetal viability, and the persistently impaired renal

  1. 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.

  2. 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-angiotensin...... system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological...

  3. Novel and validated titrimetric method for determination of selected angiotensin-II-receptor antagonists in pharmaceutical preparations and its comparison with UV spectrophotometric determination

    Directory of Open Access Journals (Sweden)

    Shrikant H. Patil

    2012-12-01

    Full Text Available A novel and simple titrimetric method for determination of commonly used angiotensin-II-receptor antagonists (ARA-IIs is developed and validated. The direct acid base titration of four ARA-IIs, namely eprosartan mesylate, irbesartan, telmisartan and valsartan, was carried out in the mixture of ethanol:water (1:1 as solvent using standardized sodium hydroxide aqueous solution as titrant, either visually using phenolphthalein as an indicator or potentiometrically using combined pH electrode. The method was found to be accurate and precise, having relative standard deviation of less than 2% for all ARA-IIs studied. Also, it was shown that the method could be successfully applied to the assay of commercial pharmaceuticals containing the above-mentioned ARA-IIs. The validity of the method was tested by the recovery studies of standard addition to pharmaceuticals and the results were found to be satisfactory. Results obtained by this method were found to be in good agreement with those obtained by UV spectrophotometric method. For UV spectrophotometric analysis ethanol was used as a solvent and wavelength of 233 nm, 246 nm, 296 nm, and 250 nm was selected for determination of eprosartan mesylate, irbesartan, telmisartan, and valsartan respectively. The proposed titrimetric method is simple, rapid, convenient and sufficiently precise for quality control purposes. Keywords: Angiotensin-II-receptor antagonists, Titrimetric assay, UV spectrophotometry, Validation

  4. Altered renal expression of angiotensin II receptors, renin receptor, and ACE-2 precede the development of renal fibrosis in aging rats.

    Science.gov (United States)

    Schulman, Ivonne Hernandez; Zhou, Ming-Sheng; Treuer, Adriana V; Chadipiralla, Kiranmai; Hare, Joshua M; Raij, Leopoldo

    2010-01-01

    The susceptibility to fibrosis and progression of renal disease is mitigated by inhibition of the renin-angiotensin system (RAS). We hypothesized that activation of the intrarenal RAS predisposes to renal fibrosis in aging. Intrarenal expression of angiotensin II type 1 (AT(1)R), type 2 (AT(2)R), and (pro)renin receptors, ACE and ACE-2, as well as pro- and antioxidant enzymes were measured in 3-month-old (young), 14-month-old (middle-aged), and 24-month-old (old) male Sprague-Dawley rats. Old rats manifested glomerulosclerosis and severe tubulointerstitial fibrosis with increased fibronectin and TGF-β expression (7-fold). AT(1)R /AT(2)R ratios were increased in middle-aged (cortical 1.6-fold, medullary 5-fold) and old rats (cortical 2-fold, medullary 4-fold). Similarly, (pro)renin receptor expression was increased in middle-aged (cortical 2-fold, medullary 3-fold) and old (cortical 5-fold, medullary 3-fold) rats. Cortical ACE was increased (+35%) in old rats, whereas ACE-2 was decreased (-50%) in middle-aged and old rats. NADPH oxidase activity was increased (2-fold), whereas antioxidant capacity and expression of the mitochondrial enzyme manganese superoxide dismutase (cortical -40%, medullary -53%) and medullary endothelial nitric oxide synthase (-48%) were decreased in old rats. Age-related intrarenal activation of the RAS preceded the development of severe renal fibrosis, suggesting that it contributes to the increased susceptibility to renal injury observed in the elderly. Copyright © 2010 S. Karger AG, Basel.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

    and to sudden injury occurring in the circulatory system. Hence, current drugs that block all AT(1) receptor actions most likely leave room for improvement. Recent developments show that two major signaling pathways used by the AT(1) receptor may be dissected by pharmacologic means. Key pathologic responses...... protein actions and simultaneous activation of G protein-dependent or -independent signaling could therefore be desirable in certain situations. The previously unappreciated concept of "functional selectivity" makes this exact strategy feasible and may yield improved drugs for cardiovascular therapy....

  7. 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.

  8. 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.

  9. Differential effects of angiotensin II receptor blocker and losartan/hydrochlorothiazide combination on central blood pressure and augmentation index.

    Science.gov (United States)

    Metoki, Hirohito; Obara, Taku; Asayama, Kei; Satoh, Michihiro; Hosaka, Miki; Elnagar, Noha; Miyawaki, Yoshinori; Kojima, Iwao; Ohkubo, Takayoshi; Imai, Yutaka

    2015-01-01

    Central systolic blood pressure (CSBP) may be a better predictor of cardiovascular risk than clinic brachial (B)SBP. The effects of dose increment from medium dose of angiotensin II receptor blockers (ARBs) to the maximum dose of ARBs (maximum) and changing from medium dose of ARBs to losartan 50 mg/hydrochlorothiazide 12.5 mg combination (combination) were compared in hypertensive patients in whom monotherapy with a medium ARB dose did not achieve goal home SBP (135 mmHg). Four weeks after treatment with a medium ARB dose monotherapy, those whose home SBP level was above 135 mmHg were randomized to receive the maximum ARB dose (n = 101) or the combination (n = 99) once daily for 8 weeks. Both regimens significantly decreased BSBP and CSBP, while a decrease in BSBP and CSBP was greater with combination. The maximum significantly decreased augmentation index (AIx), while the combination did not. The rate of a decrease in reflection to decrease in CSBP was greater in the maximum than in the combination. In the elderly subgroup, the combination more effectively lowered BSBP than the maximum, and only the combination decreased CSBP. However, in the young subgroup, the maximum decreased AIx more than combination, while both regimens lowered CSBP and BSBP to a similar extent. It is explained in part that the maximum may affect pulse wave reflection more predominantly than the combination, especially in young subjects. A weak effect on pulse wave reflection and, thus, on CSBP, of the combination may be overcome by the potent antihypertensive effect of this regimen.

  10. 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.

  11. 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

  12. 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.

  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

    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...

  14. Upregulation of ERK1/2-eNOS via AT2 receptors decreases the contractile response to angiotensin II in resistance mesenteric arteries from obese rats.

    Directory of Open Access Journals (Sweden)

    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.

  15. 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.

  16. Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system.

    Science.gov (United States)

    Peng, Hua; Jensen, Dane D; Li, Wencheng; Sullivan, Michelle N; Buller, Sophie A; Worker, Caleb J; Cooper, Silvana G; Zheng, Shiqi; Earley, Scott; Sigmund, Curt D; Feng, Yumei

    2018-03-01

    Despite advances in antihypertensive therapeutics, at least 15-20% of hypertensive patients have resistant hypertension through mechanisms that remain poorly understood. In this study, we provide a new mechanism for the regulation of blood pressure (BP) in the central nervous system (CNS) by the (pro)renin receptor (PRR), a recently identified component of the renin-angiotensin system that mediates ANG II formation in the CNS. Although PRR also mediates ANG II-independent signaling, the importance of these pathways in BP regulation is unknown. Here, we developed a unique transgenic mouse model overexpressing human PRR (hPRR) specifically in neurons (Syn-hPRR). Intracerebroventricular infusion of human prorenin caused increased BP in Syn-hPRR mice. This BP response was attenuated by a NADPH oxidase (NOX) inhibitor but not by antihypertensive agents that target the renin-angiotensin system. Using a brain-targeted genetic knockdown approach, we found that NOX4 was the key isoform responsible for the prorenin-induced elevation of BP in Syn-hPRR mice. Moreover, inhibition of ERK significantly attenuated the increase in NOX activity and BP induced by human prorenin. Collectively, our findings indicate that an ANG II-independent, PRR-mediated signaling pathway regulates BP in the CNS by a PRR-ERK-NOX4 mechanism. NEW & NOTEWORTHY This study characterizes a new transgenic mouse model with overexpression of the human (pro)renin receptor in neurons and demonstrated a novel angiotensin II-independent mechanism mediated by human prorenin and the (pro)renin receptor in the central regulation of blood pressure.

  17. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity

    Czech Academy of Sciences Publication Activity Database

    Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai, P.; Pravenec, Michal; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W.

    2004-01-01

    Roč. 43, č. 5 (2004), s. 993-1002 ISSN 0194-911X R&D Projects: GA ČR GA301/01/0278; GA MŠk LN00A079 Grant - others:NIH(US) 2R42AR44767-02A2; NIH(US) HL63709; NIH(US) TW01236 Institutional research plan: CEZ:AV0Z5011922 Keywords : receptors * insulin resistance * losartan Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.342, year: 2004

  18. Angiotensin II, tissue factor and the thrombotic paradox of hypertension.

    Science.gov (United States)

    Celi, Alessandro; Cianchetti, Silvana; Dell'Omo, Giulia; Pedrinelli, Roberto

    2010-12-01

    Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

  19. Sex differences in angiotensin II- induced hypertension

    Directory of Open Access Journals (Sweden)

    B. Xue

    2007-05-01

    Full Text Available Sex differences in the development of hypertension and cardiovascular disease have been described in humans and in animal models. In this paper we will review some of our studies which have as their emphasis the examination of the role of sex differences and sex steroids in modulating the central actions of angiotensin II (ANG II via interactions with free radicals and nitric oxide, generating pathways within brain circumventricular organs and in central sympathomodulatory systems. Our studies indicate that low-dose infusions of ANG II result in hypertension in wild-type male mice but not in intact wild-type females. Furthermore, we have demonstrated that ANG II-induced hypertension in males is blocked by central infusions of the androgen receptor antagonist, flutamide, and by central infusions of the superoxide dismutase mimetic, tempol. We have also found that, in comparison to females, males show greater levels of intracellular reactive oxygen species in circumventricular organ neurons following long-term ANG II infusions. In female mice, ovariectomy, central blockade of estrogen receptors or total knockout of estrogen a receptors augments the pressor effects of ANG II. Finally, in females but not in males, central blockade of nitric oxide synthase increases the pressor effects of ANG II. Taken together, these results suggest that sex differences and estrogen and testosterone play important roles in the development of ANG II-induced hypertension.

  20. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

    Directory of Open Access Journals (Sweden)

    Lai CC

    2018-03-01

    Full Text Available Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis and angiotensin receptor blockers (ARBs on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1 of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29 than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21 than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring

  1. Aging and Human Hormonal and Pressor Responsiveness to Angiotensin II Infusion With Simultaneous Measurement of Exogenous and Endogenous Angiotensin II

    OpenAIRE

    Duggan, Joseph; Nussberger, Juerg; Kilfeather, S.; O'Malley, K.

    2017-01-01

    A decline in the function of the renin angiotensin aldosterone system may induce adaptive changes in response to angiotensin II (ANG II) with age. We have examined platelet ANG II receptor density, blood pressure and aldosterone responses to ANG II [Asn1, Val5-ANG II] (Hypertensin, Ciba Geigy, Horsham, Sussex, England) infusion in 8 young, 24 to 30 years, and 8 older, 54 to 65 years, healthy volunteers. To measure circulating ANG II, we established a new method for specific and simultaneous m...

  2. 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...

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    PURPOSE OF REVIEW: 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 FINDINGS: Recent studies that detail the location of AT2R in ...... 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....

  4. Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

    Science.gov (United States)

    Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

    2018-03-01

    We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

  5. The angiotensin II AT1 receptor antagonist irbesartan prevents thromboxane A2-induced vasoconstriction in the rat hind-limb vascular bed in vivo.

    Science.gov (United States)

    Fukuhara, M; Neves, L A; Li, P; Diz, D I; Ferrario, C M; Brosnihan, K B

    2001-03-01

    We studied the vasoconstrictor effects of the thromboxane A2 (TxA2) analogue U46619 in the perfused hind limb of rats under constant flow before and after intravenous injection of irbesartan, an angiotensin II AT1 receptor antagonist, to test whether irbesartan interacts in vivo with the thromboxane A2/prostaglandin endoperoxidase H2 (TxA2/PGH2) receptor. Male Sprague-Dawley rats (n = 15, body weight 350-420 g) were anesthetized with thiobutabarbital sodium (Inactin, 100 mg/kg intraperitoneally). Regional vascular responses to U46619 (0.5 and 1.0 microg) were investigated in the rat hind quarter under conditions of controlled flow before and after administration of irbesartan (10 mg/kg, intravenously). In addition, to test the specificity of the effect of irbesartan on U46619, phenylephrine (0.5, 1.0 microg) and another AT1 receptor antagonist, candesartan CV11974 (0.3 mg/kg, intravenously) were used. The dose-dependent increases in hind-limb perfusion pressure produced by U46619 were significantly attenuated by prior injection of irbesartan, at a dose that blocked the angiotensin II (Ang II) pressor responses. The specificity for the response was shown with the demonstrations that the increase in vascular resistance produced by phenylephrine was unchanged by irbesartan and, furthermore, that the increase in vascular resistance produced by U46619 was unchanged by another AT1 receptor antagonist, candesartan. This study demonstrates that irbesartan interacts at the TxA2/PGH2 receptor in the rat's hind limb in vivo, to modify changes in local regional vascular resistance. The dual antagonistic actions of irbesartan, acting at both AT1 and TxA2 receptors in blood vessels, may overall enhance its therapeutic profile in the treatment of hypertension.

  6. Angiotensin II type 2 receptor signaling affects dopamine levels in the brain and prevents binge eating disorder.

    Science.gov (United States)

    Nakaoka, Hirotomo; Mogi, Masaki; Kan-No, Harumi; Tsukuda, Kana; Ohshima, Kousei; Wang, Xiao-Li; Chisaka, Toshiyuki; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-12-01

    Binge eating disorder (BED) is associated with dopaminergic activation as food reward, resulting in metabolism-related disorders. Stimulation of angiotensin type 2 (AT2) receptor is reported to inhibit dopamine synthesis. We investigated the possible roles of AT2 receptor-mediated dopamine regulation in the pathogenesis of BED. Male C57BL/6 mice, type 2 diabetic (KKAy) mice and AT2 receptor-null (AT2KO) mice at eight weeks old were treated with AT2 receptor agonist, compound 21 (C21) or saline for two weeks. Mice were subjected to fasting for two days followed by re-feeding for seven days. Treatment with C21 attenuated the rebound proportion of body weight, food intake and water intake in KKAy mice, but not in C57BL/6 and AT2KO mice. Dopamine concentration in the striatum was further increased by fasting in KKAy and AT2KO mice. Administration of C21 significantly attenuated this fasting-induced increase in dopamine level only in KKAy mice. Dopamine receptor D1, D2 expression in the substantia nigra were markedly lower in KKAy mice compared with C57BL/6 mice, while administration of C21 increased their expression in KKAy mice. Our study suggests that AT2 receptor stimulation may be a new therapeutic approach to improve eating disorder associated with dopamine resistance. © The Author(s) 2015.

  7. 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.

  8. Association of angiotensin II type 1 receptor antibodies with graft histology, function and survival in paediatric renal transplant recipients.

    Science.gov (United States)

    Fichtner, Alexander; Süsal, Caner; Schröder, Claudia; Höcker, Britta; Rieger, Susanne; Waldherr, Rüdiger; Westhoff, Jens H; Sander, Anja; Dragun, Duska; Tönshoff, Burkhard

    2018-02-12

    We analysed in a carefully phenotyped cohort of paediatric patients the association of serum angiotensin II type 1 receptor antibodies (AT1R-Ab) with specific histological lesions and with graft function and survival in conjunction with overall and complement-binding donor-specific human leucocyte antigen donor-specific antibodies (HLA-DSA). Sera of 62 patients at the time of renal graft biopsy for clinical indication >1 year post-transplant were assessed for AT1R-Ab by enzyme-linked immunosorbent assay (ELISA) and for DSA and C1q-fixing DSA by single-antigen bead technology. Serum AT1R-Ab concentration was significantly higher in antibody-mediated rejection (ABMR) than in T-cell-mediated rejection or control. By receiver operating characteristic (ROC) curve analysis, the optimal AT1R-Ab cut-off value discriminating between patients with features of ABMR and those without was 9.5 U/mL. A total of 6 of 28 patients (21.4%) with ABMR were only positive for AT1R-Ab. Patients with AT1R-Ab and HLA-DSA double positivity had a significantly higher vascular micro-inflammation score than DSA-negative patients. The 5-year graft survival was only 59% in the AT1R-Ab-positive group compared with 87% in the AT1R-Ab-negative group. Patients with AT1R-Ab and HLA-DSA double positivity tended to have a more rapid decline of estimated glomerular filtration rate (eGFR) than patients who were only positive for AT1R-Ab or HLA-DSA. In a multivariate Cox regression model of non-invasive factors, C1q-positive HLA-DSA, eGFR and AT1R-Ab positivity were significantly associated with accelerated graft function decline. Serum AT1R-Ab positivity in the context of an indication biopsy >1 year post-transplant is associated with the histopathology of ABMR and is an independent non-invasive risk factor for adverse graft outcome. © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  9. Evaluation of (131I-anti-angiotensin II type 1 receptor monoclonal antibody as a reporter for hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Pan-Pan Hao

    Full Text Available BACKGROUND: Finding a specific agent is useful for early detection of tumor. Angiotensin II type 1 receptor (AT1R was reported to be elevated in a variety of tumors and participate in tumor progression. The aim of our study was to evaluate whether (131I-anti-AT1R monoclonal antibody (mAb is an efficient imaging reporter for the detection of hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: AT1R mAb or isotype IgG was radioiodinated with (131I and the radiochemical purity and stability of the two imaging agents and the affinity of (131I-anti-AT1R mAb against AT1R were measured. 3.7 MBq (131I-anti-AT1R mAb or isotype (131I-IgG was intravenously injected to mice with hepatocellular carcinoma through tail vein, and then the whole-body autoradiography and biodistribution of the two imaging agents and the pharmacokinetics of (131I-anti-AT1R mAb were studied. (131I-anti-AT1R mAb and (131I-IgG were successfully radioiodinated and both maintained more stable in serum than in saline. The (131I-anti-AT1R mAb group showed much clearer whole-body images for observing hepatocellular carcinoma than the (131I-IgG group. The biodistributions of the two imaging agents suggested that hepatocellular carcinoma tissue uptook more (131I-anti-AT1R mAb than other tissues (%ID/g = 1.82±0.40 and T/NT ratio = 7.67±0.64 at 48 h, whereas hepatocellular carcinoma tissue did not selectively uptake (131I-IgG (%ID/g = 0.42±0.06 and T/NT ratio = 1.33±0.08 at 48 h. The pharmacokinetics of (131I-anti-AT1R mAb was in accordance with the two-compartment model, with a rapid distribution phase and a slow decline phase. These results were further verified by real-time RT-PCR, immunohistochemistry staining and Western blot. CONCLUSIONS/SIGNIFICANCE: (131I-anti-AT1R mAb may be a potential target for early detection of tumor.

  10. 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.

  11. 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

  12. Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation

    NARCIS (Netherlands)

    Smit-van Oosten, A; Navis, G; Stegeman, CA; Joles, JA; Klok, PA; Kuipers, F; Tiebosch, ATMG; van Goor, H

    Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases, This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic

  13. Natriuretic peptide receptor-C activation attenuates angiotensin II-induced enhanced oxidative stress and hyperproliferation of aortic vascular smooth muscle cells.

    Science.gov (United States)

    Madiraju, Padma; Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2018-02-07

    We showed previously that natriuretic peptide receptor-C (NPR-C) agonist, C-ANP 4-23 , attenuated the enhanced expression of Giα proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) through the inhibition of enhanced oxidative stress. Since the enhanced levels of endogenous angiotensin II (Ang II) contribute to the overexpression of Giα proteins and augmented oxidative stress in VSMC from SHR, the present study was undertaken to investigate if C-ANP 4-23 could also attenuate angiotensin II (Ang II)-induced oxidative stress and associated signaling. Ang II treatment of aortic VSMC augmented the levels of superoxide anion (O 2 - ), NADPH oxidase activity, and the expression of NADPH oxidase subunits and C-ANP 4-23 treatment attenuated all these to control levels. In addition, Ang II-induced enhanced levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyl content were also attenuated toward control levels by C-ANP 4-23 treatment. On the other hand, Ang II inhibited the levels of nitric oxide (NO) and augmented the levels of peroxynitrite (OONO - ) in VSMC which were restored to control levels by C-ANP 4-23 treatment. Furthermore, C-ANP 4-23 treatment attenuated Ang II-induced enhanced expression of Giα proteins, phosphorylation of p38, JNK, and ERK 1,2 as well as hyperproliferation of VSMC as determined by DNA synthesis, and metabolic activity. These results indicate that C-ANP 4-23 , via the activation of NPR-C, attenuates Ang II-induced enhanced nitroxidative stress, overexpression of Giα proteins, increased activation of the p38/JNK/ERK 1,2 signaling pathways, and hyperproliferation of VSMC. It may be suggested that C-ANP 4-23 could be used as a therapeutic agent in the treatment of vascular remodeling associated with hypertension and atherosclerosis.

  14. Pharmacoeconomics of angiotensin II antagonists in type 2 diabetic patients with nephropathy - Implications for decision making

    NARCIS (Netherlands)

    Boersma, C; Atthobari, J; Gansevoort, RT; de Jong-Van den Berg, LTW; de Jong, PE; de Zeeuw, D; Annemans, LJP; Postma, MJ

    2006-01-01

    Angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) are a class of antihypertensive drugs that are generally considered comparable to ACE inhibitors in the prevention of heart and kidney failure. However, these two classes of agents do interfere in different stages of the

  15. Excess of Aminopeptidase A in the Brain Elevates Blood Pressure via the Angiotensin II Type 1 and Bradykinin B2 Receptors without Dipsogenic Effect

    Directory of Open Access Journals (Sweden)

    Takuto Nakamura

    2017-01-01

    Full Text Available Aminopeptidase A (APA cleaves angiotensin (Ang II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv APA in a conscious, unrestrained state after pretreatment with (i vehicle, (ii 80 μg of telmisartan, an Ang II type-1 (AT1 receptor blocker, (iii 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg. Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg. In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.

  16. 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.

  17. Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT 2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart.

    Science.gov (United States)

    Zhang, Li-Hui; Pang, Xue-Fen; Bai, Feng; Wang, Ning-Ping; Shah, Ahmed Ijaz; McKallip, Robert J; Li, Xue-Wen; Wang, Xiong; Zhao, Zhi-Qing

    2015-06-01

    The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiotensin (Ang) II-induced cardiac fibrosis. Sprague-Dawley rats were subjected to Ang II (500 ng/kg/min) infusion using osmotic minipumps for 4 weeks. Liraglutide (0.3 mg/kg) was subcutaneously injected twice daily or linagliptin (8 mg/kg) was administered via oral gavage daily during Ang II infusion. Relative to the control, liraglutide, but not linagliptin decreased MAP (124 ± 4 vs. 200 ± 7 mmHg in control, p receptor and up-regulated the AT2 receptor as identified by a reduced AT1/AT2 ratio (0.4 ± 0.02 and 0.7 ± 0.01 vs. 1.4 ± 0.2 in control, p receptor and enhanced AT2 receptor in the myocardium and peri-coronary vessels. Both drugs significantly reduced the populations of macrophages (16 ± 6 and 19 ± 7 vs. 61 ± 29 number/HPF in control, p GLP-1 receptor expression were significantly up-regulated. Along with these modulations, the synthesis of collagen I and tissue fibrosis were inhibited as determined by the smaller collagen-rich area and more viable myocardium. These results demonstrate for the first time that preservation of GLP-1 using liraglutide or linagliptin is effective in inhibiting Ang II-induced cardiac fibrosis, suggesting that these drugs could be selected as an adjunctive therapy to improve clinical outcomes in the fibrosis-derived heart failure patients with or without diabetes.

  18. Amlodipine versus angiotensin II receptor blocker; control of blood pressure evaluation trial in diabetics (ADVANCED-J

    Directory of Open Access Journals (Sweden)

    Ikeda Shunya

    2006-10-01

    Full Text Available Abstract Background The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist. Methods/Design Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included. Discussion We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of

  19. Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats.

    Science.gov (United States)

    Gonzalez, Alexis A; Lara, Lucienne S; Luffman, Christina; Seth, Dale M; Prieto, Minolfa C

    2011-04-01

    Renin synthesis and secretion by principal cells of the collecting duct are enhanced in angiotensin (Ang) II-dependent hypertension. The presence of renin/(pro)renin and its receptor, the (pro)renin receptor ([P]RR), in the collecting duct may provide a pathway for Ang I generation with further conversion to Ang II. To assess whether (P)RR activation occurs during Ang II-dependent hypertension, we examined renal (P)RR levels and soluble (P)RR excretion in the urine of chronic Ang II-infused rats (80 ng/min; for 2 weeks; n=10) and sham-operated rats (n=10). Systolic blood pressure and Ang II levels in the plasma and kidney were increased whereas plasma renin activity was suppressed in Ang II-infused rats. Renal (P)RR transcripts were upregulated in the cortex and medulla of Ang II-infused rats. (P)RR immunoreactivity in collecting duct cells and the protein levels of the full-length form (37-kDa band) were significantly decreased in the medulla of Ang II-infused rats. The soluble (P)RR (28-kDa band) was detected in the renal medulla and urine samples of Ang II-infused rats, which also showed increases in urinary renin content. To determine whether the soluble (P)RR could stimulate Ang I formation, urine samples were incubated with recombinant human (pro)renin. Urine samples of Ang II-infused rats exhibited increased Ang I formation compared with sham-operated rats. Thus, in chronic Ang II-infused rats, the catalytic activity of the augmented renin produced in the collecting duct may be enhanced by the intraluminal soluble (P)RR and cell-surface located (P)RR, thus contributing to enhanced intratubular Ang II formation.

  20. Angiotensin II and Renal Tubular Ion Transport

    Directory of Open Access Journals (Sweden)

    Patricia Valles

    2005-01-01

    Evidence for the regulation of H+-ATPase activity in vivo and in vitro by trafficking/exocytosis has been provided. An additional level of H+-ATPase regulation via protein synthesis may be important as well. Recently, we have shown that both aldosterone and angiotensin II provide such a mechanism of regulation in vivo at the level of the medullary collecting tubule. Interestingly, in this part of the nephron, the effects of aldosterone and angiotensin II are not sodium dependent, whereas in the cortical collecting duct, both aldosterone and angiotensin II, by contrast, affect H+ secretion by sodium-dependent mechanisms.

  1. 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...

  2. 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.

  3. Strain differences in angiotensin-converting enzyme and angiotensin II type I receptor expression. Possible implications for experimental chronic renal transplant failure

    NARCIS (Netherlands)

    Smit-van Oosten, A; Henning, RH; van Goor, H

    Background The Fisher to Lewis (F-L) model of renal transplantation (Rtx) is widely used. Rtx from F to L without immunosuppressive treatment results in 50% survival, whereas L to F results in survival rates similar to syngrafts. When treated with an angiotensin-converting enzyme (ACE) inhibitor or

  4. Hyperinsulinemic rats are normotensive but sensitized to angiotensin II

    DEFF Research Database (Denmark)

    Johansson, Maria E; Andersson, Irene J; Alexanderson, Camilla

    2008-01-01

    rats received insulin (2 IU/day, INS, n=12) or insulin combined with losartan (30 mg/kg/day, INS-LOS, n=10), the angiotensin II receptor antagonist, for six weeks. Losartan-treated (LOS, n=10) and untreated rats served as controls (C, n=11). We used telemetry to measure BP and heart rate (HR...

  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. Insight into the structural requirement of substituted quinazolinone biphenyl acylsulfonamides derivatives as Angiotensin II AT1 receptor antagonist: 2D and 3D QSAR approach

    Directory of Open Access Journals (Sweden)

    Mukesh C. Sharma

    2014-01-01

    Full Text Available A series of 19 molecules substituted quinazolinone biphenyl acylsulfonamides derivatives displaying variable inhibition of Angiotensin II receptor AT1 activity were selected to develop models for establishing 2D and 3D QSAR. The compounds in the selected series were characterized by spatial, molecular and electro topological descriptors using QSAR module of Molecular Design Suite (VLife MDS™ 3.5. The best 2D QSAR model was selected, having correlation coefficient r2 (0.8056 and cross validated squared correlation coefficient q2 (0.6742 with external predictive ability of pred_r2 0.7583 coefficient of correlation of predicted data set (pred_r2se 0.2165. The results obtained from QSAR studies could be used in designing better Ang II activity among the congeners in future. The optimum QSAR model showed that the parameters SsssCHE index, SddCE-index, T_2_Cl_4, and SssNHE-index contributed in the model. 3D QSAR analysis by kNN-molecular field analysis approach developed based on principles of the k-nearest neighbor method combined with Genetic algorithms, stepwise forward variable selection approach; a leave-one-out cross-validated correlation coefficient (q2 of 0.6516 and a non-cross-validated correlation coefficient (r2 of 0.8316 and pred_r2 0.6954 were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic field effects dominantly determine binding affinities. The information rendered by 3D QSAR models may lead to a better understanding of structural requirements of Angiotensin II receptor and can help in the design of novel potent antihypertensive molecules.

  7. The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: A concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Durdagi, S.; Spyridaki, K.; Tůmová, Tereza; Slaninová, Jiřina; Giannopoulos, P.; Vlahakos, D.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

    2012-01-01

    Roč. 55, Sep (2012), s. 358-374 ISSN 0223-5234 Institutional research plan: CEZ:AV0Z40550506 Keywords : synthesis * angiotensin II receptor blockers * N-substituted 5-butylimidazole derivatives * antihypertensive activity * molecular docking Subject RIV: CC - Organic Chemistry Impact factor: 3.499, year: 2012

  8. 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.

  9. Angiotensin II during Experimentally Simulated Central Hypovolemia

    DEFF Research Database (Denmark)

    Jensen, Theo Walther; Olsen, Niels Vidiendal

    2016-01-01

    of angiotensin II during episodes of central hypovolemia. To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of Pub......Med/MEDLINE for studies that measured variables of the renin-angiotensin system or its effect during simulated hypovolemia. Twelve articles, using one of the three models, were included and showed a possible organ-protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results...... of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies, investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role...

  10. Activation of CB1receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries.

    Science.gov (United States)

    Karpińska, Olga; Baranowska-Kuczko, Marta; Kloza, Monika; Ambroz Ewicz, Ewa; Kozłowski, Tomasz; Kasacka, Irena; Malinowska, Barbara; Kozłowska, Hanna

    2017-06-01

    Recent evidence suggests that endocannabinoids acting via cannabinoid CB 1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A 2 analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct G q/11 protein-coupled receptors (thromboxane, ANG II type 1, 5-HT 2 , and α 1 -adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB 1 receptor antagonist AM251 (1 μM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 μM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 μM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 μM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration-dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB 1 receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB 1 receptor-dependent and/or CB 1 receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction. Copyright © 2017 the American Physiological

  11. 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.

  12. The renin-angiotensin system and vascular function. The role of angiotensin II, angiotensin-converting enzyme, and alternative conversion of angiotensin I

    NARCIS (Netherlands)

    Roks, A.; Buikema, H.; Pinto, Y. M.; van Gilst, W. H.

    1997-01-01

    The renin-angiotensin system has been implicated in vascular function and disease. Angiotensin-converting enzyme and angiotensin II are believed to be the most important components. However, alternative factors, such as angiotensin-I/II-(1-7) and chymase, have also been shown to be of significance

  13. 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.

  14. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker

    International Nuclear Information System (INIS)

    Sonta, Toshiyo; Inoguchi, Toyoshi; Matsumoto, Shingo; Yasukawa, Keiji; Inuo, Mieko; Tsubouchi, Hirotaka; Sonoda, Noriyuki; Kobayashi, Kunihisa; Utsumi, Hideo; Nawata, Hajime

    2005-01-01

    This study was undertaken to evaluate oxidative stress in the kidney of diabetic mice by electron spin resonance (ESR) imaging technique. Oxidative stress in the kidney was evaluated as organ-specific reducing activity with the signal decay rates of carbamoyl-PROXYL probe using ESR imaging. The signal decay rates were significantly faster in corresponding image pixels of the kidneys of streptozotocin-induced diabetic mice than in those of controls. This technique further demonstrated that administration of angiotensin II type 1 receptor blocker (ARB), olmesartan (5 mg/kg), completely restored the signal decay rates in the diabetic kidneys to control values. In conclusion, this study provided for the first time the in vivo evidence for increased oxidative stress in the kidneys of diabetic mice and its normalization by ARB as evaluated by ESR imaging. This technique would be useful as a means of further elucidating the role of oxidative stress in diabetic nephropathy

  15. 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.

  16. A PROSPECTIVE STUDY OF EFFECT OF TELMISARTAN (ANGIOTENSIN II RECEPTOR BLOCKER ON METABOLIC PARAMETERS IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    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.

  17. Calcium channel blocker enhances beneficial effects of an angiotensin II AT1 receptor blocker against cerebrovascular-renal injury in type 2 diabetic mice.

    Directory of Open Access Journals (Sweden)

    Kazi Rafiq

    Full Text Available Recent clinical trials have demonstrated that combination therapy with renin-angiotensin system inhibitors plus calcium channel blockers (CCBs elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-A(y mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day reduced blood pressure in saline-drinking KK-A(y mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes.

  18. Angiotensin II receptor type 1 blockade decreases CTGF/CCN2-mediated damage and fibrosis in normal and dystrophic skeletal muscles.

    Science.gov (United States)

    Cabello-Verrugio, Claudio; Morales, María Gabriela; Cabrera, Daniel; Vio, Carlos P; Brandan, Enrique

    2012-04-01

    Connective tissue growth factor (CTGF/CCN-2) is mainly involved in the induction of extracellular matrix (ECM) proteins. The levels of CTGF correlate with the degree and severity of fibrosis in many tissues, including dystrophic skeletal muscle. The CTGF overexpression in tibialis anterior skeletal muscle using an adenoviral vector reproduced many of the features observed in dystrophic muscles including muscle damage and regeneration, fibrotic response and decrease in the skeletal muscle strength. The renin-angiotensin system is involved in the genesis and progression of fibrotic diseases through its main fibrotic components angiotensin-II and its transducer receptor AT-1. The use of AT-1 receptor blockers (ARB) has been shown to decrease fibrosis. In this paper, we show the effect of AT-1 receptor blockade on CTGF-dependent biological activity in skeletal muscle cells as well as the response to CTGF overexpression in normal skeletal muscle. Our results show that in myoblasts ARB decreased CTGF-mediated increase of ECM protein levels, extracellular signal regulated kinases 1/2 (ERK-1/2) phosphorylation and stress fibres formation. In tibialis anterior muscle overexpressing CTGF using an adenovirus, ARB treatment decreased CTGF-mediated increase of ECM molecules, α-SMA and ERK-1/2 phosphorylation levels. Quite remarkable, ARB was able to prevent the loss of contractile force of tibialis anterior muscles overexpressing CTGF. Finally, we show that ARB decreased the levels of fibrotic proteins, CTGF and ERK-1/2 phosphorylation augmented in a dystrophic skeletal muscle from mdx mice. We propose that ARB is a novel pharmacological tool that can be used to decrease the fibrosis induced by CTGF in skeletal muscle associated with muscular dystrophies. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  19. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    Science.gov (United States)

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL

  20. Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension.

    Science.gov (United States)

    Rincón, J; Correia, D; Arcaya, J L; Finol, E; Fernández, A; Pérez, M; Yaguas, K; Talavera, E; Chávez, M; Summer, R; Romero, F

    2015-03-01

    Activation of the renin-angiotensin system (RAS), renal oxidative stress and inflammation are constantly present in experimental hypertension. Nitric oxide (NO) inhibition with N(w)-nitro-L-arginine methyl ester (L-NAME) has previously been reported to produce hypertension, increased expression of Angiotensin II (Ang II) and renal dysfunction. The use of Losartan, an Ang II type 1 receptor (AT1R) antagonist has proven to be effective reducing hypertension and renal damage; however, the mechanism by which AT1R blockade reduced kidney injury and normalizes blood pressure in this experimental model is still complete unknown. The current study was designed to test the hypothesis that AT1R activation promotes renal NAD(P)H oxidase up-regulation, oxidative stress and cytokine production during L-NAME induced-hypertension. Male Sprague-Dawley rats were distributed in three groups: L-NAME, receiving 70 mg/100ml of L-NAME, L-NAME+Los, receiving 70 mg/100ml of L-NAME and 40 mg/kg/day of Losartan; and Controls, receiving water instead of L-NAME or L-NAME and Losartan. After two weeks, L-NAME induced high blood pressure, renal overexpression of AT1R, NAD(P)H oxidase sub-units gp91, p22 and p47, increased levels of oxidative stress, interleukin-6 (IL-6) and interleukin-17 (IL-17). Also, we found increased renal accumulation of lymphocytes and macrophages. Losartan treatment abolished the renal expression of gp91, p22, p47, oxidative stress and reduced NF-κB activation and IL-6 expression. These findings indicate that NO induced-hypertension is associated with up-regulation of NADPH oxidase, oxidative stress production and overexpression of key inflammatory mediators. These events are associated with up-regulation of AT1R, as evidenced by their reversal with AT1R blocker treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. 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

  2. Angiotensin II–Induced MMP-2 Activity and MMP-14 and Basigin Protein Expression Are Mediated via the Angiotensin II Receptor Type 1–Mitogen-Activated Protein Kinase 1 Pathway in Retinal Pigment Epithelium

    Science.gov (United States)

    Pons, Marianne; Cousins, Scott W.; Alcazar, Oscar; Striker, Gary E.; Marin-Castaño, Maria E.

    2011-01-01

    Accumulation of various lipid-rich extracellular matrix (ECM) deposits under the retinal pigment epithelium (RPE) has been observed in eyes with age-related macular degeneration (AMD). RPE-derived matrix metalloproteinase (MMP)-2, MMP-14, and basigin (BSG) are major enzymes involved in the maintenance of ECM turnover. Hypertension (HTN) is a systemic risk factor for AMD. It has previously been reported that angiotensin II (Ang II), one of the most important hormones associated with HTN, increases MMP-2 activity and its key regulator, MMP-14, in RPE, inducing breakdown of the RPE basement membrane, which may lead to progression of sub-RPE deposits. Ang II exerts most of its actions by activating the mitogen-activated protein kinase (MAPK) signaling pathway. Herein is explored the MAPK signaling pathway as a potential key intracellular modulator of Ang II–induced increase in MMP-2 activity and MMP-14 and BSG protein expression. It was observed that Ang II stimulates phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in RPE cells and ERK/p38 and Jun N-terminal kinase (JNK) in mice. These effects were mediated by Ang II type 1 receptors. Blockade of ERK or p38 MAPK abrogated the increase in MMP-2 activity and MMP-14 and BSG proteins in ARPE-19 cells. A better understanding of the molecular events by which Ang II induces ECM dysregulation is of critical importance to further define its contribution to the progression of sub-RPE deposits in AMD patients with HTN. PMID:21641389

  3. Double blockade of angiotensin II (AT(1) )-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats.

    Science.gov (United States)

    Miesel, Anja; Müller-Fielitz, Helge; Jöhren, Olaf; Vogt, Florian M; Raasch, Walter

    2012-04-01

    Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT(1) ) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects. Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT(1) blocker telmisartan (8 mg·kg(bw) (-1) ·day(-1) ), the ACE inhibitor ramipril (4 mg·kg(bw) (-1) ·day(-1) ) or a combination of the two (8 + 4 mg·kg(bw) (-1) ·day(-1) ) for 12 weeks. Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril. The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT(1) receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  4. 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.

  5. 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

    is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta...

  6. 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.

  7. Angiotensin Receptors, Autoimmunity, and Preeclampsia1

    OpenAIRE

    Xia, Yang; Zhou, Cissy Chenyi; Ramin, Susan M.; Kellems, Rodney E.

    2007-01-01

    Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contri...

  8. Proximal tubule-dominant transfer of AT1a receptors induces blood pressure responses to intracellular angiotensin II in AT1a receptor-deficient mice

    Science.gov (United States)

    Li, Xiao C.

    2013-01-01

    The role of intracellular ANG II in proximal tubules of the kidney remains poorly understood. We tested the hypothesis that proximal tubule-dominant transfer of AT1a receptors in the cortex mediates intracellular ANG II-induced blood pressure responses in AT1a receptor-deficient (Agtr1a-/-) mice. A GFP-tagged AT1a receptor, AT1aR/GFP, and an enhanced cyan fluorescent intracellular ANG II fusion protein, ECFP/ANG II, were expressed in proximal tubules of Agtr1a-/- mouse kidneys via the adenoviral transfer using a sodium and glucose cotransporter 2 promoter. Transfer of AT1aR/GFP alone or with ECFP/ANG II induced proximal tubule-dominant expression of AT1aR/GFP and/or ECFP/ANG II with a peak response at 2 wk. No significant AT1aR/GFP and/or ECFP/ANG II expression was observed in the glomeruli, medulla, or extrarenal tissues. Transfer of AT1aR/GFP alone, but not ECFP/ANG II, increased systolic blood pressure by 12 ± 2 mmHg by day 14 (n = 9, P tubule-dominant transfer of AT1aR/GFP alone (P tubules (P tubules had no effect on all indices. These results suggest that AT1a receptors and intracellular ANG II in proximal tubules of the kidney play an important physiological role in blood pressure regulation. PMID:23427083

  9. Calcium signaling induced by angiotensin II in the pancreatic acinar cell line AR42J.

    Science.gov (United States)

    Barnhart, D C; Sarosi, G A; Romanchuk, G; Mulholland, M W

    1999-03-01

    The purpose of this study was to characterize the nature and mechanisms of angiotensin II-evoked calcium signaling in AR42J cells. Cytosolic calcium concentrations were determined using fura-2-based microfluorimetry. Angiotensin II causes elevations in free cytosolic calcium ([Ca2+]i) in the rat pancreatic acinar cell line AR42J. The mechanisms of angiotensin II-evoked calcium signaling were examined using fura-2-based fluorescent digital microscopy. Angiotensin II caused dose-dependent increments in [Ca2+]i over a concentration range of 0.1-1,000 nM, with an average increment of 243 +/- 16 nM at an angiotensin II concentration of 1,000 nM. Dup753, an AT1-specific antagonist, inhibited angiotensin II-evoked signaling, whereas the AT2 antagonist PD123,319 had no effect. Preincubation with the phospholipase C inhibitor U73122 reduced the response in [Ca2+]i to 25% of that of the control. Thapsigargin abolished angiotensin II-evoked calcium signaling. The inositol 1,4,5-trisphosphate receptor antagonist heparin introduced by radiofrequency electroporation inhibited responses to 46 +/- 6% of controls. Angiotensin II-evoked signals were reduced in magnitude and duration by elimination of Ca2+ from the extracellular buffer. Preincubation with pertussis toxin (100 ng/ml) had no effect. Angiotensin II did not stimulate cyclic AMP or suppress vasoactive intestinal peptide stimulated cyclic AMP production over the concentration range that caused Ca2+ signaling.

  10. Treatment of angiotensin receptor blocker-induced angioedema: A case series.

    Science.gov (United States)

    Strassen, Ulrich; Bas, Murat; Hoffmann, Thomas K; Knopf, Andreas; Greve, Jens

    2015-07-01

    Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist. We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n = 3) or prednisolone-21-hydrogen succinate/clemastine (n = 5). Both patient groups were compared with an untreated patient cohort (n = 3). All patients were previously diagnosed with essential hypertonia. Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema. Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker-induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  11. Sex differences in angiotensin II-stimulated fluid intake.

    Science.gov (United States)

    Santollo, Jessica

    2017-11-01

    What is the topic of this review? This report describes sex differences in the responses to angiotensin II, with a focus on fluid intake. What advances does it highlight? There are conflicting reports on the direction of the sex difference in fluid intake in response to angiotensin II. This review highlights how accounting for differences in body weight contributes to the discrepancies in the literature. In certain conditions, body weight influences fluid intake in a sex-specific manner. This review also highlights the divergent effects of oestrogen receptor activation on fluid intake, which are likely to underlie the discussed sex differences. Sex has a clear effect on the renin-angiotensin-aldosterone system. Although sex differences in the pressor response to angiotensin II (Ang II) are well established, understanding of the sex differences in the fluid intake response to Ang II is clouded by conflicting reports. Here, I suggest that accounting for differences in body weight contributes to the discrepancies in the literature. Our recent findings demonstrate that body weight influences Ang II-stimulated water intake in certain conditions in male, but not in female rats. When differences in body weight are corrected for in the appropriate circumstances, we found that males consume more water in response to Ang II compared with females. Males and females also show differences in drinking microstructure, i.e. bottle spout lick patterns, which provide clues into the mechanism(s) underlying this sex difference. Oestrogens, which inhibit Ang II-stimulated fluid intake and circulate at higher concentrations in females, are likely to contribute to this sex difference. This review also discusses the diversity in oestrogen signalling via multiple oestrogen receptor subtypes, which selectively inhibit Ang II-stimulated fluid intake. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

  12. beta-Endorphin release by angiotensin II: studies on the mechanism of action.

    Science.gov (United States)

    Anhut, H; Knepel, W; Holland, A; Meyer, D K

    1982-07-01

    Blood-borne angiotensin II induces release of beta-endorphin-like immunoreactivity (beta-EI) from rat anterior pituitary gland. To study the mechanism of action we investigated in rats the effect of transection of subfornical organ efferent projections on angiotensin-induced beta-EI release in vivo and also the direct action of angiotensin II on beta-EI release from isolated adenohypophyses in vitro. (i) No effect of transection of subfornical organ efferents on the increase in plasma beta-EI following intravenous infusions of angiotensin II was found. (ii) When anterior pituitary quarters were continuously superfused in vitro, angiotensin II (1-10 nM) caused release of beta-EI into the superfusion medium in a dose-dependent manner. The stimulatory effect of angiotensin II (3 nM) was blocked by the receptor antagonist saralasin (300 nM). We conclude that beta-endorphin release by blood-borne angiotensin II, in contrast to other central effects of angiotensin, is not mediated by the subfornical organ; instead a direct action of angiotensin II on the adenohypophysis could be a mechanism of action responsible.

  13. Recruitment of macrophages from the spleen contributes to myocardial fibrosis and hypertension induced by angiotensin II

    Directory of Open Access Journals (Sweden)

    Ning-Ping Wang

    2017-05-01

    Full Text Available Introduction: The purpose of this study was to determine whether macrophages migrated from the spleen are associated with angiotensin II-induced cardiac fibrosis and hypertension. Methods: Sprague-Dawley rats were subjected to angiotensin II infusion in vehicle (500 ng/kg/min for up to four weeks. In splenectomy, the spleen was removed before angiotensin II infusion. In the angiotensin II AT1 receptor blockade, telmisartan was administered by gastric gavage (10 mg/kg/day during angiotensin II infusion. The heart and aorta were isolated for Western blot analysis and immunohistochemistry. Results: Angiotensin II infusion caused a significant reduction in the number of monocytes in the spleen through the AT1 receptor-activated monocyte chemoattractant protein-1. Comparison of angiotensin II infusion, splenectomy and telmisartan comparatively reduced the recruitment of macrophages into the heart. Associated with this change, transforming growth factor β1 expression and myofibroblast proliferation were inhibited, and Smad2/3 and collagen I/III were downregulated. Furthermore, interstitial/perivascular fibrosis was attenuated. These modifications occurred in coincidence with reduced blood pressure. At week 4, invasion of macrophages and myofibroblasts in the thoracic aorta was attenuated and expression of endothelial nitric oxide synthase was upregulated, along with a reduction in aortic fibrosis. Conclusions: These results suggest that macrophages when recruited into the heart and aorta from the spleen potentially contribute to angiotensin II-induced cardiac fibrosis and hypertension.

  14. The Prognostic Role of Angiotensin II Type 1 Receptor Autoantibody in Non-Gravid Hypertension and Pre-eclampsia: A Meta-analysis and Our Studies.

    Science.gov (United States)

    Lei, Jinghui; Li, Yafeng; Zhang, Suli; Wu, Ye; Wang, Pengli; Liu, Huirong

    2016-04-01

    Angiotensin II type 1 receptor autoantibody (AT1-AA) is found in patients with non-gravid hypertension or pre-eclampsia, but the relationship is uncertain.The aim of the present study was to assess the association between AT1-AA and high blood pressure using meta-analysis, and to evaluate the prognosis value of AT1-AA for hypertensive diseases.Literature search from PubMed, Embase, and Cochrane databases were conducted using keywords "hypertension" or "pre-eclampsia," "angiotensin II receptor type 1 autoantibody," and its aliases from April 1999 to December 2015.Studies evaluating the association between AT1-AA and non-gravid hypertension or pre-eclampsia were included in this analysis. The quality of the eligible studies was assessed based on the Newcastle-Ottawa Scale with some modifications.Two researchers then independently reviewed all included studies and extracted all relevant data. Association between AT1-AA and hypertension was tested with pooled odds ratios (ORs) and 95% confidence intervals (CIs). Finally, we evaluated whether AT1-AA predicted the prognosis of hypertension by using a summary receiver-operating characteristic (ROC) curve and sensitivity analysis.Ten studies were finally included in this meta-analysis. AT1-AA showed more significant association with pre-eclampsia than that with non-gravid hypertension (pooled OR 32.84, 95% CI 17.19-62.74; and pooled OR 4.18, 95% CI 2.20-7.98, respectively). Heterogeneity among studies was also detected probably due to different hypertensive subtypes and AT1-AA measuring methods. Area under summary ROC curve (AUC) of pre-eclampsia was 0.92 (sensitivity 0.76; specificity 0.86). Area under the ROC curve of overall hypertensive diseases or non-gravid hypertension was lower than that of pre-eclampsia (0.86 and 0.72, respectively) with lower sensitivities (0.46 and 0.26, respectively).The major limitation of this analysis was the publication bias due to lack of unpublished data and the language limitation during

  15. A Concise Synthesis, Docking Studies and Biological Evaluation of N-substituted 5-Butylimidazole Analogues as Potent Angiotensin II Receptor Blockers

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Durdagi, B.; Tůmová, Tereza; Slaninová, Jiřina; Giannopoulos, P.; Spyridaki, K.; Liapakis, G.; Vlahakos, D.; Mavromoustakos, T.; Matsoukas, J.

    2012-01-01

    Roč. 18, S1 (2012), S116-S116 ISSN 1075-2617. [European Peptide Symposium /32./. 02.09.2012-07.09.2012, Athens] Institutional research plan: CEZ:AV0Z40550506 Keywords : angiotensin II * rat uterotonic test * antagonists Subject RIV: CE - Biochemistry

  16. Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system

    DEFF Research Database (Denmark)

    Füchtbauer, L; Groth-Rasmussen, Maria; Holm, Thomas Hellesøe

    2011-01-01

    in the dentate gyrus following axonal transection was totally abrogated in GFAP-IκBα-dn mice. Whereas angiotensin II was upregulated in microglia and astrocytes in the dentate gyrus post-lesion, AT1 was exclusively expressed on astrocytes. Blocking AT1 with Candesartan led to significant increase in numbers...

  17. Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients

    Science.gov (United States)

    Kusumawati, Widya; Keman, Kusnarman; Soeharto, Setyawati

    2016-01-01

    This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclamptic patients (PP), and endothelial cells exposed to PP in the presence of ethanolic extract of Punica granatum (PP + PG) at the following three doses: 14; 28; and 56 ppm. The expression of AT1-R was observed by immunohistochemistry technique, and thromboxane B2 level was done by immunoassay technique. Plasma from PP significantly increased AT1-R expression and thromboxane B2 levels compared to cells treated by normal pregnancy plasma. The increasing of AT1-R expression significantly (P Punica granatum extract. Moreover, the increasing of thromboxane B2 levels significantly (P Punica granatum extract. We further concluded that Punica granatum fruit protects and inhibits the sensitivity of endothelial cells to plasma from preeclamptic patients due to inhibition of AT1-R expression (56 ppm) and reduced thromboxane B2 levels (14 ppm). PMID:26989513

  18. Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat

    Directory of Open Access Journals (Sweden)

    Kawaratani Hideto

    2009-05-01

    Full Text Available Abstract Background Apart from simple steatosis, the non-alcoholic steatohepatitis (NASH can progress into liver fibrosis and cirrhosis. To date, however, no widely accepted therapeutic modalities have been established against NASH in the clinical practice. To find out promising new therapeutic agents, it is important to employ an appropriate experimental model of NASH, such as association with insulin resistance. Findings In the current study, we found that losartan, a clinically used angiotensin-II type 1 receptor blocker, significantly attenuated a choline-deficient L-amino acid-defined (CDAA diet-induced steatohepatitis in obese diabetic- and insulin resistance-associated Otsuka Long-Evans Tokushima Fatty (OLETF rats. The transforming growth factor-beta, a well-known major fibrogenic cytokine, was also suppressed in a similar magnitude to that of the fibrosis area. Noteworthy was the finding that these inhibitory effects were achieved even at a clinically comparable low dose. Conclusion Since losartan is widely used without serious side effects in the clinical practice, this agent may be an effective new therapeutic strategy against NASH.

  19. Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor.

    Science.gov (United States)

    Mai, Huynh Nhu; Chung, Yoon Hee; Shin, Eun-Joo; Kim, Dae-Joong; Jeong, Ji Hoon; Nguyen, Thuy-Ty Lan; Nam, Yunsung; Lee, Yu Jeung; Nah, Seung-Yeol; Yu, Dae-Yeul; Jang, Choon-Gon; Ho, Ye-Shih; Lei, Xin Gen; Kim, Hyoung-Chun

    2016-01-01

    We investigated the possible roles of angiotensin II type 1 receptor (AT1R) and oxidative stress responsive nuclear factor κB (NFκB) in renal damage caused by multiple doses of cocaine in glutathione peroxidase (GPx)-1 gene-depleted mice. Treatment with cocaine resulted in significant increases in malondialdehyde, protein carbonyl, and pro-apoptotic Bax expression and decreases in the ratio of glutathione (GSH) and its oxidized form (GSSG), GSH-dependent enzymes, and anti-apoptotic factors in the kidney. These alterations were more pronounced in GPx-1 knockout (-/-) mice than in wild type (WT) mice. Notably, the AT1R antagonist losartan protected against the renal toxicity induced by cocaine, whereas the NFκB inhibitor pyrrolidine dithiocarbamate was not protective. The toxicity was more pronounced in GPx-1 (-/-) mice than in WT mice. The protective effect afforded by losartan against cocaine toxicity appeared to be more sensitive in GPx-1 (-/-) mice than that in WT mice. These losartan-mediated protective effects were inhibited by the phosphatidyl-inositol-3-kinase (PI3K) inhibitor LY294002, indicating that losartan provides significant protection from cocaine-induced renal toxicity through PI3K/Akt signaling. Our results suggest that genetic inhibition of GPx-1 potentiates cocaine-induced renal damage via activation of AT1R by inhibition of PI3K-Akt signaling, and that AT1R can be a therapeutic target against renal toxicity induced by cocaine.

  20. A Structure-Activity Relationship Study of Imidazole-5-Carboxylic Acid Derivatives as Angiotensin II Receptor Antagonists Combining 2D and 3D QSAR Methods.

    Science.gov (United States)

    Sharma, Mukesh C

    2016-03-01

    Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies were performed for correlating the chemical composition of imidazole-5-carboxylic acid analogs and their angiotensin II [Formula: see text] receptor antagonist activity using partial least squares and k-nearest neighbor, respectively. For comparing the three different feature selection methods of 2D-QSAR, k-nearest neighbor models were used in conjunction with simulated annealing (SA), genetic algorithm and stepwise coupled with partial least square (PLS) showed variation in biological activity. The statistically significant best 2D-QSAR model having good predictive ability with statistical values of [Formula: see text] and [Formula: see text] was developed by SA-partial least square with the descriptors like [Formula: see text]count, 5Chain count, SdsCHE-index, and H-acceptor count, showing that increase in the values of these descriptors is beneficial to the activity. The 3D-QSAR studies were performed using the SA-PLS. A leave-one-out cross-validated correlation coefficient [Formula: see text] and predicate activity [Formula: see text] = 0.7226 were obtained. The information rendered by QSAR models may lead to a better understanding of structural requirements of substituted imidazole-5-carboxylic acid derivatives and also aid in designing novel potent antihypertensive molecules.

  1. Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients.

    Science.gov (United States)

    Kusumawati, Widya; Keman, Kusnarman; Soeharto, Setyawati

    2016-01-01

    This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclamptic patients (PP), and endothelial cells exposed to PP in the presence of ethanolic extract of Punica granatum (PP + PG) at the following three doses: 14; 28; and 56 ppm. The expression of AT1-R was observed by immunohistochemistry technique, and thromboxane B2 level was done by immunoassay technique. Plasma from PP significantly increased AT1-R expression and thromboxane B2 levels compared to cells treated by normal pregnancy plasma. The increasing of AT1-R expression significantly (P Punica granatum extract. Moreover, the increasing of thromboxane B2 levels significantly (P Punica granatum extract. We further concluded that Punica granatum fruit protects and inhibits the sensitivity of endothelial cells to plasma from preeclamptic patients due to inhibition of AT1-R expression (56 ppm) and reduced thromboxane B2 levels (14 ppm).

  2. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Feng [Department of Cardiology, Peking University People' s Hospital, Beijing (China); William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Ren, Jingyi [Department of Cardiology, Peking University People' s Hospital, Beijing (China); Chan, Kenneth [William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Chen, Hong, E-mail: chenhongbj@medmail.com.cn [Department of Cardiology, Peking University People' s Hospital, Beijing (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  3. Angiotensin receptors and angiotensin I-converting enzyme in rat intestine

    International Nuclear Information System (INIS)

    Duggan, K.A.; Mendelsohn, F.A.; Levens, N.R.

    1989-01-01

    The purpose of this study was to map the distribution of angiotensin II (ANG II) receptors and ANG I-converting enzyme (ACE) in rat intestine. ANG II binding sites were visualized by in vitro autoradiography using iodinated [Sar1, Ile8]ANG II. The distribution of ACE was mapped using an iodinated derivative of lisinopril. Male Sprague-Dawley rats were killed and the interior of the whole intestine washed with ice-cold saline. Segments of duodenum, jejunum, ileum, and colon were quickly frozen in a mixture of isopentane and dry ice. Twenty-micron frozen sections were thaw-mounted onto gelatin-coated slides, incubated with either ligand, and exposed to X-ray film. After exposure and subsequent development, the films were quantitated by computerized densitometry. ANG II receptors were most dense in the colon, followed by the ileum, duodenum, and jejunum. Within each segment of intestine, specific ANG II binding sites were localized exclusively to the muscularis. In contrast, ACE was present in both the mucosa and the muscularis. The colocalization of ANG II receptors and ACE may suggest a role for locally generated ANG II in the control of intestinal function. The luminal orientation of ACE in the mucosa of the small intestine may suggest that at this site ACE serves primarily to hydrolyze dietary peptides

  4. Angiotensin II in Refractory Septic Shock.

    Science.gov (United States)

    Antonucci, Elio; Gleeson, Patrick J; Annoni, Filippo; Agosta, Sara; Orlando, Sergio; Taccone, Fabio Silvio; Velissaris, Dimitrios; Scolletta, Sabino

    2017-05-01

    Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin-angiotensin-aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

  5. Differences between angiotensin-converting enzyme inhibition and angiotensin II-AT(1) antagonism on angiotensin-mediated responses in human internal mammary arteries

    NARCIS (Netherlands)

    Voors, AA; Oosterga, M; Buikema, H; Mariani, M; Grandjean, JG; van Glist, WH

    The cur-rent study aimed to demonstrate differences between angiotensin (Ang)-converting enzyme (ACE) inhibition and Ang II-AT(1) receptor antagonism on full concentration-contraction responses to Ang I. Contraction responses to increasing concentrations of Ang I (1 nM-1 muM) were evaluated in organ

  6. Development of a solid phase extraction procedure for HPLC-DAD determination of several angiotensin II receptor antagonists in human urine using mixture design.

    Science.gov (United States)

    Ferreirós, N; Iriarte, G; Alonso, R M; Jiménez, R M

    2007-10-15

    The optimisation of a solid phase extraction procedure involves several variables whose influence has been widely studied. However, in most cases, only process variables are taken into account. In this work, the influence of those process variables together with the fact of using mixtures of solvents during the elution step of the solid phase extraction of four angiotensin II receptor antagonist drugs has been studied. Since the influence on the extraction efficiency of several process variables were simultaneously tested, a D-optimal design was constructed. The composition of the elution solvent (a mixture of methanol, acetonitrile, ethanol and acetone at different proportions from 0 to 100% each solvent), the percentage and pH of the buffer solution added to the urine samples at the beginning of the extraction procedure; the percentage of the organic component and the volume of the washing solution, the drying time and the volume of the elution solvent were the studied variables. The chromatographic separation was carried out by gradient elution mode with 0.026% trifluoroacetic acid (TFA) in the organic phase and 0.031% TFA in the aqueous phase using an Atlantis dC18, 100mmx3.9mm I.D. chromatographic column at a flow rate of 1mL/min and a column temperature of 35+/-0.2 degrees C. For detection a diode array detector set at 232nm was used. The extraction procedure for spiked human urine samples was developed using C8 cartridges, phosphate buffer pH 6.8 as conditioning agent, a drying step of 10min, a washing step with methanol-phosphate buffer (20:80, v/v) and methanol as eluent. Recovery percentages obtained: 84% for eprosartan, 74% for telmisartan, 74% for irbesartan and 89% for valsartan allow the determination of these drugs concentration levels in urine.

  7. 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.

    Directory of Open Access Journals (Sweden)

    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.

  8. Weight loss has an additive effect on the proteinuria reduction of angiotensin II receptor blockers in hypertensive patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Shin Young Ahn

    2018-03-01

    Full Text Available Background : Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD. We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs and its potential mechanisms in hypertensive CKD patients. Methods : This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. Results : Fifty-eight participants (25.6% were assigned to group 1 (≥ 1.5% decrease in body weight after 16 weeks, 32 participants (14.1% were assigned to group 2 (1.5-0.1% decrease in body weight, and 136 participants (59.9% were assigned to group 3 (≥ 0.0% increase in body weight. Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017. Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913-20.315, P = 0.002. Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013. Conclusion : We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.

  9. Angiotensin II receptor blockers suppress the release of stromal cell-derived factor-1α from infarcted myocardium in patients with acute myocardial infarction.

    Science.gov (United States)

    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.

  10. Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis.

    Science.gov (United States)

    Ocaranza, Maria Paz; Moya, Jackeline; Barrientos, Victor; Alzamora, Rodrigo; Hevia, Daniel; Morales, Cristobal; Pinto, Melissa; Escudero, Nicolás; García, Lorena; Novoa, Ulises; Ayala, Pedro; Díaz-Araya, Guillermo; Godoy, Ivan; Chiong, Mario; Lavandero, Sergio; Jalil, Jorge E; Michea, Luis

    2014-04-01

    Little is known about the biological effects of angiotensin-(1-9), but available evidence shows that angiotensin-(1-9) has beneficial effects in preventing/ameliorating cardiovascular remodeling. In this study, we evaluated whether angiotensin-(1-9) decreases hypertension and reverses experimental cardiovascular damage in the rat. Angiotensin-(1-9) (600  ng/kg per min for 2 weeks) reduced already-established hypertension in rats with early high blood pressure induced by angiotensin II infusion or renal artery clipping. Angiotensin-(1-9) also improved cardiac (assessed by echocardiography) and endothelial function in small-diameter mesenteric arteries, cardiac and aortic wall hypertrophy, fibrosis, oxidative stress, collagen and transforming growth factor type β - 1 protein expression (assessed by western blot). The beneficial effect of angiotensin-(1-9) was blunted by coadministration of the angiotensin type 2(AT2) receptor blocker PD123319 (36  ng/kg per min) but not by coadministration of the Mas receptor blocker A779 (100  ng/kg per min). Angiotensin-(1-9) treatment also decreased circulating levels of Ang II, angiotensin-converting enzyme activity and oxidative stress in aorta and left ventricle. Whereas, Ang-(1-9) increased endothelial nitric oxide synthase mRNA levels in aorta as well as plasma nitrate levels. Angiotensin-(1-9) reduces hypertension, ameliorates structural alterations (hypertrophy and fibrosis), oxidative stress in the heart and aorta and improves cardiac and endothelial function in hypertensive rats. These effects were mediated by the AT2 receptor but not by the angiotensin-(1-7)/Mas receptor axis.

  11. TRPC6 enhances angiotensin II-induced albuminuria.

    LENUS (Irish Health Repository)

    Eckel, Jason

    2011-03-01

    Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.

  12. Inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission in the pithed rat: a comparison between losartan, irbesartan, telmisartan, and captopril

    NARCIS (Netherlands)

    Balt, J. C.; Mathy, M. J.; Pfaffendorf, M.; van Zwieten, P. A.

    2001-01-01

    Numerous studies have shown that angiotensin II enhances sympathetic nervous transmission. The objective of the present study was to quantify the inhibitory effect of the angiotensin II type 1 (AT1) receptor blockers losartan, irbesartan and telmisartan and the angiotensin converting enzyme (ACE)

  13. Angiotensin II inhibits cortical cholinergic function: Implications for cognition

    International Nuclear Information System (INIS)

    Barnes, J.M.; Barnes, N.M.; Costall, B.; Horovitz, Z.P.; Ironside, J.W.; Naylor, R.J.; Williams, T.J.

    1990-01-01

    In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function

  14. Role of oxidative stress in angiotensin-II mediated contraction of human conduit arteries in patients with cardiovascular disease.

    Science.gov (United States)

    Püntmann, Valentina O; Hussain, Monira B; Mayr, Manuel; Xu, Qingbo; Singer, Donald R J

    2005-10-01

    Angiotensin II is a powerful vasoconstrictor involved in the development of high blood pressure and in the regulation of cardiovascular growth. Recent reports have suggested that in addition to the classical pathways involved in transducing responses to receptor activation, formation of reactive oxygen species by angiotensin II may also be involved. We investigated the importance of oxidative stress in angiotensin II induced contraction in human conduit arteries from patients with cardiovascular disease. Isometric contraction studies using human radial arteries entailed probes modulating the redox-dependent reactions to define the oxidative pathways involved in angiotensin II contraction. In situ oxidative fluorescence was employed to detect immediate superoxide tissue production in radial and internal mammary arteries. Treatment with TEMPOL, human superoxide dismutase, diphenyleneiodonium, oxypurinol, NG-monomethyl L-arginine considerably decreased contractile response to angiotensin II in radial arteries. Similarly, angiotensin II-stimulated arterial superoxide production was reduced in the presence of the above inhibitors. On the contrary, used as controls, norepinephrine vasoconstriction was not associated with increase of superoxide and neither ciprofloxacin nor aminophylline altered basal or angiotensin II induced superoxide generation. Our findings provide evidence for the role of oxidative pathways in contractile response of human conduit arteries to angiotensin II. Angiotensin II induced superoxide anion production may be mediated by multiple inter-dependent rate-limiting enzymes in both types of artery. Our studies may have important implication for future therapeutic approaches involving inhibition of angiotensin II mediated superoxide generation in hypertension and prevention of cardiovascular disease. We studied the role of oxidant species in contraction responses to angiotensin II in human conduit arteries. Treating radial artery segments with the

  15. Angiotensin converting enzyme-independent, local angiotensin II-generation in human pancreatic ductal cancer tissues.

    Science.gov (United States)

    Ohta, Tetsuo; Amaya, Kohji; Yi, Shuangqin; Kitagawa, Hirohisa; Kayahara, Masato; Ninomiya, Itasu; Fushida, Sachio; Fujimura, Takashi; Nishimura, Gen-Ichi; Shimizu, Koichi; Miwa, Koichi

    2003-09-01

    Hypovascularity is an outstanding characteristic of pancreatic ductal cancer by diagnostic imaging: most pancreatic ductal cancers are hypovascular or avascular, and tumor vessels are seldom seen on angiography. However, we found that the vasculature was not always poor on angiography of surgically resected specimens of locally advanced pancreatic ductal cancers. To elucidate these controversial findings, we focused on angiotensin II, a vasoconstrictor which is directly produced from angiotensinogen at acidic pH by active trypsin. We examined whether a local angiotensin II-generating system exists in pancreatic ductal cancer tissue. We measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues from normal pancreas, pancreatic ductal cancers, colon cancers, and hepatocellular carcinomas. After surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and the Kasahara method, respectively. Tissue angiotensin II levels in pancreatic ductal cancer (n=13) were significantly higher than those of normal pancreas (n=7), colon cancers (n=7), or hepatocellular carcinomas (n=7). However, there was no significant difference in the ACE activity in tissue between them. This study provides in vivo evidence of an ACE-independent, angiotensin II-generating system in pancreatic ductal cancer tissues and suggests that locally formed angiotensin II may act on the pre-existing pancreatic arteries around the tumor, leading to formation of hypovascular or avascular regions.

  16. Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients

    Directory of Open Access Journals (Sweden)

    Guasti L

    2017-08-01

    Full Text Available Luigina Guasti,1,* Giovanni Gaudio,2,* Alessandro Lupi,3 Marinella D’Avino,4 Carla Sala,5,6 Amedeo Mugellini,7 Vito Vulpis,8 Salvatore Felis,9 Riccardo Sarzani,10,11 Massimo Vanasia,12 Pamela Maffioli,7 Giuseppe Derosa7 1Research Center on Dyslipidemia, Internal Medicine 1, University of Insubria, Varese, Italy; 2Internal Medicine Division, Ospedale Angelo Bellini, ASST Valle Olona Somma, Varese, Italy; 3Cardiology Unit, ASL VCO Verbania-Domodossola, Verbania, Italy; 4Unit for the Treatment of Arterial Hypertension, Ospedale Cardarelli, Napoli, Italy; 5Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 6Cardiovascular Unit, Fondazione IRCCSS Policlinico, Milano, Italy; 7Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 8Unit for the Diagnosis and Treatment of Arterial Hypertension, Department of Internal Medicine, Policlinico di Bari, Bari, Italy; 9Cardiology Unit, Ospedale Garibaldi, Catania, Italy; 10ESH Center of Hypertension, Internal Medicine and Geriatrics, University Politecnica delle Marche, Ancona, Italy; 11IRCCS-INRCA, Ancona, Italy; 12THERABEL GiEnne Pharma, Milano, Italy *These authors contributed equally to this work Background: Blockade of the renin–angiotensin–aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM has been widely confirmed for both increasing the accuracy of blood pressure (BP measurements, particularly in pharmacological trials, and focusing on 24 h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE inhibitors or angiotensin II type 1 receptor (AT1R antagonists plus hydrochlorothiazide (HCT. Methods: ABPM was performed at baseline and after 3

  17. Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

    Science.gov (United States)

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-01-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  18. Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia.

    Science.gov (United States)

    Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M

    2017-08-01

    Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10 -7 -102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME ( N G -nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10 -20 -10 -4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 log EC50 ; P Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; P =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum

  19. Retinal ganglion cell neuroprotection by an angiotensin II blocker in an ex vivo retinal explant model.

    Science.gov (United States)

    White, Andrew J R; Heller, Janosch P; Leung, Johahn; Tassoni, Alessia; Martin, Keith R

    2015-12-01

    An ex vivo organotypic retinal explant model was developed to examine retinal survival mechanisms relevant to glaucoma mediated by the renin angiotensin system in the rodent eye. Eyes from adult Sprague Dawley rats were enucleated immediately post-mortem and used to make four retinal explants per eye. Explants were treated either with irbesartan (10 µM), vehicle or angiotensin II (2 μM) for four days. Retinal ganglion cell density was estimated by βIII tubulin immunohistochemistry. Live imaging of superoxide formation with dihydroethidium (DHE) was performed. Protein expression was determined by Western blotting, and mRNA expression was determined by RT-PCR. Irbesartan (10 µM) almost doubled ganglion cell survival after four days. Angiotensin II (2 µM) reduced cell survival by 40%. Sholl analysis suggested that irbesartan improved ganglion cell dendritic arborisation compared to control and angiotensin II reduced it. Angiotensin-treated explants showed an intense DHE fluorescence not seen in irbesartan-treated explants. Analysis of protein and mRNA expression determined that the angiotensin II receptor At1R was implicated in modulation of the NADPH-dependent pathway of superoxide generation. Angiotensin II blockers protect retinal ganglion cells in this model and may be worth further investigation as a neuroprotective treatment in models of eye disease. © The Author(s) 2015.

  20. O polimorfismo A1166C do receptor tipo 1 da angiotensina II no infarto agudo do miocárdio The A1166C polymorphism of the angiotensin II type-1 receptor in acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Messias Antônio de Araújo

    2004-11-01

    Full Text Available RESUMO OBJETIVO:Avaliar a associação do polimorfismo A1166C do gene do receptor AT1 da angiotensina II (AT1R com o infarto agudo do miocárdio e a severidade da doença arterial coronariana. MÉTODOS: Estudo prospectivo, transversal de 110 pacientes com infarto agudo do miocárdio submetidos à angiografia coronariana com lesão significante (> 50% avaliada por três critérios de severidade: número de vasos lesados, morfologia da placa aterosclerótica e escore de risco coronariano. Sem lesões coronarianas 104 indivíduos controles. O polimorfismo A1166C do gene do AT1R foi determinado pela reação em cadeia da polimerase no DNA dos leucócitos do sangue periférico. Os fatores de risco coronariano clássicos foram analisados em todos os indivíduos. RESULTADOS: Na estratificação dos genótipos em relação aos fatores de risco apenas o tabagismo teve predominância nos heterozigotos AC (p = 0,02. A freqüência dos genótipos nos pacientes infartados foi de AA = 54,5%; AC = 35,5% e CC = 10%, sendo similar e não significativa em relação aos controles (p = 0,83. Não houve aumento do risco de infarto agudo do miocárdio nas comparações dos genótipos CC vs AA (OR = 1,35; IC-95% = 0,50 - 3,59, AC vs AA (OR = 1,03; IC-95% = 0,58 - 1,84 e AA+AC vs AA (OR = 1,33; IC-95% = 0,51 - 3,45. Nenhum dos critérios de severidade teve associação significativa com os genótipos. CONCLUSÃO: Os nossos resultados indicam não haver associação do polimorfismo A1166C do AT1R com o infarto agudo do miocárdio e nem com a severidade da doença arterial coronariana segundo nossos resultados.OBJECTIVE: To assess the association of the A1166C polymorphism of the angiotensin II type-1 receptor (AT1R gene with acute myocardial infarction and also with the severity of coronary artery disease. METHODS: A prospective, cross-sectional study was carried out with 110 patients with acute myocardial infarction, who, on coronary angiography, had significant

  1. Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review.

    Science.gov (United States)

    Dahlöf, B

    1995-11-01

    Activation of the renin-angiotensin system both systemically and locally seems to be of importance for cardiovascular hypertrophy and remodelling. The octapeptide angiotensin II definitively plays a central role. In the reversal, for example, of left ventricular hypertrophy, so far the most important independent risk factor for an adverse outcome, blocking of the renin-angiotensin system with ACE inhibition has been shown to be particularly effective. In cardiac tissue, however, ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed, indicating that other enzymatic pathways can be of importance. From a theoretical point of view a more complete blockade of the angiotensin II type 1 receptor would offer a more effective attenuation of the unfavourable effect of angiotensin II. Experimentally, losartan, a novel selective angiotensin II receptor type 1 antagonist has been shown to decrease cardiac hypertrophic response in models of both hypertension and volume cardiac hypertrophy as well as reverse hypertrophy in spontaneously hypertensive rats. TCV-116, another selective angiotensin II antagonist, also effectively reverses cardiac hypertophy and interstitial fibrosis in the rat. The only report so far regarding the effect of angiotensin II blockade on cardiac hypertrophy in essential hypertension suggests a more favourable short-term effect on cardiac hypertrophy for the same blood pressure reduction with losartan compared with atenolol in a small population of mild to moderate hypertensives. In the perspective of the well-established positive effects of ACE inhibition on the remodelling process in the remaining viable myocardium after myocardial infarction, involving myocyte hypertrophy, interstitial fibrosis and progressive dilatation, it is reassuring that angiotensin II blockade has been shown to perform equally well as ACE inhibition after experimental coronary ligation. In summary, the development of cardiovascular hypertrophy in

  2. EFFECT OF ANGIOTENSIN-II RECEPTOR ANTAGONIST LOSARTAN AND ITS COMBINATION WITH DIURETICS ON MYOCARDIAL MORPHO-FUNCTIONAL CONDITIONS IN HYPERTENSIVE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

    Directory of Open Access Journals (Sweden)

    S. N. Tolpygina

    2008-01-01

    Full Text Available Aim. To compare the effects of long-term therapy with angiotensin-II receptor antagonist losartan, alone or in combination with hydrochlorothiazide, and amlodipine treatment on left ventricular morpho-functional variables and blood pressure (BP in hypertensive patients.Material and methods. 25 women and 27 men (average age 52,7±1,2 y.o. with essential hypertension (1-2 grade and left ventricular hypertrophy (LVH were included into the study. After 3 week washout period the patients were randomized in 2:1 fashion to receive either losartan (n=34 or amlodipine (n=17. In 17 patients with insufficient response to losartan monotherapy (50-100mg/day hydrochlorothiazide (12,5mg was added to losartan (50mg 4 weeks later. The daily dose of amlodipine was increased from 5 to 10 mg in 10 patients. At baseline and after 24 weeks of treatment 24-h BP monitoring and echocardiography (with evaluation of cardiac chamber dimensions, inter-ventricular septal and posterior wall thickness, left ventricular mass index -LVMI were performed.Results. 4-week losartan treatment significantly decreased clinic BP (-14,1±2,2/8,2±1,4 mm Hg, p<0,01, mean daily systolic and diastolic BP (-15,1±2,4 mm Hg and -8,9±1,7 mm Hg , p<0,001, mean day-time and night-time BP and systolic and diastolic BP load in 34 patients. Addition of hydrochlorothiazide induced a further decrease of mean night-time BP, pulse BP, improved circadian rhythm and normalized BP in 75% of patients compared with 50% in losartan alone. Significant decrease of clinic BP (-24,1±3,6/15,2±2,3, p<0,01, mean daily systolic and diastolic BP and BP load were noticed at 24 week of amlodipine treatment. Circadian BP rhythm didn’t change; night-time decrease of BP was insufficient. Antihypertensive efficacy was similar in both groups. Losartan, alone or combined with hydrochlorothiazide, caused regression of LVH in all patients, normalized geometry of left ventricle in 33% of patients and improved left

  3. Effect of urine urea nitrogen and protein intake adjusted by using the estimated urine creatinine excretion rate on the antiproteinuric effect of angiotensin II type I receptor blockers.

    Science.gov (United States)

    Chin, Ho Jun; Kim, Dong Ki; Park, Jung Hwan; Shin, Sung Joon; Lee, Sang Ho; Choi, Bum Soon; Kim, Suhnggwon; Lim, Chun Soo

    2015-01-01

    The aim of this study was to determine the role of protein intake on proteinuria in chronic kidney disease (CKD), as it is presently not conclusive. This is a subanalysis of data from an open-label, case-controlled, randomized clinical trial on education about low-salt diets (NCT01552954). We estimated the urine excretion rate of parameters in a day, adjusted by using the equation for estimating urine creatinine excretion, and analyzed the effect of urine urea nitrogen (UUN), as well as estimating protein intake on the level of albuminuria in hypertensive patients with chronic kidney disease. Among 174 participants from whom complete 24-h urine specimens were collected, the estimates from the Tanaka equation resulted in the highest accuracy for the urinary excretion rate of creatinine, sodium, albumin, and UUN. Among 227 participants, the baseline value of estimated urine albumin excretion (eUalb) was positively correlated with the estimated UUN (eUUN) or protein intake according to eUUN (P = 0.012 and P = 0.038, respectively). We were able to calculate the ratios of eUalb and eUUN in 221 participants and grouped them according to the ratio of eUUN during 16-wk trial period. The proportion of patients that achieved a decrement of eUalb ≥25% during 16 wk with an angiotensin II type I receptor blocker (ARB) medication was 80% (24 of 30) in group 1, with eUUN ratio ≤-25%; 82.2% (111 of 135) in group 2, with eUUN ratio between -25% and 25%; and 66.1% (37 and 56) in group 3, with eUUN ratio ≥25% (P = 0.048). The probability of a decrease in albuminuria with ARB treatment was lower in patients with an increase of eUUN or protein intake during the 16 wk of ARB treatment, as observed in multiple logistic regression analysis as well. The estimated urine urea excretion rate showed a positive association with the level of albuminuria in hypertensive patients with chronic kidney disease. The increase of eUUN excretion ameliorated the antiproteinuric effect of ARB

  4. Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

    Science.gov (United States)

    Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F

    2017-02-01

    Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  5. Aging and human hormonal and pressor responsiveness to angiotensin II infusion with simultaneous measurement of exogenous and endogenous angiotensin II.

    Science.gov (United States)

    Duggan, J; Nussberger, J; Kilfeather, S; O'Malley, K

    1993-08-01

    A decline in the function of the renin angiotensin aldosterone system may induce adaptive changes in response to angiotensin II (ANG II) with age. We have examined platelet ANG II receptor density, blood pressure and aldosterone responses to ANG II [Asn1, Val5-ANG II] (Hypertensin, Ciba Geigy, Horsham, Sussex, England) infusion in 8 young, 24 to 30 years, and 8 older, 54 to 65 years, healthy volunteers. To measure circulating ANG II, we established a new method for specific and simultaneous measurement of exogenous [Asn1, Val5] (Hypertensin) and endogenous [Asp1,Ile5] ANG II in plasma by using isocratic HPLC and radioimmunoassays with cross-reacting antibodies and compared results with immunoreactive ANG II which was measured conventionally using monoclonal antibodies. Baseline endogenous ANG II (Asp1,Ile5-ANG II) levels in venous plasma were marginally, but not significantly, lower in the old [mean (95% confidence limits): 3.4 (Hypertensin infusion appeared consistently, but not significantly, lower in the old [0.9 (0 to 3.1) v 2.1 (0.6 to 3.7), after 3 ng/kg/min], while the same infusion rate in young and old resulted in similar plasma Hypertensin levels. Baseline systolic blood pressure (SBP) was similar in both groups but the percentage increases in SBP at infusion rates of 1, 3.0, and 10 ng/kg/min were greater in the old than in the young (9.1 v 2.8, P < .05; 16.3 v 8.0, P < .01; 30.4 v 14.0%, P < .001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Adição de Bloqueador do receptor de angiotensina II na insuficiência cardíaca descompensada Adición de bloqueante del receptor de angiotensina II en la insuficiencia cardiaca descompensada Angiotensin II receptor blocker add-on therapy for low cardiac output in decompensated heart failure

    Directory of Open Access Journals (Sweden)

    Marcelo E. Ochiai

    2010-02-01

    pacientes internados por descompensación de la insuficiencia cardiaca y con empleo por más de 15 días de dobutamina, o una o más intentos sin éxito de retirada; dosis optimizada de IECA; y FEVI BACKGROUND: During heart failure (HF decompensation, an intense activation of the renin-angiotensin-aldosterone system occurs; however, the use of angiotensin-converting enzyme inhibitor (ACEI cannot block it completely. Otherwise, the addition of angiotensin II receptor blocker (ARB can be useful when the inotropic dependence occurs. We evaluated the efficacy of the ARB-ACEI association on dobutamine withdrawal in advanced decompensated HF. OBJECTIVE: To assess the efficacy of association angiotensin receptor blocker - angiotensin converting enzyme inhibitor to withdraw the intravenous inotropic support in decompensated severe heart failure. METHODS: In a case-control study (N = 24, we selected patients admitted at the hospital due to HF that had been using dobutamine for more than 15 days, with one or more unsuccessful drug withdrawal attempts; optimized dose of ACEI and ejection fraction (EF < 0.45. Then, the patients additionally received ARB (n=12 or not (control, n=12. The outcome was the successful dobutamine withdrawal, evaluated by logistic regression, with a p < 0.05. RESULTS: The EF was 0.25 and the age was 53 years, with a dobutamine dose of 10.7 μg/kg.min. The successful drug withdrawal was observed in 8 patients from the ARB group (67.7% and in 2 patients from the control group (16.7%. The odds ratio (OR was 10.0 (95%CI: 1.4 to 69.3; p = 0.02. The worsening in renal function was similar (ARB group: 42% vs. control group: 67%; p=0.129. CONCLUSION: In this pilot study, the ARB-ACEI association was associated with successful dobutamine withdrawal in advanced decompensated heart failure. The worsening in renal function was similar in both groups. Further studies are necessary to clarify the issue.

  7. Effect of a black cumin (Nigella sativa ethanol extract on placental angiotensin II type 1-receptor autoantibody (AT1-AA serum levels and endothelin-1 (ET-1 expression in a preeclampsia mouse model

    Directory of Open Access Journals (Sweden)

    Humaira Rahma, Sp.OG

    2017-12-01

    Full Text Available Objectives: Preeclampsia affects 3%–8% of all pregnancies. Thymoquinone is the primary compound in black cumin (Nigella sativa and may have potential therapeutic effects in preeclampsia. This research analyses the effects of a black cumin seed ethanol extract on angiotensin II type 1-receptor autoantibody (AT1-AA serum levels and the expression of the endothelin-1 (ET-1 in the placenta in preeclampsia mouse model. Methods: The research design utilizes a post-test only experimental model on a control group design with 6 mice groups (negative control; positive control; and 500, 1000, 1500, and 2000 mg/kg body weight/day. Result: The results showed a decrease in serum AT1-AA levels and ET-1 expression in the placenta by increased doses of black cumin with an optimal dose of 1000 mg/kg/day. Conclusions: Black cumin seed ethanol extract reduces AT1-AA serum levels and represses ET-1 expression in the placenta in a preeclampsia mouse model. Keywords: Angiotensin II type 1-receptor autoantibody (AT1-AA, Antioxidant, Black cumin, Endothelin-1 (ET-1 placenta, Preeclampsia, Pregnancy

  8. Introductory statement: Of receptors and analogs in renin-angiotensin-aldosterone and adrenergic systems

    International Nuclear Information System (INIS)

    Eliahou, H.E.; Iaina, A.

    1980-01-01

    This article reports on the role of the octapeptides angiotensin II (A II)-effector and its receptor on hypertensive patients and in animal experiments. By applying the A-II-receptor blockers, vasodilates drugs, β-receptor blockers and by sodium depletion, the behaviour of the blood pressure, the plasmareninactivity, and of the aldosteron were investigated; a comparative investigation between the A II and A III effectors was also carried out. The iodo-hippurate uptake was reduced with an artificially produced renal arterial ischemia. In general, this investigation provided new viewpoints in the understanding of the possible pathogenetic mechanism of essential hypertonism. (APR) [de

  9. 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

  10. Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.

    Science.gov (United States)

    Tsuruda, Toshihiro; Sekita-Hatakeyama, Yoko; Hao, Yilin; Sakamoto, Sumiharu; Kurogi, Syuji; Nakamura, Midori; Udagawa, Nobuyuki; Funamoto, Taro; Sekimoto, Tomohisa; Hatakeyama, Kinta; Chosa, Etsuo; Kato, Johji; Asada, Yujiro; Kitamura, Kazuo

    2016-05-01

    Circulating and myocardial expressions of receptor activator of nuclear factor-κb ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin-angiotensin system. We conducted experiments using 8-week-old osteoprotegerin(-/-) mice and receptor activator of nuclear factor-κb ligand-transgenic mice to assess whether they affect the angiotensin II-induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin(-/-) mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen α1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-κb ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-κb ligand antibody, to the angiotensin II-infused osteoprotegerin(-/-) mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II-induced cardiac hypertrophy, independent of receptor activator of nuclear factor-κb ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms. © 2016 American Heart Association, Inc.

  11. Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Tao; Tsui, Benjamin M. W.; Li, Xin; Vranesic, Melin; Lodge, Martin A.; Gulaldi, Nedim C. M.; Szabo, Zsolt, E-mail: zszabo@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, Maryland 21287 (United States)

    2015-11-15

    Purpose: The radioligand {sup 11}C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of {sup 11}C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method in pigs with the goal of translation into human studies. Methods: The experimental animals were injected with [{sup 11}C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. Results: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent

  12. Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1.

    Science.gov (United States)

    Kraemer, Maria P; Choi, Hyehun; Reese, Jeff; Lamb, Fred S; Breyer, Richard M

    2016-09-01

    Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***Pantagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Angiotensin II (AngII) induces the expression of suppressor of cytokine signaling (SOCS)-3 in rat hypothalamus - a mechanism for desensitization of AngII signaling.

    Science.gov (United States)

    Torsoni, Márcio A; Carvalheira, José B; Calegari, Vivian C; Bezerra, Rosangela M N; Saad, Mário J A; Gontijo, José A; Velloso, Lício A

    2004-04-01

    Angiotensin II exerts a potent dypsogenic stimulus on the hypothalamus, which contributes to its centrally mediated participation in the control of water balance and blood pressure. Repetitive intracerebroventricular (i.c.v.) injections of angiotensin II lead to a loss of effect characterized as physiological desensitization to the peptide's action. In the present study, we demonstrate that angiotensin II induces the expression of suppressor of cytokine signaling (SOCS)-3 via angiotensin receptor 1 (AT1) and JAK-2, mostly located at the median preoptic lateral and anterodorsal preoptic nuclei. SOCS-3 produces an inhibitory effect upon the signal transduction pathways of several cytokines and hormones that employ members of the JAK/STAT families as intermediaries. The partial inhibition of SOCS-3 translation by antisense oligonucleotide was sufficient to significantly reduce the refractoriness of repetitive i.c.v. angiotensin II injections, as evaluated by water ingestion. Thus, by acting through AT1 on the hypothalamus, angiotensin II induces the expression of SOCS-3 which, in turn, blocks further activation of the pathway and consequently leads to desensitization to angiotensin II stimuli concerning its dypsogenic effect.

  14. Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives

    Directory of Open Access Journals (Sweden)

    Thyago Moreira Queiroz

    2013-05-01

    Full Text Available Hypertension is a multifactorial disorder which has been associated with the reduction in baroreflex sensitivity and autonomic dysfunction. Several studies have revealed that increased reactive oxygen species (ROS generated by nicotinamide adenine dinucleotide phosphate [NAD(PH] oxidase, following activation of type 1 receptor (AT1R by Angiotensin-(Ang II, the main peptide of the Renin–Angiotensin–Aldosterone System (RAAS, is the central mechanism involved in Angiotensin-II-derived hypertension. In the present review we will discuss the role of Angiotensin-II and oxidative stress in hypertension, the relationship between the baroreflex sensitivity (BRS and the genesis of hypertension and how the oxidative stress triggers baroreflex dysfunction in several models of hypertension. Finally, we will describe some novel therapeutic drugs for improving the baroreflex sensitivity during hypertension.

  15. Diuretic response to acute hypertension is blunted during angiotensin II clamp

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Zhang, Yibin; Yang, Li E

    2002-01-01

    and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic...... whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after...... ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output...

  16. Effect of triptolide on proliferation and apoptosis of angiotensin II ...

    African Journals Online (AJOL)

    Background: The effect of triptolide (TPL) on cardiac fibroblasts (CFbs) and cardiac fibrosis remain unknown till now. This study was conducted to explore the effects of TPL on proliferation and apoptosis of angiotensin II (Ang II)-induced CFbs. Materials and Methods: Ang II was used to promote proliferation of CFbs.

  17. 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

  18. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    Science.gov (United States)

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Design, synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonists based on predictive 3D QSAR models.

    Science.gov (United States)

    Vyas, V K; Gupta, N; Ghate, M; Patel, S

    2014-01-01

    In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII-AT1 receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII-AT1 receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q(2)) of 0.630 and 0.623, respectively, cross-validated coefficients (r(2)cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r(2)) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r(2)pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT1 receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II-AT1 receptor antagonism.

  20. 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.

  1. 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...

  2. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    Energy Technology Data Exchange (ETDEWEB)

    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  3. Pharmacological properties of angiotensin II antagonists: examining all the therapeutic implications

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2001-06-01

    Full Text Available Angiotensin II (Ang II, the effector peptide of the renin-angiotensin system (RAS, exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I, or more recently the Ang II AT1-receptor blockers (ARBs, has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

  4. Pharmacological properties of angiotensin II antagonists: Examining all the therapeutic implications

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2001-06-01

    Full Text Available Angiotensin II (Ang II, the effector peptide of the renin-angiotensin system (RAS, exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I, or more recently the Ang II AT1-receptor blockers (ARBs, has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

  5. Inflammation and the metabolic syndrome: role of angiotensin II and oxidative stress.

    Science.gov (United States)

    Ferder, León; Inserra, Felipe; Martínez-Maldonado, Manuel

    2006-06-01

    Excess body weight, high blood pressure, and insulin resistance together have been denominated the metabolic syndrome. In this review, we analyze the potential role of angiotensin II (Ang II) and reactive oxygen species in mediating inflammation in the metabolic syndrome. Ang II induces pro-inflammatory genes and other pro-inflammatory substances and increases oxidative stress that could damage endothelium, myocardium, and renal tissue. Activation of nuclear factor-kappaB and NAD(P)H oxidase are fundamental steps in these pro-inflammatory mechanisms in which intramitochondrial oxidative stress could play a critical role. This sequence of events might explain why reduction in Ang II synthesis by angiotensin-converting enzyme inhibitors (ACEIs) and Ang II type 1 (AT1) receptor blockers (ARBs) have a protective effect against cardiovascular disease.

  6. Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells.

    Science.gov (United States)

    Kim, Seungbum; Zingler, Michael; Harrison, Jeffrey K; Scott, Edward W; Cogle, Christopher R; Luo, Defang; Raizada, Mohan K

    2016-03-01

    Emerging evidence indicates that differentiation and mobilization of hematopoietic cell are critical in the development and establishment of hypertension and hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of the hyperactive renin-angiotensin system in hypertension, led us to investigate the hypothesis that chronic angiotensin II (Ang II) infusion affects hematopoietic stem cell (HSC) regulation at the level of the bone marrow. Ang II infusion resulted in increases in hematopoietic stem/progenitor cells (83%) and long-term HSC (207%) in the bone marrow. Interestingly, increases of HSCs and long-term HSCs were more pronounced in the spleen (228% and 1117%, respectively). Furthermore, we observed higher expression of C-C chemokine receptor type 2 in these HSCs, indicating there was increased myeloid differentiation in Ang II-infused mice. This was associated with accumulation of C-C chemokine receptor type 2(+) proinflammatory monocytes in the spleen. In contrast, decreased engraftment efficiency of GFP(+) HSC was observed after Ang II infusion. Time-lapse in vivo imaging and in vitro Ang II pretreatment demonstrated that Ang II induces untimely proliferation and differentiation of the donor HSC resulting in diminished HSC engraftment and bone marrow reconstitution. We conclude that (1) chronic Ang II infusion regulates HSC proliferation, mediated by angiotensin receptor type 1a, (2) Ang II accelerates HSC to myeloid differentiation resulting in accumulation of C-C chemokine receptor type 2(+) HSCs and inflammatory monocytes in the spleen, and (3) Ang II impairs homing and reconstitution potentials of the donor HSCs. These observations highlight the important regulatory roles of Ang II on HSC proliferation, differentiation, and engraftment. © 2016 American Heart Association, Inc.

  7. New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde.

    Science.gov (United States)

    Poirier, O; Georges, J L; Ricard, S; Arveiler, D; Ruidavets, J B; Luc, G; Evans, A; Cambien, F; Tiret, L

    1998-10-01

    In an earlier report, we suggested that a polymorphism located in the 3' untranslated region of the angiotensin II type 1 receptor gene (AT1R+1166 A/C) might interact with the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism to increase the risk of myocardial infarction. Since the AT1R+1166 A/C polymorphism does not appear to be functional, we postulated that it might be in linkage disequilibrium with an unidentified functional variant which would affect the regulation of the gene in response to angiotensin II. The present study was conducted to identify new polymorphisms of the AT1R gene that might be responsible for this interaction. The first four exons, which are untranslated, and 2.2 kb in the 5' flanking region of the AT1R gene were explored by polymerase chain reaction/single-strand conformation polymorphism. Seven polymorphisms were detected in the 5' region at positions -1424, -810, -713, -521, -214, -213 and -153 upstream from the start of transcription. The genotypes of the -810, -713, -214, -213 and -153 polymorphisms were completely concordant. One substitution was detected at the 55th nucleotide of exon 4. These polymorphisms, together with the +1166 A/C polymorphism and a previously described T/C substitution at the 573th nucleotide of exon 5, were genotyped in the Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) study, a multicentre study comparing 651 patients who had survived a myocardial infarction and 728 controls from Belfast (United Kingdom) and Lille, Strasbourg and Toulouse (France). The newly identified polymorphisms were not in linkage disequilibrium with the +1166 A/C polymorphism and therefore could not explain the interaction observed with ACE I/D. None of the polymorphisms was associated with blood pressure levels in control subjects. In the four populations, the A allele of the -810 polymorphism was associated with a lower risk of myocardial infarction (population-adjusted odds ratio of 0.80, confidence

  8. Angiotensin II facilitates breast cancer cell migration and metastasis.

    Directory of Open Access Journals (Sweden)

    Sylvie Rodrigues-Ferreira

    Full Text Available Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

  9. Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade.

    Directory of Open Access Journals (Sweden)

    Ina M Ott

    Full Text Available The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN, is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d, riociguat (3 mg/kg/d, riociguat+telmisartan (3+1 mg/kg/d, and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p = 0.071. Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg. Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p = 0.002 reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h, whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h or riociguat (97.1±15.7 µg/24 h was not statistically significant. The combination treatment led to a significant (p<0.01 decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary

  10. Effects of angiotensin II and ionomycin on fluid and bicarbonate absorption in the rat proximal tubule

    International Nuclear Information System (INIS)

    Chatsudthipong, V.; Chan, Y.L.

    1986-01-01

    Microperfusion of proximal convoluted tubule(PCT) and peritubular capillaries was performed to examine the effects of angiotensin II(Ang II) and ionomycin on fluid and bicarbonate absorption. Bicarbonate was determined by microcalorimetry and C-14 inulin was used as a volume marker. The rates of bicarbonate absorption (JHCO 3 ) was 143 peq/min x mm and fluid absorption(Jv) was 2.70 nl/min x mm, when PCT and capillary perfusate contained normal Ringer solution. Addition of Ang II (10 -6 M) to the capillary perfusate caused reductions of JHCO 3 and Jv by 35%. A similar effect was observed when ionomycin was added to the capillary perfusate. Ang II antagonist, (Sar 1 , Ile 8 )-Angiotensin II(10 -6 M), completely blocked the inhibitory effect of Ang II on Jv and JHCO 3 . Removal of calcium from both luminal and capillary perfusate did not change the effect of Ang II on Jv and JHCO 3 . Our results indicate that Ang II inhibits the sodium-hydrogen exchanger in the proximal tubule via interacting with angiotensin receptor. The mechanism of Ang II action may involve mobilization of intracellular calcium

  11. Role of endothelium in angiotensin II formation by the rat aorta and mesenteric arterial bed

    Directory of Open Access Journals (Sweden)

    R. Leite

    1997-05-01

    Full Text Available We investigated the angiotensin II (Ang II-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin I (Ang I, and tetradecapeptide (TDP renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM. The angiotensin converting enzyme (ACE inhibitor captopril (36 µM completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 µM significantly reduced (80-90% the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95% the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition

  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

    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...

  13. Physiopathological implications of P2X1 and P2X7 receptors in regulation of glomerular hemodynamics in angiotensin II-induced hypertension.

    Science.gov (United States)

    Franco, Martha; Bautista-Pérez, Rocío; Cano-Martínez, Agustina; Pacheco, Ursino; Santamaría, José; Del Valle Mondragón, Leonardo; Pérez-Méndez, Oscar; Navar, L Gabriel

    2017-07-01

    Deleterious effects of purinergic P2X 1 and P2X 7 receptors (P2XRs) in ANG II-dependent hypertension include increased renal vascular resistance, and impaired autoregulation and pressure natriuresis. However, their specific effects on the determinants of glomerular hemodynamics remain incompletely delineated. To investigate the P2XR contributions to altered glomerular hemodynamics in hypertension, the effects of acute blockade of P2X 1 R, P2X 7 R, and P2X 4 R with NF449, A438079, and PSB12054, respectively, were evaluated in ANG II-infused rats (435 ng·kg -1 ·min -1 ). P2X 1 R or P2X 7 R blockade reduced afferent (6.85 ± 1.05 vs. 2.37 ± 0.20 dyn·s -1 ·cm -5 ) and efferent (2.85 ± 0.38 vs. 0.99 ± 0.07 dyn·s -1 ·cm -5 ) arteriolar resistances, leading to increases in glomerular plasma flow (75.82 ± 5.58 vs. 206.7 ± 16.38 nl/min), ultrafiltration coefficient (0.0198 ± 0.0024 vs. 0.0512 ± 0.0046 nl·min -1 ·mmHg -1 ), and single-nephron glomerular filtration rate (22.73 ± 2.02 vs. 51.56 ± 3.87 nl/min) to near normal values. Blockade of P2X 4 R did not elicit effects in hypertensive rats. In normotensive sham-operated rats, only the P2X 1 R antagonist caused an increase plasma flow and single-nephron glomerular filtration rate, whereas the P2X 4 R antagonist induced glomerular vasoconstriction that was consistent with evidence that P2X 4 R stimulation increases release of nitric oxide from endothelial cells. Mean arterial pressure remained unchanged in both hypertensive and normotensive groups. Western blot analysis showed overexpression of P2X 1 R, P2X 7 R, and P2X 4 R proteins in hypertensive rats. Whereas it has been generally assumed that the altered glomerular vascular resistances in ANG II hypertension are due to AT 1 receptor-mediated vasoconstriction, these data indicate a predominant P2X 1 R and P2X 7 R control of glomerular hemodynamics in ANG II hypertension. Copyright © 2017 the American Physiological Society.

  14. Low sodium diet inhibits the local counter-regulator effect of angiotensin-(1-7) on angiotensin II

    NARCIS (Netherlands)

    Roks, Anton J M; Nijholt, Jeroen; van Buiten, Azuwerus; van Gilst, Wiek H; de Zeeuw, Dick; Henning, Robert H

    2004-01-01

    Objective The heptapeptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a versatile, endogenous inhibitor of the renin-angiotensin system (RAS). As the therapeutic response to exogenous RAS inhibitors, such as AT, receptor antagonists, is altered by changes in salt intake, we investigated

  15. Alternative pathways for angiotensin II generation in the cardiovascular system

    Directory of Open Access Journals (Sweden)

    C. Becari

    2011-09-01

    Full Text Available The classical renin-angiotensin system (RAS consists of enzymes and peptides that regulate blood pressure and electrolyte and fluid homeostasis. Angiotensin II (Ang II is one of the most important and extensively studied components of the RAS. The beneficial effects of angiotensin converting enzyme (ACE inhibitors in the treatment of hypertension and heart failure, among other diseases, are well known. However, it has been reported that patients chronically treated with effective doses of these inhibitors do not show suppression of Ang II formation, suggesting the involvement of pathways alternative to ACE in the generation of Ang II. Moreover, the finding that the concentration of Ang II is preserved in the kidney, heart and lungs of mice with an ACE deletion indicates the important role of alternative pathways under basal conditions to maintain the levels of Ang II. Our group has characterized the serine protease elastase-2 as an alternative pathway for Ang II generation from Ang I in rats. A role for elastase-2 in the cardiovascular system was suggested by studies performed in heart and conductance and resistance vessels of normotensive and spontaneously hypertensive rats. This mini-review will highlight the pharmacological aspects of the RAS, emphasizing the role of elastase-2, an alternative pathway for Ang II generation.

  16. Retrieval improvement is induced by water shortage through angiotensin II.

    Science.gov (United States)

    Frenkel, Lia; Maldonado, Héctor; Delorenzi, Alejandro

    2005-03-01

    Angiotensin II (ANGII) has an evolutionary preserved role in determining adaptative responses to water-shortages. In addition, it has been shown to modulate diverse phases of memory. Still, it is not clear whether ANGII improves or spoils memory. We demonstrated that endogenous angiotensins enhance consolidation of a long-term associative memory in the crab Chasmagnathus and that water shortage improves memory consolidation through brain ANGII actions. Here, we show that weakly trained crabs, when water-deprived, exhibit enhanced retrieval. Subsequently, memory retention is indistinguishable from that of strongly trained crabs. ANGII, but not angiotensin IV, is a necessary and sufficient condition for such enhancing effect. We conclude that ANGII released due to water shortage leads to enhanced memory retrieval. Thus, it seems that ANGII has an evolutionary preserved role as a multifunction coordinator that enables an adaptative response to water-shortage. The facilitation of memory consolidation and retrieval would be among those coordinated functions.

  17. Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the management of atrial fibrillation.

    Science.gov (United States)

    Anis, Rafik R

    2009-01-01

    Atrial fibrillation (AF) is the most common clinical arrhythmia, and is difficult to treat. Current treatment strategies are far from optimal. Antiarrhythmic drug therapy to maintain sinus rhythm is limited by inadequate efficacy and potentially serious side effects. New areas of research include targeting the AF substrate and examining whether drugs can produce atrial structural and/or electrophysiological remodelling, and whether this results in a reduction in AF burden. There are two approaches to the treatment of AF. The first approach is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm. The other approach is the use of rate-controlling drugs allowing AF to persist. In both approaches, the use of anticoagulant drugs is recommended. There is an increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor II blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy, hypertension, chronic heart failure and left ventricular dysfunction. While experimental studies have shown that the pathogenic structural and electrical remodelling of the atria are prevented by inhibition of angiotensin II, the clinical potential and mechanisms of this approach are still under active investigation. The present article will discuss information pertaining to the mechanism of action and clinical use of ACEIs and ARBs in AF. It will also review the current data on the use of ACEIs and ARBs in a high-risk group of AF patients (heart failure, hypertensive with left ventricular hypertrophy, and myocardial infarction), together with the potential benefit of this class type of pharmacological therapy in direct current cardioversion and after radiofrequency catheter ablation.

  18. Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Ishizuka, Toshiaki, E-mail: tishizu@ndmc.ac.jp [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan); Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

  19. Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected β-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.

    Science.gov (United States)

    Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias

    2013-11-01

    The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used β-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, waters valsartan acid was found just as relevant as the analyzed β-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (≥90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. 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.

  1. Estrogen effects on angiotensin receptors are modulated by pituitary in female rats

    International Nuclear Information System (INIS)

    Douglas, J.G.

    1987-01-01

    The present studies were designed to test the hypothesis that changes in angiotensin II (ANG II) receptors might modulate the layered target tissue responsiveness accompanying estradiol administration. Estradiol was infused continuously in oophorectomized female rats. Aldosterone was also infused in control and experimental animals to avoid estrogen-induced changes in renin and ANG II. ANG II binding constants were determined in radioreceptor assays. Estradiol increased binding site concentration in adrenal glomerulosa by 76% and decreased binding sites of uterine myometrium and glomeruli by 45 and 24%, respectively. There was an accompanying increase in the affinity of ANG II binding to adrenal glomerulosa and uterine myometrium. Because estrogen is a potent stimulus of prolactin release from the pituitary of rodents, studies were also designed to test the hypothesis that prolactin may mediate some or all of the estrogen-induced effects observed. Hypophysectomy abolished estradiol stimulation of prolactin release and most ANG II receptor changes. Prolactin administration to pituitary intact rats was associated with a 50% increase in receptor density of adrenal glomerulosa simulating estradiol administration. However, the changes in glomeruli and uterine myometrium were opposite in that both tissues also increased receptor density, suggesting that prolactin was not the sole mediator of the estrogen-induced receptor changes. In conclusion, regulation of ANG II receptors in a number of diverse target tissues by estradiol is complex with contributions from estrogens and pituitary factors, which include but do not exclusively involve prolactin

  2. 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

  3. 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

  4. Rational Design, Efficient Synthesis, Biological Evaluation of New Ν,Ν'-bis-substituted Butylimidazole Analogs as Potent Angiotensin Receptor Blockers

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Koukoulitsa, C.; Afantitis, A.; Melagraki, G.; Siafaka, A.; Gkini, E.; Tůmová, Tereza; Spyridaki, K.; Kalavrizioti, D.; Androutsou, M-E.; Slaninová, Jiřina; Liapakis, G.; Vlahakos, D.; Mavromoustakos, T.; Matsoukas, J.

    2012-01-01

    Roč. 18, S1 (2012), S123-S123 ISSN 1075-2617. [European Peptide Symposium /32./. 02.09.2012-07.09.2012, Athens] Institutional research plan: CEZ:AV0Z40550506 Keywords : angiotensin II AT1 receptor * in vitro * antagonism * inhibitor * in vitro antagonism * synthesis Subject RIV: CE - Biochemistry

  5. Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats.

    Science.gov (United States)

    Jin, Zhu; Zhang, Wenhui; Yang, Hailiang; Wang, Xiaofang; Zheng, Yanqian; Zhang, Qiaoyan; Zhi, Jianming

    2013-01-01

    Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE) are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI) in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV) at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring.

  6. Angiotensin II induces human astrocyte senescence through reactive oxygen species production.

    Science.gov (United States)

    Liu, Gang; Hosomi, Naohisa; Hitomi, Hirofumi; Pelisch, Nicolas; Fu, Hua; Masugata, Hisashi; Murao, Koji; Ueno, Masaki; Matsumoto, Masayasu; Nishiyama, Akira

    2011-04-01

    Angiotensin II (Ang II)-induced astrocyte senescence may be involved in cerebral ischemic injury and age-associated neurodegenerative disease. This study was conducted to determine the roles of reactive oxygen species production in Ang II-induced cellular senescence in cultured human astrocytes. Human astrocytes were stimulated with Ang II either with or without an angiotensin type 1 receptor blocker, CV11974, or an antioxidant, tempol. Application of Ang II to human astrocytes resulted in a concentration-dependent increase in staining for dihydroethidium. Ang II (100 nM for 30 min) increased the translocation of two cytosolic components of NADPH oxidase, p47phox and p67phox, to the cell membrane and formation of the complex of p47phox, p67phox and p22phox. Ang II concentration-dependently induced an increase in β-galactosidase staining. Pretreatment with CV11974 (100 nM) or tempol (3 mM) abolished Ang II-induced astrocyte β-galactosidase staining. Moreover, Ang II significantly upregulated p16 mRNA expression, which was inhibited by pretreatment with CV11974 or tempol. These findings indicate that superoxide production contributes to Ang II-induced astrocyte senescence.

  7. 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

  8. Central angiotensin II has catabolic action at white and brown adipose tissue.

    Science.gov (United States)

    de Kloet, Annette D; Krause, Eric G; Scott, Karen A; Foster, Michelle T; Herman, James P; Sakai, Randall R; Seeley, Randy J; Woods, Stephen C

    2011-12-01

    Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.

  9. Statin Treatment in Hypercholesterolemic Men Does Not Attenuate Angiotensin II-Induced Venoconstriction

    Science.gov (United States)

    Schindler, Christoph; Guenther, Kristina; Hermann, Cosima; Ferrario, Carlos M.; Schroeder, Christoph; Haufe, Sven

    2014-01-01

    Experimental studies suggested that statins attenuate vascular AT1 receptor responsiveness. Moreover, the augmented excessive pressor response to systemic angiotensin II infusions in hypercholesterolemic patients was normalized with statin treatment. In 12 hypercholesterolemic patients, we tested the hypothesis that statin treatment attenuates angiotensin II-mediated vasoconstriction in hand veins assessed by a linear variable differential transducer. Subjects ingested daily doses of either atorvastatin (40 mg) or positive control irbesartan (150 mg) for 30 days in a randomized and cross-over fashion. Ang II–induced venoconstriction at minute 4 averaged 59%±10% before and 28%±9% after irbesartan (mean ± SEM; Pblood pressure buffering reflexes. Trial Registration ClinicalTrials.gov NCT00154024 PMID:25264877

  10. The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man

    Science.gov (United States)

    Alessandra, Del Fiorentino; Cianchetti, Silvana; Celi, Alessandro; Dell’Omo, Giulia; Pedrinelli, Roberto

    2009-01-01

    Anti-inflammatory properties may contribute to the pharmacological effects of angiotensin II receptor blockers (ARBs), a leading therapeutic class in the management of hypertension and related cardiovascular and renal diseases. That possibility, supported by consistent evidence from in-vitro and animal studies showing pro-inflammatory properties of angiotensin II, has been evaluated clinically by measuring the effect of ARBs on C-reactive protein and other circulating indices of inflammation (e-selectin, adhesion molecules, interleukin-6, tissue necrosis factor-alpha, monocyte chemoattractant protein-1) of potential clinical relevance, a body of evidence that this paper aims to review. PMID:19436669

  11. Vasopressin and angiotensin II stimulate oxygen uptake in the perfused rat hindlimb

    DEFF Research Database (Denmark)

    Colquhoun, E Q; Hettiarachchi, M; Ye, J M

    1988-01-01

    Vasopressin and angiotensin II markedly stimulated oxygen uptake in the perfused rat hindlimb. The increase due to each agent approached 70% of the basal rate, and was greater than that produced by a maximal concentration of norepinephrine. Half-maximal stimulation occurred at 60 pM vasopressin, 0.......5 nM angiotensin II and 10 nM norepinephrine. Angiotensins I and III were less potent than angiotensin II. For each agent, the dose-dependent increase in oxygen uptake coincided with a dose-dependent increase in perfusion pressure. The effects of both vasopressin and angiotensin to increase oxygen...

  12. Exercise training prevents arterial baroreflex dysfunction in rats treated with central angiotensin II.

    Science.gov (United States)

    Pan, Yan-Xia; Gao, Lie; Wang, Wei-Zhong; Zheng, Hong; Liu, Dongmei; Patel, Kaushik P; Zucker, Irving H; Wang, Wei

    2007-03-01

    Angiotensin II (Ang II)-induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II-superoxide mechanism. Four groups of rats were used: non-EX artificial cerebrospinal fluid infused, non-EX Ang II infused, EX artificial cerebrospinal fluid infused, and EX Ang II infused. Rats were treadmill trained for 3 to 4 weeks and subjected to intracerebroventricular infusion of Ang II over the last 3 days of EX. Twenty-four hours after the end of EX, the arterial baroreflex was assessed in anesthetized rats. Compared with non-EX artificial cerebrospinal fluid-infused rats, Ang II significantly decreased baroreflex sensitivity (maximum gain: 3.0+/-0.2% of maximum per millimeter of mercury versus 1.6+/-0.1% of maximum per millimeter of mercury; Pbaroreflex sensitivity and downregulated Ang II type 1 receptor and NADPH oxidase subunit protein expression in the paraventricular nucleus of Ang II-infused rats. Finally, EX decreased superoxide production in the paraventricular nucleus of Ang II-infused rats. These results indicate that EX improves arterial baroreflex function in conditions of high brain Ang II, which is mediated by the central Ang II type 1 receptor and associated with a reduction in central oxidative stress.

  13. Antihypertensive efficacy of angiotensin receptor blockers in combination with hydrochlorothiazide: a review of the factorial-design studies.

    Science.gov (United States)

    Ram, C Ventika S

    2004-10-01

    Most hypertensive patients require more than one drug for adequate blood pressure (BP) control. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends starting treatment with a thiazide diuretic or, when BP is >20/10 mm Hg above goal or in patients with diabetes, using two different antihypertensive agents. Searches of Medline, EMBASE, and BIOSIS databases identified four similarly designed, randomized, factorial studies comparing various doses of angiotensin II receptor blockers with hydrochlorothiazide as monotherapy and in combination. The methodology and results of these studies were compared. The primary efficacy end point in these studies was a decrease from baseline in mean diastolic BP after 8 weeks of therapy. All currently available angiotensin I receptor blocker/hydrochlorothiazide combinations evaluated (irbesartan, olmesartan medoxomil, telmisartan, and valsartan plus hydrochlorothiazide) produced significant systolic BP and diastolic BP reductions. Olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg provided the largest mean reduction in absolute and placebo-corrected systolic BP/diastolic BP. For all angiotensin II receptor blocker/hydrochlorothiazide combinations evaluated, > or =63% of patients achieved a diastolic BP response (diastolic BP or =10-mm Hg reduction). In conclusion, the combination of an angiotensin II receptor blocker and hydrochlorothiazide produces more substantial BP responses than monotherapy with either component.

  14. Molecule-specific Effects of Angiotensin II–Receptor Blockers Independent of the Renin–Angiotensin System

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2008-01-01

    Roč. 21, č. 8 (2008), s. 852-859 ISSN 0895-7061 R&D Projects: GA MŠk(CZ) 1M0520; GA MZd(CZ) NR8545 Grant - others:EURATOOLS(XE) LSHG-CT-2005-019015; HHMI(US) 55005624 Institutional research plan: CEZ:AV0Z50110509 Keywords : angiotensin-receptor blockers * cardiovascular protection * renin-angiotensin system Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.122, year: 2008

  15. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection.

    Science.gov (United States)

    Zablocki, Daniela; Sadoshima, Junichi

    2013-11-08

    A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.

  16. 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.

  17. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    Science.gov (United States)

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. © 2016 American Heart Association, Inc.

  18. 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.

  19. 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......-arrestin dependent signalling. Two complimentary global phosphoproteomics studies have analyzed the complex signalling induced by the AT1aR. Here we integrate the data sets from these studies and perform a joint analysis using a novel method for prediction of differential kinase activity from phosphoproteomics data....... The method builds upon NetworKIN, which applies sophisticated linear motif analysis in combination with contextual network modelling to predict kinase-substrate associations with high accuracy and sensitivity. These predictions form the basis for subsequently nonparametric statistical analysis to identify...

  20. Increased perfusion pressure enhances the expression of endothelin (ETB) and angiotensin II (AT1, AT2) receptors in rat mesenteric artery smooth muscle cells

    DEFF Research Database (Denmark)

    Lindstedt, Isak; Xu, Cang-Bao; Zhang, Yaping

    2009-01-01

    In the present study, we hypothesized that changes in perfusion pressure result in altered expression of mRNA and protein encoding for the ETA-, ETB-, AT1- and AT2-receptors in rat mesenteric vessels. Segments of the rat mesenteric artery were cannulated with glass micropipettes, pressurized and ...

  1. Rational design, efficient syntheses and biological evaluation of N,N '-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Koukoulitsa, C.; Tůmová, Tereza; Slaninová, Jiřina; Kalavrizioti, D.; Spyridaki, K.; Afantitis, A.; Melagraki, G.; Siafaka, A.; Gkini, E.; Megariotis, G.; Grdadolnik, S. G.; Papadopoulos, M. G.; Vlahakos, D.; Maragoudakis, M.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

    2013-01-01

    Roč. 62, Apr (2013), s. 352-370 ISSN 0223-5234 Institutional support: RVO:61388963 Keywords : AT1 receptor blockers * N,N '-Bis-alkylated butylimidazole analogs * synthesis * Wittig reaction * hydroxymethylation * structure elucidation Subject RIV: CC - Organic Chemistry Impact factor: 3.432, year: 2013

  2. Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat

    International Nuclear Information System (INIS)

    Rabinovitch, M.; Mullen, M.; Rosenberg, H.C.; Maruyama, K.; O'Brodovich, H.; Olley, P.M.

    1988-01-01

    Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, the authors investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. They instrumented the rats with indwelling cardiovascular catheters and compared the hemodynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. They then determine whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. They observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effects of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both antiotensin II and prostacyclin infusion similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins

  3. The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

    Czech Academy of Sciences Publication Activity Database

    Vaněčková, Ivana; Dobešová, Zdenka; Kuneš, Jaroslav; Zicha, Josef

    2012-01-01

    Roč. 35, č. 7 (2012), s. 761-768 ISSN 0916-9636 R&D Projects: GA AV ČR(CZ) IAA500110902; GA ČR(CZ) GAP304/12/0259 Institutional support: RVO:67985823 Keywords : AT(1) receptor * BP regulation * gene therapy * oligodeoxynucleotides * vasodilator and vasoconstrictor systems Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.791, year: 2012

  4. Elevated AT1 receptor protein but lower angiotensin II-binding in adipose tissue of rats with monosodium glutamate-induced obesity

    Czech Academy of Sciences Publication Activity Database

    Pinterová, L.; Železná, Blanka; Ficková, M.; Macho, L.; Križanová, O.; Ježová, D.; Zórad, Š.

    2001-01-01

    Roč. 33, č. 12 (2001), s. 708-12 ISSN 0018-5043 R&D Projects: GA ČR GA204/99/1453 Grant - others:VEGA(SK) VEGA 2/7213; VEGA(SK) VEGA 2/6084; VEGA(SK) VEGA 2/7158 Keywords : AT1 receptor * fat tissue * MSG rat Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.910, year: 2001

  5. Angiotensin II potentiates prostaglandin stimulation of cyclic AMP levels in intact bovine adrenal medulla cells but not adenylate cyclase in permeabilized cells.

    Science.gov (United States)

    Boarder, M R; Plevin, R; Marriott, D B

    1988-10-25

    The level of cyclic AMP in primary cultures of bovine adrenal medulla cells is elevated by prostaglandin E1. Angiotensin II is commonly reported to act on receptors linked to phosphoinositide metabolism or to inhibition of adenylate cyclase. We have investigated the effect of angiotensin II on prostaglandin E1-stimulated cyclic AMP levels in these primary cultures. Rather than reducing cyclic AMP levels, we have found that angiotensin II powerfully potentiates prostaglandin E1-stimulated cyclic AMP accumulation in intact cells, both in the presence and absence of phosphodiesterase inhibitors. The 50% maximal response was similar to that for stimulation of phosphoinositide breakdown by angiotensin II in these cultures. The potentiation of stimulated cyclic AMP levels was seen, although to a smaller maximum, with the protein kinase C (Ca2+/phospholipid-dependent enzyme) activating phorbol ester tetradecanoyl phorbolacetate and with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol; pretreatment (24 h) with active phorbol ester, which would be expected to diminish protein kinase C levels, attenuated the angiotensin II potentiation of cyclic AMP. Using digitonin-permeabilized cells we showed that adenylate cyclase activity was stimulated by prostaglandin E1 with the same dose-response relationship as was cyclic AMP accumulation in intact cells, but the permeabilized cells showed no response to angiotensin II. The results are discussed with respect to the hypothesis that the angiotensin II influence on cyclic AMP levels is mediated, in part, by diacylglycerol stimulation of protein kinase C.

  6. Rate of angiotensin II generation within the human pulmonary vascular bed

    DEFF Research Database (Denmark)

    Giese, Jacob; Kappelgaard, A M; Tønnesen, K H

    1980-01-01

    concentration in mixed venous blood and in systemic arterial blood. The pulmonary angiotensin II production rate was measured in fourteen patients. This parameter was linearly correlated with plasma renin concentration in systemic arterial blood. The plasma clearance of angiotensin II across the systemic......Plasma angiotensin II concentration gradients across the pulmonary vascular bed were measured during diagnostic renal venous/right heart catheterization in twenty-seven hypertensive patients with renal or renovascular disease. There was a linear correlation between the plasma angiotensin II...

  7. Rate of angiotensin II generation within the human pulmonary vascular bed

    DEFF Research Database (Denmark)

    Giese, Jacob; Kappelgaard, A M; Tønnesen, K H

    1980-01-01

    Plasma angiotensin II concentration gradients across the pulmonary vascular bed were measured during diagnostic renal venous/right heart catheterization in twenty-seven hypertensive patients with renal or renovascular disease. There was a linear correlation between the plasma angiotensin II...... concentration in mixed venous blood and in systemic arterial blood. The pulmonary angiotensin II production rate was measured in fourteen patients. This parameter was linearly correlated with plasma renin concentration in systemic arterial blood. The plasma clearance of angiotensin II across the systemic...

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    International Nuclear Information System (INIS)

    Wang, Xianwei; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L.

    2012-01-01

    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 phox , p47 phox , p67 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 2 O 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 fibroblast growth and collagen

  10. Affinity chromatography purification of angiotensin II reactor using photoactivable biotinylated probes

    Energy Technology Data Exchange (ETDEWEB)

    Marie, J.; Seyer, R.; Lombard, C.; Desarnaud, F.; Aumelas, A.; Jard, A.; Bonnafous, J.C. (Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Montpellier (France))

    1990-09-25

    The authors have developed biotinylated photoactivable probes that are suitable for covalent labeling of angiotensin II (AII) receptors and the subsequent purification of covalent complexes through immobilized avidin or streptavidin. One of these probes, biotin-NH(CH{sub 2}){sub 2}SS(CH{sub 2}){sub 2}CO-(Ala{sup 1}, Phe(4N{sub 3}){sup 8})AII, which contains a cleavage disulfide bridge in its spacer arm and which displays, in its radioiodinated form, very high affinity for AII receptors (K{sub d}{approximately}1 nM), proved to be suitable for indirect affinity chromatography of rate liver receptor with facilitated recovery from avidin gels by use of reducing agents. This constituted the central step of an efficient partial purification scheme involving hydroxylapatite chromatography, streptavidin chromatography, and thiopropyl-Sepharose chromatography. SDS-PAGE analysis and autoradiography established the identity of the purified entity (molecular weight 65K) as the AII receptor. Possible ways of completing purification to homogeneity and extrapolation of the protocols to a preparative scale are discussed, as well as the potential contribution of our new probes to the study of the structural properties of angiotensin receptors.

  11. Synthesis of Novel 1,4- Dihydropyridine Derivatives Bearing Biphenyl-2'-Tetrazole Substitution as Potential Dual Angiotensin II Receptors and Calcium Channel Blockers

    Directory of Open Access Journals (Sweden)

    Javid Shahbazi Mojarrad

    2011-06-01

    Full Text Available Introduction: We report the synthesis of novel 1,4-dihydropyridine derivatives containing biphenyl-2'-tetrazole moieties. We hypothesized that merging the key structural elements present in an AT1 receptor antagonist with key structural elements in 1,4-dihydropyridine calcium channel blockers would yield novel analogs with potential dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[2΄-(1H-tetrazole-5-yl biphenyl -4-yl] methyl] imidazole-4(or 5-yl]- 3, 5-pyridinedicarboxylate analogs. Methods: These compounds were obtained by two methods starting from biphenyltetrazolyl-4-(or 5-imidazolecarboxaldehyde intermediates employing in classical Hantzsch condensation reaction. In the first method, triphenylmethyl protecting group of 4- or 5-carboxaldehyde intermediate was first removed in acidic media and then classical Hantzsch reaction was employed in order to obtain the final products. In the second method, without further deprotection process, protected 4- or 5-carboxaldehyde intermediate directly was used in Hantzsch reaction. Results: The second method was more efficient than the first method since the deprotection and ring closure reaction occurs simultaneously in one pot. Conclusion: Eight novel dihydropridines analogs were synthesized using classic Hantzsch condensation reaction. Chemical structures of the compounds were characterized by 1H NMR, infrared and mass spectroscopy.

  12. Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.

    Science.gov (United States)

    Chu, Pei-Lun; Gigliotti, Joseph C; Cechova, Sylvia; Bodonyi-Kovacs, Gabor; Chan, Fang; Ralph, Donna Lee; Howell, Nancy; Kalantari, Kambiz; Klibanov, Alexander L; Carey, Robert M; McDonough, Alicia A; Le, Thu H

    2017-06-01

    Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout ( Tmem27 Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27 Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27 Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27 Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity. Copyright © 2017 by the American Society of Nephrology.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats

    DEFF Research Database (Denmark)

    Kwon, Tae-Hwan; Nielsen, Jakob; Knepper, M.A.

    2005-01-01

    ) vehicle infusion as the control (n = 8). All rats were maintained on a NaCl-deficient diet (0.1 meq Na+·200 g body wt−1·day−1) during the experiment. DDAVP treatment alone resulted in a significant decrease in urine output (3.1 ± 0.2 ml/day) compared with controls (11.5 ± 2.2 ml/day, P ...Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized......,476 ± 182 mosmol/kgH2O, P PKA phosphorylation consensus site Ser-256 (p-AQP2) in response to DDAVP and candesartan cotreatment compared with DDAVP treatment...

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

    Science.gov (United States)

    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.

  16. Csk regulates angiotensin II-induced podocyte apoptosis.

    Science.gov (United States)

    Zhang, Lu; Ren, Zhilong; Yang, Qian; Ding, Guohua

    2016-07-01

    Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis. In vivo, Wistar rats were randomly subjected to a normal saline or Ang II infusion. In vitro, we exposed differentiated mouse podocytes to Ang II. Ang II increased Csk expression and induced podocyte apoptosis, stimulated Csk translocation and binding to Caveolin-1, and stimulated decreased Fyn pY416, increased Fyn pY529, and nephrin dephosphorylation. Csk knockdown prevented Ang II-induced podocyte apoptosis, reduced Fyn kinase inactivation, and increased the interaction between nephrin and the activated form of Fyn, accompanied by a reduced interaction between Csk and Caveolin-1. These findings indicate that Ang II induces podocyte injury via a Csk-dependent pathway.

  17. Angiotensin II in the Human Physiology: Novel Ways for Synthetic Compounds Utilization.

    Science.gov (United States)

    Herichová, Iveta

    2016-01-01

    Renin-angiotensin system (RAS) and its main product Angiotensin II (AngII) are in the focus of the pharmacological industry mainly because of hypertension treatment. Up-regulated RAS is generally associated with cardiovascular diseases and consequent organs injuries. The classic inhibition of RAS is based on the blocking of the type 1 AngII receptors and inhibition of ACE. The concept of the circulating and tissue RAS opens new challenges for the drug targeting. In spite of a big effort invested, in some cases a traditional RAS manipulation is struggling with unwanted side effects and/or resistance to treatment. To improve the efficiency of the classic RAS inhibitors specific complications issuing from feed-back circuits inside the RAS have to be elucidated. Moreover, new peptidases identified in the AngII biosynthesis and Angiotensin 1-7/MAS pathways with opposing effects to AngII are tested for the clinical use. The aim of this review is also to bring attention to new tools in RAS manipulation based on the RNA interference (RNAi). RNAi employs small non-coding nucleic acids that interfere with the mRNA translation. The usefulness of this approach has been demonstrated in the treatment of oncological diseases and progress was also made in the field of the cardiovascular medicine. We suppose that in the near future, in addition to traditional pharmacological tools, RNAi will contribute to the control of RAS and AngII production. RNAi may also be of importance in the manipulation of tissue RAS that is not easily accessible by the traditional chemical substances.

  18. Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na⁺ Current: Experimental and Theoretical Studies.

    Science.gov (United States)

    Chang, Tzu-Tung; Yang, Chia-Jung; Lee, Yu-Chi; Wu, Sheng-Nan

    2018-02-28

    Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na⁺ (NaV) current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of INa in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented to predict changes in membrane potentials (V) as a function of maximal Na⁺ (GNa), K⁺ conductance (GK), or both. As inactivation time course of INa was increased, the bifurcation point of V versus GNa became lower, and the range between subcritical and supercritical values at the bifurcation of V versus GK correspondingly became larger. During a slowing in INa inactivation, the critical boundary between GNa and GK was shifted towards the left. Simulation studies demonstrated that progressive slowing in the inactivation time course of INa resulted in unanticipated increase of neuronal excitability by mimicking the effect of Tel in neuronal cells. Collectively, Tel can directly interact with the NaV channel to increase peak INa as well as to slow INa inactivation. It is thus highly likely that the effects of Tel or its structurally similar drugs could be another intriguing mechanism underlying their pharmacological actions in neurons or neuroendocrine cells occurring in vivo.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. The effects of angiotensin II and angiotensin-(1-7 in the rostral ventrolateral medulla of rats on stress-induced hypertension.

    Directory of Open Access Journals (Sweden)

    Dongshu Du

    Full Text Available We have shown that angiotensin II (Ang II and angiotensin-(1-7 [Ang-(1-7] increased arterial blood pressure (BP via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM in normotensive rats (control. In the present study, we tested the hypothesis that Ang II and Ang-(1-7 in the RVLM are differentially activated in stress-induced hypertension (SIH by comparing the effects of microinjection of Ang II, Ang-(1-7, and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate and less inhibitory (taurine and γ-aminobutyric acid amino acid release in SIH than in control animals. Losartan, a selective AT₁ receptor (AT₁R antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT₂ receptor (AT₂R antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1-7 and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT₁R, ACE protein expression (western blot and ACE mRNA (real-time PCR were significantly higher, whereas AT₂R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT₁R, not Ang-(1-7, system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release.

  1. EPOXYEICOSATRIENOIC ACID ANALOG ATTENUATES ANGIOTENSIN II HYPERTENSION AND KIDNEY INJURY

    Directory of Open Access Journals (Sweden)

    Md. Abdul Hye Khan

    2014-09-01

    Full Text Available Epoxyeicosatrienoic acids (EETs contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end-organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II-induced hypertension. EET-B was administered in drinking water for 14 days (10mg/kg/d and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

  2. Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

    Directory of Open Access Journals (Sweden)

    Pedley Kevin C

    2002-02-01

    Full Text Available Abstract Background Absorption of water and Na+ in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na+ diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated. Methods The levels of Angiotensin II type 1 receptor (AT1, ACE, collagen type IV, transforming growth factor-β type 1 receptor (TGF-βR1, OB cadherin and α-smooth muscle actin in both descending colon and caecum were evaluated, using immunocytochemistry and confocal microscopy, in rats fed on high and low Na+ diets (LS. These parameters were also determined during 3 months post-irradiation with 8Gy from a 60Co source in the presence and absence of the angiotensin converting enzyme inhibitor, Captopril. Results Increases in AT1 receptor (135.6% ± 18.3, P Conclusions These results demonstrate an activation of descending colonic myofibroblasts to trophic stimuli, or irradiation, which can be attenuated by Captopril, indicative of local trophic control by angiotensin II and TGF-β release.

  3. Exercício de força ativa a via AKT/mTor pelo receptor de angiotensina II tipo I no músculo cardíaco de ratos Activation of AKT-mTor signaling pathways by angiotensin II receptor type 1 after a session of strength exercise in cardiac muscle of rats

    Directory of Open Access Journals (Sweden)

    Stéphano Freitas Soares Melo

    2011-09-01

    Full Text Available O receptor de angiotensina II tipo I (AT1 tem uma importante participação no desenvolvimento da hipertrofia cardíaca. Em um trabalho publicado anteriormente, por nosso grupo, demonstramos que o bloqueio do receptor AT1 durante o treinamento de força inibiu a hipertrofia cardíaca em ratos. Por isso, o objetivo deste trabalho foi estudar a participação do receptor AT1 na ativação de vias de sinalização intracelular relacionadas com o aumento da síntese de proteína em ratos submetidos a uma sessão de exercício de força. Para isso, realizamos um experimento com seis grupos de animais (n = 6; cada: controle (Con, exercitado e sacrificado cinco minutos após o exercício (Exe 5, exercitado e sacrificado 30 minutos após o exercício (Exe 30, controle tratado com losartan (Con Los, tratado com losartan, exercitado e sacrificado cinco minutos após o exercício (Exe 5 Los, tratado com losartan, exercitado e sacrificado 30 minutos após o exercício (Exe 30 Los. Os resultados mostram que no grupo Exe 5 e Exe 30 ocorreu um aumento de 63% (P The angiotensin II type I (AT1 receptor has an important participation in the development of cardiac hypertrophy. Previously, we have shown that AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats. Here, we studied the involvement of AT1 receptor in the activation of intracellular signaling pathways related to the concentric HC in rats submitted to a session of strength exercise. Male Wistar rats were divided into 6 groups (n= 6 each: control (Con; exercised and killed 5 minutes after exercise (Exe 5; exercised and killed 30 minutes after exercise (Exe 30; control treated with Losartan (Con Los; treated with Losartan, exercised and killed 5 minutes after the exercise (Exe Los 5; treated with Losartan, exercised and killed 30 minutes after training (Exe Los 30. The results show that phosphorylation activity of AKT in group Exe 5 and Exe 30 increased 63% (P < 0

  4. Facilitative interaction between angiotensin II and oxidised LDL in cultured human coronary artery endothelial cells

    Directory of Open Access Journals (Sweden)

    Jawahar L Mehta

    2001-03-01

    Full Text Available Background Several studies have shown that angiotensin II (Ang II and oxidised low-density lipoprotein (ox-LDL are critical factors in atherosclerosis. In this study, we examined the molecular basis of mutually facilitative interactions between Ang II and ox-LDL in human coronary artery endothelial cells (HCAECs.Methods and results We observed that incubation of cultured HCAECs with Ang II (10-12 to 10-6 M for 24 hours caused a concentration-dependent increase in the expression of mRNA and protein of a specialised receptor for ox-LDL (LOX-1. These effects of Ang II were completely blocked by pretreatment of HCAECs with candesartan (10-6 M, a specific AT1-receptor blocker, but not by PD 123319 (10-6 M, a specific AT2-receptor blocker. On the other hand, incubation of HCAECs with ox-LDL (10 and 40 µg/ml for 24 hours progressively upregulated AT1-, but not AT 2-, receptor mRNA and protein. Pretreatment of cells with the anti-oxidant alpha-tocopherol (1—5 x 10-6 M inhibited the upregulation of AT1-receptor expression induced by ox-LDL (p<0.05. To determine the significance of expression of AT1-receptors and LOX-1, we measured cell injury in response to Ang II and ox-LDL. Incubation of cells with both ox-LDL and Ang II synergistically increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone (both p<0.05. Alpha-tocopherol, as well as candesartan, attenuated cell injury in response to Ang II and ox-LDL (both p<0.05.Conclusions These observations show that Ang II upregulates a novel endothelial receptor for ox-LDL (LOX-1 gene expression and ox-LDL in turn upregulates Ang II AT 1receptor gene expression. This interaction between Ang II and ox-LDL further augments cell injury in HCAECs. These findings provide basis for the use of AT1-receptor blockers and anti-oxidants in designing therapy for atherosclerosis and myocardial ischaemia.

  5. 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, 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...

  6. Angiotensin II receptors on colorectal carcinoma cells

    Czech Academy of Sciences Publication Activity Database

    Kučerová, Dana; Železná, Blanka; Šloncová, Eva; Sovová, Vlasta

    1998-01-01

    Roč. 2, č. 5 (1998), s. 593-595 ISSN 1107-3756 R&D Projects: GA ČR GA312/97/1188 Grant - others:Copernicus(BE) CIPA CT:94-0239 Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  7. Inhibitory effects of benzyl benzoate and its derivatives on angiotensin II-induced hypertension.

    Science.gov (United States)

    Ohno, Osamu; Ye, Mao; Koyama, Tomoyuki; Yazawa, Kazunaga; Mura, Emi; Matsumoto, Hiroshi; Ichino, Takao; Yamada, Kaoru; Nakamura, Kazuhiko; Ohno, Tomohiro; Yamaguchi, Kohji; Ishida, Junji; Fukamizu, Akiyoshi; Uemura, Daisuke

    2008-08-15

    Hypertension is a lifestyle-related disease which often leads to serious conditions such as heart disease and cerebral hemorrhage. Angiotensin II (Ang II) plays an important role in regulating cardiovascular homeostasis. Consequently, antagonists that block the interaction of Ang II with its receptors are thought to be effective in the suppression of hypertension. In this study, we searched for plant compounds that had antagonist-like activity toward Ang II receptors. From among 435 plant samples, we found that EtOH extract from the resin of sweet gum Liquidambar styraciflua strongly inhibited Ang II signaling. We isolated benzyl benzoate and benzyl cinnamate from this extract and found that those compounds inhibited the function of Ang II in a dose-dependent manner without cytotoxicity. An in vivo study showed that benzyl benzoate significantly suppressed Ang II-induced hypertension in mice. In addition, we synthesized more than 40 derivatives of benzyl benzoate and found that the meta-methyl and 3-methylbenzyl 2'-nitrobenzoate derivatives showed about 10-fold higher activity than benzyl benzoate itself. Thus, benzyl benzoate, its derivatives, and benzyl cinnamate may be useful for reducing hypertension.

  8. 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.

  9. 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.

  10. Captopril avoids hypertension, the increase in plasma angiotensin II but increases angiotensin 1-7 and angiotensin II-induced perfusion pressure in isolated kidney in SHR.

    Science.gov (United States)

    Castro-Moreno, P; Pardo, J P; Hernández-Muñoz, R; López-Guerrero, J J; Del Valle-Mondragón, L; Pastelín-Hernández, G; Ibarra-Barajas, M; Villalobos-Molina, R

    2012-10-01

    We investigated captopril effects, an ACE inhibitor, on hypertension development, on Ang II and Ang-(1-7) plasma concentrations, on Ang II-induced contraction in isolated kidneys, and on kidney AT1R from spontaneously hypertensive (SHR) rats. Five weeks-old SHR and Wistar Kyoto (WKY) rats were treated with captopril at 30 mg/kg/day, in drinking water for 2 or 14 weeks. Systolic blood pressure (SBP) was measured, and isolated kidneys were tested for perfusion pressure and AT1R expression; while Ang II and Ang-(1-7) concentrations were determined in plasma. Captopril did not modify SBP in WKY rats and avoided its increase as SHR aged. Plasma Ang-II concentration was ∼4-5 folds higher in SHR rats, and captopril reduced it (Pcaptopril increased Ang-(1-7) by ∼2 fold in all rat groups. Captopril increased Ang II-induced pressor response in kidneys of WKY and SHR rats, phenomenon not observed in kidneys stimulated with phenylephrine, a α₁-adrenoceptor agonist. Captopril did not modify AT1R in kidney cortex and medulla among rat strains and ages. Data indicate that captopril increased Ang II-induced kidney perfusion pressure but not AT₁R density in kidney of WKY and SHR rats, due to blockade of angiotensin II synthesis; however, ACE inhibitors may have other actions like activating signaling processes that could contribute to their diverse effects. © 2012 Blackwell Publishing Ltd.

  11. TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiao-Qing; Zhang, Dao-Liang [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-Feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhao, Liang, E-mail: zhaol_zg@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Wang, Quan-Xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Liu, Xu, E-mail: liuxu_xk@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China)

    2015-08-14

    Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. Methods and results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. - Highlights: • Compared with SR, AF showed higher TRIF expression in left atrial appendage. • TRIF siRNA reversed macrophage chemotaxis induced by AngII-treated fibroblast. • TRIF siRNA reversed chemokines expressions induced by AngII in fibroblast. • AngII-stimulated atrial fibroblast proliferation was enhanced by macrophage.

  12. An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies.

    Directory of Open Access Journals (Sweden)

    Graziela S Ceravolo

    Full Text Available The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R contributes to vascular hypertrophy in angiotensin II (ANG II-induced hypertension, through a mechanism involving reactive oxygen species (ROS generation and extracellular signal-regulated kinase (ERK1/2 activation. Male Wistar rats were infused with vehicle (control rats, 400 ng/Kg/min ANG II (ANG II rats or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9-Leu(8-bradykinin (ANGII+DAL rats, via osmotic mini-pumps (14 days or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats. After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE: 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1 and ERK1/2 phosphorylation (137 ± 20.7% in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC stimulated with low concentrations (0.1 nM of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM, B1R antagonist (10 µM and Tiron (superoxide anion scavenger, 10 mM. These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth

  13. Life and death in the microcirculation: a role for angiotensin II

    Science.gov (United States)

    Greene, A. S.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    OBJECTIVE: Angiotensin II (ANGII) plays a critical role in the maintenance of the microcirculation and in the anatomical loss of microvessels (rarefaction) that occurs in low renin forms of hypertension and in animals fed a high-salt diet. Elevations in sodium intake can trigger a series of hemodynamic and hormonal responses culminating in a substantial rarefaction of small arterioles and capillaries in both normal and reduced renal mass hypertensive rats. METHODS: Immunohistochemistry, Northern blot, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of microdissected blood vessels were used to localize ANGII receptors in the microcirculation. Chronic infusion of ANGII and other physiologic and pharmacologic manipulations of the reninangiotensin system in rats was combined with morphologic and mathematical analysis of the network architecture. RESULTS: We have shown that rarefaction of the microcirculation can cause an increase in total peripheral resistance, reduced tissue perfusion, decreased oxygen delivery, and impaired organ function. Although the mechanisms by which this occurs are not well understood, a number of key observations point to a role for the renin-angiotensin system in this effect. First, ANGII infused systemically at subpressor levels, or locally into the skeletal muscle interstitium, can induce significant microvessel growth. Second, localization of ANGII receptor proteins by immunohistochemistry and Western blotting and RNA localization by RT-PCR confirm the presence of AT1 receptors, which are growth-stimulatory, and AT2 receptors, which are growth-inhibitory in the microcirculation. Third, maintenance of ANGII at normal levels during periods of hypertension or high-salt diet completely eliminates rarefaction. CONCLUSIONS: Taken together, these results support the hypothesis that ANGII acting through AT1- and AT2-receptor mechanisms modulate vessel density during high-salt diet and hypertension.

  14. Central metabolism of angiotensins

    International Nuclear Information System (INIS)

    Camara, C.G.

    1984-01-01

    High performance liquid chromatography analyses of the radioactivity derived from 125 I-angiotensins and bound to cellular receptors in the brain and peripheral tissue reveal that, first, the specifically bound radioactivity is a heterogeneous mixture of several molecular species. Second, the observed patterns of 125 I-angiotensin degradation are largely the result of the activity of membrane-bound amino peptidases, which are enriched in the crude mitochrondrial tissue fraction; third, in general, peptidase inhibitors decrease the apparent binding of 125 I-angiotensins to brain tissue, and they decrease this binding more than they decrease the degradation of the radioligands; fourth, peptidase inhibitors specific for individual enzymes, but not broad-spectrum peptidase inhibitors, actually decrease the amount of 125 I-angiotensin II bound to brain tissue, suggesting that angiotensin receptors in the brain may be associated with membrane-bound peptidases; fifth, tyrosine and other aromatic and branched-chain aliphatic amino acids, end products of angiotensin degradation by membrane peptidases, are quickly removed from the extracellular compartment by the activity of a high-affinity transport system, identical with the leucine-preferring uptake system, which is enriched in the crude mitochondrial tissue fraction, containing the synaptosomes; and sixth, the distribution of this uptake system in rat and gerbil brain is nearly identical and corresponds with the central distribution of 125 I-angiotensin binding in the gerbil, but neither with the distribution of 125 I-angiotensin II binding in the rat brain

  15. Intracrine angiotensin II functions originate from noncanonical pathways in the human heart.

    Science.gov (United States)

    Ferrario, Carlos M; Ahmad, Sarfaraz; Varagic, Jasmina; Cheng, Che Ping; Groban, Leanne; Wang, Hao; Collawn, James F; Dell Italia, Louis J

    2016-08-01

    Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

  16. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

    DEFF Research Database (Denmark)

    NN, NN; Yusuf, S; Teo, K

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...... of cardiovascular death, myocardial infarction, or stroke. FUNDING: Boehringer Ingelheim....

  17. Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.

    Directory of Open Access Journals (Sweden)

    Carolina Lavoz

    Full Text Available Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1 has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

  18. 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.

  19. 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....

  20. ANGIOTENSIN II REGULATES ADRENAL VASCULAR TONE THROUGH ZONA GLOMERULOSA CELL-DERIVED EETS AND DHETS

    Science.gov (United States)

    Kopf, Phillip G.; Gauthier, Kathryn M.; Zhang, David X.; Falck, John R.; Campbell, William B.

    2011-01-01

    Elevated concentrations of aldosterone are associated with several cardiovascular diseases. Angiotensin II increases aldosterone secretion and adrenal blood flow. This concurrent increase in steroidogenesis and adrenal blood flow is not understood. We investigated the role of zona glomerulosa cells in the regulation of vascular tone of bovine adrenal cortical arteries by angiotensin II. Zona glomerulosa cells enhance endothelium-dependent relaxations to angiotensin II. The zona glomerulosa cell-dependent relaxations to angiotensin II are unchanged by removing the endothelium-dependent response to angiotensin II. These zona glomerulosa cell-mediated relaxations are ablated by cytochrome P450 inhibition, epoxyeicostrienoic acid antagonism, and potassium channel blockade. Analysis of zona glomerulosa cell epoxyeicosatrienoic acid production by liquid chromatography/mass spectrometry demonstrates an increase in epoxyeicosatrienoic and dihydroxyeicosatrienoic acids with angiotensin II stimulation. These epoxyeicosatrienoic and dihydroxyeicosatrienoic acids produced similar concentration-dependent relaxations of adrenal arteries, which were attenuated by epoxyeicosatrienoic acid antagonism. Whole cell potassium current of adrenal artery smooth muscle cells were increased by angiotensin II stimulation in the presence of zona glomerulosa cells but decreased in the absence of zona glomerulosa cells. This increase in potassium current was abolished by iberiotoxin. Similarly, 14,15-epoxyeicosatrienoic acid induced concentration-dependent increases in potassium current, which was abolished by iberiotoxin. Zona glomerulosa cell aldosterone release is not directly altered by epoxyeicosatrienoic acids. These data suggest that angiotensin II stimulates zona glomerulosa cells to release epoxyeicosatrienoic and dihydroxyeicosatrienoic acids, resulting in potassium channel activation and relaxation of adrenal arteries. This provides a mechanism by which Ang II concurrently increases

  1. Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Touyz R.M.

    2004-01-01

    Full Text Available Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.

  2. Exercise training enhances baroreflex sensitivity by an angiotensin II-dependent mechanism in chronic heart failure.

    Science.gov (United States)

    Mousa, Tarek M; Liu, Dongmei; Cornish, Kurtis G; Zucker, Irving H

    2008-03-01

    Exercise training (EX) has become an important modality capable of enhancing the quality of life and survival of patients with chronic heart failure (CHF). Although 4 wk of EX in animals with CHF evoked a reduction in renal sympathetic nerve activity and ANG II plasma levels and an enhancement in baroreflex sensitivity at rest (Liu JL, Irvine S, Reid IA, Patel KP, Zucker IH, Circulation 102: 1854-1862, 2000; Liu JL, Kulakofsky J, Zucker IH, J Appl Physiol 92: 2403-2408, 2002), it is unclear whether these phenomena are causally related. CHF was induced in rabbits by ventricular pacing (360-380 beats/min) for 3 wk. CHF rabbits were EX for 4 wk at 15-18 m/min, 6 days/wk, 30-40 min/day. Three groups of rabbits were studied: CHF (with no EX), CHF-EX, and CHF-EX + ANG II infusion [in which ANG II levels were kept at or near levels observed in CHF (non-EX) rabbits by subcutaneous osmotic minipump infusion]. EX prevented the increase in plasma ANG II levels shown in CHF rabbits. CHF and CHF-EX + ANG II infusion rabbits had significantly depressed baroreflex sensitivity slopes (P baroreflex function in CHF after EX are due to the concomitant reduction in ANG II and angiotensin receptors in the central nervous system.

  3. 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.

  4. 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...

  5. Clusterin/apolipoprotein J attenuates angiotensin II-induced renal fibrosis.

    Directory of Open Access Journals (Sweden)

    Gwon-Soo Jung

    Full Text Available The blockade of angiotensin II (Ang II is a major therapeutic strategy for diabetic nephropathy. The main roles of Ang II in renal disease are mediated via the Ang type 1 receptor (AT1R. Upregulation of clusterin/apolipoprotein J has been reported in nephropathy models, suggesting it has a protective role in nephropathogenesis. Here, we studied how clusterin acts against Ang II-induced renal fibrosis. Levels of AT1R and fibrotic markers in clusterin-/- mice and Ang II infused rats transfected with an adenovirus encoding clusterin were evaluated by immunoblot analysis, real time RT-PCR, and immunohistochemical staining. The effect of clusterin on renal fibrosis was evaluated in NRK-52E cells, a cultured renal tubular epithelial cell line, using immunoblot analysis and real time RT-PCR. Nuclear localization of NF-κB was evaluated using immunofluorecence and co-immunoprecipitation. Renal fibrosis and expression of AT1R was higher in the kidneys of clusterin-/- mice than in those of wild-type mice. Furthermore, loss of clusterin accelerated Ang II-stimulated renal fibrosis and AT1R expression. Overexpression of clusterin in proximal tubular epithelial cells decreased the levels of Ang II-stimulated fibrotic markers and AT1R. Moreover, intrarenal delivery of clusterin attenuated Ang II-mediated expression of fibrotic markers and AT1R in rats. Fluorescence microscopy and co-immunoprecipitation in conjunction with western blot revealed that clusterin inhibited Ang II-stimulated nuclear localization of p-NF-κB via a direct physical interaction and subsequently decreased the AT1R level in proximal tubular epithelial cells. These data suggest that clusterin attenuates Ang II-induced renal fibrosis by inhibition of NF-κB activation and subsequent downregulation of AT1R. This study raises the possibility that clusterin could be used as a therapeutic target for Ang II-induced renal diseases.

  6. Angiotensin receptor blockade improves cardiac mitochondrial activity in response to an acute glucose load in obese insulin resistant rats

    Directory of Open Access Journals (Sweden)

    Max Thorwald

    2018-04-01

    Full Text Available Hyperglycemia increases the risk of oxidant overproduction in the heart through activation of a multitude of pathways. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer, contributing to mitochondrial dysfunction. Furthermore, the renin-angiotensin system (RAS becomes inappropriately activated during metabolic syndrome, increasing oxidant production. To combat excess oxidant production, the transcription factor, nuclear factor erythriod-2- related factor 2 (Nrf2, induces expression of many antioxidant genes. We hypothesized that angiotensin II receptor type 1 (AT1 blockade improves mitochondrial function in response to an acute glucose load via upregulation of Nrf2. To address this hypothesis, an oral glucose challenge was performed in three groups prior to dissection (n = 5–8 animals/group/time point of adult male rats: 1 Long Evans Tokushima Otsuka (LETO; lean strain-control, 2 insulin resistant, obese Otsuka Long Evans Tokushima Fatty (OLETF, and 3 OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 6 weeks. Hearts were collected at T0, T60, and T120 minutes post-glucose infusion. ARB increased Nrf2 binding 32% compared to OLETF at T60. Total superoxide dismutase (SOD and catalase (CAT activities were increased 45% and 66% respectively in ARB treated animals compared to OLETF. Mitochondrial enzyme activities of aconitase, complex I, and complex II increased by 135%, 33% and 66%, respectively in ARB compared to OLETF. These data demonstrate the protective effects of AT1 blockade on mitochondrial function during the manifestation of insulin resistance suggesting that the inappropriate activation of AT1 during insulin resistance may impair Nrf2 translocation and subsequent antioxidant activities and mitochondrial function. Keywords: Angiotensin II, Mitochondria, Cardiac, Antioxidant enzymes, TCA cycle

  7. The role of angiotensin II in the regulation of breast cancer cell adhesion and invasion.

    Science.gov (United States)

    Puddefoot, J R; Udeozo, U K I; Barker, S; Vinson, G P

    2006-09-01

    As breast cancer remains the most common cause of cancer death in women, there is a continuing need not only to further characterise the processes of cancer progression, but also to improve accuracy of prognostic markers. Breast epithelial cells express components of the renin angiotensin system and studies suggest that these may be altered in disease progression. In addition, altered integrin expression correlates with lymph node metastasis. The aim of this study was to investigate the relationship between angiotensin II (AII) and integrins in breast tissue and, in particular, their role in breast cancer cell metastasis. Using in vitro assays, AII (10(-6) M)-treated MCF-7 and T47D breast cancer cells both show reduced adhesion to extracellular matrix proteins collagen-, fibronectin- and laminin-coated wells (Plaminin-coated membranes (Pintegrin alpha3 and beta1. Using specific inhibitors, this was shown to occur through protein kinase C signalling. These data suggest that AII reduces cell adhesion and invasion through the type 1 receptor and that this effect may be due to reduced expression of integrins, and in particular alpha3 and beta1.

  8. Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

    Directory of Open Access Journals (Sweden)

    T.M.C. Pereira

    2009-07-01

    Full Text Available Nitric oxide (NO influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS. Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight divided into 2K1C (N = 19 and sham-operated (N = 19 groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9 was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan (10 mg·kg-1·day-1; N = 5 or the superoxide scavenger tempol (0.2 mmol·kg-1·day-1; N = 5, which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.

  9. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    Science.gov (United States)

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

  10. Mesenteric Responsiveness To Angiotensin I, II And Captopril During Renovascular Hypertension Induction

    Directory of Open Access Journals (Sweden)

    Sharifi A M

    2003-08-01

    Full Text Available Essential hypertension is one of the risk factors of cardiovascular diseases. Hypertension etiology is not completely known, it seems that rennin-Angiotensin system has an important role in its etiology, Thus better recognition of this system and its activity changes or vascular reaction changes to different parts of this system during progressive hypertension can be more effective in better recognition of the disease progress and treatment."nMaterials and Methods: In this study responsiveness of mesenteric vessels of Goldblatt two kidney- one clip (2k-lc renovascular hypertensive rats to angiotensin / and II with and with out captopril during a time of two , four , six and eight weeks after hypertension induction was investigated and compared with control and surgical sham groups."nResults: This study shows that vascular responsiveness to angiotensin // in animals that passed four weeks of their hypertension , (p< 0.05 and in the sixth and eight week of post induction hypertension (p< 0.01 and p< 0.001 has a significant different with both sham and control groups. Also it has been observed that an increased reaction to angiotensin II with an increased significant rate of arterial hypertension in hypertensive group. In the other hand in spite of inhibition of angiotensin converting enzyme by captopril in animals that have been eight weeks hypertension , on the contrary to other groups reactive to angiotensin /."nConclusion: Results of this study show that vessels reaction to angiotensin /and II increased due to six to eight weeks post induction renal hypertension. Captopril does not inhibite mesenteric vessels reaction to Angiotensin / in hypertensive Rats after eight weeks. Try to completely inhibit production of angiotensin II maybe a hopful way in controlling essential hypertension.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  12. Leptin Mediate High Fat Diet Sensitization of Angiotensin II-elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation

    Science.gov (United States)

    Xue, Baojian; Yu, Yang; Zhang, Zhongming; Guo, Fang; Beltz, Terry G.; Thunhorst, Robert L.; Felder, Robert B.; Johnson, Alan Kim

    2016-01-01

    Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin (Ang) II administration that is mediated at least in part by increased activity of brain renin-angiotensin system (RAS) and proinflammatory cytokines (PICs). The present study tested whether leptin mediates this HFD-induced sensitization of Ang II-elicited hypertension by interacting with brain RAS and PICs mechanisms. Rats fed a HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels and mRNA expression of leptin and its receptors in the lamina terminalis (LT) and hypothalamic paraventricular nucleus (PVN). Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of Ang II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the AT1-R antagonist irbesartan, the TNF-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the RAS and PICs in the LT and PVN. The leptin antagonist and the inhibitors of AT1-R, TNF-α synthesis and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by leptin through upregulation of central RAS and PICs. PMID:27021010

  13. 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

  14. Standardization of radioimmunoassay for dosage of angiotensin II (ang-II) and its methodological evaluation

    International Nuclear Information System (INIS)

    Mantovani, Milene; Mecawi, Andre S.; Elias, Lucila L.K.; Antunes-Rodrigues, Jose

    2011-01-01

    This paper standardizes the radioimmunoassay (RIA) for dosage of ANG-II of rats, after experimental conditions of saline hypertonic (2%), treating with losartan (antagonist of ANG-II), hydric privation, and acute hemorrhage (25%). After that, the plasmatic ANG-II was extracted for dosage of RIA, whose sensitiveness was of 1.95 pg/m L, with detection of 1.95 to 1000 pg/m L. The treatment with saline reduced the concentration of ANG-II, while the administration pf losartan, the hydric administration and the hemorrhage increase the values, related to the control group. Those results indicate variations in the plasmatic concentration of ANG-II according to the experimental protocols, validating the method for evaluation of activity renin-angiotensin

  15. Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Kastrup, J; Christensen, N J

    1985-01-01

    1. Plasma noradrenaline and adrenaline concentrations were measured in ten subjects before, during and after intravenous infusion of angiotensin II (ANG II) in order to determine the sympathoadrenal response of ANG II challenge in man. In five subjects ganglionic blockade was additionally performed...

  16. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    Science.gov (United States)

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  17. Angiotensin II inhibits the Na+-K+ pump via PKC-dependent activation of NADPH oxidase.

    Science.gov (United States)

    White, Caroline N; Figtree, Gemma A; Liu, Chia-Chi; Garcia, Alvaro; Hamilton, Elisha J; Chia, Karin K M; Rasmussen, Helge H

    2009-04-01

    The sarcolemmal Na(+)-K(+) pump, pivotal in cardiac myocyte function, is inhibited by angiotensin II (ANG II). Since ANG II activates NADPH oxidase, we tested the hypothesis that NADPH oxidase mediates the pump inhibition. Exposure to 100 nmol/l ANG II increased superoxide-sensitive fluorescence of isolated rabbit ventricular myocytes. The increase was abolished by pegylated superoxide dismutase (SOD), by the NADPH oxidase inhibitor apocynin, and by myristolated inhibitory peptide to epsilon-protein kinase C (epsilonPKC), previously implicated in ANG II-induced Na(+)-K(+) pump inhibition. A role for epsilonPKC was also supported by an ANG II-induced increase in coimmunoprecipitation of epsilonPKC with the receptor for the activated kinase and with the cytosolic p47(phox) subunit of NADPH oxidase. ANG II decreased electrogenic Na(+)-K(+) pump current in voltage-clamped myocytes. The decrease was abolished by SOD, by the gp91ds inhibitory peptide that blocks assembly and activation of NADPH oxidase, and by epsilonPKC inhibitory peptide. Since colocalization should facilitate NADPH oxidase-dependent regulation of the Na(+)-K(+) pump, we examined whether there is physical association between the pump subunits and NADPH oxidase. The alpha(1)-subunit coimmunoprecipitated with caveolin 3 and with membrane-associated p22(phox) and cytosolic p47(phox) NADPH oxidase subunits at baseline. ANG II had no effect on alpha(1)/caveolin 3 or alpha(1)/p22(phox) interaction, but it increased alpha(1)/p47(phox) coimmunoprecipitation. We conclude that ANG II inhibits the Na(+)-K(+) pump via PKC-dependent NADPH oxidase activation.

  18. Role of Kidneys in Sex Differences in Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Wang, Lei; Wang, Ximing; Qu, Helena Y; Jiang, Shan; Zhang, Jie; Fu, Liying; Buggs, Jacentha; Pang, Bo; Wei, Jin; Liu, Ruisheng

    2017-12-01

    The significance of kidneys in regulation of sodium and water balance and hemodynamics has been demonstrated both in patients and animal models. In the present study, we tested our hypothesis that kidneys play an essential role in control of sex differences in angiotensin II (Ang II)-dependent hypertension. Kidney transplantations (KTXs) were performed between male (M) and female (F) C57BL/6 mice (donor→recipient: F→F, M→M, F→M, and M→F). Radiotelemetry transmitters were implanted for measurement of mean arterial pressure during the infusion of Ang II (600 ng·kg -1 ·min -1 ). Gene expressions and inflammatory responses in the transplanted grafts were assessed. We found that same-sex-KTX mice still exhibited sex differences in Ang II-dependent hypertension (31.3±0.8 mm Hg in M→M versus 12.2±0.6 mm Hg in F→F), which were reduced between males and females when they received kidneys of the opposite sex (32.9±1 mm Hg in M→F versus 22.3±0.7 mm Hg in F→M). The sex differences in gene expressions, including AT 1 R (angiotensin II receptor, type 1), AT 1 R/AT 2 R, ET-1 (endothelin-1), ETA (endothelin receptor type A), NHE3 (sodium-hydrogen exchanger 3), α-ENaC (α-epithelial sodium channel), and γ-ENaC, were unaltered in same-sex KTXs and much lessened in cross-sex KTXs. In addition, the cross-sex KTXs exhibited more robust inflammatory responses reflected by higher expression of IL-6 (interleukin 6), TNFα (tumor necrosis factor α), and KC (keratinocyte-derived chemokine) than same-sex KTX. Our results indicate that kidneys play an essential role in sex differences of Ang II-dependent hypertension. KTX of male kidneys to females augmented the blood pressure response, whereas KTX of female kidneys to males attenuated the blood pressure response. The host's extrarenal systems modulate expressions of many genes and inflammatory response, which may also contribute to the sex differences in blood pressure regulation. © 2017 American Heart

  19. Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles

    Directory of Open Access Journals (Sweden)

    Siu-Lung eChan

    2013-06-01

    Full Text Available Angiotensin II is an important determinant of inward remodeling in cerebral arterioles. Many of the vascular effects of angiotensin II are mediated by reactive oxygen species generated from homologues of NADPH oxidase with Nox2 predominating in small arteries and arterioles. Therefore, we tested the hypothesis that superoxide generated by Nox2 plays a role in angiotensin II-induced cerebral arteriolar remodeling. We examined Nox2-deficient and wild-type mice in which a pressor or a non-pressor dose of angiotensin II (1000 or 200 ng/kg/day or saline was infused for 4 weeks via osmotic minipumps. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area (by histology and superoxide level (by hydroethidine staining of cerebral arterioles were determined ex vivo. The pressor, but not the non-pressor, dose of angiotensin II significantly increased systolic arterial pressure in both wild-type and Nox2-deficient mice. Both doses of angiotensin II increased superoxide levels and significantly reduced external diameter in maximally dilated cerebral arterioles in wild-type mice. Increased superoxide and inward remodeling were prevented in Nox2-deficient mice. Moreover, only the pressor dose of AngII increased cross-sectional area of arteriolar wall in wild-type mice and was prevented in Nox2-deficient mice. In conclusion, superoxide derived from Nox2-containing NADPH oxidase plays an important role in angiotensin II-mediated inward remodeling in cerebral arterioles. This effect appears to be independent of pressure and different from that of hypertrophy.

  20. GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Zhuo [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, 105 Jiefang Road, Jinan, 250013 (China); Wang, Hao; Lin, Marina [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Groban, Leanne, E-mail: lgroban@wakehealth.edu [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Hypertension and Vascular Disease Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States); Office of Women in Medicine and Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States)

    2015-03-27

    Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression.

  1. 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.

  2. Altered renal function and the development of angiotensin II-dependent hypertension

    OpenAIRE

    Ashek, Ali

    2011-01-01

    Inappropriate modulation of the renin angiotensin system (RAS) can lead to derangements of blood pressure homeostasis in humans. Cyp1a1-mRen2.F transgenic rats were used to define the renal mechanisms underlying the development of angiotensin II-dependent hypertension. These transgenic rats were previously generated by introducing the mouse Ren2 gene into the rat genome under the control of a Cyp1a1 inducible promoter. The aim of the current investigation was to establish th...

  3. Angiotensin II inactivation process in cultured mouse spinal cord cells

    Energy Technology Data Exchange (ETDEWEB)

    Allard, M.; Simonnet, G.; Dupouy, B.; Vincent, J.D.

    1987-05-01

    The pattern of hydrolysis of (/sup 3/H)angiotensin II ( (/sup 3/H)AII; 20 nM) by intact cells was studied on cultured mouse spinal cord cells. Degradation products were identified by HPLC analysis after incubation for 2 h at 37 degrees C. In the absence of peptidase inhibitors, 70% of (/sup 3/H)AII was degraded, and the main labeled metabolite was (/sup 3/H)tyrosine (40% of total radioactivity). Minor quantities of (/sup 3/H)AII1-5 and (/sup 3/H)AII4-8 were formed. Results obtained in the presence of various inhibitors indicate that several enzymes were involved in the AII-hydrolyzing process. Dipeptidyl aminopeptidase III (EC 3.4.14.4) could play a critical role, as suggested by the formation of (/sup 3/H)Val3-Tyr4 and (/sup 3/H)-Tyr4-Ile5 in the presence of bestatin (2 X 10(-5) M). This hypothesis was confirmed by the potency of dipeptidyl amino-peptidase III inhibitors to inhibit both (/sup 3/H)AII hydrolysis and formation of these /sup 3/H-labeled dipeptides. An arylamidase-like activity could also be participating in (/sup 3/H)AII hydrolysis, because higher concentrations of bestatin (10(-4) M) in association with dipeptidyl aminopeptidase III inhibitors totally inhibited (/sup 3/H)tyrosine formation, increased protection of (/sup 3/H)AII and (/sup 3/H)AII1-7 formed, and provoked a slight accumulation of (/sup 3/H)AII2-8. These results suggest that the formation of (/sup 3/H)AII2-8 is due to the action of a bestatin-insensitive acidic aminopeptidase and that the Pro7-Phe8 cleavage is also a step of AII hydrolysis, resulting from the action of an unidentified peptidase different from prolyl endopeptidase.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension.

    Science.gov (United States)

    Chan, Christopher T; Sobey, Christopher G; Lieu, Maggie; Ferens, Dorota; Kett, Michelle M; Diep, Henry; Kim, Hyun Ah; Krishnan, Shalini M; Lewis, Caitlin V; Salimova, Ekaterina; Tipping, Peter; Vinh, Antony; Samuel, Chrishan S; Peter, Karlheinz; Guzik, Tomasz J; Kyaw, Tin S; Toh, Ban-Hock; Bobik, Alexander; Drummond, Grant R

    2015-11-01

    Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R(-/-)) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R(-/-) (Δ30±4 mm Hg) relative to wild-type (Δ41±5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R(-/-) mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor-β expression. BAFF-R(-/-) mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by ≈35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension. © 2015 American Heart Association, Inc.

  5. Spiral CT during pharmacoangiography with angiotensin II in patients with pancreatic disease. Technique and diagnostic efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, C.; Mihara, N.; Hosomi, N.; Inoue, E.; Fujita, M. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Diagnostic Radiology; Ohigashi, H.; Ishikawa, O. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Surgery; Nakaizumi, A. [Osaka Medical Center for Cancer and Cardiovascular Deseases (Japan). Dept. of Internal Medicine; Ishiguro, S. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Pathology

    1998-03-01

    Purpose: To compare the diagnostic efficacy of pancreatic pharmacoangiographic CT using angiotensin II with conventional angiographic CT. Material and Methods: Eighteen patients with space-occupying pancreatic disease were examined in this study. Pharmacoangiographic CT was performed with a 1-3-{mu}/6-ml solution of angiotensin II injected through a catheter into the celiac artery during spiral CT. Results: In 17 of the 18 (94%) patients, the area of pancreatic parenchymal enhancement was the same or larger at pharmacoangiographic CT than at conventional angiographic CT. The attenuation value of the pancreatic parenchyma was significantly increased at pharmacoangiographic CT (p=0.0010). Although the attenuation value of tumors was also increased on images obtained after the injection of angiotensin II, the tumor-to-pancreas contrast was significantly greater at pharmacoangiographic CT (p=0.0479). The mean differences in attenuation between tumor and pancreas at angiographic CT with and without angiotensin II were respectively 182 HU and 115 HU. Conclusion: Pharmacoangiographic CT with angiotensin II proved superior to conventional angiographic CT in the diagnosis of pancreatic disease. We therefore recommend it as a supplementary technique at the angiographic examination of patients with suspected pancreatic tumor. (orig.).

  6. Sex differences in the drinking response to angiotensin II (AngII): Effect of body weight.

    Science.gov (United States)

    Santollo, Jessica; Torregrossa, Ann-Marie; Daniels, Derek

    2017-07-01

    Sex differences in fluid intake stimulated by angiotensin II (AngII) have been reported, but the direction of the differences is inconsistent. To resolve these discrepancies, we measured water intake by male and female rats given AngII. Males drank more than females, but when intake was normalized to body weight, the sex difference was reversed. Weight-matched males and females, however, had no difference in intake. Using a linear mixed model analysis, we found that intake was influenced by weight, sex, and AngII dose. We used linear regression to disentangle these effects further. Comparison of regression coefficients revealed sex and weight differences at high doses of AngII. Specifically, after 100ng AngII, weight was a predictor of intake in males, but not in females. Next, we tested for differences in AngII-induced intake in male and females allowed to drink both water and saline. Again, males drank more water than females, but females showed a stronger preference for saline. Drinking microstructure analysis suggested that these differences were mediated by postingestive signals and more bottle switches by the females. Finally, we probed for differences in the expression of components of the renin-angiotensin system in the brains of males and females and found sex differences in several genes in discrete brain regions. These results provide new information to help understand key sex differences in ingestive behaviors, and highlight the need for additional research to understand baseline sex differences, particularly in light of the new NIH initiative to balance sex in biomedical research. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. New perspectives in the renin-angiotensin-aldosterone system (RAAS) II: albumin suppresses angiotensin converting enzyme (ACE) activity in human.

    Science.gov (United States)

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M; Fülöp, Gábor Á; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7 ± 0.7 and 9.5 ± 1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14 ± 1.34 mN, without HSA: 13.54 ± 2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73 ± 2.17 mN, without HSA: 19.22 ± 3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.

  8. Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiao-qing [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China); Liu, Xu, E-mail: xkliuxu@126.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China); Wang, Quan-xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Zhang, Ming-jian; Guo, Meng; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Jiang, Wei-feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China)

    2015-01-01

    The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transforming growth factor-β1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway. - Highlights: • Angiotensin II increased atrial fibrosis and related gene expressions in mice. • Angiotensin II induced atrial fibroblasts proliferation by activating signaling pathway. • Pioglitazone reversed both aforementioned changes.

  9. Evidence for an angiotensin II-like material and for a rapid metabolism of angiotensin II in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Simonnet, G.; Carayon, A.; Alard, M.; Cesselin, F.; Lagoguey, A. (Institut National de la Sante et de la Recherche Medicale (INSERM), 33-Bordeaux (France). Unite de Neurobiologie des Comportements)

    1984-06-18

    Radioimmunoassay and radioreceptor assay for angiotensin II (AII) have been developed to detect AII-like material in rat brain extracts using HCl extraction and boiling. The amount of AII-like material found was 270 +- 39 fmol/brain with radioimmunoassay and 67 +- 7.8 pmol/brain with radioreceptor assay. However, chromatographic separation by gel filtration on a Sephadex G25 column revealed that this material was not authentic AII, but of higher molecular weight. Column chromatography on Sephacryl S300 combined with radioimmunoassay permitted us to show that the major part of the AII-like material has a molecular weight of about 10,000. To test the hypothesis that very rapid degradation of AII could explain the difficulty in detecting endogenous AII in the rat brain, we studied the metabolism of AII using HPLC analysis of the in vitro degradation of (/sup 3/H)AI and (/sup 3/H)AII (20 nM) by brain homogenates. HPLC analysis showed no detectable (/sup 3/H)AII generation from (/sup 3/H)AI. (/sup 3/H)AI and (/sup 3/H)AII yielded the same (/sup 3/H)metabolites corresponding to two peaks ..cap alpha.. and ..beta... Nevertheless, by adding an excess of unlabeled Ileu/sup 5/-AII, which competitively inhibits AII-angiotensinase activity, it was possible to detect the formation of (/sup 3/H)AII from (/sup 3/H)AI. We suggest that very low levels of AII could coexist with a higher molecular weight AII-like compound in the rat brain and that very rapid degradation of AII may account for the difficulty in detecting this peptide in the brain.

  10. Effects of angiotensin II blockade on intermediate cardiovascular endpoints in haemodialysis patients: a randomised double-blind placebo-controlled one-year intervention trial (SAFIR study)

    DEFF Research Database (Denmark)

    Peters, Christian Daugaard; Kjærgaard, Krista Dybtved; Jensen, Jens Dam

    such as central aortic BP, carotid-femoral pulse wave velocity, left ventricular mass index, N-terminal prohormone of brain natriuretic peptide, heart rate variability, and plasma catecholamines were not significantly affected by irbesartan treatment. Changes in systolic BP during the study period correlated......Agents blocking the renin-angiotensin-aldosterone system are frequently used in end-stage renal disease patients, but whether they exert beneficial cardiovascular (CV) effects is unclear. The long-term effects of the angiotensin II receptor blocker irbesartan was investigated in 82 haemodialysis...

  11. Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles

    DEFF Research Database (Denmark)

    Gustafsson, F; Holstein-Rathlou, N H

    1999-01-01

    the effect of intravenous infusion of angiotensin II (ANG II), losartan or methoxamine on conducted vasoconstriction to local application of norepinephrine (NE) or local electrical stimulation onto the surface of rat mesenteric arterioles in vivo. METHODS: In anesthetized male Wistar rats (n = 43) NE (0.1 m...

  12. LPO and antioxidant defense in the stomach of albino rats injected with angiotensin II and enalapril maleate.

    Science.gov (United States)

    Pikalova, V M; Postupaev, V V; Timoshin, S S

    2003-04-01

    The effects of components of angiotensin II system on LPO and antioxidant defense in the stomach of adult albino rats were studied using biochemical and chemiluminescent methods. Five intraperitoneal injections of angiotensin II in a dose of 100 micro/kg activated LPO and inhibited antioxidant processes in the studied tissues. Oral therapy with enalapril maleate (inhibitor of angiotensin-converting enzyme) in a daily dose of 10 mg/kg for 2 weeks normalized stress-activated LPO processes in gastric tissue.

  13. Fetal betamethasone exposure attenuates angiotensin-(1-7)-Mas receptor expression in the dorsal medulla of adult sheep.

    Science.gov (United States)

    Marshall, Allyson C; Shaltout, Hossam A; Nautiyal, Manisha; Rose, James C; Chappell, Mark C; Diz, Debra I

    2013-06-01

    Glucocorticoids including betamethasone (BM) are routinely administered to women entering into early preterm labor to facilitate fetal lung development and decrease infant mortality; however, fetal steroid exposure may lead to deleterious long term consequences. In a sheep model of fetal programming, BM-exposed (BMX) offspring exhibit elevated mean arterial pressure (MAP) and decreased baroreflex sensitivity (BRS) for control of heart rate by 0.5-years of age associated with changes in the circulating and renal renin-angiotensin systems (RAS). In the brain solitary tract nucleus, angiotensin (Ang) II actions through the AT1 receptor oppose the beneficial actions of Ang-(1-7) at the Mas receptor for BRS regulation. Therefore, we examined Ang peptides, angiotensinogen (Aogen), and receptor expression in this brain region of exposed and control offspring of 0.5- and 1.8-years of age. Mas protein expression was significantly lower (>40%) in the dorsal medulla of BMX animals at both ages; however, AT1 receptor expression was not changed. BMX offspring exhibited a higher ratio of Ang II to Ang-(1-7) (2.30±0.36 versus 0.99±0.28; p<0.01) and Ang II to Ang I at 0.5-years. Although total Aogen was unchanged, Ang I-intact Aogen was lower in 0.5-year BMX animals (0.78±0.06 vs. 1.94±0.41; p<0.05) suggesting a greater degree of enzymatic processing of the precursor protein in exposed animals. We conclude that in utero BM exposure promotes an imbalance in the central RAS pathways of Ang II and Ang-(1-7) that may contribute to the elevated MAP and lower BRS in this model. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Kastrup, J; Christensen, N J

    1985-01-01

    1. Plasma noradrenaline and adrenaline concentrations were measured in ten subjects before, during and after intravenous infusion of angiotensin II (ANG II) in order to determine the sympathoadrenal response of ANG II challenge in man. In five subjects ganglionic blockade was additionally performed...... by intravenous infusion of trimethaphan. 2. During ANG II infusion mean arterial blood pressure increased by 30% (P adrenaline decreased less. 3. During ganglionic blockade plasma noradrenaline decreased significantly (P

  15. Exercise Training Prevents Arterial Baroreflex Dysfunction in Rats Treated With Central Angiotensin II

    OpenAIRE

    Pan, Yan-Xia; Gao, Lie; Wang, Wei-Zhong; Zheng, Hong; Liu, Dongmei; Patel, Kaushik P.; Zucker, Irving H.; Wang, Wei

    2007-01-01

    Angiotensin II (Ang II)–induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II–superoxide mechanism. Four groups of rats were used: non-EX artificial cereb...

  16. Activation of central angiotensin type 2 receptors by compound 21 improves arterial baroreflex sensitivity in rats with heart failure.

    Science.gov (United States)

    Gao, Juan; Zucker, Irving H; Gao, Lie

    2014-10-01

    In a previous study we demonstrated that central administration of compound 21 (C21), a nonpeptide AT2R agonist, inhibited sympathetic tone in normal rats. In this study, we hypothesized that C21 exerts a similar effect in rats with coronary ligation-induced heart failure (HF). C21 was intracerebroventricularly infused for 7 days by osmotic mini pump. Blood pressure (BP) and heart rate (HR) were recorded by radiotelemetry in the conscious state to measure spontaneous arterial baroreflex sensitivity. Urine was collected for measurement of norepinephrine excretion. On the last day of C21 treatment, renal sympathetic nerve activity, BP, and HR were directly recorded under anesthesia, and the induced arterial baroreflex sensitivity was evaluated. Protein expressions of neuronal nitric oxide synthase (nNOS) and angiotensin II type 1 receptor (AT1R) in the subfornical organ, paraventricular nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius were determined by Western blot analysis. C21-treated HF rats displayed significantly less norepinephrine excretion (2,385.6 ± 121.1 vs. 3,677.3 ± 147.6 ng/24 hours; P baroreflex sensitivity and induced arterial baroreflex sensitivity. Bolus intracerebroventricular injection of angiotensin II-evoked pressor and sympatho-excitatory responses were attenuated in the C21-treated HF rats, which displayed upregulated nNOS and downregulated AT1R expression in the subfornical organ, paraventricular nucleus, and rostral ventrolateral medulla. Activation of central angiotensin II type 2 receptor AT2R by C21 suppresses sympathetic outflow in rats with HF by improving baroreflex sensitivity and may provide important benefit in the HF syndrome. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Angiotensin receptor-binding molecule in leukocytes in association with the systemic and leukocyte inflammatory profile.

    Science.gov (United States)

    Haruhara, Kotaro; Wakui, Hiromichi; Azushima, Kengo; Kurotaki, Daisuke; Kawase, Wataru; Uneda, Kazushi; Haku, Sona; Kobayashi, Ryu; Ohki, Kohji; Kinguchi, Sho; Ohsawa, Masato; Minegishi, Shintaro; Ishigami, Tomoaki; Matsuda, Miyuki; Yamashita, Akio; Nakajima, Hideaki; Tamura, Tomohiko; Tsuboi, Nobuo; Yokoo, Takashi; Tamura, Kouichi

    2018-02-01

    The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1β, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1β mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells.

    Directory of Open Access Journals (Sweden)

    Su-Mi Kim

    Full Text Available Angiotensin II (Ang II-induced activation of nicotinamide adenine dinucleotide phosphate (NAD(PH oxidase leads to increased production of reactive oxygen species (ROS, an important intracellular second messenger in renal disease. Recent findings suggest that Ang II induces mitochondrial depolarization and further amplifies mitochondrial generation of ROS. We examined the hypothesis that ROS injury mediated by Ang II-induced mitochondrial Nox4 plays a pivotal role in mitochondrial dysfunction in tubular cells and is related to cell survival. In addition, we assessed whether angiotensin (1-7 peptide (Ang-(1-7 was able to counteract Ang II-induced ROS-mediated cellular injury. Cultured NRK-52E cells were stimulated with 10(-6 M Ang II for 24 h with or without Ang-(1-7 or apocynin. Ang II simulated mitochondrial Nox4 and resulted in the abrupt production of mitochondrial superoxide (O(2 (- and hydrogen peroxide (H(2O(2. Ang II also induced depolarization of the mitochondrial membrane potential, and cytosolic secretion of cytochrome C and apoptosis-inducing factor (AIF. Ang-(1-7 attenuated Ang II-induced mitochondrial Nox4 expression and apoptosis, and its effect was comparable to that of the NAD(PH oxidase inhibitor. These findings suggest that Ang II-induced activation of mitochondrial Nox4 is an important endogenous source of ROS, and is related to cell survival. The ACE2-Ang-(1-7-Mas receptor axis should be investigated further as a novel target of Ang II-mediated ROS injury.

  19. Increased sensitivity to angiotensin II is present postpartum in women with a history of hypertensive pregnancy.

    Science.gov (United States)

    Saxena, Aditi R; Karumanchi, S Ananth; Brown, Nancy J; Royle, Caroline M; McElrath, Thomas F; Seely, Ellen W

    2010-05-01

    Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; Phistory of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus -18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

  20. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Arsenescu, Violeta [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Arsenescu, Razvan [Digestive Diseases and Nutrition, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Parulkar, Madhura; Karounos, Michael [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Zhang, Xuan [Graduate Center for Toxicology, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Baker, Nicki [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Cassis, Lisa A., E-mail: lcassis@uky.edu [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States)

    2011-11-15

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) -/- mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE-/- mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 {+-} 6 vs 137 {+-} 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 {+-} 0.4 vs 0.9 {+-} 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: Black-Right-Pointing-Pointer Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. Black-Right-Pointing-Pointer PCB77 augments AngII

  1. ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?

    NARCIS (Netherlands)

    B. Tom (Beril); I.M. Garrelds (Ingrid); E. Scalbert; A.P.A. Stegmann (Sander); F. Boomsma (Frans); P.R. Saxena (Pramod Ranjan); A.H.J. Danser (Jan)

    2003-01-01

    textabstractOBJECTIVE: The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II,

  2. 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...... blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal...

  3. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond

    Directory of Open Access Journals (Sweden)

    Singh JSS

    2015-06-01

    Full Text Available Jagdeep SS Singh, Chim C Lang Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK Abstract: Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction. Keywords: heart failure, angiotensin receptor-neprilysin inhibitor, heart failure with preserved ejection fraction, nesiritide, candoxatril, omapatrilat, hypertension, renal impairment, myocardial infarction

  4. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats.

    Science.gov (United States)

    Ali, Quaisar; Patel, Sanket; Hussain, Tahir

    2015-06-15

    High-sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type 2 receptor (AT2R) activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg·kg(-1)·day(-1), oral) while maintained on either normal-sodium diet (NSD; 0.4%) or HSD (4%) for 2 wk. Radiotelemetric recording showed a time-dependent increase in systolic blood pressure in HSD-fed obese rats, being maximal increase (∼27 mmHg) at day 12 of the HSD regimen. C21 treatment completely prevented the increase in blood pressure of HSD-fed rats. Compared with NSD controls, HSD-fed obese rats had greater natriuresis/diuresis and urinary levels of nitrates, and these parameters were further increased by C21 treatment. Also, C21 treatment improved glomerular filtration rate in HSD-fed rats. HSD-fed rats expressed higher level of cortical ANG II, which was reduced to 50% by C21 treatment. HSD feeding and/or C21 treatment had no effects on cortical renin activity and the expression of angiotensin-converting enzyme (ACE) and chymase, which are ANG II-producing enzymes. However, ANG(1-7) concentration and ACE2 activity in the renal cortex were reduced by HSD feeding, and C21 treatment rescued both the parameters. Also, C21 treatment reduced the cortical expression of AT1R in HSD-fed rats, but had no effect of AT2R expression. We conclude that chronic treatment with the AT2R agonist C21 prevents salt-sensitive hypertension in obese rats, and a reduction in the renal ANG II/AT1R and enhanced ACE2/ANG(1-7) levels may play a potential role in this phenomenon. Copyright © 2015 the American Physiological Society.

  5. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction

    NARCIS (Netherlands)

    Voors, Adriaan A.; Gori, Mauro; Liu, Licette C. Y.; Claggett, Brian; Zile, Michael R.; Pieske, Burkert; McMurray, John J. V.; Packer, Milton; Shi, Victor; Lefkowitz, Martin P.; Solomon, Scott D.

    BackgroundIncreases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection

  6. 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.

  7. The effect of taurine on chronic heart failure: actions of taurine against catecholamine and angiotensin II.

    Science.gov (United States)

    Ito, Takashi; Schaffer, Stephen; Azuma, Junichi

    2014-01-01

    Taurine, a ubiquitous endogenous sulfur-containing amino acid, possesses numerous pharmacological and physiological actions, including antioxidant activity, modulation of calcium homeostasis and antiapoptotic effects. There is mounting evidence supporting the utility of taurine as a pharmacological agent against heart disease, including chronic heart failure (CHF). In the past decade, angiotensin II blockade and β-adrenergic inhibition have served as the mainstay in the treatment of CHF. Both groups of pharmaceutical agents decrease mortality and improve the quality of life, a testament to the critical role of the sympathetic nervous system and the renin--angiotensin system in the development of CHF. Taurine has also attracted attention because it has beneficial actions in CHF, in part by its demonstrated inhibition of the harmful actions of the neurohumoral factors. In this review, we summarize the beneficial actions of taurine in CHF, focusing on its antagonism of the catecholamines and angiotensin II.

  8. Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP/TIMP in aged rats

    Directory of Open Access Journals (Sweden)

    Zhengqian eLi

    2016-04-01

    Full Text Available Reversible BBB disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD. Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2 and -9 (MMP-9, as well as three of their endogenous tissue inhibitors (TIMP-1, -2, -3, and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II and Ang II receptor type 1 (AT1 after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1, as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.

  9. Angiotensin II in the paraventricular nucleus stimulates sympathetic outflow to the cardiovascular system and make vasopressin release in rat.

    Science.gov (United States)

    Khanmoradi, Mehrangiz; Nasimi, Ali

    2016-10-06

    The hypothalamic paraventricular nucleus (PVN) plays essential roles in neuroendocrine and autonomic functions, including cardiovascular regulation. It was shown that microinjection of angiotensin II (AngII) into the PVN produced a pressor response. In this study, we explored the probable mechanisms of this pressor response. AngII was microinjected into the PVN and cardiovascular responses were recorded. Then, the responses were re-tested after systemic injection of a ganglionic blocker, Hexamethonium, or a vasopressin V1 receptor blocker. Hexamethonium pretreatment (i.v.) greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that the sympathetic system is involved in the cardiovascular effect of AngII in the PVN. Systemic pretreatment (i.v.) with V1 antagonist greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that vasopressin release is involved in the cardiovascular effect of AngII in the PVN. Overall, we found that AngII microinjected into the PVN produced a pressor response mediated by the sympathetic system and vasopressin release, indicating that other than circulating AngII, endogenous AngII of the PVN increases the vasopressin release from the PVN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Congcong Shen

    2017-02-01

    Full Text Available While angiotensin II (ang II has been implicated in the pathogenesis of cardiac cachexia (CC, the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT but not in TNF alpha type 1 receptor knockout (TNFR1KO mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC, the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

  11. Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

    Science.gov (United States)

    Umesalma, Shaikamjad; Houwen, Frederick Keith; Baumbach, Gary L; Chan, Siu-Lung

    2016-03-01

    Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1(-/-)), MMP9-deficient (MMP9(-/-)), and wild-type mice were infused with either Ang II (1000 ng/kg per minute) or saline via osmotic minipumps for 28 days (n=6-8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated epidermal growth factor receptor, and Akt was determined by Western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased the expression of Cav-1, phosphorylated epidermal growth factor receptor, and Akt in wild-type mice, which was attenuated in Cav-1(-/-) mice. Ang II-induced hypertrophy, inward remodeling, and increased MMP9 expression in pial arterioles were prevented in Cav-1(-/-) mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, were prevented in MMP9(-/-) mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1-induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy. © 2016 American Heart Association, Inc.

  12. Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man

    DEFF Research Database (Denmark)

    Henriksen, J H; Kastrup, J; Christensen, N J

    1985-01-01

    1. Plasma noradrenaline and adrenaline concentrations were measured in ten subjects before, during and after intravenous infusion of angiotensin II (ANG II) in order to determine the sympathoadrenal response of ANG II challenge in man. In five subjects ganglionic blockade was additionally performed...... by intravenous infusion of trimethaphan. 2. During ANG II infusion mean arterial blood pressure increased by 30% (P ....005) and similarly to the decrease obtained with ANG II infusion. 4. The results indicate that a decrease in sympathoadrenal activity occurs during ANG II-induced acute hypertension in man. This may be elicited by the arterial baroreflex, which seems to dominate any direct sympathoadrenergic facilitating effect...

  13. Inhibitory effects of alpha-zearalenol on angiotensin II-induced integrin beta3 mRNA via suppression of nuclear factor-kappaB.

    Science.gov (United States)

    Li, Su-Min; Wang, Xiao-Ming; Qiu, Jin; Si, Qin; Guo, Heng-Yi; Sun, Ren-Yu; Wu, Qi-Xia

    2005-10-01

    To investigate the effect of alpha-zearalenol on angiotensin II-induced beta3 integrin mRNA expression in human umbilical vein endothelial cells (HUVECs). The mRNA level in integrin beta3 was determined by reverse transcription-polymerase chain reaction. Endothelial NF-kappaB activity was determined by the luciferase activity assay of plasmid NF-kappaB-LUC. The angiotensin II-induced beta3 integrin mRNA expression was inhibited by alpha-zearalenol and 17beta-estradiol (10 nmol/L -1 micromol/L), but not influenced by ICI 182, 780, a pure competitive antagonist for estrogen receptor or a nitric oxide inhibitor Nomega-Nitro-L-arginine methyl ester hydrochloride. Alpha-zearalenol and 17beta-estradiol suppressed the angiotensin II-induced activation of NF-kappaB in endothelial cells. Alpha-zearalenol inhibits angiotensin II-induced integrin beta3 mRNA expression by suppressing NF-kappaB activation in endothelial cells.

  14. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity

    Science.gov (United States)

    de Kloet, Annette D.; Pati, Dipanwita; Wang, Lei; Hiller, Helmut; Sumners, Colin; Frazier, Charles J.; Seeley, Randy J.; Herman, James P.; Woods, Stephen C.; Krause, Eric G.

    2013-01-01

    Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type-1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we utilized the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole cell patch clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain. PMID:23486953

  15. 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

  16. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Jun [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Liu, Xu, E-mail: xkliuxu@yahoo.cn [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Wang, Quan-xing, E-mail: shmywqx@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Tan, Hong-wei [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Guo, Meng [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China)

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.

  17. 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...

  18. HEMODYNAMIC AND STRUCTURAL MODIFICATIONS IN CONTINUOUS INFUSION WITH ANGIOTENSIN. II. AN EXPERIMENTAL STUDY

    Directory of Open Access Journals (Sweden)

    Minela Aida Maranduca

    2011-09-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS is a hormonal system which contributes to the regulation of both arterial pressure and extra cellular fluids volume. The increase of RAAS, especially at angiotensin II (Ang II level, affects the target organs and increases the risk of cardio-vascular issues, by increasing arterial pressure and through the direct effect of Ang II upon the vascular endothelium and the renal and cardiac tissue. Ang II reduces the renal capacity of sodium excretion and initiates a set of events which increase arterial pressure. Increase of arterial pressure is necessary for re-establishing sodium excretion, being realized by the pressure-natriuresis relationship. Arterial hypertension affects the target organs (heart, kidneys and leads to a vicious circle which contributes to maintaining a high arterial pressure. Materials and Method: Male Wistar rats subjected on a normal diet, received either a sham operation (n=9 or continuous angiotensin II (Ang II infusion (300ng/kgc/ min subcutaneously, via mini pumps. Water ingestion and systolic blood pressure were measured for 14 days, after which the animals were sacrificed under anesthesia with ketamin, and the xylasin body weight, water ingestion, heart mass, right and left ventricular mass, right and left kidney mass were measured. Results: After 14 days of Ang II infusion, bodily weight decreased, systolic blood pressure increased, heart and left ventricular mass indexed to body weight were significantly enhanced compared with the sham group, and kidneys mass indexed to body weight was similar in the two groups.

  19. Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

    Science.gov (United States)

    Flarakos, Jimmy; Du, Yancy; Bedman, Timothy; Al-Share, Qusai; Jordaan, Pierre; Chandra, Priya; Albrecht, Diego; Wang, Lai; Gu, Helen; Einolf, Heidi J; Huskey, Su-Er; Mangold, James B

    2016-11-01

    1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.

  20. Analysis of angiotensin II binding to human platelets: Differences in young and old subjects

    International Nuclear Information System (INIS)

    Siebers, M.J.; Goodfriend, T.L.; Ball, D.; Elliott, M.E.

    1990-01-01

    We examined the binding of radiolabeled angiotensin II (AII) to human platelets to characterize the apparent increase in AII receptors observed in older subjects. At 22 degrees C, the amount of radioactivity associated with platelets from older subjects increased continuously for more than 2 hours. The same amount of radioactivity was displaced by addition of unlabeled AII at 30 min and 60 min. In the presence of phenylarsine oxide, in the cold, or when labeled antagonist was the ligand, binding came to equilibrium by 30 min. High pressure liquid chromatography demonstrated that 125 I-AII was the major radioactive compound in the supernatant and platelets after incubation, but the platelets also contained radiolabeled AII fragments. Thus, some degradation accompanied interaction of AII and platelets. Phenylarsine oxide did not prevent degradation of bound AII, suggesting that degradation precedes internalization. On average, maximum binding was greater in older subjects whether platelets were incubated with 125 I-AII alone, with 125 I-AII and phenylarsine oxide to prevent internalization, or when the competitive inhibitor 125 I-sar1,ile8-AII was the radioligand. Variability of binding among subjects also increased with age. Thus, platelets bind, degrade, and internalize AII, and the three processes occur to a greater extent in platelets from some, but not all older subjects

  1. SIRT1 Functions as an Important Regulator of Estrogen-Mediated Cardiomyocyte Protection in Angiotensin II-Induced Heart Hypertrophy

    Directory of Open Access Journals (Sweden)

    Tao Shen

    2014-01-01

    Full Text Available Background. Sirtuin 1 (SIRT1 is a member of the sirtuin family, which could activate cell survival machinery and has been shown to be protective in regulation of heart function. Here, we determined the mechanism by which SIRT1 regulates Angiotensin II- (AngII- induced cardiac hypertrophy and injury in vivo and in vitro. Methods. We analyzed SIRT1 expression in the hearts of control and AngII-induced mouse hypertrophy. Female C57BL/6 mice were ovariectomized and pretreated with 17β-estradiol to measure SIRT1 expression. Protein synthesis, cardiomyocyte surface area analysis, qRT-PCR, TUNEL staining, and Western blot were performed on AngII-induced mouse heart hypertrophy samples and cultured neonatal rat ventricular myocytes (NRVMs to investigate the function of SIRT1. Results. SIRT1 expression was slightly upregulated in AngII-induced mouse heart hypertrophy in vivo and in vitro, accompanied by elevated cardiomyocyte apoptosis. SIRT1 overexpression relieves AngII-induced cardiomyocyte hypertrophy and apoptosis. 17β-Estradiol was able to protect cardiomyocytes from AngII-induced injury with a profound upregulation of SIRT1 and activation of AMPK. Moreover, estrogen receptor inhibitor ICI 182,780 and SIRT1 inhibitor niacinamide could block SIRT1’s protective effect. Conclusions. These results indicate that SIRT1 functions as an important regulator of estrogen-mediated cardiomyocyte protection during AngII-induced heart hypertrophy and injury.

  2. At 1 antagonism and renin inhibition in mice: Pivotal role of targeting angiotensin II in chronic kidney disease

    NARCIS (Netherlands)

    C. Fraune (Christoph); S. Lange (Simon); C. Krebs (Christian); A. Hölzel (Alexandra); J. Baucke (Jana); N. Divac (Nevena); E. Schwedhelm (Edzard); T. Streichert (Thomas); J. Velden (Joachim); I.M. Garrelds (Ingrid); A.H.J. Danser (Jan); A.-R. Frenay (Anne-Roos); H. van Goor (Harry); J.A. Jankowski (Janusz Antoni); R. Stahl (Rolf); G. Nguyen (Genevieve); U. Wenzel (Ulrich)

    2012-01-01

    textabstractThe role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT 1 antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better

  3. Influence of prenatal application of angiotensin II and postnatal salt diet on GABAergic and oxytocin system in rat brain steam and cerebellum

    International Nuclear Information System (INIS)

    Jackova, L.; Olexova, L.; Svitok, P.; Senko, T.; Stefanik, P.

    2015-01-01

    Our goal was to determinate how gene expression of GABA transporter 1 (GAT1), glutamate decarboxylase 67 (GAD67) and oxytocin receptor (OTR) is influenced with prenatal exposition to angiotensin II (Ang II) and postnatal salt diet in nucleus tractus solitarii (NTS) and cerebellum in rats. In NTS we observed strong tendency in different reaction of OTR gene expression between Ang II prenatal treatment and control rats after high salt diet. We observed significant influence of sex on GAD67 gene expression in cerebellum. Also, sex in combination with salt diet is significant factor in expression of GAT1 gene in cerebellum. (authors)

  4. Between-patient differences in the renal response to renin-angiotensin system intervention : clue to optimising renoprotective therapy?

    NARCIS (Netherlands)

    Laverman, GD; de Zeeuw, D; Navis, G

    2002-01-01

    Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide,

  5. 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

    2017-12-01

    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 AT 1 receptors. What is the main finding and its importance? Angiotensin-(1-7)-induced diuresis and natriuresis is mediated by intrarenal Mas receptors. However, intrarenal AT 1 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 AT 1 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 (AT 1 ) receptors. The renin-angiotensin system was enhanced in anaesthetized rats by prior manipulation of dietary sodium intake. Angiotensin-(1-7) and AT 1 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 < 0.05). Interstitial Ang-(1-7) infusion increased urine flow twofold and fractional sodium excretion threefold (P < 0.05) in rats receiving a normal-sodium diet and to a greater extent, approximately three- and fourfold, respectively, in rats receiving the low-sodium diet (both P < 0.05). Angiotensin-(1-7)-induced increases in urine flow and

  6. Combination inhibition of the renin-angiotensin system: is more better?

    Science.gov (United States)

    Krause, Michelle W; Fonseca, Vivian A; Shah, Sudhir V

    2011-08-01

    Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.

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

    DEFF Research Database (Denmark)

    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...... AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms......(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1...

  8. Maternal Gestational Hypertension-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Renal Denervation or Angiotensin-Converting Enzyme Inhibition in Rat Offspring.

    Science.gov (United States)

    Xue, Baojian; Yin, Haifeng; Guo, Fang; Beltz, Terry G; Thunhorst, Robert L; Johnson, Alan Kim

    2017-04-01

    Numerous findings demonstrate that there is a strong association between maternal health during pregnancy and cardiovascular disease in adult offspring. The purpose of the present study was to test whether maternal gestational hypertension modulates brain renin-angiotensin-aldosterone system (RAAS) and proinflammatory cytokines that sensitizes angiotensin II-elicited hypertensive response in adult offspring. In addition, the role of renal nerves and the RAAS in the sensitization process was investigated. Reverse transcription polymerase chain reaction analyses of structures of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAAS components and proinflammatory cytokines in 10-week-old male offspring of hypertensive dams. Most of these increases were significantly inhibited by either renal denervation performed at 8 weeks of age or treatment with an angiotensin-converting enzyme inhibitor, captopril, in drinking water starting at weaning. When tested beginning at 10 weeks of age, a pressor dose of angiotensin II resulted in enhanced upregulation of mRNA expression of RAAS components and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented pressor response in male offspring of hypertensive dams. The augmented blood pressure change and most of the increases in gene expression in the offspring were abolished by either renal denervation or captopril. The results suggest that maternal hypertension during pregnancy enhances pressor responses to angiotensin II through overactivity of renal nerves and the RAAS in male offspring and that upregulation of the brain RAAS and proinflammatory cytokines in these offspring may contribute to maternal gestational hypertension-induced sensitization of the hypertensive response to angiotensin II. © 2017 American Heart Association, Inc.

  9. Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptors Subtypes within the Kidney

    OpenAIRE

    Gwathmey, TanYa M.; Shaltout, Hossam A.; Rose, James C.; Diz, Debra I.; Chappell, Mark C.

    2011-01-01

    We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80–81 days gestation with full term delivery. Renal nuclear and plasma membrane fractions were isolated from 1.0–1.5 year old sheep for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were sign...

  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. 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

  12. 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.

  13. Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Zhou, Yi; Wu, Wenxue; Lindholt, Jes S

    2015-01-01

    AIMS: Regulatory T cells (Tregs) protect mice from angiotensin II (Ang-II)-induced abdominal aortic aneurysms (AAA). This study tested whether AAA patients are Treg-insufficient and the Treg molecular mechanisms that control AAA pathogenesis. METHODS AND RESULTS: ELISA determined the Foxp3...... (r = -0.147, P = 0.007) and after (r = -0.153, P = 0.006) adjustment for AAA risk factors. AAA in apolipoprotein E-deficient (Apoe(-/-)) mice that received different doses of Ang-II exhibited a negative correlation of lesion Foxp3(+) Treg numbers with AAA size (r = -0.883, P

  14. Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

    DEFF Research Database (Denmark)

    Hilliard, Lucinda M; Chow, Charis L E; Mirabito, Katrina M

    2014-01-01

    in female hypertensive rats (PTreatmentarterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion...... vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT2R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT2R as a therapeutic target......Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R...

  15. 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

  16. 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 the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake...... during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared...

  17. Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Sharma, Girish; Goalstone, Marc Lee

    2007-01-01

    ERK5 is involved in proliferation of vascular smooth muscle cells (VSMC). The proliferative actions of insulin and angiotensin-II (A-II) in VSMC are mediated in part by ERK1/2. We hypothesized that insulin and A-II also regulate ERK5 activity in VSMC. Acute treatment ( 50 for insulin treatment effecting ERK1/2 and ERK5 phosphorylation was 1.5 and 0.1 nM, whereas the EC 50 for A-II was 2 nM, each. Insulin plus A-II induced an additive effect only on ERK5 phosphorylation. Inhibition of insulin- and A-II-stimulated phosphorylation of ERK5 and ERK1/2 by PD98059 and Wortmannin exhibited differential and time-dependent effects. Taken together, these data indicate that insulin and A-II regulate the activity of ERK5, but different from that seen for ERK1/2

  18. Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats.

    Science.gov (United States)

    Varagic, Jasmina; Ahmad, Sarfaraz; Voncannon, Jessica L; Moniwa, Norihito; Simington, Stephen W; Brosnihan, Bridget K; Gallagher, Patricia E; Habibi, Javad; Sowers, James R; Ferrario, Carlos M

    2012-09-01

    Increased sympathetic outflow, renin-angiotensin system (RAS) activity, and oxidative stress are critical mechanisms underlying the adverse cardiovascular effects of dietary salt excess. Nebivolol is a third-generation, highly selective β1-receptor blocker with RAS-reducing effects and additional antioxidant properties. This study evaluated the hypothesis that nebivolol reduces salt-induced cardiac remodeling and dysfunction in spontaneous hypertensive rats (SHRs) by suppressing cardiac RAS and oxidative stress. Male SHRs (8 weeks of age) were given an 8% high salt diet (HSD; n = 22), whereas their age-matched controls (n = 10) received standard chow. In a subgroup of HSD rats (n = 11), nebivolol was given at a dose of 10 mg/kg per day by gastric gavage. After 5 weeks, HSD exacerbated hypertension as well as increased left-ventricular weight and collagen deposition while impairing left-ventricular relaxation. Salt-induced cardiac remodeling and dysfunction were associated with increased plasma renin concentration (PRC), cardiac angiotensin II immunostaining, and angiotensin-converting enzyme (ACE)/ACE2 mRNA and activity ratio. HSD also increased cardiac 3-nitrotyrosine staining indicating enhanced oxidative stress. Nebivolol treatment did not alter the salt-induced increase in arterial pressure, left-ventricular weight, and cardiac dysfunction but reduced PRC, cardiac angiotensin II immunostaining, ACE/ACE2 ratio, oxidative stress, and fibrosis. Our data suggest that nebivolol, in a blood pressure-independent manner, ameliorated cardiac oxidative stress and associated fibrosis in salt-loaded SHRs. The beneficial effects of nebivolol may be attributed, at least in part, to the decreased ACE/ACE2 ratio and consequent reduction of cardiac angiotensin II levels.

  19. MiR-30-Regulated Autophagy Mediates Angiotensin II-Induced Myocardial Hypertrophy

    Science.gov (United States)

    Pan, Wei; Zhong, Yun; Cheng, Chuanfang; Liu, Benrong; Wang, Li; Li, Aiqun; Xiong, Longgen; Liu, Shiming

    2013-01-01

    Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy. PMID:23326547

  20. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.

    Science.gov (United States)

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M; Farley, Michelle; Roy, Nilay; Chin, Matthew S; von Andrian, Ulrich H; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J; Bonventre, Joseph V; Siedlecki, Andrew M

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation.

  1. Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway.

    Science.gov (United States)

    Yang, Weiwei; Zhang, Jia; Wang, Haiya; Gao, Pingjin; Singh, Manpreet; Shen, Kai; Fang, Ningyuan

    2011-12-01

    Angiotensin II (Ang II) plays a profound regulatory effect on NADPH oxidase and the functional features of vascular adventitial fibroblasts, but its role in antioxidant enzyme defense remains unclear. This study investigated the effect of Ang II on expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in adventitial fibroblasts and the possible mechanism involved. Ang II decreased the expression and activity of CAT in a dose- and time-dependent manner, but not that of SOD and GPx. The effects were abolished by the angiotensin II type 1 receptor (AT1R) blocker losartan and AT1R small-interfering RNA (siRNA). Incubation with polyethylene glycol-CAT prevented the Ang II-induced effects on reactive oxygen species (ROS) generation and myofibroblast differentiation. Moreover, Ang II rapidly induced phosphorylation of ERK1/2, which was reversed by losartan and AT1R siRNA. Pharmacological blockade of ERK1/2 improved Ang II-induced decrease in CAT protein expression. These in vitro results indicate that Ang II induces ERK1/2 activation, contributing to the downregulation of CAT as well as promoting oxidative stress and adventitial fibroblast phenotypic differentiation in an AT1R-mediated manner.

  2. Radioimmunoassay of angiotensin-II: methodology and standardization.

    Science.gov (United States)

    Lall, S B; Peshin, S S; Seth, S D

    1995-12-01

    The study was planned to set up and standardize the radioimmunoassay of Ang-II and to validate the procedure in terms of precision, sensitivity, specificity and recovery. The application of the developed assay was studied in normal healthy volunteers and in patients of renovascular hypertension (RVHT) and renal hypertension (RH). Synthetic human Ang-II was coupled to BSA by carbodimide condensation to get the hapten carrier conjugate which was injected in rabbits to raise the antibodies. The titre of 1:250 showed significant binding (56.79%) and was used for the assay. The sensitivity of the assay was 2 pg/ml and cross-reactivity with analogues of Ang-II was minimum. Mean Ang-II levels in normal subjects was 16 +/- 3.6 pg/ml. In patients of RVHT and RH, the peripheral blood Ang-II levels were found to be 876 +/- 8.6 and 108 +/- 2.3 pg/ml respectively. In patients of unilateral RVHT, renal vein Ang-II levels of the affected side were significantly higher than the unaffected side (P < 0.001). The results indicate that unextracted samples can be successfully utilized to estimate Ang-II levels.

  3. Effect of angiotensin II, ATP, and ionophore A23187 on potassium efflux in adrenal glomerulosa cells

    International Nuclear Information System (INIS)

    Lobo, M.V.; Marusic, E.T.

    1986-01-01

    Angiotensin II stimulus on perifused bovine adrenal glomerulosa cells elicited an increase in 86Rb efflux from cells previously equilibrated with the radioisotope. When 45Ca fluxes were measured under similar conditions, it was observed that Ca and Rb effluxes occurred within the first 30 s of the addition of the hormone and were independent of the presence of external Ca. The 86Rb efflux due to angiotensin II was inhibited by quinine and apamin. The hypothesis that the angiotensin II response is a consequence of an increase in the K permeability of the glomerulosa cell membrane triggered by an increase in cytosolic Ca is supported by the finding that the divalent cation ionophore A23187 also initiated 86Rb or K loss (as measured by an external K electrode). This increased K conductance was also seen with 10(-4) M ATP. Quinine and apamin greatly reduced the effect of ATP or A23187 on 86Rb or K release in adrenal glomerulosa cells. The results suggest that Ca-dependent K channels or carriers are present in the membranes of bovine adrenal glomerulosa cells and are sensitive to hormonal stimulus

  4. Haemodynamics and myocardial metabolism of phosphorus depleted dogs: effects of catecholamines and angiotensin II.

    Science.gov (United States)

    Kreusser, W; Vetter, H O; Mittmann, U; Hörl, W H; Ritz, E

    1982-06-01

    The responses of arterial pressure and myocardial contractile force (VPM) to infusion of angiotensin II, noradrenaline and orciprenaline were examined in twelve dogs during a control phase, after 30 days of dietary phosphorus deprivation and after 21 days of phosphorus repletion. In the phosphorus depletion period, animals had low skeletal and heart muscle Pi content, low magnesium, ATP and creatine phosphate in skeletal and heart muscle with no change of ADP, AMP or energy charge. In the basal state, VPM was diminished with no change of end-diastolic and systolic pressure. Infusion of angiotensin II caused a significantly smaller rise of arterial pressure (angiotensin II resistance), and the stimulatory effect of noradrenaline and orciprenaline on VPM was diminished (catecholamine resistance). These effects were reversible with Pi repletion. In phosphorus depletion, arterial concentrations were increased for lactate, unchanged for FFA and decreased for acetoacetate/beta-hydroxybutyrate. Unchanged myocardial extraction of lactate or beta-hydroxybutyrate and preserved cell Pi uptake for glycogenolysis were observed. The initial rate of uptake of calcium and concentrating ability of myocardial sarcoplasmic reticulum were unchanged.

  5. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

    Science.gov (United States)

    Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

    2016-06-15

    Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Association of interleukin 17 / angiotensin II with refractory ...

    African Journals Online (AJOL)

    Table 2 Multiple linear regression analysis showing relationship between IL 17, Ang II and mean arterial pressure in hemodialysis patients. Variables. B t value. P value. IL 17. 6.320. 10.221. 0.000. Ang II. 0.143. 2.442. 0.017. Discussion. This study aimed to investigate the association between. IL 17 and the risk of refractory ...

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

    African Journals Online (AJOL)

    Egyptian Journal of Pediatric Allergy and Immunology (The). Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 12, No 1 (2014) >. Log in or Register to get access to full text downloads.

  8. Outcome of Angiotensin II Inhibition in Pregnant Irradiated Rats and their Embryos

    International Nuclear Information System (INIS)

    Ramadan, F. L.; Ashry, Kh. M.

    2010-01-01

    The study aims to evaluate the synergism of losartan and or irradiation stress on the female rat mothers and their developing embryos as judged by the maternal biochemical pathways during gestation and teratogenic effects on the embryos. Losartan is an angiotensin II AT1-receptor antagonist used to regulate blood pressure. Losartan (5 mg/kg b.wt day) was daily orally administrated to pregnant rats from the 6 th to 18 th gestational days during which they were subjected to intermittent radiation dose levels of 0.5 Gy/4 times at the 9 th, 10 th, 11 th and 12 th days of gestation whereas investigation has been carried out one day prior to parturition. Dual treatment of losartan and radiation resulted in increased maternal serum levels of creatinine and bilirubin.The developing embryos in the uteri due to their high sensitivity showed various teratological, skeletal and histological impairment. Losartan and/or radiation induced effects were detected as growth retardation, malformations expressed as anopthalmia, kypophysis, subcutaneous haemorrhage and microtia as well as elevated intrauterium death and embryonic resorption. Moreover, the examination of endo skeletal system of fetuses showed retardation in the ossification of the skull bones and lack of ossification at the vertebrae and edges. Also, maternal and embryonic histological examination revealed that losartan and gamma radiation induced injury to kidney tissue manifested in rupture and shrinkage of renal corpuscle, infiltration, disappearance of glomularies, while the kidney of fetuses showed loss of renal pattern. Results point out that losartan should be used with caution in women at the reproductive age and those occupationally exposed to irradiation

  9. Oxygen sensitivity of potassium- and angiotensin II-stimulated aldosterone release by bovine adrenal cells.

    Science.gov (United States)

    Brickner, R C; Raff, H

    1991-04-01

    Angiotensin II (AII) and extracellular K+, acting through different intracellular mechanisms, stimulate aldosterone release in a synergistic fashion. We have previously shown that decreases in oxygen (O2) within the physiological range inhibit AII, cyclic AMP (cAMP) and ACTH-stimulated aldosterone release. The present experiment evaluated the effect of various concentrations of O2 on K+-stimulated aldosterone release in the presence and absence of AII. Dispersed bovine adrenal glomerulosa cells were incubated with different concentrations of K+ (0.9-5.4 mmol/l) without and with AII (10 nmol/l) under different concentrations of O2 (0, 5 or 50%); 21% O2 (pO2 = 19.9 +/- 0.5 kPa,n = 9) was used as reference control for comparison. In all cases, increases in K+ stimulated aldosterone release, an effect augmented by AII. Under 0% O2 (pO2 = 8.1 +/- 0.3 kPa, n = 3) and 5% O2 (pO2 = 12.8 +/- 0.5 kPa, n = 3), aldosterone release stimulated by K+ or K+/AII was significantly inhibited compared with that under 21% O2. Conversely, under 50% O2 (pO2 = 36.3 +/- 2.5 kPa, n = 3), aldosterone release stimulated by K+ or K+/AII was significantly augmented. Cortisol secretion was not significantly affected by 5% or 50% O2 but was significantly decreased under 0% O2. The effect of O2 on K+/AII stimulation of aldosterone release, as well as previous experiments with cAMP, progesterone and ACTH, suggest a final common post-receptor oxygen-sensitive component of the aldosterone synthetic pathway. It is suggested that one or more enzymes in the aldosterone synthetic pathway is/are exquisitely sensitive to small changes in O2 within the physiological range.

  10. Grape-Derived Polyphenols Prevent Doxorubicin-Induced Blunted EDH-Mediated Relaxations in the Rat Mesenteric Artery: Role of ROS and Angiotensin II

    Directory of Open Access Journals (Sweden)

    Noureddine Idris-Khodja

    2013-01-01

    Full Text Available This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO and endothelium-derived hyperpolarization (EDH in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs, a rich natural source of antioxidants. Male Wistar rats were assigned into 4 groups: control, RWPs, doxorubicin, and doxorubicin + RWPs. Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS using dihydroethidine and the expression levels of small and intermediate conductance calcium-activated potassium channels (SKCa, IKCa and connexin 40 (Cx40, which are involved in EDH-type relaxations, endothelial NO synthase (eNOS, angiotensin II, and AT1 receptors by immunofluorescence. The doxorubicin treatment impaired EDH-mediated relaxations, whereas those mediated by NO were minimally affected. This effect was associated with reduced expression levels of SKCa, IKCa, and Cx40, increased expression levels of eNOS, angiotensin II, and AT1 receptors, and formation of ROS in mesenteric arteries. RWPs prevented both the doxorubicin-induced blunted EDH-type relaxations and the increased vascular oxidative stress, and they improved the expression levels of target proteins. These findings suggest that polyphenol-rich natural products might be of interest in the management of doxorubicin-induced vascular injury possibly by improving the vascular angiotensin system.

  11. Angiotensin II does not acutely regulate conduction velocity in rat atrial tissue

    DEFF Research Database (Denmark)

    Olsen, Kristine B; Braunstein, Thomas H; Sørensen, Charlotte M

    2011-01-01

    Abstract Aim. Atrial angiotensin II (Ang II) levels are increased in atrial fibrillation and are believed to be important in the pathogenesis of atrial arrhythmias. Ang II reduces intercellular coupling by inhibiting gap junctions (connexins) and may thereby increase the risk of reentry arrhythmia....... The aim of the current study was to investigate the acute effect of Ang II on conduction velocity (CV) in atrial tissue from normal and chronically infarcted rats. Methods. Contractile force was measured and CV was determined from the conduction time between electrodes placed on the tissue preparation......-5 weeks ventricular MI was examined. Although CV was significantly reduced by MI, no effect on CV of Ang II was seen. Conclusion. Ang II does not acutely regulate CV in tissue preparations from the free wall of the left atria or the left auricle. Although ventricular MI reduces CV, this does not sensitize...

  12. 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

  13. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Suo, Yu-Ping [Department of Obstetrics and Gynecology, Shanxi Provincial People' s Hospital, Taiyuan 030012 (China); Yue, Li-Ying [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China)

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  14. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    International Nuclear Information System (INIS)

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-01-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  15. 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

  16. Cholera toxin but not pertussis toxin inhibits angiotensin II-enhanced contractions in the rat portal vein

    NARCIS (Netherlands)

    Zhang, J.; van Meel, J. C.; Pfaffendorf, M.; van Zwieten, P. A.

    1993-01-01

    Angiotensin II (Ang II)-enhanced phasic contractions in the rat portal vein were concentration dependently inhibited by cholera toxin (0.1-10 micrograms/ml) and dibutyryl cyclic AMP (0.1-1 mM), but not by pertussis toxin (1 micrograms/ml), which suggests that Gi is not involved in the Ang II signal

  17. Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney.

    Science.gov (United States)

    Gwathmey, TanYa M; Shaltout, Hossam A; Rose, James C; Diz, Debra I; Chappell, Mark C

    2011-03-01

    We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80 to 81 days gestation with full-term delivery. Renal nuclear and plasma membrane fractions were isolated from sheep age 1.0 to 1.5 years for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were significantly higher in the BMX-exposed adult offspring versus CON sheep. The proportion of nuclear AT(1) receptors sensitive to losartan was 2-fold higher (67 ± 6% vs 27 ± 9%; Psheep (16 ± 3% vs 6 ± 4%; Pfetal programming.

  18. Changes in Angiotensin Receptor Distribution and in Aortic Morphology Are Associated with Blood Pressure Control in Aged Metabolic Syndrome Rats

    Directory of Open Access Journals (Sweden)

    Verónica Guarner-Lans

    2016-01-01

    Full Text Available The role of the renin-angiotensin system (RAS in blood pressure regulation in MS during aging is unknown. It participates in metabolic syndrome (MS and aging regulating vascular tone and remodeling. RAS might participate in a compensatory mechanism decreasing blood pressure and allowing MS rats to reach 18 months of age and it might form part of therapeutical procedures to ameliorate MS. We studied histological changes and distribution of RAS receptors in aortas of MS aged rats. Electron microscopy images showed premature aging in MS since the increased fibrosis, enlarged endothelium, and invasion of this layer by muscle cells that was present in control 18-month-old aortas were also found in 6-month-old aortas from MS rats. AT1, AT2, and Mas receptors mediate the effects of Ang II and Ang 1-7, respectively. Fluorescence from AT2 decreased with age in control and MS aortas, while fluorescence of AT1 increased in aortas from MS rats at 6 months and diminished during aging. Mas expression increased in MS rats and remained unchanged in control rats. In conclusion, there is premature aging in the aortas from MS rats and the elevated expression of Mas receptor might contribute to decrease blood pressure during aging in MS.

  19. Overexpression of ß-Arrestin1 in the Rostral Ventrolateral Medulla Downregulates Angiotensin Receptor and Lowers Blood Pressure in Hypertension.

    Science.gov (United States)

    Sun, Jia-Cen; Liu, Bing; Zhang, Ru-Wen; Jiao, Pei-Lei; Tan, Xing; Wang, Yang-Kai; Wang, Wei-Zhong

    2018-01-01

    Background: Hypertension is characterized by sympathetic overactivity, which is associated with an enhancement in angiotensin receptor type I (AT1R) in the rostral ventrolateral medulla (RVLM). β-arrestin1, a canonical scaffold protein, has been suggested to show a negative effect on G protein-coupled receptors via its internalization and desensitization and/or the biased signaling pathway. The major objectives of the present study were to observe the effect of β-arrestin1 overexpression in the RVLM on cardiovascular regulation in spontaneously hypertensive rats (SHR), and further determine the effect of β-arrestin1 on AT1R expression in the RVLM. Methods: The animal model of β-arrestin1 overexpression was induced by bilateral injection of adeno-associated virus containing Arrb1 gene (AAV-Arrb1) into the RVLM of WKY and SHR. Results: β-arrestin1 was expressed on the pre-sympathetic neurons in the RVLM, and its expression in the RVLM was significantly ( P Overexpression of β-arrestin1 in SHR significantly decreased baseline levels of blood pressure and renal sympathetic nerve activity, and attenuated cardiovascular effects induced by RVLM injection of angiotensin II (100 pmol). Furthermore, β-arrestin1 overexpression in the RVLM significantly reduced the expression of AT1R by 65% and NF-κB p65 phosphorylation by 66% in SHR. It was confirmed that β-arrestin1 overexpression in the RVLM led to an enhancement of interaction between β-arrestin1 and IκB-α. Conclusion: Overexpression of β-arrestin1 in the RVLM reduces BP and sympathetic outflow in hypertension, which may be associated with NFκB-mediated AT1R downregulation.

  20. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    International Nuclear Information System (INIS)

    Yogi, Alvaro; Callera, Glaucia E.; Mecawi, André S.; Batalhão, Marcelo E.; Carnio, Evelin C.; Antunes-Rodrigues, José; Queiroz, Regina H.; Touyz, Rhian M.; Tirapelli, Carlos R.

    2012-01-01

    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 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 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 1 receptor activation. ► Translocation of p