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Sample records for angiotensin ii induces

  1. Sex differences in angiotensin II- induced hypertension

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    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.

  2. Csk regulates angiotensin II-induced podocyte apoptosis.

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    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.

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

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    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.

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

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    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.

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

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    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.

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

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    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.

  7. TRPC6 enhances angiotensin II-induced albuminuria.

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    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.

  8. 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.

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    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.

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

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    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

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

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    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.

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

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    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.

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

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

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    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

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

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    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.

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

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    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

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

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    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.

  17. 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

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

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    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

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

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    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.

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

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    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

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

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    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.

  2. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

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    Galán, María; Varona, Saray; Guadall, Anna; Orriols, Mar; Navas, Miquel; Aguiló, Silvia; de Diego, Alicia; Navarro, María A; García-Dorado, David; Rodríguez-Sinovas, Antonio; Martínez-González, José; Rodriguez, Cristina

    2017-09-01

    Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H 2 O 2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy. © FASEB.

  3. Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2

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    Yonggang Wang

    2017-01-01

    Full Text Available Although angiotensin II (Ang II was reported to facilitate sperm motility and intratesticular sperm transport, recent findings shed light on the efficacy of Ang II in stimulating inflammatory events in testicular peritubular cells, effect of which may play a role in male infertility. It is still unknown whether Ang II can induce testicular apoptotic cell death, which may be a more direct action of Ang II in male infertility. Therefore, the present study aims to determine whether Ang II can induce testicular apoptotic cell death and whether this action can be prevented by sulforaphane (SFN via activating nuclear factor (erythroid-derived 2-like 2 (NRF2, the governor of antioxidant-redox signalling. Eight-week-old male C57BL/6J wild type (WT and Nrf2 gene knockout mice were treated with Ang II, in the presence or absence of SFN. In WT mice, SFN activated testicular NRF2 expression and function, along with a marked attenuation in Ang II-induced testicular oxidative stress, inflammation, endoplasmic reticulum stress, and apoptotic cell death. Deletion of the Nrf2 gene led to a complete abolishment of these efficacies of SFN. The present study indicated that Ang II may result in testicular apoptotic cell death, which can be prevented by SFN via the activation of NRF2.

  4. 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

  5. Sulforaphane protects H9c2 cardiomyocytes from angiotensin II-induced hypertrophy.

    Science.gov (United States)

    Wu, Q-Q; Zong, J; Gao, L; Dai, J; Yang, Z; Xu, M; Fang, Y; Ma, Z-G; Tang, Q-Z

    2014-05-01

    Cardiac hypertrophy is an adaptive process of the heart in response to various stimuli, but sustained cardiac hypertrophy will finally lead to heart failure. Sulforaphane-extracted from cruciferous vegetables of the genus Brassica such as broccoli, brussels sprouts, and cabbage-has been evaluated for its anticarcinogenic and antioxidant effects. To investigate the effect of sulforaphane on angiotensin II (Ang II)-induced cardiac hypertrophy in vitro. Embryonic rat heart-derived H9c2 cells were co-incubated with sulforaphane and Ang II. The cell surface area and mRNA levels of hypertrophic markers were measured to clarify the effect of sulforaphane on cardiac hypertrophy. The underlying mechanism was further investigated by detecting the activation of Akt and NF-κB signaling pathways. We found that H9c2 cells pretreated with sulforaphane were protected from Ang II-induced hypertrophy. The increasing mRNA levels of ANP, BNP, and β-MHC in Ang II-stimulated cells were also down-regulated after sulforaphane treatment. Moreover, sulforaphane repressed the Ang II-induced phosphorylation of Akt, GSK3β, mTOR, eIF4e, as well as of IκBα and NF-κB. Based on our results, sulforaphane attenuates Ang II-induced hypertrophy of H9c2 cardiomyocytes mediated by the inhibition of intracellular signaling pathways including Akt and NF-κB.

  6. 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.

  7. 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.

  8. 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.

  9. Aldosterone and angiotensin II induce protein aggregation in renal proximal tubules.

    Science.gov (United States)

    Cheema, Muhammad U; Poulsen, Ebbe T; Enghild, Jan J; Hoorn, Ewout J; Hoorn, Ewout; Fenton, Robert A; Praetorius, Jeppe

    2013-09-01

    Renal tubules are highly active transporting epithelia and are at risk of protein aggregation due to high protein turnover and/or oxidative stress. We hypothesized that the risk of aggregation was increased upon hormone stimulation and assessed the state of the intracellular protein degradation systems in the kidney from control rats and rats receiving aldosterone or angiotensin II treatment for 7 days. Control rats formed both aggresomes and autophagosomes specifically in the proximal tubules, indicating a need for these structures even under baseline conditions. Fluorescence sorted aggresomes contained various rat keratins known to be expressed in renal tubules as assessed by protein mass spectrometry. Aldosterone administration increased the abundance of the proximal tubular aggresomal protein keratin 5, the ribosomal protein RPL27, ataxin-3, and the chaperone heat shock protein 70-4 with no apparent change in the aggresome-autophagosome markers. Angiotensin II induced aggregation of RPL27 specifically in proximal tubules, again without apparent change in antiaggregating proteins or the aggresome-autophagosome markers. Albumin endocytosis was unaffected by the hormone administration. Taken together, we find that the renal proximal tubules display aggresome formation and autophagy. Despite an increase in aggregation-prone protein load in these tubules during hormone treatment, renal proximal tubules seem to have sufficient capacity for removing protein aggregates from the cells.

  10. 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.

  11. Angiotensin II Induces Region-Specific Medial Disruption during Evolution of Ascending Aortic Aneurysms

    Science.gov (United States)

    Rateri, Debra L.; Davis, Frank M.; Balakrishnan, Anju; Howatt, Deborah A.; Moorleghen, Jessica J.; O’Connor, William N.; Charnigo, Richard; Cassis, Lisa A.; Daugherty, Alan

    2015-01-01

    Angiotensin II (Ang II) promotes development of ascending aortic aneurysms (AAs), but progression of this pathology is undefined. We evaluated factors potentially involved in progression, and determined the temporal sequence of tissue changes during development of Ang II–induced ascending AAs. Ang II infusion into C57BL/6J mice promoted rapid expansion of the ascending aorta, with significant increases within 5 days, as determined by both in vivo ultrasonography and ex vivo sequential acquisition of tissues. Rates of expansion were not significantly different in LDL receptor–null mice fed a saturated fat-enriched diet, demonstrating a lack of effect of hypercholesterolemia. Augmenting systolic blood pressure with norepinephrine infusion had no significant effect on ascending aortic expansion. Pathological changes observed within 5 days of Ang II infusion included increased medial thickness and intramural hemorrhage characterized by erythrocyte extravasation in outer lamellar layers of the media. Intramedial hemorrhage was not observed after prolonged Ang II infusion, although partial medial disruption was present. Elastin fragmentation and transmural medial breaks of the ascending aorta were observed with continued Ang II infusion, which were restricted to anterior aspects. CD45+ cells accumulated in adventitia but were minimal in media. Similar pathology was observed in tissues obtained from patients with ascending AAs. In conclusion, Ang II promotes ascending AAs through region-specific changes that are independent of hypercholesterolemia or systolic blood pressure. PMID:25038458

  12. Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling.

    Science.gov (United States)

    Liu, Cun-Fei; Zhang, Jia; Shen, Kai; Gao, Ping-Jin; Wang, Hai-Ya; Jin, Xin; Meng, Chao; Fang, Ning-Yuan

    2015-04-01

    Vascular adventitia and adventitia‑derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti‑oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII‑induced vascular remodeling in vivo. Adenoviruses co‑expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague‑Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen‑activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII‑induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII‑induced media hypertrophy compared with that of the control virus (Padventitial α‑smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII‑induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII‑induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation.

  13. 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...

  14. 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.

  15. 81mKr scintigraphic evaluation of hemodynamics in gynecologic malignancies under condition of Angiotensin II-induced hypertension

    International Nuclear Information System (INIS)

    Sumi, Yukiharu; Ozaki, Yutaka; Amemiya, Ken; Kyogoku, Shinsuke; Shirakata, Akihiro; Tamamoto, Fumihiko; Katayama, Hitoshi; Utsuno, Hiroshi; Kubota, Takeyoshi

    1992-01-01

    Transcatheter arterial infusion chemotherapy is one of the most useful therapeutic procedures for gynecologic malignancies. Although several reports have been published about Angiotensin II-induced hypertension chemotherapy and the efficacy of the method, there have been no reports to evaluate an application for gynecologic malignancies. We evaluated the usefulness of the method for gynecologic malignancies demonstrating the changes of hemodynamics of the tumor using 81m Kr scintigraphy. Thirteen patients with pathologically confirmed gynecologic malignancies were evaluated by angiography and continuous infusion of 81m Kr via the catheter with and without Angiotensin II. At first, continuous infusion of 81m Kr was performed under the superselective catheterization of the uterine artery. The radioactivities in the ROI were counted. Then, withdrew the catheter from the uterine artery to the internal iliac artery, and again continuously infused 81m Kr and counted the radioactivities in the same ROI. Finally, keeping the catheter in the internal iliac artery, Angiotensin II and 81m Kr were infused simultaneously. And counted the radioactivities. The radioactivities were highest when the catheter tip was placed in uterine arteries and lowest when the catheter tip was placed in internal iliac arteries. But radioactivities in the ROIs were definitely increased when Angiotensin II was used, even if the catheter tip was keeping in the internal iliac arteries. The optimal catheter position of transcatheter arterial chemotherapy for gynecologic malignancies is at proximal uterine artery. Since Angiotensin II-induced hypertension may increase blood flow of tumors, it seems to have indication for postoperative cases, highly advanced cases and cases with difficulties to perform superselective catheterization. From our experience, we believe chemotherapeutic agents must be administrated via catheter within 3 minutes after infusion of Angiotensin II. (author)

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

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

    OpenAIRE

    Shen, Tao; Ding, Ling; Ruan, Yang; Qin, Weiwei; Lin, Yajun; Xi, Chao; Lu, Yonggang; Dou, Lin; Zhu, Yuping; Cao, Yuan; Man, Yong; Bian, Yunfei; Wang, Shu; Xiao, Chuanshi; Li, Jian

    2014-01-01

    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...

  2. Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro

    Directory of Open Access Journals (Sweden)

    Celeste Trejo-Moreno

    2018-02-01

    Full Text Available Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II in human microvascular endothelial cells-1 (HMEC-1 cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 μg/mL of SF1, SF2, or SF3, or 10 μmol of losartan as a control. IL-6 (Interleukin 6 concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS, and the bioavailability of nitric oxide (NO were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 μg/mL each was the most effective combination to inhibit the production of IL-6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects.

  3. 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.

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

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    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.

  5. 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

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

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    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

  7. 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-induced

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

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    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.

  9. 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.

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

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    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.

  11. Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein E-knockout mouse.

    Science.gov (United States)

    Moran, Corey S; Jose, Roby J; Biros, Erik; Golledge, Jonathan

    2014-12-01

    Mounting evidence links osteoprotegerin with cardiovascular disease. Elevated serum and aortic tissue osteoprotegerin are associated with the presence and growth of abdominal aortic aneurysm in humans; however, a role for osteoprotegerin in abdominal aortic aneurysm pathogenesis remains to be shown. We examined the functional significance of osteoprotegerin in aortic aneurysm using an Opg-deficient mouse model and in vitro investigations. Homozygous deletion of Opg in apolipoprotein E-deficient mice (ApoE(-/-)Opg(-/-)) inhibited angiotensin II-induced aortic dilatation. Survival free from aortic rupture was increased from 67% in ApoE(-/-)Opg(+/+) controls to 94% in ApoE(-/-)Opg(-/-) mice (P=0.040). Serum concentrations of proinflammatory cytokines/chemokines, and aortic expression for cathepsin S (CTSS), matrix metalloproteinase 2, and matrix metalloproteinase 9 after 7 days (early-phase) of angiotensin II infusion were significantly reduced in ApoE(-/-)Opg(-/-) mice compared with ApoE(-/-)Opg(+/+) controls. In addition, aortic expression of markers for an inflammatory phenotype in aortic vascular smooth muscle cells in response to early-phase of angiotensin II infusion was significantly lower in Opg-deficient mice. In vitro, human abdominal aortic aneurysm vascular smooth muscle cells produced more CTSS and exhibited increased CTSS-derived elastolytic activity than healthy aortic vascular smooth muscle cells, whereas recombinant human osteoprotegerin stimulated CTSS-dependent elastase activity in aortic vascular smooth muscle cells. These findings support a role for osteoprotegerin in aortic aneurysm through upregulation of CTSS, matrix metalloproteinase 2, and matrix metalloproteinase 9 within the aorta, promoting an inflammatory phenotype in aortic vascular smooth muscle cells in response to angiotensin II. © 2014 American Heart Association, Inc.

  12. Angiotensin II induces interleukin-6 expression in astrocytes: Role of reactive oxygen species and NF-κB.

    Science.gov (United States)

    Gowrisankar, Yugandhar V; Clark, Michelle A

    2016-12-05

    Previously, we showed that the bio-peptide angiotensin (Ang) II induces interleukin-6 (IL-6) in cultured astrocytes; however, the mechanism(s) involved in this effect were unknown. In the current study, we determined in brainstem and cerebellum astrocytes from the spontaneously hypertensive rat (SHR), the effect of Ang II to induce IL-6 as well as reactive oxygen species (ROS) generation. Results from this study showed that Ang II significantly induced the differential expression of IL-6 mRNA and protein levels in astrocytes from both regions of Wistar and SHRs. There were differences in the ability of Ang II to induce IL-6 mRNA and protein levels, but these differences were not apparent at all time points examined. Ang II also induced ROS generation, but there were no significant differences between ROS generation in SHR samples as compared to the Wistar samples. Ang II-induced IL-6 levels were mediated via the AT 1 /Nuclear Factor Kappa beta/ROS pathway. Overall, our findings suggest that there may be dysregulation in IL-6 production from astrocytes, contributing to differences observed in SHRs versus its normotensive control. Elucidating the mechanisms involved in Ang II pro-inflammatory effects in the central nervous system may lead to the development of novel therapeutic strategies that can be harnessed not just to treat hypertension, but other Ang II-mediated diseases as well. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. 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

  14. Angiotensin II Facilitates Matrix Metalloproteinase-9-Mediated Myosin Light Chain Kinase Degradation in Pressure Overload-Induced Cardiac Hypertrophy

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    Shun Wang

    2017-12-01

    Full Text Available Background/Aims: Angiotensin II (Ang II has been shown to promote cardiac remodeling during the process of hypertrophy. Myosin light chain kinase (MLCK, a specific kinase for the phosphorylation of myosin light chain 2 (MLC2, plays an important role in regulating cardiac muscle contraction and hypertrophy. However, whether Ang II could facilitate cardiac hypertrophy by altering the expression of MLCK remains unclear. This study aimed to investigate this effect and the underlying mechanisms. Methods: Cardiac hypertrophy was induced via pressure overload in rats, which were then evaluated via histological and biochemical measurements and echocardiography. Angiotensin-converting enzyme inhibitor (ACEI was used to inhibit Ang II. Neonatal rat cardiomyocytes were stimulated with Ang II to induce hypertrophy and were treated with a matrix metalloproteinase 9 (MMP9 inhibitor. Myocyte hypertrophy was evaluated using immunofluorescence and qRT-PCR. Degradation of recombinant human MLCK by recombinant human MMP9 was tested using a cleavage assay. The expression levels of MLCK, MLC2, phospho-myosin light chain 2 (p-MLC2, myosin phosphatase 2 (MYPT2, and calmodulin (CaM were measured using western blotting. Results: ACEI improved cardiac function and remodeling and increased the levels of MLCK and p-MLC2 as well as reduced the expression of MMP9 in pressure overload-induced cardiac hypertrophy. Moreover, the MMP9 inhibitor alleviated myocyte hypertrophy and upregulated the levels of MLCK and p-MLC2 in Ang II-induced cardiomyocyte hypertrophy. Recombinant human MLCK was concentration- and time-dependently degraded by recombinant human MMP9 in vitro, and this process was prevented by the MMP9 inhibitor. Conclusion: Our results suggest that Ang II is involved in the degradation of MLCK in pressure overload-induced cardiac hypertrophy and that this process was mediated by MMP9.

  15. 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.

  16. Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension.

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    Li Hua Wei

    Full Text Available Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO and wild-type (WT mice by subcutaneous infusion of Ang II (1.46 mg/kg/day for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV mass (P<0.01,reduction of LV ejection fraction(P<0.001 and fractional shortening(P<0.001. Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, interleukin-1β, TNF-α, and infiltration of CD3(+ T cells and F4/80(+ macrophages. Further studies revealed that enhanced activation of the Sp1-TGFβ/Smad3-NF-κB pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-β/Smad3-NF.κB-miR-29 regulatory network.

  17. 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

  18. A heptameric peptide purified from Spirulina sp. gastrointestinal hydrolysate inhibits angiotensin I-converting enzyme- and angiotensin II-induced vascular dysfunction in human endothelial cells

    Science.gov (United States)

    Heo, Seong-Yeong; Ko, Seok-Chun; Kim, Chang Su; Oh, Gun-Woo; Ryu, Bomi; Qian, Zhong-Ji; Kim, Geunhyung; Park, Won Sun; Choi, Il-Whan; Phan, Thi Tuong Vy; Heo, Soo-Jin; Kang, Do-Hyung; Yi, Myunggi; Jung, Won-Kyo

    2017-01-01

    In this study, a marine microalga Spirulina sp.-derived protein was hydrolyzed using gastrointestinal enzymes to produce an angiotensin I (Ang I)-converting enzyme (ACE) inhibitory peptide. Following consecutive purification, the potent ACE inhibitory peptide was composed of 7 amino acids, Thr-Met-Glu-Pro-Gly-Lys-Pro (molecular weight, 759 Da). Analysis using the Lineweaver-Burk plot and molecular modeling suggested that the purified peptide acted as a mixed non-competitive inhibitor of ACE. The inhibitory effects of the peptide against the cellular production of vascular dysfunction-related factors induced by Ang II were also investigated. In human endothelial cells, the Ang II-induced production of nitric oxide and reactive oxygen species was inhibited, and the expression of inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) was downregulated when the cells were cultured with the purified peptide. Moreover, the peptide blocked the activation of p38 mitogen-activated protein kinase. These results indicated that this Spirulina sp.-derived peptide warrants further investigation as a potential pharmacological inhibitor of ACE and vascular dysfunction. PMID:28393188

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Atorvastatin inhibits the apoptosis of human umbilical vein endothelial cells induced by angiotensin II via the lysosomal-mitochondrial axis.

    Science.gov (United States)

    Chang, Ye; Li, Yuan; Ye, Ning; Guo, Xiaofan; Li, Zhao; Sun, Guozhe; Sun, Yingxian

    2016-09-01

    This study was aimed to evaluate lysosomes-mitochondria cross-signaling in angiotensin II (Ang II)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and whether atorvastatin played a protective role via lysosomal-mitochondrial axis. Apoptosis was detected by flow cytometry, Hoechst 33342 and AO/EB assay. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of Cathepsin D (CTSD) was suppressed by pharmacological and genetic approaches. Proteins production were measured by western blotting. Our study showed that Ang II could induce the apoptosis of HUVECs in a dose-depended and time-depended manner. Exposure to 1 μM Ang II for 24 h resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and CTSD redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. These effects were all suppressed by atorvastatin. Either pharmacological or genetic inhibition of CTSD preserved mitochondrial function and decreased apoptosis in HUVECs. Most importantly, we found that the protective effect of atorvastatin was significantly greater than pharmacological or genetic inhibition of CTSD. Finally, overexpression of CTSD without exposure to Ang II had no effect on mitochondrial function and apoptosis. Our data strongly suggested that Ang II induced apoptosis through the lysosomal-mitochondrial axis in HUVECs. Furthermore, atorvastatin played an important role in the regulation of lysosomes and mitochondria stability, resulting in an antagonistic role against Ang II on HUVECs.

  4. Angiotensin II modulates interleukin-1β-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-κB crosstalk

    International Nuclear Information System (INIS)

    Xu, Shanqin; Zhi, Hui; Hou, Xiuyun; Jiang, Bingbing

    2011-01-01

    Highlights: → We examine how angiotensin II modulates ERK-NF-κB crosstalk and gene expression. → Angiotensin II suppresses IL-1β-induced prolonged ERK and NF-κB activation. → ERK-RSK1 signaling is required for IL-1β-induced prolonged NF-κB activation. → Angiotensin II modulates NF-κB responsive genes via regulating ERK-NF-κB crosstalk. → ERK-NF-κB crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1β-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-κB, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1β-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1β, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE -/- ) mice. VCAM-1 and iNOS expression were higher in ApoE -/- than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE -/- mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells

  5. Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shanqin [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Zhi, Hui [Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Hou, Xiuyun [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Jiang, Bingbing, E-mail: bjiang1@rics.bwh.harvard.edu [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States)

    2011-07-08

    Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin

  6. 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

  7. 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

  8. Aldosterone and angiotensin II induced protein aggregation in renal proximal tubules

    DEFF Research Database (Denmark)

    Cheema, Muhammad Umar; Poulsen, Ebbe Toftgaard; Enghild, Jan J

    2013-01-01

    systems in the kidney from control rats and rats receiving aldosterone or angiotensin II treatment for 7 days. Control rats formed both aggresomes and autophagosomes specifically in the proximal tubules, indicating a need for these structures even under baseline conditions. Fluorescence sorted aggresomes......Renal tubules are highly active transporting epithelia and are at risk of protein aggregation due to high protein turnover and/or oxidative stress. We hypothesized that the risk of aggregation was increased upon hormone stimulation and assessed the state of the intracellular protein degradation...... contained various rat keratins known to be expressed in renal tubules as assessed by protein mass spectrometry. Aldosterone administration increased the abundance of the proximal tubular aggresomal protein keratin 5, the ribosomal protein RPL27, ataxin-3, and the chaperone heat shock protein 70...

  9. Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice

    DEFF Research Database (Denmark)

    Liu, Cong-Lin; Wang, Yi; Liao, Mengyang

    2016-01-01

    sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth...... and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth...... factor-β, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation...

  10. The murine angiotensin II-induced abdominal aortic aneurysm model: rupture risk and inflammatory progression patterns

    Directory of Open Access Journals (Sweden)

    Richard Y Cao

    2010-07-01

    Full Text Available An abdominal aortic aneurysm (AAA is an enlargement of the greatest artery in the body defined as an increase in diameter of 1.5-fold. AAAs are common in the elderly population and thousands die each year from their complications. The most commonly used mouse model to study the pathogenesis of AAA is the angiotensin II (Ang II infusion method delivered via osmotic mini-pump for 28 days. Here, we studied the site-specificity and onset of aortic rupture, characterized three-dimensional (3D images and flow patterns in developing AAAs by ultrasound imaging, and examined macrophage infiltration in the Ang II model using 65 apolipoprotein E deficient mice. Aortic rupture occurred in 16 mice (25 % and was nearly as prevalent at the aortic arch (44 % as it was in the suprarenal region (56 % and was most common within the first seven days after Ang II infusion (12 of 16; 75 %. Longitudinal ultrasound screening was found to correlate nicely with histological analysis and AAA volume renderings showed a significant relationship with AAA severity index. Aortic dissection preceded altered flow patterns and macrophage infiltration was a prominent characteristic of developing AAAs. Targeting the inflammatory component of AAA disease with novel therapeutics will hopefully lead to new strategies to attenuate aneurysm growth and aortic rupture.

  11. Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo.

    Science.gov (United States)

    Wang, Qiongxin; Ding, Ye; Song, Ping; Zhu, Huaiping; Okon, Imoh; Ding, Yang-Nan; Chen, Hou-Zao; Liu, De-Pei; Zou, Ming-Hui

    2017-12-05

    Abnormal amino acid metabolism is associated with vascular disease. However, the causative link between dysregulated tryptophan metabolism and abdominal aortic aneurysm (AAA) is unknown. Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Mice with deficiencies in both apolipoprotein e (Apoe) and IDO (Apoe -/- /IDO -/- ) were generated by cross-breeding IDO -/- mice with Apoe -/- mice. The acute infusion of angiotensin II markedly increased the incidence of AAA in Apoe -/- mice, but not in Apoe -/- /IDO -/- mice, which presented decreased elastic lamina degradation and aortic expansion. These features were not altered by the reconstitution of bone marrow cells from IDO +/+ mice. Moreover, angiotensin II infusion instigated interferon-γ, which induced the expression of IDO and kynureninase and increased 3-hydroxyanthranilic acid (3-HAA) levels in the plasma and aortas of Apoe -/- mice, but not in IDO -/- mice. Both IDO and kynureninase controlled the production of 3-HAA in vascular smooth muscle cells. 3-HAA upregulated matrix metallopeptidase 2 via transcription factor nuclear factor-κB. Furthermore, kynureninase knockdown in mice restrained 3-HAA, matrix metallopeptidase 2, and resultant AAA formation by angiotensin II infusion. Intraperitoneal injections of 3-HAA into Apoe -/- and Apoe -/- /IDO -/- mice for 6 weeks increased the expression and activity of matrix metallopeptidase 2 in aortas without affecting metabolic parameters. Finally, human AAA samples had stronger staining with the antibodies against 3-HAA, IDO, and kynureninase than those in adjacent nonaneurysmal aortic sections of human AAA samples. These data define a previously undescribed causative role for 3-HAA, which is a product of tryptophan metabolism, in AAA formation. Furthermore, these findings suggest that 3-HAA reduction may be a new target for treating cardiovascular diseases. © 2017 American Heart Association, Inc.

  12. 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.

  13. Blackberry, raspberry and black raspberry polyphenol extracts attenuate angiotensin II-induced senescence in vascular smooth muscle cells.

    Science.gov (United States)

    Feresin, Rafaela G; Huang, Jingwen; Klarich, DawnKylee S; Zhao, Yitong; Pourafshar, Shirin; Arjmandi, Bahram H; Salazar, Gloria

    2016-10-12

    Activation of angiotensin II (Ang II) signaling during aging increases reactive oxygen species (ROS) leading to vascular senescence, a process linked to the onset and progression of cardiovascular diseases (CVD). Consumption of fruits and vegetables, particularly berries, is associated with decreased incidence of CVD, which has mainly been attributed to the polyphenol content of these foods. Thus, the objective of this study was to investigate the role of blackberry (BL), raspberry (RB), and black raspberry (BRB) polyphenol extracts in attenuating Ang II-induced senescence in vascular smooth muscle cells (VSMCs) and to determine the molecular mechanisms involved. BL, RB and BRB polyphenol extracts (200 μg ml -1 ) attenuated Ang II-induced senescence, denoted by decreased number of cells positive for senescence associated β-galactosidase (SA-β-gal) and down-regulation of p21 and p53 expression, which were associated with decreased ROS levels and Ang II signaling. BL polyphenol extract increased superoxide dismutase (SOD) 1 expression, attenuated the up-regulation of Nox1 expression and the phosphorylation of Akt, p38MAPK and ERK1/2 induced by Ang II, and reduced senescence in response to Nox1 overexpression. In contrast, RB and BRB polyphenol extracts up-regulated the expression of SOD1, SOD2, and glutathione peroxidase 1 (GPx1), but exerted no effect on Nox1 expression nor on senescence induced by Nox1 overexpression. BRB reduced signaling similar to BL, while RB was unable to reduce Akt phosphorylation. Furthermore, we demonstrated that inhibition of Akt, p38MAPK and ERK1/2 as well as down-regulation of Nox1 by siRNA prevented senescence induced by Ang II. Our findings indicate that Ang II-induced senescence is attenuated by BL polyphenols through a Nox1-dependent mechanism and by RB and BRB polyphenols in a Nox1-independent manner, likely by increasing the cellular antioxidant capacity.

  14. 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.

  15. Amelioration of angiotensin II-induced salt-sensitive hypertension by liver-type fatty acid-binding protein in proximal tubules.

    Science.gov (United States)

    Osaki, Ken; Suzuki, Yusuke; Sugaya, Takeshi; Tanifuji, Chiaki; Nishiyama, Akira; Horikoshi, Satoshi; Tomino, Yasuhiko

    2013-10-01

    Inappropriate activation of the intrarenal renin-angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid-binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid-binding protein on post-angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid-binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II-induced SSHT. Overexpression of tubular liver-type fatty acid-binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin-angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid-binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid-binding protein, and found that gene transfection of liver-type fatty acid-binding protein and, in part, recombinant liver-type fatty acid-binding protein administration had significantly attenuated angiotensin II-induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid-binding protein in the proximal tubules may protect against angiotensin II-induced SSHT by attenuating activation of the intrarenal renin-angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid-binding protein in the proximal tubules may be a novel therapeutic target for SSHT.

  16. 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.

  17. 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.

  18. 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

    .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...

  19. 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice.

    Science.gov (United States)

    Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala; Khan, Nayaab S; Katsurada, Akemi; Majid, Dewan S A; Gonzalez, Frank J; Navar, L Gabriel; Malik, Kafait U

    2017-06-01

    Cytochrome P450 1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1 -/- , ovariectomized female, and Cyp1b1 +/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1 -/- and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1 +/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice and Cyp1b1 +/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice but not in Cyp1b1 +/+ male mice. The G protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1 +/+ female mice. These data suggest that 2-methoxyestradiol reduces Ang II-induced hypertension and associated end-organ damage in intact Cyp1b1 -/- , ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice, and Cyp1b1 +/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. © 2017 American Heart Association, Inc.

  20. 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.

  1. 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.

  2. Angiotensin II-induced hypertension increases plasma membrane Na pump activity by enhancing Na entry in rat thick ascending limbs.

    Science.gov (United States)

    Gonzalez-Vicente, Agustin; Garvin, Jeffrey L

    2013-11-01

    Thick ascending limbs (TAL) reabsorb 30% of the filtered NaCl load. Na enters the cells via apical Na-K-2Cl cotransporters and Na/H exchangers and exits via basolateral Na pumps. Chronic angiotensin II (ANG II) infusion increases net TAL Na transport and Na apical entry; however, little is known about its effects on the basolateral Na pump. We hypothesized that in rat TALs Na pump activity is enhanced by ANG II-infusion, a model of ANG II-induced hypertension. Rats were infused with 200 ng·kg(-1)·min(-1) ANG II or vehicle for 7 days, and TAL suspensions were obtained. We studied plasma membrane Na pump activity by measuring changes in 1) intracellular Na (Nai) induced by ouabain; and 2) ouabain-sensitive oxygen consumption (QO2). We found that the ouabain-sensitive rise in Nai in TALs from ANG II-infused rats was 12.8 ± 0.4 arbitrary fluorescent units (AFU)·mg(-1)·min(-1) compared with only 9.9 ± 1.1 AFU·mg(-1)·min(-1) in controls (P Na pump expression, the number of Na pumps in the plasma membrane, or the affinity for Na. When furosemide (1.1 mg·kg(-1)·day(-1)) was coinfused with ANG II, no increase in plasma membrane Na pump activity was observed. We concluded that in ANG II-induced hypertension Na pump activity is increased in the plasma membrane of TALs and that this increase is caused by the chronically enhanced Na entry occurring in this model.

  3. 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).

  4. 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.

  5. 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

  6. Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin II in human hepatic cancer

    International Nuclear Information System (INIS)

    Sasaki, Y.; Imaoka, S.; Hasegawa, Y.

    1985-01-01

    Changes in the distribution of the hepatic blood flow induced by intra-arterial infusion of angiotensin II (AT-II) were studied in human hepatic cancers using extremely short-lived radioisotope (RI) (krypton 81 m [/sup 81m/Kr]; half-life, 13 seconds). After the start of continuous infusion of AT-II, the radioactivity of the tumor showed about a two-fold increase, whereas that of the nontumor region decreased to about one half as much as the level before the infusion. Consequently, the mean ratio of the arterial blood flow in the tumor region to that in the nontumor region (T/N ratio) increased to 3.30 (P less than 0.001). The T/N ratio showed a peak before the peripheral blood pressure reached the maximum, and thereafter tended to decrease. Intra-arterial infusion of AT-II raised the T/N ratio more obviously than did intravenous infusion of the drug, with less rise in the peripheral blood pressure. It is believed that intra-arterial infusion chemotherapy with local use of AT-II enables better accessibility of chemotherapeutic drugs to tumors

  7. Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy.

    Science.gov (United States)

    Chen, Fan; Chen, Dandan; Zhang, Yubin; Jin, Liang; Zhang, Han; Wan, Miyang; Pan, Tianshu; Wang, Xiaochuan; Su, Yuheng; Xu, Yitao; Ye, Junmei

    2017-12-16

    Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Magnesium supplementation prevents angiotensin II-induced myocardial damage and CTGF overexpression.

    Science.gov (United States)

    Finckenberg, Piet; Merasto, Saara; Louhelainen, Marjut; Lindgren, Leena; Vapaatalo, Heikki; Müller, Dominik N; Luft, Friedrich C; Mervaala, Eero M A

    2005-02-01

    Magnesium deficiency promotes vasoconstriction and myocardial damage. Recent studies provide evidence that Ang II mobilizes intracellular Mg through AT1 receptor-mediated pathways. We tested the hypothesis of whether magnesium supplementation prevents Ang II-induced myocardial damage and induction of the profibrotic connective tissue growth factor (CTGF). Four-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGR) were given dietary magnesium supplementation (0.6%) for 3 weeks. Control dTGR and normotensive Sprague-Dawley (SD) rats received normal diet (Mg 0.2%). Histopathological, immunohistochemical and mRNA analysis were used to detect the treatment-related effects of dietary magnesium in dTGR. Magnesium (Mg) supplementation decreased blood pressure, ameliorated cardiac hypertrophy, protected against the development of Ang II-induced myocardial damage and increased serum ionized Mg2+ concentration (all variables P protein expressions were increased by 300% in dTGR (P supplementation prevented Ang II-induced myocardial CTGF overexpression (P supplementation also improved the therapeutic effects of the calcineurin inhibitor tacrolimus, which produced marked hypomagnesemia when given as monotherapy. Our findings suggest a salutary effect for magnesium supplementation in the treatment of Ang II-induced myocardial complications.

  9. 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.

  10. 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 ...

  11. 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.

  12. 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.

  13. β-Carotene Attenuates Angiotensin II-Induced Aortic Aneurysm by Alleviating Macrophage Recruitment in Apoe(-/- Mice.

    Directory of Open Access Journals (Sweden)

    Kaliappan Gopal

    Full Text Available Abdominal aortic aneurysm (AAA is a common chronic degenerative disease characterized by progressive aortic dilation and rupture. The mechanisms underlying the role of α-tocopherol and β-carotene on AAA have not been comprehensively assessed. We investigated if α-tocopherol and β-carotene supplementation could attenuate AAA, and studied the underlying mechanisms utilized by the antioxidants to alleviate AAA. Four-months-old Apoe(-/- mice were used in the induction of aneurysm by infusion of angiotensin II (Ang II, and were orally administered with α-tocopherol and β-carotene enriched diet for 60 days. Significant increase of LDL, cholesterol, triglycerides and circulating inflammatory cells was observed in the Ang II-treated animals, and gene expression studies showed that ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9 and MMP-12 were upregulated in the aorta of aneurysm-induced mice. Extensive plaques, aneurysm and diffusion of inflammatory cells into the tunica intima were also noticed. The size of aorta was significantly (P = 0.0002 increased (2.24±0.20 mm in the aneurysm-induced animals as compared to control mice (1.17±0.06 mm. Interestingly, β-carotene dramatically controlled the diffusion of macrophages into the aortic tunica intima, and circulation. It also dissolved the formation of atheromatous plaque. Further, β-carotene significantly decreased the aortic diameter (1.33±0.12 mm in the aneurysm-induced mice (β-carotene, P = 0.0002. It also downregulated ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9, MMP-12, PPAR-α and PPAR-γ following treatment. Hence, dietary supplementation of β-carotene may have a protective function against Ang II-induced AAA by ameliorating macrophage recruitment in Apoe(-/- mice.

  14. ADAMTS-7 Expression Increases in the Early Stage of Angiotensin II-Induced Renal Injury in Elderly Mice

    Directory of Open Access Journals (Sweden)

    Yan-Xiang Gao

    2014-03-01

    Full Text Available Background/Aims: We investigated the recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs, and matrix metalloproteinases (MMPs as inflammatory mediators in inflammatory kidney damage by studying ADAMTS-1, -4, and -7 and MMP-9 expression in elderly mouse kidneys after angiotensin II (Ang II administration. Methods: Ang II (2.5 µg/kg/min or norepinephrine (8.3 µg/kg/min was subcutaneously infused in old mice. Renal injury was assessed by hematoxylin-eosin staining, 24-h albuminuria, and immunohistochemistry to evaluate inflammatory cell markers. The mRNA and protein expression of ADAMTS-1, -4, and -7 and MMP-9 were determined using real-time PCR, Western blot, and immunohistochemistry 3 days after Ang II or norepinephrine administration. Results: Elderly mice in the Ang II group developed hypertension and pathological kidney damage. The mRNA and protein levels of ADAMTS-7 in the Ang II group were 3.3 ± 1.1 (P = 0.019 and 1.6 ± 0.1 (P = 0.047 vs. 1.0 ± 0.1 and 1.0 ± 0.1 in the control group on day 3. In contrast, treatment with the hypertensive agent norepinephrine did not lead to obvious renal damage or an increase in renal ADAMTS-7 expression. Conclusions: Renal ADAMTS-7 expression was induced by Ang II in elderly mice. The overexpression of ADATMTS-7 might contribute to early inflammatory kidney damage associated with aging.

  15. Effects of hydroxysafflor yellow A on proliferation and collagen synthesis of rat vascular adventitial fibroblasts induced by angiotensin II.

    Science.gov (United States)

    Yuan, Wendan; Yang, Dongxia; Sun, Xuhong; Liu, Wei; Wang, Liang; Li, Xiaoyan; Man, Xuejing; Fu, Qiang

    2014-01-01

    1) examine the effects of hydroxysafflor yellow A (HSYA) on the proliferation, collagen and cytokine synthesis of vascular adventitial fibroblasts as induced by angiotensin II (Ang II) in normal Sprague-Dawley (SD) rats in vitro, and 2) to assess the effects of HSYA on morphological changes and collagen accumulation of vascular adventitia in spontaneously hypertensive rats (SHR) in vivo. In vitro experiment, vascular adventitial fibroblasts from SD rats were isolated, cultured, and divided into control groups, model groups and HSYA groups. Cell morphology of adventitial fibroblasts was assessed using laser confocal microscopy, while cell proliferation with the MTT assay, and collagen synthesis was determined using hydroxyproline chromatometry. Immunocytochemistry and reverse transcription PCR were used for detecting the expression of TGF-β1, MMP-1, α-SMA and NF-κB in adventitial fibroblasts. In vivo experiment, vascular adventitia proliferation and collagen synthesis were analyzed using hematoxylin-eosin and Sirius staining. Our results showed that: 1) in vitro experiment of SD rats, HSYA inhibited proliferative activity and collagen synthesis of adventitial fibroblasts as induced by Ang II, and the inhibitory effects of HSYA on the increased expression of MMP-1, TGF-β1, α-SMA and NF-κB p65 as induced by Ang II were assessed, and 2) in vivo experiment of SHR, histological analysis displayed fewer pathological changes of vascular adventitia in HSYA treatment groups as compared with no HSYA treatment groups, and MMP-1, TGF-β1, α-SMA and NF-κB p65 expression significantly reduced after HSYA treatment (P adventitia components. This study provides experimental evidence demonstrating that HSYA has the capacity to decrease vascular adventitia proliferation and hyperplasia during vascular remodeling.

  16. 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...

  17. 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.

  18. Rcan1-1L overexpression induces mitochondrial autophagy and improves cell survival in angiotensin II-exposed cardiomyocytes

    Energy Technology Data Exchange (ETDEWEB)

    Duan, Hongyan; Li, Yongqiang; Yan, Lijie; Yang, Haitao; Wu, Jintao; Qian, Peng; Li, Bing; Wang, Shanling, E-mail: shanglingwang@126.com

    2015-07-01

    Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200 nmol/L Ang II for 4 days. Enhanced H{sub 2}O{sub 2} production, cytochrome C release and mitochondrial permeability were observed in these cells, which were blocked by valsartan. Consistently, Ang II exposure significantly reduced cardiomyocyte viability. However, transfection of Rcan1-1L vector promoted cell viability and ameliorated the apoptosis caused by Ang II. Rcan1-1L clearly promoted mitochondrial autophagy in HACMs, with elevated autophagy protein (ATG) 5 and light chain 3 (LC3) expression. Transient mitochondrial biogenesis and reduced cytochrome C release was also induced by Rcan1-1L. Additionally, Rcan1-1L significantly inhibited calcineurin/nuclear factor of activated T cells (NFAT) signaling. We thus conclude that Rcan1-1L may play a protective role in Ang II-treated cardiomyocytes through the induction of mitochondrial autophagy, and may be an alternative method of cardiac protection. - Highlights: • Transfection of Rcan1-1L into HACMs promoted cell viability and reduced apoptosis. • Transfection of Rcan1-1L promoted mitochondrial autophagy in HACMs. • Rcan1-1L inhibited the calcineurin/nuclear factor of activated T cells signaling.

  19. 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

  20. 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

  1. 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)

  2. Tumor vascularity under hypertension induced by intravenous infusion of angiotensin II

    International Nuclear Information System (INIS)

    Kato, Toshio

    1986-01-01

    We studied whether or not the blood flow of tumors was increased by AT-II-induced hypertension in patients. Angiograms of 51 patients before and after intravenous infusion of AT-II were compared carefully from 5 points of view which suggested increased tumor blood flow. These were, 1) Contraction of small arteries feeding normal tissue, 2) Enhanced visualization of tumor vessels, 3) Enhanced visualization of tumor stain, 4) Increase of venous return from tumor-bearing region, and 5) Enhanced visualization of metastatic lymph nodes. The results were as follows. Contractions of small arteries feeding normal tissue [Finding 1)] were observed in 34 cases (66.6 %) and enhanced visualization of tumor vessels, tumor stain and so on [Finding 2)-5] were observed in 18 cases (35.3 %). Concequently, an increase of tumor blood flow was suggested in 40 cases (78.4 %). Blood flow of human tumors and normal tissue during the full course of induced hypertension with AT-II were measures by means of radionuclide angiography ( 99m Tc-RBC) and laser Doppler velocimetry. Activities of the tumor-bearing region and the mid-portion of the thigh (selected as normal tissue) were measured continuously by collimated scintillation detectors. In 26 measurements out of 31 (83.8 %), the activity in the thigh decreased promptly and returned to the baseline synchronously with the rise and fall of blood pressure. In contrast, in 11 measurements (34.4 %) the activity of the tumor-bearing region increased and returned to the baseline accompanying the change of blood pressure. Preliminary observations using laser Doppler velocimetry revealed an increase of blood flow in 5 tumors. In conclusion, the blood flow of human tumors was increased by AT-II, in agreement with the findings in animal tumors. (J.P.N.)

  3. 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.

  4. Female Mice with an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms

    Science.gov (United States)

    Alsiraj, Yasir; Thatcher, Sean E.; Charnigo, Richard; Chen, Kuey; Blalock, Eric; Daugherty, Alan; Cassis, Lisa A.

    2017-01-01

    Background Abdominal aortic aneurysms (AAAs) are a deadly pathology with strong sexual dimorphism. Similar to humans, female mice exhibit far lower incidences of angiotensin II (AngII)-induced AAAs than males. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, we defined the effect of female (XX) versus male (XY) sex chromosome complement on AngII-induced AAA formation and rupture in phenotypically female mice. Methods Female low density lipoprotein receptor (Ldlr) mice with an XX or XY sex chromosome complement were infused with AngII for 28 days to induce AAAs. Abdominal aortic lumen diameters were quantified by ultrasound, while AAA diameters were quantified at study endpoint. DNA microarrays were performed on abdominal aortas. To mimic males, female mice were administered a single dose of testosterone as neonates or as adults prior to AngII infusions. Results Female Ldlr−/− deficient mice with an XX and XY sex chromosome complement had similar sex organ weights and low serum testosterone concentrations. Abdominal aortas from female XY mice selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of aortic gene differences in XY versus XX females fell within inflammatory pathways. AAA incidences doubled and aneurysms ruptured in XY females. AAAs from XY females exhibited inflammation, and plasma IL1β concentrations were increased in XY females. Moreover, aortas from XY females had augmented matrix metalloproteinase activity and increased oxidative stress. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX adult females. Conclusions An XY sex chromosome complement in phenotypic females profoundly influenced aortic gene expression profiles and promoted AAA severity. When XY females were exposed to

  5. Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

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    Haller Hermann

    2002-01-01

    Full Text Available Abstract Background We are investigating a double transgenic rat (dTGR model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1 are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. Methods We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc and age-matched SD rats.. Blood-pressure- and albuminuria- measurements were monitored during the treatement period (four weeks. The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analsis. Results Chronic treatment with the antioxidant PDTC decreased blood pressure (162 ± 8 vs. 190 ± 7 mm Hg, p = 0.02. Cardiac hypertrophy index was significantly reduced (4.90 ± 0.1 vs. 5.77 ± 0.1 mg/g, p Conclusion Our data show that inhibition of NF-κB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-κB activation plays an important role in ANG II-induced end-organ damage.

  6. 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...

  7. 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

  8. Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice.

    Science.gov (United States)

    Pei, Jian-Fei; Yan, Yun-Fei; Tang, Xiaoqiang; Zhang, Yang; Cui, Shen-Shen; Zhang, Zhu-Qin; Chen, Hou-Zao; Liu, De-Pei

    2016-11-01

    Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene (PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type (WT) control. The same protective tendency was also observed with an Apoe -/- background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. The water channel AQP1 is expressed in human atherosclerotic vascular lesions and AQP1 deficiency augments angiotensin II-induced atherosclerosis in mice

    DEFF Research Database (Denmark)

    Wintmo, P.; Johansen, S. H.; Hansen, P. B. L.

    2017-01-01

    aneurysms. Apolipoprotein E (ApoE) knockout (-/-) and AQP1-/-ApoE-/- mice were developed and fed Western diet (WD) for 8 and 16 weeks to accelerate the atherosclerosis process. In ApoE-/- and AQP1-/-ApoE-/- mice abdominal aortic aneurysms (AAA) were induced by angiotensin II (ANGII) infusion by osmotic...... increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes. Conclusion: AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse...

  14. UAP56 is an important mediator of Angiotensin II/platelet derived growth factor induced vascular smooth muscle cell DNA synthesis and proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Sahni, Abha [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 (United States); Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 (United States); Wang, Nadan [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 (United States); Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Alexis, Jeffrey, E-mail: jeffrey_alexis@urmc.rochester.edu [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 (United States)

    2013-02-15

    Highlights: ► Knockdown of UAP56 inhibits Angiotensin II/PDGF induced vascular smooth muscle cell proliferation. ► UAP56 is a positive regulator of E2F transcriptional activation. ► UAP56 is present in the vessel wall of low flow carotid arteries. -- Abstract: Angiotensin (Ang) II and platelet-derived growth factor (PDGF) are important mediators of pathologic vascular smooth muscle cell (VSMC) proliferation. Identifying downstream mediators of Ang II and PDGF signaling may provide insights for therapies to improve vascular proliferative diseases. We have previously demonstrated that breakpoint cluster region (Bcr) is an important mediator of Ang II/PDGF signaling in VSMC. We have recently reported that the DExD/H box protein UAP56 is an interacting partner of Bcr in regulating VSMC DNA synthesis. We hypothesized that UAP56 itself is an important regulator of VSMC proliferation. In this report we demonstrate that knockdown of UAP56 inhibits Ang II/PDGF induced VSMC DNA synthesis and proliferation, and inhibits E2F transcriptional activity. In addition, we demonstrate that UAP56 is present in the vessel wall of low-flow carotid arteries. These findings suggest that UAP56 is a regulator of VSMC proliferation and identify UAP56 as a target for preventing vascular proliferative disease.

  15. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

    Science.gov (United States)

    Martín-Sánchez, Paloma; Luengo, Alicia; Griera, Mercedes; Orea, María Jesús; López-Olañeta, Marina; Chiloeches, Antonio; Lara-Pezzi, Enrique; de Frutos, Sergio; Rodríguez-Puyol, Manuel; Calleros, Laura; Rodríguez-Puyol, Diego

    2018-02-01

    Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H- ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. In this study, we analyzed the consequences of H- ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H -ras -/- ) and control wild-type (H -ras +/+ ) mice, as were extracellular matrix protein expression. Increased cardiac PKG-Iβ protein expression in H -ras -/- mice suggests the involvement of this protein in heart protection. Ex vivo experiments on cardiac explants could support this mechanism, as PKG blockade blunted protection against AngII-induced cardiac hypertrophy and fibrosis markers in H -ras -/- mice. Genetic modulation studies in cardiomyocytes and cardiac and embryonic fibroblasts revealed that the lack of H-Ras down-regulates the B-RAF/MEK/ERK pathway, which induces the glycogen synthase kinase-3β-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-Iβ overexpression in H -ras -/- mouse embryonic fibroblasts. This study demonstrates that H- ras deletion protects against AngII-induced cardiac remodeling, possibly via a mechanism in which PKG-Iβ overexpression could play a partial role, and points to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.-Martín-Sánchez, P., Luengo, A., Griera, M., Orea, M. J., López-Olañeta, M., Chiloeches, A., Lara-Pezzi, E., de Frutos, S., Rodríguez-Puyol, M., Calleros, L., Rodríguez-Puyol, D. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

  16. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

    Directory of Open Access Journals (Sweden)

    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  17. 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

  18. Angiotensin-II inhibitor (olmesartan)-induced collagenous sprue with resolution following discontinuation of drug.

    Science.gov (United States)

    Nielsen, Jennifer A; Steephen, Anita; Lewin, Matthew

    2013-10-28

    Collagenous sprue (CS) is a pattern of small-bowel injury characterized histologically by marked villous blunting, intraepithelial lymphocytes, and thickened sub-epithelial collagen table. Clinically, patients present with diarrhea, abdominal pain, malabsorption, and weight loss. Gluten intolerance is the most common cause of villous blunting in the duodenum; however, in a recent case series by the Mayo Clinic, it has been reported that olmesartan can have a similar effect. In this case report, a 62-year-old female with a history of hypothyroidism and hypertension managed for several years with olmesartan presented with abdominal pain, weight loss, and nausea. Despite compliance to a gluten-free diet, the patient's symptoms worsened, losing 20 pounds in 3 wk. Endoscopy showed thickening, scalloping, and mosaiform changes of the duodenal mucosa. The biopsy showed CS characterized by complete villous atrophy, lymphocytosis, and thickened sub-epithelial collagen table. After 2 mo cessation of olmesartan, the patient's symptoms improved, and follow-up endoscopy was normal with complete villous regeneration. These findings suggest that olmesartan was a contributing factor in the etiology of this patient's CS. Clinicians should be aware of the possibility of drug-induced CS and potential reversibility after discontinuation of medication.

  19. 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

  20. 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.

  1. EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress.

    Science.gov (United States)

    Niazi, Zahid Rasul; Silva, Grazielle C; Ribeiro, Thais Porto; León-González, Antonio J; Kassem, Mohamad; Mirajkar, Abdur; Alvi, Azhar; Abbas, Malak; Zgheel, Faraj; Schini-Kerth, Valérie B; Auger, Cyril

    2017-12-01

    Eicosapentaenoic acid:docosahexaenoic acid (EPA:DHA) 6:1, an omega-3 polyunsaturated fatty acid formulation, has been shown to induce a sustained formation of endothelial nitric oxide (NO) synthase-derived NO, a major vasoprotective factor. This study examined whether chronic intake of EPA:DHA 6:1 prevents hypertension and endothelial dysfunction induced by angiotensin II (Ang II) in rats. Male Wister rats received orally corn oil or EPA:DHA 6:1 (500 mg kg -1 per day) before chronic infusion of Ang II (0.4 mg kg -1 per day). Systolic blood pressure was determined by tail cuff sphingomanometry, vascular reactivity using a myograph, oxidative stress using dihydroethidium and protein expression by immunofluorescence and western blot analysis. Ang II-induced hypertension was associated with reduced acetylcholine-induced relaxations of secondary branch mesenteric artery rings affecting the endothelium-dependent hyperpolarization (EDH)- and the NO-mediated relaxations, both of which were improved by the NADPH oxidase inhibitor VAS-2870. The Ang II treatment induced also endothelium-dependent contractile responses (EDCFs), which were abolished by the cyclooxygenase (COX) inhibitor indomethacin. An increased level of vascular oxidative stress and expression of NADPH oxidase subunits (p47 phox and p22 phox ), COX-1 and COX-2, endothelial NO synthase and Ang II type 1 receptors were observed in the Ang II group, whereas SK Ca and connexin 37 were downregulated. Intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction by improving both the NO- and EDH-mediated relaxations, and by reducing EDCFs and the expression of target proteins. The present findings indicate that chronic intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction in rats, most likely by preventing NADPH oxidase- and COX-derived oxidative stress.

  2. Metamizol acts as an ATP sensitive potassium channel opener to inhibit the contracting response induced by angiotensin II but not to norepinephrine in rat thoracic aorta smooth muscle.

    Science.gov (United States)

    Valenzuela, Fermín; García-Saisó, Sebastián; Lemini, Cristina; Ramírez-Solares, Rafael; Vidrio, Horacio; Mendoza-Fernández, Víctor

    2005-08-01

    Clinically metamizol (MZ) has been related to alteration on haemodynamic parameters and modifications on blood pressure in humans when administered intravenously. These effects have been observed at MZ therapeutic doses. Experimentally, MZ is able to induce relaxation on several types of vascular smooth muscles and modulates the contraction induced by phenylephrine. However, the mechanism underlying the MZ effects on vascular reactivity is not clear. Potassium channels (K) present on vascular smooth muscle cells closely regulate the vascular reactivity and membrane potential. There are four described types of K in vascular tissue: K voltage sensitive (K(V)), K calcium sensitive (K(Ca)2+), K ATP sensitive (K(ATP) and K inward rectification (K(IR), voltage sensitive). The aim of this work was to investigate MZ effects on angiotensin II (AT II) and noradrenaline (NA) induced contraction and to evaluate the K participation on MZ modulating effect on vascular smooth muscle contraction, using isometric and patch clamp techniques. MZ induces relaxation in a concentration dependent manner. Furthermore, MZ strongly inhibits in a concentration dependent fashion the contraction induced by AT II. However, MZ inhibition on NA induced contraction was moderated compared with that observed on AT II. MZ effects on AT II induced contraction was blocked by glybenclamide (a specific K(ATP) blocker, 3 microM, *p < 0.01). In patch clamp experiments, MZ (3 mM) induces an increase on potassium current (K+) mediated by K(ATP) in similar way as diazoxide (a specific K(ATP) opener, 3 microM). Our results suggest that MZ induces relaxation and inhibits contraction induced by AT II acting as a K(ATP) opener.

  3. 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...

  4. HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells.

    Science.gov (United States)

    Kunieda, Yasufumi; Nakagawa, Katsumi; Nishimura, Hiromi; Kato, Hisato; Ukimura, Naoki; Yano, Shingo; Kawano, Hidehiko; Kimura, Shinzo; Nakagawa, Masao; Tsuji, Hajime

    2003-06-01

    It has been demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) reduce the incidence of acute cardiovascular events in patients with hyperlipidemia. Recent reports have shown that the protective effects of these drugs against cardiovascular events are also observed in patients without hyperlipidemia, but the mechanism of this favorable effect still remains unclear. In this study, the effects of HRIs on the endothelial regulation of thrombus formation were elucidated. The mRNA and protein expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by angiotensin II (Ang II) were evaluated in cultured rat aortic endothelial cells. Pretreatment with simvastatin (0.03-3 microg/ml) significantly inhibited TF and PAI-1 induction by Ang II in a dose- and time-dependent manner. These inhibitions were significantly attenuated by mevalonic acid or geranylgeranyl pyrophosphate. Both Rho inhibitor, C3 exoenzyme, and Rho kinase inhibitor, Y-27632, mimicked the inhibitory effects of simvastatin against TF and PAI-1 induced by Ang II. This result suggested that the Rho/Rho kinase pathway is related to the TF and PAI-1 induction by Ang II. It was indicated that simvastatin maintains endothelial cells to be antithrombotic by inhibiting TF and PAI-1 expression via the Rho/Rho kinase pathways in which AngII induces TF and PAI-1 expression. These observations explain, at least partly, the mechanism of the favorable effects of simvastatin in reducing the thrombotic events.

  5. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

    Directory of Open Access Journals (Sweden)

    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  6. Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report.

    Science.gov (United States)

    Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju; Graham, Mark J; Mullick, Adam E; Daugherty, Alan

    2016-09-01

    Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms. In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y). AAV at 3 doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose dependently in mice injected with AAV containing PCSK9D377Y mutation and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein receptor(-/-) mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor(-/-) mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor(-/-) mice did not influence AngII-induced abdominal aortic aneurysms. AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with AngII

  7. Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development.

    Science.gov (United States)

    Kim, Seonwook; Yang, Lihua; Kim, Seongu; Lee, Richard G; Graham, Mark J; Berliner, Judith A; Lusis, Aldons J; Cai, Lei; Temel, Ryan E; Rateri, Debra L; Lee, Sangderk

    2017-01-01

    The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model. Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin II (AngII, 1,000ng/kg/min) for the last 4 weeks of ASO administration. We confirmed that the HB-EGF ASO administration significantly downregulated HB-EGF expression in multiple tissues including the liver. Importantly, the HB-EGF ASO administration significantly suppressed development of aortic aneurysms including thoracic and abdominal types. Interestingly, the HB-EGF ASO administration induced a remarkable anti-hyperlipidemic effect by suppressing very low density lipoprotein (VLDL) level in the blood. Mechanistically, the HB-EGF targeting suppressed hepatic VLDL secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate. This result suggested that the HB-EGF targeting induced protection against aneurysm development through anti-hyperlipidemic effects. Suppression of hepatic VLDL production process appears to be a key mechanism for the anti-hyperlipidemic effects by the HB-EGF targeting.

  8. Myocyte-specific enhancer factor 2C: a novel target gene of miR-214-3p in suppressing angiotensin II-induced cardiomyocyte hypertrophy.

    Science.gov (United States)

    Tang, Chun-Mei; Liu, Fang-Zhou; Zhu, Jie-Ning; Fu, Yong-Heng; Lin, Qiu-Xiong; Deng, Chun-Yu; Hu, Zhi-Qin; Yang, Hui; Zheng, Xi-Long; Cheng, Jian-Ding; Wu, Shu-Lin; Shan, Zhi-Xin

    2016-10-31

    The role of microRNA-214-3p (miR-214-3p) in cardiac hypertrophy was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced mouse cardiac hypertrophy. In mice with either Ang-II infusion or transverse aortic constriction (TAC) model, miR-214-3p expression was markedly decreased in the hypertrophic myocardium. Down-regulation of miR-214-3p was observed in the myocardium of patients with cardiac hypertrophy. Expression of miR-214-3p was upregulated in Ang-II-induced hypertrophic neonatal mouse ventricular cardiomyocytes. Cardiac hypertrophy was attenuated in Ang-II-infused mice by tail vein injection of miR-214-3p. Moreover, miR-214-3p inhibited the expression of atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC) in Ang-II-treated mouse cardiomyocytes in vitro. Myocyte-specific enhancer factor 2C (MEF2C), which was increased in Ang-II-induced hypertrophic mouse myocardium and cardiomyocytes, was identified as a target gene of miR-214-3p. Functionally, miR-214-3p mimic, consistent with MEF2C siRNA, inhibited cell size increase and protein expression of ANP and β-MHC in Ang-II-treated mouse cardiomyocytes. The NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in cardiomyocytes. Taken together, our results revealed that MEF2C is a novel target of miR-214-3p, and attenuation of miR-214-3p expression may contribute to MEF2Cexpressionin cardiac hypertrophy.

  9. Inhibition of angiotensin II-induced cardiac hypertrophy and associated ventricular arrhythmias by a p21 activated kinase 1 bioactive peptide.

    Science.gov (United States)

    Wang, Rui; Wang, Yanwen; Lin, Wee K; Zhang, Yanmin; Liu, Wei; Huang, Kai; Terrar, Derek A; Solaro, R John; Wang, Xin; Ke, Yunbo; Lei, Ming

    2014-01-01

    Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias.

  10. 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

  11. 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.

  12. 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

  13. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE−/− mice through inhibiting vascular inflammatory response

    International Nuclear Information System (INIS)

    Chen, Yi xi; Zhang, Man; Cai, Yuehua; Zhao, Qihui; Dai, Wenjian

    2015-01-01

    Activation of the silent mating type information regulation 2 homolog 1 (SIRT1) has been shown consistent antiinflammatory function. However, little information is available on the function of SIRT1 during Angiotensin II (AngII)-induced atherosclerosis. Here we report atheroprotective effects of sirt1 activation in a model of AngII-accelerated atherosclerosis, characterized by suppression pro-inflammatory transcription factors Nuclear transcription factor (NF)-κB and Signal Transducers and Activators of Transcription. (STAT) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the SIRT1 agonist SRT1720 substantially attenuated AngII-accelerated atherosclerosis with decreasing blood pressure and inhibited NF-κB and STAT3 activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated VSMCs and macrophages: SIRT1 activation inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of SIRT1 activation to inhibit AngII signaling, which is atheroprotective. - Highlights: • SRT1720 reduced atherosclerotic lesion size in aortic arches and atherosclerotic lesion macrophage content. • SRT1720 could inhibit the phosphorylation of STAT3 and p65 phosphorylation and translocation. • SRT1720 could inhibit the expression of proinflammatory factor.

  14. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE{sup −/−} mice through inhibiting vascular inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi xi; Zhang, Man; Cai, Yuehua; Zhao, Qihui; Dai, Wenjian, E-mail: wjdai@126.com

    2015-10-02

    Activation of the silent mating type information regulation 2 homolog 1 (SIRT1) has been shown consistent antiinflammatory function. However, little information is available on the function of SIRT1 during Angiotensin II (AngII)-induced atherosclerosis. Here we report atheroprotective effects of sirt1 activation in a model of AngII-accelerated atherosclerosis, characterized by suppression pro-inflammatory transcription factors Nuclear transcription factor (NF)-κB and Signal Transducers and Activators of Transcription. (STAT) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the SIRT1 agonist SRT1720 substantially attenuated AngII-accelerated atherosclerosis with decreasing blood pressure and inhibited NF-κB and STAT3 activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated VSMCs and macrophages: SIRT1 activation inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of SIRT1 activation to inhibit AngII signaling, which is atheroprotective. - Highlights: • SRT1720 reduced atherosclerotic lesion size in aortic arches and atherosclerotic lesion macrophage content. • SRT1720 could inhibit the phosphorylation of STAT3 and p65 phosphorylation and translocation. • SRT1720 could inhibit the expression of proinflammatory factor.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent β1-subunit glutathionylation: implications for angiotensin II-induced vascular dysfunction.

    Science.gov (United States)

    Liu, Chia-Chi; Karimi Galougahi, Keyvan; Weisbrod, Robert M; Hansen, Thomas; Ravaie, Ramtin; Nunez, Andrea; Liu, Yi B; Fry, Natasha; Garcia, Alvaro; Hamilton, Elisha J; Sweadner, Kathleen J; Cohen, Richard A; Figtree, Gemma A

    2013-12-01

    Glutathionylation of the Na(+)-K(+) pump's β1-subunit is a key molecular mechanism of physiological and pathophysiological pump inhibition in cardiac myocytes. Its contribution to Na(+)-K(+) pump regulation in other tissues is unknown, and cannot be assumed given the dependence on specific β-subunit isoform expression and receptor-coupled pathways. As Na(+)-K(+) pump activity is an important determinant of vascular tone through effects on [Ca(2+)]i, we have examined the role of oxidative regulation of the Na(+)-K(+) pump in mediating angiotensin II (Ang II)-induced increases in vascular reactivity. β1-subunit glutathione adducts were present at baseline and increased by exposure to Ang II in rabbit aortic rings, primary rabbit aortic vascular smooth muscle cells (VSMCs), and human arterial segments. In VSMCs, Ang II-induced glutathionylation was associated with marked reduction in Na(+)-K(+)ATPase activity, an effect that was abolished by the NADPH oxidase inhibitory peptide, tat-gp91ds. In aortic segments, Ang II-induced glutathionylation was associated with decreased K(+)-induced vasorelaxation, a validated index of pump activity. Ang II-induced oxidative inhibition of Na(+)-K(+) ATPase and decrease in K(+)-induced relaxation were reversed by preincubation of VSMCs and rings with recombinant FXYD3 protein that is known to facilitate deglutathionylation of β1-subunit. Knock-out of FXYD1 dramatically decreased K(+)-induced relaxation in a mouse model. Attenuation of Ang II signaling in vivo by captopril (8 mg/kg/day for 7 days) decreased superoxide-sensitive DHE levels in the media of rabbit aorta, decreased β1-subunit glutathionylation, and enhanced K(+)-induced vasorelaxation. Ang II inhibits the Na(+)-K(+) pump in VSMCs via NADPH oxidase-dependent glutathionylation of the pump's β1-subunit, and this newly identified signaling pathway may contribute to altered vascular tone. FXYD proteins reduce oxidative inhibition of the Na(+)-K(+) pump and may have an

  20. 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.

  1. 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.

  2. Over-Expression of Copper/Zinc Superoxide Dismutase in the Median Preoptic Nucleus Attenuates Chronic Angiotensin II-Induced Hypertension in the Rat

    Directory of Open Access Journals (Sweden)

    John P. Collister

    2014-12-01

    Full Text Available The brain senses circulating levels of angiotensin II (AngII via circumventricular organs, such as the subfornical organ (SFO, and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD, an intracellular superoxide (O2·− scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·− in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD or control vector (AdEmpty were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min for ten days. Rats over-expressing CuZnSOD (n = 7 in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9. These results support the hypothesis that production of O2·− in the MnPO contributes to the development of chronic AngII-dependent hypertension.

  3. 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.

  4. 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.

  5. Modulation of angiotensin II-induced inflammatory cytokines by the Epac1-Rap1A-NHE3 pathway: implications in renal tubular pathobiology

    Science.gov (United States)

    Xie, Ping; Joladarashi, Darukeshwara; Dudeja, Pradeep; Sun, Lin

    2014-01-01

    Besides the glomerulus, the tubulointerstitium is often concomitantly affected in certain diseases, e.g., diabetic nephropathy, and activation of the renin-angiotensin system, to a certain extent, worsens its outcome because of perturbations in hemodynamics and possibly tubuloglomerular feedback. Certain studies suggest that pathobiology of the tubulointerstitium is influenced by small GTPases, e.g., Rap1. We investigated the effect of ANG II on inflammatory cytokines, while at the same time focusing on upstream effector of Rap1, i.e., Epac1, and some of the downstream tubular transport molecules, i.e., Na/H exchanger 3 (NHE3). ANG II treatment of LLC-PK1 cells decreased Rap1a GTPase activity in a time- and dose-dependent manner. ANG II treatment led to an increased membrane translocation of NHE3, which was reduced with Epac1 and PKA activators. ANG II-induced NHE3 translocation was notably reduced with the transfection of Rap1a dominant positive mutants, i.e., Rap1a-G12V or Rap1a-T35A. Transfection of cells with dominant negative Rap1a mutants, i.e., Rap1a-S17A, or Epac1 mutant, i.e., EPAC-ΔcAMP, normalized ANG II-induced translocation of NHE3. In addition, ANG II treatment led to an increased expression of inflammatory cytokines, i.e., IL-1β, IL-6, IL-8, and TNF-α, which was reduced with Rap1a-G12V or Rap1a-T35A transfection, while it reverted to previous comparable levels following transfection of Rap1a-S17A or EPAC-ΔcAMP. ANG II-induced expression of cytokines was reduced with the treatment with NHE3 inhibitor S3226 or with Epac1 and PKA activators. These data suggest that this novel Epac1-Rap1a-NHE3 pathway conceivably modulates ANG II-induced expression of inflammatory cytokines, and this information may yield the impetus for developing strategies to reduce tubulointertstitial inflammation in various renal diseases. PMID:24553435

  6. 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...

  7. 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

  8. 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

  9. 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...

  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. 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

  12. The Angiotensin-Converting-Enzyme-Induced Angioedema.

    Science.gov (United States)

    Bas, Murat

    2017-02-01

    The bradykinin B2 receptor antagonist icatibant is effective in angiotensin-converting enzyme inhibitor-induced angioedema. The drug is not approved officially for this indication and has to be administered in an emergency situation off-label. Corticosteroids or antihistamines do not seem to work in this condition. The effectiveness of C1-esterase-inhibitor in angiotensin-converting enzyme-induced angioedema must be verified in a double-blind study. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Oral administration of bisphenol A induces high blood pressure through angiotensin II/CaMKII-dependent uncoupling of eNOS.

    Science.gov (United States)

    Saura, Marta; Marquez, Susana; Reventun, Paula; Olea-Herrero, Nuria; Arenas, María Isabel; Moreno-Gómez-Toledano, Rafael; Gómez-Parrizas, Mónica; Muñóz-Moreno, Carmen; González-Santander, Marta; Zaragoza, Carlos; Bosch, Ricardo J

    2014-11-01

    Bisphenol A (BPA) is found in human urine and fat tissue. Higher urinary BPA concentrations are associated with arterial hypertension. To shed light on the underlying mechanism, we orally administered BPA (4 nM to 400 μM in drinking water) to 8-wk-old CD11 mice over 30 d. Mice developed dosage-dependent high blood pressure (systolic 130 ± 12 vs. 170 ± 12 mmHg; EC50 0.4 μM), impairment of acetylcholine (AcH)-induced carotid relaxation (0.66 ± 0.08 vs. 0.44 ± 0.1 mm), a 1.7-fold increase in arterial angiotensin II (AngII), an 8.7-fold increase in eNOS mRNA and protein, and significant eNOS-dependent superoxide and peroxynitrite accumulation. AngII inhibition with 0.5 mg/ml losartan reduced oxidative stress and normalized blood pressure and endothelium-dependent relaxation, which suggests that AngII uncouples eNOS and contributes to the BPA-induced endothelial dysfunction by promoting oxidative and nitrosative stress. Microarray analysis of mouse aortic endothelial cells revealed a 2.5-fold increase in expression of calcium/calmodulin-dependent protein kinase II-α (CaMKII-α) in response to 10 nM BPA, with increased expression of phosphorylated-CaMKII-α in carotid rings of BPA-exposed mice, whereas CaMKII-α inhibition with 100 nM autocamptide-2-related inhibitor peptide (AIP) reduced BPA-mediated increase of superoxide. Administration of CaMKII-α inhibitor KN 93 reduced BPA-induced blood pressure and carotid blood velocity in mice, and reverted BPA-mediated carotid constriction in response to treatment with AcH. Given that CaMKII-α inhibition prevents BPA-mediated high blood pressure, our data suggest that BPA regulates blood pressure by inducing AngII/CaMKII-α uncoupling of eNOS. © FASEB.

  14. Protective effect of Boerhaavia diffusa L. against mitochondrial dysfunction in angiotensin II induced hypertrophy in H9c2 cardiomyoblast cells.

    Directory of Open Access Journals (Sweden)

    Ayyappan Prathapan

    Full Text Available Mitochondrial dysfunction plays a critical role in the development of cardiac hypertrophy and heart failure. So mitochondria are emerging as one of the important druggable targets in the management of cardiac hypertrophy and other associated complications. In the present study, effects of ethanolic extract of Boerhaavia diffusa (BDE, a green leafy vegetable against mitochondrial dysfunction in angiotensin II (Ang II induced hypertrophy in H9c2 cardiomyoblasts was evaluated. H9c2 cells challenged with Ang II exhibited pathological hypertrophic responses and mitochondrial dysfunction which was evident from increment in cell volume (49.09±1.13%, protein content (55.17±1.19%, LDH leakage (58.74±1.87%, increased intracellular ROS production (26.25±0.91%, mitochondrial superoxide generation (65.06±2.27%, alteration in mitochondrial transmembrane potential (ΔΨm, opening of mitochondrial permeability transition pore (mPTP and mitochondrial swelling. In addition, activities of mitochondrial respiratory chain complexes (I-IV, aconitase, NADPH oxidase, thioredoxin reductase, oxygen consumption rate and calcium homeostasis were evaluated. Treatment with BDE significantly prevented the generation of intracellular ROS and mitochondrial superoxide radicals and protected the mitochondria by preventing dissipation of ΔΨm, opening of mPTP, mitochondrial swelling and enhanced the activities of respiratory chain complexes and oxygen consumption rate in H9c2 cells. Activities of aconitase and thioredoxin reductase which was lowered (33.77±0.68% & 45.81±0.71% respectively due to hypertrophy, were increased in BDE treated cells (P≤0.05. Moreover, BDE also reduced the intracellular calcium overload in Ang II treated cells. Overall results revealed the protective effects of B. diffusa against mitochondrial dysfunction in hypertrophy in H9c2 cells and the present findings may shed new light on the therapeutic potential of B. diffusa in addition to its

  15. Rosiglitazone Inhibits Angiotensin II-Induced Proliferation of Glomerular Mesangial Cells via the Gαq/Plcβ4/TRPC Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Linting Wei

    2017-12-01

    Full Text Available Background/Aims: Mesangial cell proliferation and extracellular matrix accumulation (ECM deposition play an important role in the pathogenesis of glomerulosclerosis. TRPC and PPAR-γ can regulate cell proliferation. Angiotensin II (AngII can induce mesangial cell proliferation and affect TRPC expression. However, the mechanism has not been fully elucidated. This study was designed to investigate the role of TRPC and the effect of rosiglitazone (RSG in the proliferation of rat glomerular mesangial cells (HBZY-1 that were stimulated by AngII and the underlying mechanisms. Methods: Immunofluorescence staining and qRT-PCR were performed to examine the expression levels of TRPCs in HBZY-1. Gene expression levels of TRPC, PPAR-γ, RGS4 (regulators of G protein signaling, the GPCR/Gαq/PLCβ4/TRPC signaling pathway and major downstream molecules (PCNA, SKP2, P21 and P27 were detected by qRT-PCR and western blotting. Additionally, changes in intracellular Ca2+ levels were determined through Fluo-4 Ca2+ imaging, and the cell cycle was analyzed by flow cytometry. Results: Our results found that TRPC1 and 6 were at higher expression levels in HBZY-1 cells. Following AngII stimulation, there were increased levels of TRPC1 and 6, Ca2+ entry, PCNA and SKP2, decreased expression levels of P21 and P27 and a reduced G0/G1 percentage. Silencing TRPC1 and 6 by siRNAs led to decrease in Ca2+ influx, G0/G1 cell cycle arrest and cell proliferation. Notably, PPAR-γ activation by RSG upregulated RGS4 expression, which can interact with the Gαq family to inhibit the Gαq-mediated signaling cascade. The results were similar to silencing TRPC1 and 6 by siRNAs. Conclusion: All these results indicate that RSG could inhibit HBZY-1 cell proliferation via the Gαq/PLCβ4/TRPC signaling pathway.

  16. 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

  17. 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)

  18. 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.

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

    Science.gov (United States)

    Dahlöf, B

    1995-11-01

    hypertension is a serious prognostic indicator and selective angiotensin II blockade is a new anti-hypertensive treatment modality with promising properties, especially for prevention and reversal of cardiac hypertrophy including pathological fibrosis and cardiac remodelling after myocardial infarction. Thus, taking into account the shortcomings of today's anti-hypertensive treatment to achieve normalisation of excessive cardiovascular morbidity and mortality, as well as the seemingly great importance of the renin-angiotensin system for hypertension-induced functional and structural abnormalities, a therapy based on a specific All antagonist could offer obvious advantages in a high risk hypertensive patient with cardiovascular hypertrophy. This hypothesis will be investigated in a large prospective trial (Losartan Intervention For End-point reduction in hypertension: The LIFE Study).

  20. 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.

  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). PMID:26989513

  2. 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).

  3. 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...

  4. 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.

  5. 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.

  6. Effect of RXR/PPAR interaction in angiotensin II-induced vascular inflammation and angiogenesis. Role of CXCL16/CXCR6 axis in angiotensin II or cigarette smoke-induced vascular inflammation

    OpenAIRE

    Escudero Díaz, Paula

    2016-01-01

    Aumentos en los niveles circulantes de mediadores, incluyendo angiotensina II (Ang-II) y citoquinas, han sido detectados en enfermedades cardiovasculares y cardiometabólicas como la hipertensión, la obesidad y la diabetes, y parecen ejercer efectos negativos sobre la función endotelial (Granger et al., 2004; Marinou et al., 2010). Estos agentes inician una cascada inflamatoria de señalización que promueve la generación de especies reactivas del oxígeno, aumento en la superficie celular de la ...

  7. 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...

  8. Prenatal Nicotine Exposure Results in the Inhibition of Baroreflex Sensitivity Induced by Intravenous Injection Angiotensin II in the Adult Male Offspring Rats.

    Science.gov (United States)

    Yu, Feng; Li, Yuexia; Yang, Jian; Qian, Jin; Li, Xining; Liu, Chongbin

    2017-04-01

    Epidemiological studies show that maternal cigarette smoking is associated with an increased risk of cardiovascular diseases in postnatal life. Baroreflex sensitivity (BRS) is an important index for evaluating the homeostasis of the cardiovascular system. This experiment was designed to investigate the possible mechanism of prenatal nicotine on the adult male offspring's heart rate (HR) increase due to BRS. Pregnant rats received the 0.3 ml of saline or nicotine (1.5 mg kg -1 ) by subcutaneous injection from gestational days 3 to 21. The male offsprings of saline injected dams were the control group, and the male offsprings of the nicotine injected dams were the nicotine group. The 90-day-old male offsprings' funny current (I f ) of their sinoatrial node (SAN) cells, BRS induced by intravenous injection of angiotensin (Ang) II in the presence or absence of the L-nitro-arginine methylester (L-NAME), cervical vagal activity, c-fos protein levels of the cervical spinal cord-8 to the thoracic spinal cord-5 (C 8 -T 5 ) lateral horn neuron, and blood hormones were tested. The results showed that prenatal nicotine exposure had no effect on the offsprings' I f of their SAN cells, but it significantly decreased the offsprings' BRS. The c-fos protein levels of the C 8 -T 5 lateral horn neurons and the blood catecholamine levels were increased in the nicotine group, but the cervical vagal activity was not changed. After intraventricular injection of L-NAME, the nicotine exposed offsprings' BRS was partly recovered. These data suggest that prenatal nicotine exposure results in hyper reactivity of the spinal sympathetic nerve center and a higher peripheral catecholamine hormone state of 90-day-old male offsprings, and these may be the reason for the BRS inhibition and HR increase. Nitric oxide (NO) may participate in the process acting as an important neurotransmitter.

  9. 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...

  10. Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes

    Science.gov (United States)

    Alvin, Zikiar; Laurence, Graham G.; Coleman, Bernell R.; Zhao, Aiqiu; Hajj-Moussa, Majd; Haddad, Georges E.

    2011-01-01

    Summary Background Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. Material/Methods Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. Results Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10−6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. Conclusions Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K. PMID:21709626

  11. Adrenoceptors of the medial septal area modulate water intake and renal excretory function induced by central administration of angiotensin II

    Directory of Open Access Journals (Sweden)

    Saad W.A.

    2002-01-01

    Full Text Available We investigated the role of alpha-adrenergic antagonists and clonidine injected into the medial septal area (MSA on water intake and the decrease in Na+, K+ and urine elicited by ANGII injection into the third ventricle (3rdV. Male Holtzman rats with stainless steel cannulas implanted into the 3rdV and MSA were used. ANGII (12 nmol/µl increased water intake (12.5 ± 1.7 ml/120 min. Clonidine (20 nmol/µl injected into the MSA reduced the ANGII-induced water intake (2.9 ± 0.5 ml/120 min. Pretreatment with 80 nmol/µl yohimbine or prazosin into the MSA also reduced the ANGII-induced water intake (3.0 ± 0.4 and 3.1 ± 0.2 ml/120 min, respectively. Yohimbine + prazosin + clonidine injected into the MSA abolished the ANGII-induced water intake (0.2 ± 0.1 and 0.2 ± 0.1 ml/120 min, respectively. ANGII reduced Na+ (23 ± 7 µEq/120 min, K+ (27 ± 3 µEq/120 min and urine volume (4.3 ± 0.9 ml/120 min. Clonidine increased the parameters above. Clonidine injected into the MSA abolished the inhibitory effect of ANGII on urinary sodium. Yohimbine injected into the MSA also abolished the inhibitory effects of ANGII. Yohimbine + clonidine attenuated the inhibitory effects of ANGII. Prazosin injected into the MSA did not cause changes in ANGII responses. Prazosin + clonidine attenuated the inhibitory effects of ANGII. The results showed that MSA injections of alpha1- and alpha2-antagonists decreased ANGII-induced water intake, and abolished the Na+, K+ and urine decrease induced by ANGII into the 3rdV. These findings suggest the involvement of septal alpha1- and alpha2-adrenergic receptors in water intake and electrolyte and urine excretion induced by central ANGII.

  12. 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...

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    Energy Technology Data Exchange (ETDEWEB)

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio, E-mail: toshio_n@cc.tuat.ac.jp

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  20. CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression

    Directory of Open Access Journals (Sweden)

    Ming-Horng Tsai

    2017-08-01

    Full Text Available Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9 induced migration of human aortic smooth muscle cells (HASMCs is the most common and basic pathological feature. Carbon monoxide (CO, a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2 on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.

  1. 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.

  2. 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.

  3. 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, ...

  4. 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....

  5. 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...

  6. Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway

    Directory of Open Access Journals (Sweden)

    Ying Xin

    2018-05-01

    Conclusion: These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3β/Fyn-mediated Nrf2 activation.

  7. 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.

  8. 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.

  9. Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway.

    Science.gov (United States)

    Yu, Qi-Hong; Guo, Jie-Fang; Chen, Yan; Guo, Xiao-Rong; Du, Yi-Qi; Li, Zhao-Shen

    2016-09-01

    Acute pancreatitis (AP) usually causes acute lung injury, which is also known as acute pancreatitis associated lung injury (APALI). This study aimed to investigate whether captopril pretreatment was able to protect lung against APALI via inhibiting angiotensin II (Ang II) production and suppressing Rho/ROCK (Rho kinase) pathway in rats. Severe AP (SAP) was introduced to rats by bile-pancreatic duct retrograde injection of 5% sodium taurocholate. Rats were randomly divided into three groups. In the sham group, sham operation was performed; in the SAP group, SAP was introduced; in the pre-cpl + SAP group, rats were intragastrically injected with 5 mg/kg captopril 1 hour prior to SAP induction. Pathological examination of the lung and pancreas, evaluation of pulmonary vascular permeability by wet/dry ratio and Evans Blue staining, detection of serum amylase, Western blot assay for Ang II receptor type 1 (AT1), RhoA, ROCK (Rho kinase), and MLCK (myosin light chain kinase) were performed after the animals were sacrificed at 24 hours. After the surgery, characteristic findings of pancreatitis were observed, accompanied by lung injury. The serum amylase, Ang II, and lung expression of AT1, RhoA, ROCK, and MLCK increased dramatically in SAP rats. However, captopril pretreatment improved the histological changes, reduced the pathological score of the pancreas and lung, inhibited serum amylase and Ang II production, and decreased expression of AT1, RhoA, ROCK, and MLCK in the lung. These findings suggest that captopril pretreatment is able to protect the lung against APALI, which is, at least partially, related to the inhibition of Ang II production and the suppression of the Rho/ROCK pathway. Copyright © 2016. Published by Elsevier Taiwan.

  10. 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....

  11. 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.

  12. 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.

  13. 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

  14. 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...

  15. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular...

  16. 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

  17. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles.

    Science.gov (United States)

    Matsuura-Hachiya, Yuko; Arai, Koji Y; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    2013-12-06

    Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. 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.

  19. 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.

  20. 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.

  1. miR-34a Modulates Angiotensin II-Induced Myocardial Hypertrophy by Direct Inhibition of ATG9A Expression and Autophagic Activity

    Science.gov (United States)

    Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3′-UTR, but not to the mutated 3′-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  2. Transcriptional up-regulation of antioxidant genes by PPAR{delta} inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyo Jung; Ham, Sun Ah [Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju (Korea, Republic of); Paek, Kyung Shin [Department of Nursing, Semyung University, Jechon (Korea, Republic of); Hwang, Jung Seok; Jung, Si Young; Kim, Min Young; Jin, Hanna; Kang, Eun Sil; Woo, Im Sun; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl [Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju (Korea, Republic of); Han, Chang Woo [Department of Internal Medicine, Pusan National University School of Korean Medicine, Yangsan (Korea, Republic of); Seo, Han Geuk, E-mail: hgseo@gnu.ac.kr [Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju (Korea, Republic of)

    2011-03-25

    Research highlights: {yields} Activation of PPAR{delta} by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. {yields} Agonist-activated PPAR{delta} suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. {yields} GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. {yields} Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) {delta} as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPAR{delta} by GW501516, a specific agonist of PPAR{delta}, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPAR{delta} suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPAR{delta}-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  3. 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...

  4. 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...

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Yang, Li E; McDonough, Alicia A

    2002-01-01

    Acute hypertension inhibits proximal tubule (PT) sodium reabsorption. The resultant increase in NaCl delivery to the macula densa suppresses renin release. We tested whether the sustained pressure-induced inhibition of PT sodium reabsorption requires a renin-mediated decrease in ANG II levels...... hypertension, including diuresis and redistribution of PT NHE3 into intracellular membranes, require a responsive renin-angiotensin system and that the responses may be induced by the sustained increase in NaCl delivery to the macula densa during acute hypertension....

  11. 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

  12. Angiotensin II's role in sodium lactate-induced panic-like responses in rats with repeated urocortin 1 injections into the basolateral amygdala

    DEFF Research Database (Denmark)

    Johnson, Philip L; Sajdyk, Tammy J; Fitz, Stephanie D

    2013-01-01

    Rats treated with three daily urocortin 1 (UCN) injections into the basolateral amygdala (BLA; i.e., UCN/BLA-primed rats) develop prolonged anxiety-associated behavior and vulnerability to panic-like physiological responses (i.e., tachycardia, hypertension and tachypnea) following intravenous......-injected with saralasin, but not PD123319 or vehicle, had reduced NaLac-induced anxiety-associated behavior and panic-associated tachycardia and tachypnea responses. We then confirmed the presence of AT1rs in the BLA using immunohistochemistry which, combined with the previous data, suggest that A-II's panicogenic...

  13. 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.

  14. Medicinal effect and its JP2/RyR2-based mechanism of Smilax glabra flavonoids on angiotensin II-induced hypertrophy model of cardiomyocytes.

    Science.gov (United States)

    Cai, Yueqin; Tu, Jue; Pan, Shuizhen; Jiang, Jianping; Shou, Qiyang; Ling, Yun; Chen, Yunxiang; Wang, Dejun; Yang, Weiji; Shan, Letian; Chen, Minli

    2015-07-01

    Rhizome and root of Smilax glabra Roxb (Liliaceae family) is a widely used traditional Chinese medicine (TCM) named Tu-fu-ling (TFL) for cardiac disease therapy. The TFL flavonoids (TFLF) has been extracted and proven to possess the anti-cardiac hypertrophy effect in our previous reports. Such effect could be mediated by the modulation of intracellular Ca(2+) flux in myocardial cells, in which junctophilin-2 (JP2) and ryanodine receptor 2 (RyR2) play an important role. However, its mechanism of the anti-cardiac hypertrophy effect remains unclarified. 2μmol/L Ang II was applied to induce hypertrophy model of rat primary cardiomyocytes. After treatment of TFLF at 0.25, 0.5 and 1.0mg/ml, the cell size was microscopic measured, and the protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were estimated by immunofluorescence imaging, ELISA and real-time PCR assay. Obvious hypertrophy of cardiomyocytes was induced by Ang II but reversed by TFLF from 0.5 to 1.0mg/ml. The protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were also inhibited by Ang II but restored by TFLF at its dose range. Such effect of TFLF was exerted at a dose dependent manner, which was even better than that of verapamil. Our findings may evidence the correlation between JP2/RyR2 and myocardiac hypertrophy, and indicate the JP2/RyR2-mediated anti-hypertrophy mechanism of TFLF for the first time. It deserves to be developed as a promising TCM candidate of new drug for myocardial hypertrophy treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Qian Yang Yu Yin Granule-containing serum inhibits angiotensin II-induced proliferation, reactive oxygen species production, and inflammation in human mesangial cells via an NADPH oxidase 4-dependent pathway.

    Science.gov (United States)

    Ding, Kang; Wang, Yan; Jiang, Weimin; Zhang, Yu; Yin, Hongping; Fang, Zhuyuan

    2015-03-25

    Qian Yang Yu Yin Granule (QYYYG), a traditional Chinese herbal medicine, has been indicated for renal damage in hypertension for decades in China, but little remains known regarding its underlying molecular mechanism. Therefore, we performed the current study in order to investigate the underlying molecular mechanism of QYYYG in the treatment of hypertensive renal damage. We hypothesize that QYYYG relieves hypertensive renal injury through an angiotensin II (Ang II)-nicotinamide adenine dinucleotide phosphate (NAPDH)-oxidase (NOX)-reactive oxygen species (ROS) pathway. In this study, we investigated the effects of QYYYG-containing serum (QYGS) in human mesangial cells (HMCs) against Ang II-induced cell proliferation, ROS production, and inflammation through the seropharmacological method. We found that QYGS could inhibit cell proliferation in Ang II-treated HMCs. In addition, QYGS considerably suppressed production of ROS, decreased mRNA and protein expression of NAPDH-oxidase 4 (NOX4), p22 (phox) , and activated Ras-related C3 botulinum toxin substrate 1 (GTP-Rac1); as well as counteracted the up-regulation of inflammatory markers including tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) p65, and interleukin 6 (IL-6). These effects were further confirmed in HMCs transfected with specific small interfering RNA (siRNA) targeting NOX4. Taken together, these results suggest that a NOX4-dependent pathway plays an important role in regulating the inhibitory effect of QYGS. Our findings provide new insights into the molecular mechanisms of QYYYG and their role in the treatment of hypertensive nephropathy.

  16. 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

  17. 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.

  18. Contribution of the renin-angiotensin system in chronic foot-shock induced hypertension in rats.

    Science.gov (United States)

    Wang, Lin-Hui; Dong, Tao; Liu, Bei-Bei; Zhao, Xiao-Dong; Chen, Jing-Wei; Murao, Koji; Zhu, Wei; Zhang, Guo-Xing

    2015-01-15

    Chronic foot shock has been demonstrated to induce hypertension. The present study was designed to explore whether the renin-angiotensin system (RAS) plays a role in this process and the possible mechanisms involved in chronic-foot-shock-induced hypertension. Male Sprague-Dawley rats were subjected to a two-week foot shock with or without an angiotensin II (Ang II) type 1 receptor blocker (ARB, candesartan) or an angiotensin I converting enzyme inhibitor (ACEI, captopril). The expression of RAS components in the central nervous and circulatory systems was examined. Antioxidant levels in the plasma were monitored. Two-week foot shock significantly increased systolic blood pressure (SBP). Angiotensinogen, angiotensin I converting enzyme (ACE)-1, ACE-2, angiotensin type 1a and type 1b receptors, and vasopressin (VAP) mRNA expression in the cerebral cortex and hypothalamus were increased along with the concentration of renin and Ang II in the plasma; these changes were accompanied by decreased glutathione peroxidase activity and increased lipid peroxidation levels and plasma corticosterone concentrations. Both candesartan and captopril suppressed not only the increases in SBP but also the increases in VAP expression in the hypothalamus and RAS components in the central nervous system and the circulatory system. The decreases in antioxidant levels and the increases in lipid peroxidation and corticosterone levels were also partially reversed by candesartan or captopril treatment. Chronic foot shock increases expression of the main RAS components, which play an important role in the development of high blood pressure through increased VAP levels, oxidative stress levels and stress hormone levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. 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 ...

  20. Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia.

    Science.gov (United States)

    Rosa, Rodolfo Mattar; Colucci, Juliana Almada; Yokota, Rodrigo; Moreira, Roseli Peres; Aragão, Danielle Sanches; Ribeiro, Amanda Aparecida; Arita, Danielle Yuri; Watanabe, Ingrid Kazue Mizuno; Palomino, Zaira; Cunha, Tatiana Sousa; Casarini, Dulce Elena

    2016-09-01

    Sepsis is an uncontrolled systemic inflammatory response against an infection and a major public health issue worldwide. This condition affects several organs, and, when caused by Gram-negative bacteria, kidneys are particularly damaged. Due to the importance of renin-angiotensin system (RAS) in regulating renal function, in the present study, we aimed to investigate the effects of endotoxemia over the renal RAS. Wistar rats were injected with Escherichia coli lipopolysaccharide (LPS) (4 mg/kg), mimicking the endotoxemia induced by Gram-negative bacteria. Three days after treatment, body mass, blood pressure, and plasma nitric oxide (NO) were reduced, indicating that endotoxemia triggered cardiovascular and metabolic consequences and that hypotension was maintained by NO-independent mechanisms. Regarding the effects in renal tissue, inducible NO synthase (iNOS) was diminished, but no changes in the renal level of NO were detected. RAS was also highly affected by endotoxemia, since renin, angiotensin-converting enzyme (ACE), and ACE2 activities were altered in renal tissue. Although these enzymes were modulated, only angiotensin (ANG) II was augmented in kidneys; ANG I and ANG 1-7 levels were not influenced by LPS. Cathepsin G and chymase activities were increased in the endotoxemia group, suggesting alternative pathways for ANG II formation. Taken together, our data suggest the activation of noncanonical pathways for ANG II production and the presence of renal vasoconstriction and tissue damage in our animal model. In summary, the systemic administration of LPS affects renal RAS, what may contribute for several deleterious effects of endotoxemia over kidneys. Copyright © 2016 the American Physiological Society.

  1. Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ai-Lan [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Ou, Cai-Wen [The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); He, Zhao-Chu [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Liu, Qi-Cai [Experimental Medical Research Center, Guangzhou Medical University, Guangzhou (China); Dong, Qi [Department of Physiology, Guangzhou Medical University, Guangzhou (China); Chen, Min-Sheng [Guangzhou Key Laboratory of Cardiovascular Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou (China)

    2012-10-15

    Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [{sup 3}H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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-...

  8. Rapid metabolism of exogenous angiotensin II by catecholaminergic neuronal cells in culture media.

    Science.gov (United States)

    Basu, Urmi; Seravalli, Javier; Madayiputhiya, Nandakumar; Adamec, Jiri; Case, Adam J; Zimmerman, Matthew C

    2015-02-01

    Angiotensin II (AngII) acts on central neurons to increase neuronal firing and induce sympathoexcitation, which contribute to the pathogenesis of cardiovascular diseases including hypertension and heart failure. Numerous studies have examined the precise AngII-induced intraneuronal signaling mechanism in an attempt to identify new therapeutic targets for these diseases. Considering the technical challenges in studying specific intraneuronal signaling pathways in vivo, especially in the cardiovascular control brain regions, most studies have relied on neuronal cell culture models. However, there are numerous limitations in using cell culture models to study AngII intraneuronal signaling, including the lack of evidence indicating the stability of AngII in culture media. Herein, we tested the hypothesis that exogenous AngII is rapidly metabolized in neuronal cell culture media. Using liquid chromatography-tandem mass spectrometry, we measured levels of AngII and its metabolites, Ang III, Ang IV, and Ang-1-7, in neuronal cell culture media after administration of exogenous AngII (100 nmol/L) to a neuronal cell culture model (CATH.a neurons). AngII levels rapidly declined in the media, returning to near baseline levels within 3 h of administration. Additionally, levels of Ang III and Ang-1-7 acutely increased, while levels of Ang IV remained unchanged. Replenishing the media with exogenous AngII every 3 h for 24 h resulted in a consistent and significant increase in AngII levels for the duration of the treatment period. These data indicate that AngII is rapidly metabolized in neuronal cell culture media, and replenishing the media at least every 3 h is needed to sustain chronically elevated levels. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  9. 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...

  10. Hypoxia-Induced Collagen Synthesis of Human Lung Fibroblasts by Activating the Angiotensin System

    Directory of Open Access Journals (Sweden)

    Shan-Shan Liu

    2013-12-01

    Full Text Available The exact molecular mechanism that mediates hypoxia-induced pulmonary fibrosis needs to be further clarified. The aim of this study was to explore the effect and underlying mechanism of angiotensin II (Ang II on collagen synthesis in hypoxic human lung fibroblast (HLF cells. The HLF-1 cell line was used for in vitro studies. Angiotensinogen (AGT, angiotensin converting enzyme (ACE, angiotensin II type 1 receptor (AT1R and angiotensin II type 2 receptor (AT2R expression levels in human lung fibroblasts were analysed using real-time polymerase chain reaction (RT-PCR after hypoxic treatment. Additionally, the collagen type I (Col-I, AT1R and nuclear factor κappaB (NF-κB protein expression levels were detected using Western blot analysis, and NF-κB nuclear translocation was measured using immunofluorescence localization analysis. Ang II levels in HLF-1 cells were measured with an enzyme-linked immunosorbent assay (ELISA. We found that hypoxia increased Col-I mRNA and protein expression in HLF-1 cells, and this effect could be inhibited by an AT1R or AT2R inhibitor. The levels of NF-κB, RAS components and Ang II production in HLF-1 cells were significantly increased after the hypoxia exposure. Hypoxia or Ang II increased NF-κB-p50 protein expression in HLF-1 cells, and the special effect could be inhibited by telmisartan (TST, an AT1R inhibitor, and partially inhibited by PD123319, an AT2R inhibitor. Importantly, hypoxia-induced NF-κB nuclear translocation could be nearly completely inhibited by an AT1R or AT2R inhibitor. Furthermore pyrrolidine dithiocarbamate (PDTC, a NF-κB blocker, abolished the expression of hypoxia-induced AT1R and Col-I in HLF-1 cells. Our results indicate that Ang II-mediated NF-κB signalling via ATR is involved in hypoxia-induced collagen synthesis in human lung fibroblasts.

  11. 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...

  12. 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

  13. 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.

  14. Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

    Science.gov (United States)

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  15. Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats.

    Science.gov (United States)

    Yuan, Yi-Ming; Luo, Li; Guo, Zhen; Yang, Ming; Ye, Ren-Song; Luo, Chuan

    2015-06-01

    To explore the role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of pulmonary arterial hypertension (PAH) induced by chronic exposure to cigarette smoke. 48 healthy male SD rats were randomly divided into four groups (12/group): control group (group A); inhibitor alone group (group B); cigarette induction group (group C); cigarette induction + inhibitor group (group D). After the establishment of smoking-induced PAH rat model, the right ventricular systolic pressure (RVSP) was detected using an inserted catheter; western blotting was used to detect the protein expression of angiotensin-converting enzyme-2 (ACE2) and angiotensin-converting enzyme (ACE); expression levels of angiotensin II (AngII) in lung tissue were measured by radioimmunoassay. After six months of cigarette exposure, the RVSP of chronic cigarette induction group was significantly higher than that of the control group; expression levels of AngII and ACE increased in lung tissues, but ACE2 expression levels reduced. Compared with cigarette exposure group, after losartan treatment, RVSP, ACE and AngII obviously decreased (Psmoking-induced PAH. © The Author(s) 2015.

  16. 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

  17. Data supporting the angiotensin II activates MEL18 to deSUMOylate HSF2 for hypertension-related heart failure

    Directory of Open Access Journals (Sweden)

    Chih-Yang Huang

    2018-02-01

    Full Text Available In association with the published article “Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy” (Huang et al., 2017 [1], this data article contains information about deSUMOylation of HSF2 on lysine 82 on angiotensin II (ANG II -induced cardiac hypertrophy, which is mediated by MEL18. Isolated adult human whole heart tissue showed MEL18-mediated HSF2-IGF-IIR pathway is upregulated in hypertension human heart, compared to health human heart.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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...

  3. 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...

  4. 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.

  5. 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.

  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. 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.

  8. 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)

  9. Alpha-Asarone Protects Endothelial Cells from Injury by Angiotensin II

    Directory of Open Access Journals (Sweden)

    Hai-Xia Shi

    2014-01-01

    Full Text Available α-Asarone is the major therapeutical constituent of Acorus tatarinowii Schott. In this study, the potential protective effects of α-asarone against endothelial cell injury induced by angiotensin II were investigated in vitro. The EA.hy926 cell line derived from human umbilical vein endothelial cells was pretreated with α-asarone (10, 50, 100 µmol/L for 1 h, followed by coincubation with Ang II (0.1 µmol/L for 24 h. Intracellular nitric oxide (NO and reactive oxygen species (ROS were detected by fluorescent dyes, and phosphorylation of endothelial nitric oxide synthase (eNOS at Ser1177 was determined by Western blotting. α-Asarone dose-dependently mitigated the Ang II-induced intracellular NO reduction (P0.05 was not affected after 24 h of incubation with α-asarone at 1–100 µmol/L. Therefore, α-asarone protects against Ang II-mediated damage of endothelial cells and may be developed to prevent injury to cardiovascular tissues.

  10. Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/Angiotensin-(1-7) Axis and Decreasing Inflammation Responses in Rats.

    Science.gov (United States)

    Hao, Yuewen; Liu, Yan

    2016-01-01

    Studies have shown that angiotensin-converting enzyme 2 (ACE2) plays modulating roles in lung pathophysiology, including pulmonary fibrosis (PF) and acute lung injury. Pulmonary fibrosis is a common complication in these interstitial lung diseases, and PF always has a poor prognosis and short survival. To date, there are few promising methods for treating PF, and they are invariably accompanied by severe side effects. Recent studies have showed that the traditional Chinese herbal extract, osthole, had beneficial effects on lipopolysaccharide (LPS) induced acute lung injury (ALI) via an ACE2 pathway. Here we further investigated the protective effects of osthole on bleomycin induced pulmonary fibrosis and attempted to determine the underlying mechanism. PF mode rats were induced by bleomycin (BLM) and then subsequently administered osthole. Histopathological analyses were employed to identify PF changes. The results showed that BLM resulted in severe PF and diffuse lung inflammation, together with significant elevation of inflammatory factors and a marked increase in expression of angiotensin II (ANG II) and transforming growth factor-beta 1 (TGF-β1). ACE2 and angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. Meanwhile, osthole treatment attenuated BLM induced PF and inflammation, decreased the expression of these inflammatory mediators, ANG II, and TGF-β1, and reversed ACE2 and ANG-(1-7) production in rat lungs. We conclude that osthole may exert beneficial effects on BLM induced PF in rats, perhaps via modulating the ACE2/ANG-(1-7) axis and inhibiting lung inflammation pathways.

  11. 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.).

  12. Effect of Cyclosporin A and Angiotensin II on cytosolic calcium levels in primary human gingival fibroblasts

    Directory of Open Access Journals (Sweden)

    Ajitkumar Supraja

    2016-01-01

    Full Text Available Background: To evaluate the effect of Cyclosporin A (CsA and angiotensin II (Ang II on cytosolic calcium levels in cultured human gingival fibroblasts (HGFs. Materials and Methods: Healthy gingival samples from six volunteers were obtained, and primary HGFs were cultured. Cell viability and proliferation assay were performed to identify the ideal concentrations of CsA and Ang II. Cytosolic calcium levels in cultured gingival fibroblasts treated with CsA and Ang II were studied using colorimetric assay, confocal and fluorescence imaging. Statistical analyses were done using SPSS software and GraphPad Prism. Results: Higher levels of cytosolic levels were evident in cells treated with CsA and Ang II when compared to control group and was statistically significant (P < 0.05 in both colorimetric assay and confocal imaging. Fluorescent images of the cultured HGFs revealed the same. Conclusion: Thus calcium being a key player in major cellular functions, plays a major role in the pathogenesis of drug-induced gingival overgrowth.

  13. 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.

  14. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22{sup phox} expression

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun; He, Yanhao [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Department of Pharmacology, Xi' an Jiaotong University School of Medicine, Key Laboratory of Environment and Genes Related to Disease, Ministry of Education, Xi' an, Shaanxi 710061 (China); Yang, Ming; Sun, Hongliu; Zhang, Shuping [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Wang, Chunhua, E-mail: chunhuawang2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-15

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22{sup phox}, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22{sup phox}. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression.

  15. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22phox expression

    International Nuclear Information System (INIS)

    Wang, Chaoyun; He, Yanhao; Yang, Ming; Sun, Hongliu; Zhang, Shuping; Wang, Chunhua

    2013-01-01

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22 phox , increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22 phox . • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression

  16. 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.

  17. 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...

  18. 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...

  19. Release of beta-lipotropin- and beta-endorphin-like material induced by angiotensin in the conscious rat

    NARCIS (Netherlands)

    Beuers, U.; HERTTING, G.; KNEPEL, W.

    1982-01-01

    1 The influence of the renin-angiotensin system on plasma beta-endorphin-like immunoreactivity (beta-EI) was investigated in the conscious rat by use of a radioimmunoassay for beta-endorphin without prior extraction.2 Intravenous infusion of angiotensin I, II or (des-1-Asp)angiotensin II

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. Angiotensin-converting enzyme inhibitor-induced angioedema.

    Science.gov (United States)

    Bezalel, Shira; Mahlab-Guri, Keren; Asher, Ilan; Werner, Ben; Sthoeger, Zev Moshe

    2015-02-01

    Angiotensin-converting enzyme inhibitors (ACE-I) are widely used, effective, and well-tolerated antihypertensive agents. The mechanisms by which those agents act can cause side effects such as decreased blood pressure, hyperkalemia, and impaired renal function. ACE-I can induce cough in 5%-35% and angioedema in up to 0.7% of treated patients. Because cough and angioedema are considered class adverse effects, switching treatment to other ACE-I agents is not recommended. Angioedema due to ACE-I has a low fatality rate, although deaths have been reported when the angioedema involves the airways. Here, we review the role of bradykinin in the development of angioedema in patients treated with ACE-I, as well as the incidence, risk factors, clinical presentation, and available treatments for ACE-I-induced angioedema. We also discuss the risk for recurrence of angioedema after switching from ACE-I to angiotensin receptor blockers treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. 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...

  7. 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.

  8. 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,

  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. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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...

  17. 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.

  18. 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)

  19. 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.

  20. 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...

  1. 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 ...

  2. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors.

    Science.gov (United States)

    Scalese, Michael J; Reinaker, Travis S

    2016-06-15

    The published evidence on pharmacologic approaches to the management of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema is reviewed. Angioedema is a serious, potentially life-threatening adverse effect of ACEI use. Although the underlying mechanism is not fully understood, excess bradykinin produced through a complex interplay between the kallikrein-kinin and renin-angiotensin-aldosterone systems is thought to play a major role. The nonallergic nature of the reaction renders traditional therapies (corticosteroids and antihistamines) ineffective because those agents do not modify the proposed pathophysiology. Fresh frozen plasma (FFP) provides kinase II, a protein that breaks down bradykinin. Case reports support FFP as a treatment for ACEI-induced angioedema, but no formal evaluations have been completed to date. Both ecallantide and complement 1 esterase (C1) inhibitor concentrate reduce bradykinin production through upstream inhibition of kallikrein. C1 inhibitor concentrate has been used successfully to manage ACEI-induced angioedema in a few reported cases, but robust supportive studies are lacking. Conversely, ecallantide has been evaluated in multiple randomized trials but has not been shown to offer advantages over traditional therapies. The use of icatibant, a direct antagonist of bradykinin B2 receptors, was reported to be beneficial in several case reports and in a small Phase II study, safely and rapidly reducing symptoms of ACEI-induced angioedema. An ongoing Phase III trial (NCT01919801) will better define the role of icatibant in the management of ACEI-induced angioedema. FFP, C1 inhibitor, and icatibant appear to be safe and effective therapeutic options for the management of ACEI-induced angioedema, whereas it appears ecallantide should be avoided. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. [Effect of noradrenaline and angiotensin II on the brain and kidney blood supply with changes in systemic arterial pressure].

    Science.gov (United States)

    Beketov, A I; Korneliuk, I K

    1981-01-01

    Hydrogen clearance was used in experiments on anesthetized cats to demonstrate that intravenous infusions of noradrenaline induced an increase in cerebral blood supply and reduction of renal blood flow both in anesthetized animals and in the presence of hypotension. In these conditions, angiotensin II lowered the cerebral and renal blood flow. Hypotension enhanced the reactions of the cerebral and renal blood flow to the action of vasopressor agents. The intensity of the reactions was consistent with the degree of vascular autocontrol preservation in the brain and kidneys.

  8. 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.

  9. 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.

  10. Modification of vascular responsiveness to angiotensin II in pregnant women by intravenously infused 5alpha-dihydroprogesterone.

    Science.gov (United States)

    Everett, R B; Worley, R J; MacDonald, P C; Gant, N F

    1978-06-15

    In gravid women who are destined to develop pregnancy-induced hypertension (PIH), normal pregnancy-associated refractoriness to the pressor effects of administered angiotensin II (A-II) is lost several weeks before the onset of hypertension. From a study of the determinants of A-II pressor responsiveness in normal gravid women, it appears likely that the loss of resistance to A-II is principally unrelated to plasma renin activity or to plasma A-II levels. However, it recently has been shown that the vascular refractoriness to A-II in normal women can be reduced significantly by the administration of the prostaglandin synthetase inhibitors, indomethacin or aspirin. In seven women who had developed PIH and who had lost their refractoriness to A-II, the infusion of 5alpha-pregnan-3,20-dione (5alpha-DHP) was associated with restoration of refractoriness to the pressor effects of A-II. Moreover, in five normotensive gravid women beyond 28 weeks' gestation in whom the refractoriness to A-II was reduced by the administration of indomethacin, the intravenous infusion of 5alpha-DPH was associated with restoration of refractoriness to the pressor effects of A-II. These observations are consistent with the view that a progesterone metabolite(s) may be important in the maintenance of normal blood pressure during human pregnancy.

  11. 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.

  12. 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.

  13. Chronic Renin-Angiotensin System (RAS) Blockade May Not Induce Hypotension During Anaesthesia for Bariatric Surgery.

    Science.gov (United States)

    Salvetti, Guido; Di Salvo, Claudio; Ceccarini, Giovanni; Abramo, Antonio; Fierabracci, Paola; Magno, Silvia; Piaggi, Paolo; Vitti, Paolo; Santini, Ferruccio

    2016-06-01

    The use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) for the treatment of hypertensive obese patients is steadily increasing. Some studies have reported that the use of these drugs was associated with an increased risk of hypotensive episodes, during general anaesthesia. The number of bariatric procedures is also increasing worldwide, but there is a lack of studies investigating the hypotensive effect of renin-angiotensin system (RAS) blockers in severely obese patients during general anaesthesia for bariatric surgery. The aim of this pilot study was to evaluate hemodynamic changes induced by general anaesthesia in obese patients chronically treated with ACE-I or ARB compared to a control group not treated with antihypertensive therapy. Fourteen obese subjects (mean body mass index (BMI) 47.5 kg/m(2)) treated with ACE-I or ARB and twelve obese (mean BMI 45.7 kg/m2) controls not treated with antihypertensive therapy underwent general anaesthesia to perform laparoscopic bariatric surgery. Systolic blood pressure, diastolic blood pressure, and heart rate were monitored continuously and registered at different time points: T0 before induction, then at 2, 5, 7, 10, 15, 20, 30, 60, 90, 120, and 150 min after induction, and the last time point taken following recovery from anaesthesia. A progressive reduction of both systolic and diastolic blood pressure values was observed without significant differences between the two groups. A similar trend of heart rate values was observed. In conclusion, our pilot study suggests that RAS blockers may be continued during the perioperative period in patients undergoing bariatric surgery, without increasing the risk of hypotensive episodes.

  14. Angiotensin 1-7, but not the thrombin-cleaved osteopontin C-terminal fragment, attenuates osteopontin-mediated macrophage-induced endothelial-cell inflammation.

    Science.gov (United States)

    Hamias, Rachel; Rudich, Assaf; Greenberg, George; Szendro, Gabriel; Wolak, Talya

    2018-03-01

    Evaluating the pro-/anti-inflammatory activity of the C-terminal cleavage product of osteopontin in comparison to angiotensin 1-7. Human coronary endothelial cells (hcEC) treated with conditioned media from human U937 macrophages. Macrophages were (pre)treated with C-terminal, full-length or N-terminal osteopontin (OPN-C, OPN-FL, OPN-N, respectively), angiotensin II, angiotensin 1-7 or TNF-α. OPN-C modulatory capacity was compared to that of Ang1-7 in inhibiting subsequent Ag II, OPN-FL or OPN-N-induced macrophage-mediated endothelial inflammation. Protein expression of NFκB, IκB, vCAM-1 and iCAM-1 was assessed using western blot. Promotor activation by NFκB was also assessed by dual-luciferase reporter assay. Conditioned media of macrophages treated with OPN-C induced hcECs' NfκB activation to a lower degree than OPN-FL or OPN-N. Priming of macrophages with angiotensin 1-7 attenuated the endothelial pro-inflammatory effect induced by subsequent exposure of the macrophages to angiotensin II, OPN-FL or OPN-N. This was evidenced by both NfκB activation and vCAM and iCAM expression. In contrast, priming macrophages with OPN-C did not significantly attenuate the subsequent response to the pro-inflammatory cytokines. OPN-C induces lower macrophage-induced endothelial inflammation compared to OPN-FL or OPN-N, but unlike angiotensin 1-7, fails to prevent endothelial inflammation induced by subsequent pro-inflammatory macrophage stimulation.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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 ...

  8. 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...

  9. 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.

  10. 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.

  11. Atorvastatin protects the proliferative ability of human umbilical vein endothelial cells inhibited by angiotensin II by changing mitochondrial energy metabolism.

    Science.gov (United States)

    Chang, Ye; Li, Yuan; Ye, Ning; Guo, Xiaofan; Li, Zhao; Sun, Guozhe; Sun, Yingxian

    2018-01-01

    This study aimed to explore whether angiotensin II (Ang II) inhibits the proliferation of human umbilical vein endothelial cells (HUVECs) by changing mitochondrial energy metabolism, and whether atorvastatin has a protective role via restoration of endothelial function. HUVECs were treated with 1 µM Ang II alone or with 10 µM atorvastatin for 24 h. Proliferation was detected by MTT assay, cell counting, 5‑ethynyl‑2'‑deoxyuridine assay and real‑time cell analyzer. Mitochondrial energy metabolism including oxygen consumption rate and extracellular acidification rate were measured using a Seahorse metabolic flux analyzer. Mitochondrial membrane potential was detected under fluorescence microscope following staining with tetramethylrhodamine. Respiratory chain complexes I‑V were detected using western blotting. The current study showed that Ang II inhibits the proliferation of HUVECs. Results from the Seahorse metabolic flux analyzer indicated that Ang II decreased basal oxygen consumption, maximal respiration capacity, spare respiration capacity, adenosine triphosphate‑linked respiration and non‑mitochondrial respiration. By contrast, Ang II increased the proton leak. Additionally, Ang II increased glycolysis, glycolytic capacity and non‑glycolytic acidification. Furthermore, these effects were all suppressed by atorvastatin. The results indicated that atorvastatin prevents cellular energy metabolism switching from oxidative phosphorylation to glycolysis induced by Ang II and protected the proliferative ability of HUVECs.

  12. 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.

  13. 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

  14. 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...

  15. 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

  16. 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...

  17. 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...

  18. 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.

  19. 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.

  20. 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.

  1. Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells.

    Science.gov (United States)

    Kelsen, Silvia; Patel, Bijal J; Parker, Lawson B; Vera, Trinity; Rimoldi, John M; Gadepalli, Rama S V; Drummond, Heather A; Stec, David E

    2008-10-01

    Heme oxygenase (HO)-1 induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure is not clear. The goal of this study was to test the hypothesis that induction of HO-1 can reduce the ANG II-mediated increase in superoxide production in cultured thick ascending loop of Henle (TALH) cells. Studies were performed on an immortalized cell line of mouse TALH (mTALH) cells. HO-1 was induced in cultured mTALH cells by treatment with cobalt protoporphyrin (CoPP, 10 microM) or hemin (50 microM) or by transfection with a plasmid containing the human HO-1 isoform. Treatment of mTALH cells with 10(-9) M ANG II increased dihydroethidium (DHE) fluorescence (an index of superoxide levels) from 35.5+/-5 to 136+/-18 relative fluorescence units (RFU)/microm2. Induction of HO-1 via CoPP, hemin, or overexpression of the human HO-1 isoform significantly reduced ANG II-induced DHE fluorescence to 64+/-5, 64+/-8, and 41+/-4 RFU/microm2, respectively. To determine which metabolite of HO-1 is responsible for reducing ANG II-mediated increases in superoxide production in mTALH cells, cells were preincubated with bilirubin or carbon monoxide (CO)-releasing molecule (CORM)-A1 (each at 100 microM) before exposure to ANG II. DHE fluorescence averaged 80+/-7 RFU/microm2 after incubation with ANG II and was significantly decreased to 55+/-7 and 53+/-4 RFU/microm2 after pretreatment with bilirubin and CORM-A1. These results demonstrate that induction of HO-1 in mTALH cells reduces the levels of ANG II-mediated superoxide production through the production of both bilirubin and CO.

  2. Angiotensin converting enzyme induced angioedema: The need for ...

    African Journals Online (AJOL)

    Background: Angiotensin converting enzyme (ACE) inhibitor related angioneurotic edema or simply angioedema is a rare but common condition not well noticed in health facilities especially in developing countries. The complication can be life threatening with serious morbidity and mortality if not promptly diagnosed from ...

  3. An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

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    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.

  4. Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin

    International Nuclear Information System (INIS)

    Abhold, R.H.; Sullivan, M.J.; Wright, J.W.; Harding, J.W.

    1987-01-01

    In the metabolism of angiotensin peptides by tissue angiotensinases, aminopeptidases A, B, M and leucine aminopeptidase have been identified as being particularly effective. Because the inhibitory actions of amastatin (AM) and bestatin (BE) are relatively specific for these aminopeptidases, we have examined the effects of these inhibitors on the binding, degradation and pressor activity of angiotensin II (AII) and angiotensin III (AIII). Within 30 min at 37 degrees C, significant metabolism of 125 I-AII and 125 I-AIII by homogenates of a block of tissue containing hypothalamus, thalamus, septum and anteroventral third ventricle regions of the brain was observed. A majority of 125 I-AIII metabolism was due to soluble peptidases, whereas that of 125 I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of 125 I-AII and 125 I-AIII. After appropriate adjustments to reflect the proportion of intact radioligand bound, temperature- or inhibitor-induced decreases in metabolism were matched by corresponding increases in specific binding. Heat-treated bovine serum albumin, as a nonspecific peptidase inhibitor, had no effect on either the metabolism or binding of the ligands used. In accordance with their actions in vitro, i.c.v. administration of AM and BE prolonged the pressor activity of subsequently applied AII and AIII. Unexpectedly, the amplitude of the pressor response to AIII was increased by BE, whereas that to AII was decreased by AM. The results of this study indicate that the metabolism of AII and AIII by aminopeptidases is relatively specific and acts to modulate the actions of these peptides

  5. Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; von Buchwald, Christian; Wadelius, Mia

    2017-01-01

    Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study...... Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995-2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1.8), with a mean age of 63 [range 26-86] years. Female...... gender was associated with a significantly higher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema. Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7% needed...

  6. 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.

  7. Effect of Angiotensin II on the Left Ventricular Function in a Near-Term Fetal Sheep with Metabolic Acidemia

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    Ganesh Acharya

    2011-01-01

    Full Text Available We tested the hypothesis that, in acute metabolic acidemia, the fetal left ventricle (LV has the capacity to increase its contractility in response to angiotensin II infusion. Eleven ewes and their fetuses were instrumented at 127–138/145 days of gestation. The effect of angiotensin II on fetal LV function was assessed using intraventricular pressure catheter and tissue Doppler imaging (TDI. Angiotensin II increased fetal arterial blood pressure, whereas pH and pO2 decreased. The heart rate and systemic venous pressure were not affected significantly. The LV end-diastolic and end-systolic pressures, as well as dP/dtmax, increased. The TDI-derived LV longitudinal myocardial isovolumic contraction velocity and its acceleration and velocity during early filling were higher than those at baseline. The incidence of absent isovolumic relaxation velocity was greater during angiotensin II infusion. In summary, during acute metabolic acidemia, the fetal left ventricle could increase its contractility in response to inotropic stimulus even in the presence of increased afterload. The diastolic LV function parameters were altered by angiotensin II.

  8. Angiotensin II Evokes Angiogenic Signals within Skeletal Muscle through Co-ordinated Effects on Skeletal Myocytes and Endothelial Cells

    Science.gov (United States)

    Gorman, Jennifer L.; Liu, Sammy T. K.; Slopack, Dara; Shariati, Khashayar; Hasanee, Adam; Olenich, Sara; Olfert, I. Mark; Haas, Tara L.

    2014-01-01

    Skeletal muscle overload induces the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2, leading to new capillary growth. We found that the overload-induced increase in angiogenesis, as well as increases in VEGF, MMP-2 and MT1-MMP transcripts were abrogated in muscle VEGF KO mice, highlighting the critical role of myocyte-derived VEGF in controlling this process. The upstream mediators that contribute to overload-induced expression of VEGF have yet to be ascertained. We found that muscle overload increased angiotensinogen expression, a precursor of angiotensin (Ang) II, and that Ang II signaling played an important role in basal VEGF production in C2C12 cells. Furthermore, matrix-bound VEGF released from myoblasts induced the activation of endothelial cells, as evidenced by elevated endothelial cell phospho-p38 levels. We also found that exogenous Ang II elevates VEGF expression, as well as MMP-2 transcript levels in C2C12 myotubes. Interestingly, these responses also were observed in skeletal muscle endothelial cells in response to Ang II treatment, indicating that these cells also can respond directly to the stimulus. The involvement of Ang II in muscle overload-induced angiogenesis was assessed. We found that blockade of AT1R-dependent Ang II signaling using losartan did not attenuate capillary growth. Surprisingly, increased levels of VEGF protein were detected in overloaded muscle from losartan-treated rats. Similarly, we observed elevated VEGF production in cultured endothelial cells treated with losartan alone or in combination with Ang II. These studies conclusively establish the requirement for muscle derived VEGF in overload-induced angiogenesis and highlight a role for Ang II in basal VEGF production in skeletal muscle. However, while Ang II signaling is activated following overload and plays a role in muscle VEGF production, inhibition of this pathway is not sufficient to halt overload-induced

  9. 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.

  10. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible...... to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...

  16. Sandwich immunoassay for the hapten angiotensin II. A novel assay principle based on antibodies against immune complexes.

    Science.gov (United States)

    Towbin, H; Motz, J; Oroszlan, P; Zingel, O

    1995-04-26

    Immunoassays for haptens such as short peptides or drugs are usually based on the principle of competition for a limited number of binding sites on antibody molecules. Owing to the small size of these antigens it has been thought that two specific antibodies cannot simultaneously bind a hapten. However, antisera containing so called anti-metatypic antibodies have been reported (Voss et al. (1988) Mol. Immunol. 25, 751-759) that bind to hapten-mAb complexes in a reaction where conformational changes on the primary antibody are important. Here, we report on monoclonal antibody pairs able to form ternary complexes with the octapeptide angiotensin II. The first mAb (mAb1) is conventional and binds angiotensin II with high affinity (Kd 10(-11) M). The secondary (anti-metatypic) mAbs (mAbs2s) recognize the immune complex consisting of angiotensin II bound to mAb1, but only poorly recognize mAb1 alone. An immunization technique involving tolerization with uncomplexed mAb1 was used to generate mAb2s. None of the mAbs2s were able to bind angiotensin II by themselves but all efficiently bound the complex of angiotensin II and mAb1. All mAb2s stabilized the angiotensin II-mAb1 complex and one mAb2 distinctly improved the specificity of the assay for angiotensin II. By either labelling mAb1 and immobilizing mAb2 (or vice versa) two-site immunometric assays with detection limits of 1 pg/ml angiotensin II have been established. The kinetics of the complex formation was investigated by fiber optic biospecific interaction analysis (FOBIA), a system allowing real time observation of binding events on the surface of a glass fiber. The association rate towards the liganded conformation of mAb1 was higher than towards the free mAb1. By contrast, the mAb2s dissociated at similar rates from complexed and uncomplexed mAb1.

  17. Tachyphylaxis of juxtaglomerular epithelioid cells to angiotensin II. Differences between the electrical membrane response and renin secretion

    DEFF Research Database (Denmark)

    Bührle, C P; Hackenthal, E; Nobiling, R

    1987-01-01

    A study has been made of desensitization of the depolarizing response to angiotensin II of juxtaglomerular epithelioid and vascular smooth muscle cells in the mouse kidney afferent arteriole, of media cells from the mesenteric artery as well as of cultured smooth muscle and mesangial cells. In all...... recycling, such as chloroquine and monensin, did not block the recovery of the cells from desensitization after removal of the octapeptide. Desensitization to the action of angiotensin II was also observed with respect to its vasoconstrictor effect in the isolated perfused rat kidney. In contrast...

  18. Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema

    Science.gov (United States)

    von Buchwald, Christian; Prasad, Sumangali Chandra; Kamaleswaran, Shailajah; Ajgeiy, Kawa Khaled; Authried, Georg; Pallesen, Kristine Appel U.

    2017-01-01

    Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995–2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1.8), with a mean age of 63 [range 26–86] years. Female gender was associated with a significantly higher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema. Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7% needed intubation or tracheostomy. 74 admissions took place during the study period with a total of 143 days spent in the hospital. The diagnosis codes most often used for this condition were “DT783 Quincke's oedema” and “DT78.4 Allergy unspecified”. Complement C1 inhibitor was normal in all tested patients. Conclusion. Female gender predisposes to angiotensin converting enzyme-inhibitor induced angioedema, whereas diabetes seems to be a protective factor. PMID:28286522

  19. Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

    International Nuclear Information System (INIS)

    Han Suxia; He Guangming; Wang Tao; Chen Lei; Ning Yunye; Luo Feng; An Jin; Yang Ting; Dong Jiajia; Liao Zenglin; Xu Dan; Wen Fuqiang

    2010-01-01

    Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

  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

  1. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yogi, Alvaro; Callera, Glaucia E. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Mecawi, André S. [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Batalhão, Marcelo E.; Carnio, Evelin C. [Department of General and Specialized Nursing, College of Nursing of Ribeirão Preto, USP, São Paulo (Brazil); Antunes-Rodrigues, José [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Queiroz, Regina H. [Department of Clinical, Toxicological and Food Science Analysis, Faculty of Pharmaceutical Sciences, USP, São Paulo (Brazil); Touyz, Rhian M. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Tirapelli, Carlos R., E-mail: crtirapelli@eerp.usp.br [Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP (Brazil)

    2012-11-01

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT{sub 1} receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT{sub 1}-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT{sub 1} receptor activation.

  2. 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.

  3. 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.

  4. Angiotensin II-mediated biphasic regulation of proximal tubular Na+/H+ exchanger 3 is impaired during oxidative stress.

    Science.gov (United States)

    Banday, Anees Ahmad; Lokhandwala, Mustafa F

    2011-08-01

    Angiotensin (ANG) II via AT1 receptors (AT1Rs) maintains sodium homeostasis by regulating renal sodium transporters including Na(+)/H(+) exchanger 3 (NHE3) in a biphasic manner. Low-ANG II concentration stimulates whereas high concentrations inhibit NHE3 activity. Oxidative stress has been shown to upregulate AT1R function that could modulate the ANG II-mediated NHE3 regulation. This study was designed to identify the signaling pathways responsible for ANG II-mediated biphasic regulation of proximal tubular NHE3 and the effect of oxidative stress on this phenomenon. Male Sprague-Dawley rats were chronically treated with a pro-oxidant L-buthionine sulfoximine (BSO) with and without an antioxidant tempol in tap water for 3 wk. BSO-treated rats exhibited oxidative stress and high blood pressure. At low concentration (1 pM) ANG II increased NHE3 activity in proximal tubules from all animals. However, in BSO-treated rats, the stimulation was more robust and was normalized by tempol treatment. ANG II (1 pM)-mediated NHE3 activation was abolished by AT1R blocker, intracellular Ca(2+) chelator, and inhibitors of phospholipase C (PLC) and Ca(2+)-dependent calmodulin (CaM) but it was insensitive to Giα and protein kinase C inhibitors or AT2R antagonist. A high concentration of ANG II (1 μM) inhibited NHE3 activity in control and tempol-treated rats. However, in BSO-treated rats, ANG II (1 μM) continued to induce NHE3 stimulation. Tempol restored the inhibitory effect of ANG II (1 μM) in BSO-treated rats. The inhibitory effect of ANG II (1 μM) involved AT1R-dependent, cGMP-dependent protein kinase (PKG) activation and was independent of AT2 receptor and nitric oxide signaling. We conclude that ANG II stimulates NHE3 via AT1R-PLC-CaM pathway and inhibits NHE3 by AT1R-PKG activation. Oxidative stress impaired ANG II-mediated NHE3 biphasic response in that stimulation was observed at both high- and low-ANG II concentration.

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

    Directory of Open Access Journals (Sweden)

    Trbojević-Stanković Jasna B.

    2015-01-01

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

  6. 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.

  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. 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.

  9. Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

    Science.gov (United States)

    Brooks, V. L.; Keil, L. C.

    1992-01-01

    Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

  10. 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.

  11. Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes.

    Science.gov (United States)

    Diao, Teng-Yue; Pan, Hai; Gu, Sa-Sa; Chen, Xi; Zhang, Fang-Yi; Wong, Man-Sau; Zhang, Yan

    2014-05-01

    There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-κB ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-β and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice.

  12. 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...

  13. AT(1) antagonism and renin inhibition in mice : pivotal role of targeting angiotensin II in chronic kidney disease

    NARCIS (Netherlands)

    Fraune, Christoph; Lange, Sascha; Krebs, Christian; Hoelzel, Alexandra; Baucke, Jana; Divac, Nevena; Schwedhelm, Edzard; Streichert, Thomas; Velden, Joachim; Garrelds, Ingrid M.; Danser, A. H. Jan; Frenay, Anne-Roos; van Goor, Harry; Jankowski, Vera; Stahl, Rolf; Nguyen, Genevieve; Wenzel, Ulrich Otto

    2012-01-01

    Fraune C, Lange S, Krebs C, Holzel A, Baucke J, Divac N, Schwedhelm E, Streichert T, Velden J, Garrelds IM, Danser AH, Frenay A, van Goor H, Jankowski V, Stahl R, Nguyen G, Wenzel UO. AT(1) antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease.

  14. 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....

  15. 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.

  16. Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice

    Science.gov (United States)

    Li, Xiao C.; Cook, Julia L.; Rubera, Isabelle; Tauc, Michel; Zhang, Fan

    2011-01-01

    The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT1 (AT1a) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P tubules (P kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT1a receptors and increasing sodium reabsorption in proximal tubules. PMID:21307128

  17. 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...

  18. PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct.

    Science.gov (United States)

    Gonzalez, Alexis A; Liu, Liu; Lara, Lucienne S; Bourgeois, Camille R T; Ibaceta-Gonzalez, Cristobal; Salinas-Parra, Nicolas; Gogulamudi, Venkateswara R; Seth, Dale M; Prieto, Minolfa C

    2015-11-15

    In contrast to the negative feedback of angiotensin II (ANG II) on juxtaglomerular renin, ANG II stimulates renin in the principal cells of the collecting duct (CD) in rats and mice via ANG II type 1 (AT1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT1R activation through protein kinase C (PKC), but the exact mechanisms are unknown. We hypothesize that ANG II stimulates CD renin synthesis through AT1R via PKC and the subsequent activation of cAMP/PKA/CREB pathway. In M-1 cells, ANG II increased cAMP, renin mRNA (3.5-fold), prorenin, and renin proteins, as well as renin activity in culture media (2-fold). These effects were prevented by PKC inhibition with calphostin C, PKC-α dominant negative, and by PKA inhibition. Forskolin-induced increases in cAMP and renin expression were prevented by calphostin C. PKC inhibition and Ca2+ depletion impaired ANG II-mediated CREB phosphorylation and upregulation of renin. Adenylate cyclase 6 (AC) siRNA remarkably attenuated the ANG II-dependent upregulation of renin mRNA. Physiological activation of AC with vasopressin increased renin expression in M-1 cells. The results suggest that the ANG II-dependent upregulation of renin in the CD depends on PKC-α, which allows the augmentation of cAMP production and activation of PKA/CREB pathway via AC6. This study defines the intracellular signaling pathway involved in the ANG II-mediated stimulation of renin in the CD. This is a novel mechanism responsible for the regulation of local renin-angiotensin system in the distal nephron. Copyright © 2015 the American Physiological Society.

  19. 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...

  20. Angiotensin II suppresses water absorption through the ventral skin of Japanese tree-frogs in vitro.

    Science.gov (United States)

    Tokuda, C; Kimura, K; Kamishima, Y

    1995-04-01

    We previously described two different water absorption systems in the ventral skin of the Japanese tree-frog, Hyla arborea japonica: i.e., a rapid enhanced flow, which is observed in dehydrated tree-frogs or those stimulated by adrenaline beta-agonists or vasotocin, and a slow basal flow, which is observed in normally hydrated frogs during the non-breeding season. The rapid flow is completely blocked by ouabain, which has no effects on the slow basal flow. In the present experiment, we show that the vaso-constrictive hormone angiotensin II completely inhibits basal water absorption, but has no effect on rapid water absorption. These results confirm our previous finding that the two water absorption systems in the ventral skin of the Japanese tree-frog are independent of each other.

  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. 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...

  3. 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...

  4. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible...... to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...... used urinary isoprostane as a marker for oxidative stress. RESULTS: Although high-salt diet per se did not affect plaque extension, high salt combined with Ang II increased plaque area significantly in both the aorta and the innominate artery as compared with Ang II or salt alone (P

  5. 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.

  6. Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure.

    Science.gov (United States)

    Packer, M

    1988-06-01

    Despite a dramatic fall in renal blood flow, glomerular filtration rate is usually preserved in patients with congestive heart failure until the terminal stages of the disease. This maintenance of renal function appears to be achieved in part by the synthesis of two vasoactive factors within the kidney--angiotensin II and prostaglandins--which are rapidly released whenever renal perfusion is compromised or sympathetic nerve traffic to the kidneys is increased. Although these two hormonal systems exert opposite effects on systemic and renal blood flow and sodium and water excretion, both act to preserve glomerular filtration rate: prostaglandins by a vasodilator action exerted primarily on the afferent arteriole and angiotensin II by a vasoconstrictor effect on the efferent arteriole. Consequently, when the synthesis of these hormones is experimentally blocked, renal function deteriorates, especially in subjects with marked renal hypoperfusion and sodium depletion; these two factors interact to determine the importance of intrarenal hormonal release in the modulation of renal function. Clinically, four specific factors have been identified that predispose patients with heart failure to the development of functional renal insufficiency after treatment with converting-enzyme or cyclo-oxygenase inhibitors: (1) marked renal hypoperfusion, (2) vigorous diuretic therapy, (3) diabetes mellitus, and (4) intensity of hormonal inhibition within the kidney. This last risk factor may provide the basis for differentiating among enzyme-inhibitory drugs and suggests that renal insufficiency in low-output states may be minimized by the development of therapeutic agents that block hormonal synthesis selectively at sites that are critical to the disease process but spare the homeostatic tissue-based enzyme systems that exist within the kidney.

  7. Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

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    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.

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

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    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.

  9. 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

  10. The methanol seed extract of Garcinia kola attenuated angiotensin II- and lipopolyssacharide-inducedvascular smooth muscle cell proliferation and nitric oxide production

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    Adeolu A. Adedapo

    2016-10-01

    Full Text Available All over the world, cardiovascular diseases are a risk factor for poor health and early death with predisposing factors to include age, gender, tobacco use, physical inactivity, excessive alcohol consumption, unhealthy diet, obesity, family history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, psychosocial factors, poverty and low educational status, and air pollution. It is envisaged that herbal products that can stem this trend would be of great benefit. Garcinia kola (GK, also known as bitter kola is one of such plants. Generally used as a social snack and offered to guests in some cultural settings, bitter kola has been indicated in the treatment of laryngitis, general inflammation, bronchitis, viral infections and diabetes. In this study, the effects of methanol seed extract of Garcinia kola on the proliferation of Vascular Smooth Muscle Cells (VSMCs in cell culture by Angiotensin II (Ang II and LPS-induced NO production were carried out. Confluent VSMCs were exposed to GK (25, 50 and 100 μg/ml before or after treatment with lipopolyssacharide (100μg/ml, and Angiotensin II (10-8-10-6M. Cellular proliferation was determined by MTT assay and NO production by Griess assay. Treatment with Angiotensin II (10-8, 10-6 or LPS significantly enhanced proliferation of VSM cells while LPS significantly increased nitric oxide (NO production. Treatment with GK (25, 50 & 100 μg/ml attenuated VSM cell proliferation. The results indicate that GK has potential to inhibit mitogen activated vascular cell growth and possibly inhibit inflammatory responses to LPS. Thus GK may be useful in condition that is characterized by cellular proliferation and inflammatory responses.

  11. Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation.

    Science.gov (United States)

    Rudolph, Tanja K; Ravekes, Thorben; Klinke, Anna; Friedrichs, Kai; Mollenhauer, Martin; Pekarova, Michaela; Ambrozova, Gabriela; Martiskova, Hana; Kaur, Jatinder-Jit; Matthes, Bianca; Schwoerer, Alex; Woodcock, Steven R; Kubala, Lukas; Freeman, Bruce A; Baldus, Stephan; Rudolph, Volker

    2016-01-01

    Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF. Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation. OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  12. STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.

    Science.gov (United States)

    Chen, Lei; Zhao, Lin; Samanta, Anweshan; Mahmoudi, Seyed Morteza; Buehler, Tanner; Cantilena, Amy; Vincent, Robert J; Girgis, Magdy; Breeden, Joshua; Asante, Samuel; Xuan, Yu-Ting; Dawn, Buddhadeb

    2017-01-01

    Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and β-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and β-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling.

  13. Increased expression of the renin-angiotensin system and mast cell density but not of angiotensin-converting enzyme II in late stages of human heart failure.

    Science.gov (United States)

    Batlle, Montserrat; Roig, Eulàlia; Perez-Villa, Fèlix; Lario, Sergio; Cejudo-Martin, Pilar; García-Pras, Ester; Ortiz, José; Roqué, Mercé; Orús, Josefina; Rigol, Montserrat; Heras, Magdalena; Ramírez, José; Jimenez, Wladimiro

    2006-09-01

    The activation of the renin-angiotensin system (RAS) contributes to the progression of left ventricular dysfunction. A novel human homologue of the angiotensin-converting enzyme (ACE), named ACE2, has been described but its role in human heart failure (HF) has not been elucidated. Besides, there is controversy as to whether the major angiotensin II-forming-activity in heart is ACE or chymase released from mast cells. Furthermore, long-term blockade of nitric oxide (NO) synthesis has been shown to increase ACE activity. To assess the locally activated vasoactive mediators that may contribute to the ventricular deterioration process, we sought to simultaneously analyze their expression in failing hearts. We analyzed left ventricular biopsies from 30 patients with heart failure undergoing heart transplantation and 12 organ donors. The mRNA levels of ACE, ACE2, chymase and endothelial nitric oxide synthase (eNOS), were quantified by real-time polymerase chain reaction and mast cell density was assessed by immunohistochemistry. The mRNA levels of the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) were also quantified as controls. There was higher ACE and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in ACE2 expression were detected. eNOS mRNA levels were lower in failing hearts. Both ANP and BNP expression were higher in pathological than in control samples. These data document a decompensation of vasoactive systems that may contribute to the progressive impairment of the myocardial function in HF. On the other hand, ACE2 mRNA expression is not altered in human end-stage HF.

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

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    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.

  15. Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling. Fan, ACE2 improves atrial substrate remodeling.

    Science.gov (United States)

    Fan, Jinqi; Zou, Lili; Cui, Kun; Woo, Kamsang; Du, Huaan; Chen, Shaojie; Ling, Zhiyu; Zhang, Quanjun; Zhang, Bo; Lan, Xianbin; Su, Li; Zrenner, Bernhard; Yin, Yuehui

    2015-01-01

    The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1-7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin-angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF.

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

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    Hon-Yen Wu

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

  17. 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...

  18. The angiotensin-converting enzyme inhibitor captopril rescues mice from endotoxin-induced lethal hepatitis.

    Science.gov (United States)

    Ge, Pu; Jiang, Rong; Yao, Xin; Li, Jing; Dai, Jie; Zhang, Li; Ye, Bin

    2017-02-01

    The renin-angiotensin system is classically regarded as a crucial regulator of circulatory homeostasis, but recent studies also revealed its pro-inflammatory roles. The beneficial effects of the angiotensin-converting enzyme inhibitor (ACEI) in severe inflammatory injury in the lung and heart have been previously reported, but its potential effects on lethal hepatitis were unknown. In this study, a mouse model with LPS/d-galactosamine (GalN)-induced fulminant hepatitis were used to test the protective potential of captopril, a representative ACEI. The results indicated that treatment with captopril significantly decreased the plasma level of alanine aminotransferase and aspartate aminotransferase, alleviated the histopathological damage of the liver tissue and improve the survival rate of LPS/GalN-challenged mice. These effects were accompanied by reduced mRNA levels of TNF-α and IL-6 in the liver, and decreased protein level of TNF-α and IL-6 in the plasma. In addition, the activation of caspases 3, 8 and 9, and the presence of TUNEL-positive apoptotic cells, were also suppressed by captopril treatment. The above evidence suggested that the renin-angiotensin system might be involved in the development of LPS/GalN-induced fulminant hepatitis and ACEI might have potential value in lethal hepatitis.

  19. Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.

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    Ali Ashek

    Full Text Available Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage. Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.

  20. Systemic vascular resistance during brief withdrawal of angiotensin converting enzyme inhibition in heart failure

    DEFF Research Database (Denmark)

    Gabrielsen, A; Bie, P; Christensen, N J

    2002-01-01

    We tested the hypothesis that moderate increases in endogenous angiotensin II (Ang II) concentrations, induced by withdrawal of angiotensin converting enzyme inhibition (ACE-I) in patients with compensated heart failure (HF) on chronic medical therapy, do not increase or impair control of systemi...

  1. Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.

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    Kosuke Nagayama

    Full Text Available Angiotensin II (Ang II is a main pathophysiological culprit peptide for hypertension and atherosclerosis by causing vascular smooth muscle cell (VSMC proliferation and migration. Exendin-4, a glucagon-like peptide-1 (GLP-1 receptor agonist, is currently used for the treatment of type-2 diabetes, and is believed to have beneficial effects for cardiovascular diseases. However, the vascular protective mechanisms of GLP-1 receptor agonists remain largely unexplained. In the present study, we examined the effect of exendin-4 on Ang II-induced proliferation and migration of cultured rat aortic smooth muscle cells (RASMC. The major findings of the present study are as follows: (1 Ang II caused a phenotypic switch of RASMC from contractile type to synthetic proliferative type cells; (2 Ang II caused concentration-dependent RASMC proliferation, which was significantly inhibited by the pretreatment with exendin-4; (3 Ang II caused concentration-dependent RASMC migration, which was effectively inhibited by the pretreatment with exendin-4; (4 exendin-4 inhibited Ang II-induced phosphorylation of ERK1/2 and JNK in a pre-incubation time-dependent manner; and (5 U0126 (an ERK1/2 kinase inhibitor and SP600125 (a JNK inhibitor also inhibited both RASMC proliferation and migration induced by Ang II stimulation. These results suggest that exendin-4 prevented Ang II-induced VSMC proliferation and migration through the inhibition of ERK1/2 and JNK phosphorylation caused by Ang II stimulation. This indicates that GLP-1 receptor agonists should be considered for use in the treatment of cardiovascular diseases in addition to their current use in the treatment of diabetes mellitus.

  2. Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.

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    Alfredo Csibi

    Full Text Available Angiotensin II (Ang II plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2(*--dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt. Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473 and Thr(308 as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(PHoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr(156/139, close to their active site Asp(166/149, in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein

  3. 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.

  4. 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.

  5. 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.

  6. Angiotensin II of paraventricular nucleus is exaggerated the renal ischemia-reperfusion injury

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    Behjat Seifi

    2014-05-01

    Conclusion: These data showed that the PVN is a responsive site for central Ang II-induced damage in renal IR injury. We suggested the central effects of Ang II in the PVN on renal IR injury are mediated by oxidative stress in the PVN, and the peripheral effects by a sympathetic pathway.

  7. Gender-dependent difference in cell calcium handling in VSMC isolated from SHR: the effect of angiotensin II

    Czech Academy of Sciences Publication Activity Database

    Loukotová, Jana; Kuneš, Jaroslav; Zicha, Josef

    2002-01-01

    Roč. 20, č. 11 (2002), s. 2213-2219 ISSN 0263-6352 R&D Projects: GA ČR GP305/02/P066; GA AV ČR IAA7011805; GA MŠk LN00A069 Institutional research plan: CEZ:AV0Z5011922 Keywords : gender * female * angiotensin s II Subject RIV: ED - Physiology Impact factor: 3.534, year: 2002

  8. 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

  9. 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.

  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. Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides.

    Directory of Open Access Journals (Sweden)

    Victor Barbosa Saraiva

    2011-02-01

    Full Text Available Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7. Parasite infection decreased Ang-(1-7 and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7 decreased the level of infection in an A779 (specific antagonist of Ang-(1-7 receptor, MAS-sensitive manner. 10(-7 M PD123319, an AT(2 receptor antagonist, partially reversed the effects of Ang-(1-7 and Ang II. However, 10(-6 M losartan, an antagonist of the AT(1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA activity; 10(-8 M Ang II or 10(-8 M Ang-(1-7 inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7 M A779. 10(-6 M dibutyryl-cAMP increased the level of infection and 10(-7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7 on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7 in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.

  12. 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...

  13. 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

  14. 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.

  15. Cytoplasmic Ca2+ signalling and reduction of mitochondrial pyridine nucleotides in adrenal glomerulosa cells in response to K+, angiotensin II and vasopressin.

    Science.gov (United States)

    Rohács, T; Nagy, G; Spät, A

    1997-01-01

    We have examined the mitochondrial formation of NAD(P)H in rat adrenal glomerulosa cells. A short-term elevation of the K+ concentration from 3.6 to 8.4 mM induced a reversible increase in the formation of reduced pyridine nucleotides. Potassium applied after the addition of rotenone had no further effect, confirming that the redox signal was of mitochondrial origin. Inhibition of aldosterone synthesis by aminoglutethimide in K+-stimulated cells decreased the rate of decay of the NAD(P)H signal upon the termination of stimulation, indicating that the NADPH formed was consumed in aldosterone synthesis. When the NAD(P)H signal was measured simultaneously with the cytoplasmic free Ca2+ concentration ([Ca2+]i), elevation of the K+ concentration to 6.6 or 8.4 mM induced parallel increases in [Ca2+]i and NAD(P)H formation. The rates of increase and decrease of NAD(P)H were lower than for [Ca2+]i, confirming that the redox signal was secondary to the Ca2+ signal. Angiotensin II (100 pM-1 nM) induced an oscillatory NAD(P)H signal which usually returned to a lower baseline concentration, while a sustained signal with superimposed oscillations was observed at higher concentrations. Simultaneous measurements showed that NAD(P)H levels followed the [Ca2+]i pattern evoked by angiotensin II. Vasopressin (100 nM) also induced parallel oscillations of [Ca2+]i and NAD(P)H. A sustained rise in the extramitochondrial Ca2+ concentration to 1 microM induced a sustained elevation of the intramitochondrial Ca2+ concentration in permeabilized cells, as measured with rhod-2. A sustained rise in [Ca2+]i evoked by long-term stimulation with 8.4 mM K+ or 2.5 nM angiotensin II resulted in sustained NAD(P)H production. These Ca2+-dependent changes in the mitochondrial redox state support the biological response, i.e. aldosterone secretion by glomerulosa cells. PMID:9148750

  16. 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...

  17. 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

  18. The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice.

    Science.gov (United States)

    Dolber, Paul C; Jin, Huixia; Nassar, Rashid; Coffman, Thomas M; Gurley, Susan B; Fraser, Matthew O

    2015-01-01

    Diabetes is associated with both dysfunction of the lower urinary tract (LUT) and overactivity of the renin-angiotensin system (RAS). Although it is well known that the RAS affects normal LUT function, very little is known about RAS effects on the diabetic LUT. Accordingly, we investigated the effects of chronic angiotensin II (AngII) treatment on the LUT in a model of type 1 diabetes. Ins2(Akita) diabetic mice (20 weeks old) and their age-matched background controls underwent conscious cystometric evaluation after 4 weeks of chronic AngII treatment (700 ng/kg/min by osmotic pump) or vehicle (saline). Diabetic mice had compensated LUT function with bladder hypertrophy. Specifically, micturition volume, residual volume, and bladder capacity were all increased, while voiding efficiency and pressure generation were unchanged as bladder mass, contraction duration, and phasic urethral function were increased. AngII significantly increased voiding efficiency and peak voiding pressure and decreased phasic frequency irrespective of diabetic state and, in diabetic but not normoglycemic control mice, significantly decreased residual volume and increased contraction duration and nonphasic contraction duration. The Ins2(Akita) diabetic mice had compensated LUT function at 20 weeks of age. Even under these conditions, AngII had beneficial effects on LUT function, resulting in increased voiding efficiency. Future studies should therefore be conducted to determine whether AngII can rescue the decompensated LUT function occurring in end-stage diabetic uropathy. © 2013 Wiley Periodicals, Inc.

  19. Restriction of placental and fetal growth in sheep alters fetal blood pressure responses to angiotensin II and captopril

    Science.gov (United States)

    Edwards, L J; Simonetta, G; Owens, J A; Robinson, J S; McMillen, I C

    1999-01-01

    We have measured arterial blood pressure between 115 and 145 days gestation in normally grown fetal sheep (control group; n = 16) and in fetal sheep in which growth was restricted by experimental restriction of placental growth and development (PR group; n = 13). There was no significant difference in the mean gestational arterial blood pressure between the PR (42.7 ± 2.6 mmHg) and control groups (37.7 ± 2.3 mmHg). Mean arterial blood pressure and arterial PO2 were significantly correlated in control animals (r = 0.53, P captopril (7.5 μg captopril min−1; PR group n = 7, control group n = 6) between 115 and 125 days gestation. After 135 days gestation, there was a significant decrease (P captopril infusion (15 μg captopril min−1; PR group n = 7, control group n = 6).There was a significant effect (F = 14.75; P < 0.001) of increasing doses of angiotensin II on fetal diastolic blood pressure in the PR and control groups. The effects of angiotensin II were different (F = 8.67; P < 0.05) in the PR and control groups at both gestational age ranges.These data indicate that arterial blood pressure may be maintained by different mechanisms in growth restricted fetuses and normally grown counterparts and suggests a role for the fetal renin-angiotensin system in the maintenance of blood pressure in growth restricted fetuses. PMID:10066914

  20. 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.

  1. Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory pathway.

    Science.gov (United States)

    Bihl, Ji C; Zhang, Cheng; Zhao, Yuhui; Xiao, Xiang; Ma, Xiaotang; Chen, Yusen; Chen, Shuzhen; Zhao, Bin; Chen, Yanfang

    2015-10-01

    Angiotensin (Ang)-(1-7) is a potential vasoprotective peptide. In the present study, we investigated its counteractive effects to Ang II on vascular smooth muscle cells (VSMCs) and intracerebral hemorrhagic stroke (ICH) through inflammatory mechanism. In in vitro experiments, human brain VSMCs (HBVSMCs) were treated with vehicle, Ang II, Ang II+Ang-(1-7), Ang II+A-779 or Ang II+Ang-(1-7)+A-779 (Mas receptor antagonist). HBVSMC proliferation, migration and apoptosis were determined by methyl thiazolyltetrazolium, wound healing assay and flow cytometry, respectively. In in vivo experiments, C57BL/6 mice were divided into vehicle, Ang II, Ang II+Ang-(1-7), Ang II+A-779 or Ang II+Ang-(1-7)+A-779 groups before they were subjected to collagenase-induced ICH or sham surgery. Hemorrhage volume and middle cerebral artery (MCA) remodeling were determined by histological analyses. Levels of NFκB, inhibitor of κBα (IκBα), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and interleukin (IL-8) were measured by western blot or ELISA. We found that 1) Ang II increased HBVSMC migration, proliferation and apoptosis, and increased the blood pressure (BP), neurological deficit score, MCA remodeling and hemorrhage volume in ICH mice. 2) Ang-(1-7) counteracted these effects of Ang II, which was independent of BP, with the down-regulation of NFκB, up-regulation of IκBα, and decreased levels of TNF-α, MCP-1 and IL-8. 3) The beneficial effects of Ang-(1-7) could be abolished by A-779. In conclusion, Ang-(1-7) counteracts the effects of Ang II on ICH via modulating NFκB inflammation pathway in HBVSMCs and cerebral microvessels. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Angiotensin-(1-7) attenuates hyposmolarity-induced ANP secretion via the Na+-K+ pump.

    Science.gov (United States)

    Shah, Amin; Oh, Young-Bin; Shan, Gao; Song, Chang Ho; Park, Byung-Hyun; Kim, Suhn Hee

    2010-09-01

    The alteration in osmolarity challenges cell volume regulation, a vital element for cell survival. Hyposmolarity causes an increase in cell volume. Recently, it has been reported that the renin-angiotensin system (RAS) plays a role in cell volume regulation. We investigated the effect of angiotensin-(1-7) [Ang-(1-7)] on hyposmolarity-induced atrial natriuretic peptide (ANP) secretion in normal and diabetic (DM) rat atria and modulation of the effect of Ang-(1-7) by the Na(+)-K(+) pump. Using isolated control rat atria, we observed that perfusion of hyposmotic solution into the atria increased ANP secretion. When Ang-(1-7) [0.1 microM or 1 microM] was perfused in a hyposmolar solution, it decreased the hyposmolarity-induced ANP secretion in a dose-dependent manner. This effect of Ang-(1-7) could be mediated by the Na(+)-K(+) pump, since ouabain, an Na(+)-K(+) pump inhibitor, significantly decreased the effect of Ang-(1-7) on hyposmolarity-induced ANP secretion. In contrast, N(omega) Nitro-l-arginine methyl ester hydrochloride (l-NAME) did not modify the effect of Ang-(1-7) on the hyposmolarity-induced ANP secretion. Interestingly, the ANP secretion was increased robustly by the perfusion of the hyposmolar solution in the DM atria, as compared to the control atria. However, the inhibitory effect of Ang-(1-7) on the hyposmolarity-induced ANP secretion was not observed in the DM atria. In the DM atria, atrial contractility was significantly increased. Taken together, we concluded that Ang-(1-7) attenuated hyposmolarity-induced ANP secretion via the Na(+)-K(+) pump and a lack of Ang-(1-7) response in DM atria may partly relate to change in Na(+)-K(+) pump activity. Copyright 2010 Elsevier Inc. All rights reserved.

  7. Different contributions of the angiotensin-converting enzyme C-domain and N-domain in subjects with the angiotensin-converting enzyme II and DD genotype.

    NARCIS (Netherlands)

    Esch, JH van; Gool, JM van; Bruin, R.J. de; Payne, J.R.; Montgomery, Henry; Hectors, M.; Deinum, J.; Dive, V.; Danser, A.H.

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism-related differences in ACE concentration do not result in differences in angiotensin levels. METHODS AND RESULTS: To investigate whether this relates to differences in the contribution of the ACE C-domain and

  8. Features of 24-hour monitoring of blood pressure, serum urotensin II and angiotensin II levels, vascular remodeling and extracranial blood flow in patients with hypertension

    Directory of Open Access Journals (Sweden)

    V. A. Vizir

    2015-12-01

    Full Text Available Hypertension is the main cause of morbidity, disability and mortality in the adult population in most countries of the world. Aim. Aiming to establish the features of 24-hour monitoring of blood pressure, serum urotensin II and angiotensin II concentrations, vascular remodeling and extracranial blood flow in patients with stage II hypertension associated with carotid atherosclerosis, cerebral blood flow indexes were studied in 102 patients using duplex scanning of extracranial arteries, 24-hour blood pressure monitoring. Serum urotensin II and angiotensin II levels were determined with immunoenzymatic method. Results. It was found that the average 24-hour, average daytime values of systolic and diastolic blood pressure, variability indicators and blood pressure load were significantly higher in the patients of the first group of observation. Among cerebral blood flow indexes, statistically significant differences were showed by linear blood flow velocity, intima-media thickness, RI and PI. The patients with stage II hypertension associated with extracranial arterial lesions had probably higher serum urotensin II concentrations. Conclusion. This indicates higher levels of 24-hour blood pressure monitoring indexes, severe disorders of cerebral blood flow and neurohormonal activation in case of simultaneous hypertension and atherosclerotic lesion of brachiocephalic arteries.

  9. The Renal Protective Effect of Jiangya Tongluo Formula, through Regulation of Adrenomedullin and Angiotensin II, in Rats with Hypertensive Nephrosclerosis

    Directory of Open Access Journals (Sweden)

    Lin Han

    2015-01-01

    Full Text Available We investigated the effect of Jiangya Tongluo (JYTL formula on renal function in rats with hypertensive nephrosclerosis. A total of 21 spontaneously hypertensive rats (SHRs were randomized into 3 groups: valsartan (10 mg/kg/d valsartan, JYTL (14.2 g/kg/d JYTL, and a model group (5 mL/kg/d distilled water; Wistar Kyoto rats comprised the control group (n = 7, 5 mL/kg/d distilled water. Treatments were administered by gavage every day for 8 weeks. Blood pressure, 24-h urine protein, pathological changes in the kidney, serum creatinine, and blood urea nitrogen (BUN levels were estimated. The contents of adrenomedullin (ADM and angiotensin II (Ang II in both the kidney and plasma were evaluated. JYTL lowered BP, 24-h urine protein, serum creatinine, and BUN. ADM content in kidneys increased and negatively correlated with BP, while Ang II decreased and negatively correlated with ADM, but there was no statistically significant difference of plasma ADM between the model and the treatment groups. Possibly, activated intrarenal renin-angiotensin system (RAS plays an important role in hypertensive nephrosclerosis and the protective function of ADM via local paracrine. JYTL may upregulate endogenous ADM level in the kidneys and antagonize Ang II during vascular injury by dilating renal blood vessels.

  10. Resveratrol inhibits the intracellular calcium increase and angiotensin/endothelin system activation induced by soluble uric acid in mesangial cells

    Directory of Open Access Journals (Sweden)

    G. Albertoni

    2015-01-01

    Full Text Available Resveratrol (Resv is natural polyphenol found in grapes. This study evaluated the protective effect of Resv against the effects of uric acid (UA in immortalized human mesangial cells (ihMCs. ihMCs were preincubated with Resv (12.5 µM for 1 h and treated with UA (10 mg/dL for 6 or 12 h. The intracellular calcium concentration [Ca2+]i was quantified by fluorescence using flow cytometry. Angiotensinogen (AGT and pre-pro endothelin-1 (ppET-1 mRNA were assayed by quantitative real-time RT-PCR. Angiotensin II (AII and endothelin-1 (ET-1 were assayed by ELISA. UA significantly increased [Ca2+]i. Pre-incubation with Resv significantly reduced the change in [Ca2+]i induced by UA. Incubation with UA for 6 or 12 h also increased AGT mRNA expression and AII protein synthesis. Resv blunted these increases in AGT mRNA expression and AII protein. Incubation with UA in the ihMCs increased ppET-1 expression and ET-1 protein synthesis at 6 and 12 h. When ihMCs were pre-incubated with Resv, UA had a significantly diminished effect on ppET-1 mRNA expression and ET-1 protein synthesis at 6 and 12 h, respectively. Our results suggested that UA triggers reactions including AII and ET-1 production in mesangial cells. The renin-angiotensin system may contribute to the pathogenesis of renal function and chronic kidney disease. Resv can minimize the impact of UA on AII, ET-1 and the increase of [Ca2+]i in mesangial cells, suggesting that, at least in part, Resv can prevent the effects of soluble UA in mesangial cells.

  11. Resveratrol inhibits the intracellular calcium increase and angiotensin/endothelin system activation induced by soluble uric acid in mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Albertoni, G.; Schor, N. [Divisão de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2014-10-24

    Resveratrol (Resv) is natural polyphenol found in grapes. This study evaluated the protective effect of Resv against the effects of uric acid (UA) in immortalized human mesangial cells (ihMCs). ihMCs were preincubated with Resv (12.5 µM) for 1 h and treated with UA (10 mg/dL) for 6 or 12 h. The intracellular calcium concentration [Ca{sup 2+}]i was quantified by fluorescence using flow cytometry. Angiotensinogen (AGT) and pre-pro endothelin-1 (ppET-1) mRNA were assayed by quantitative real-time RT-PCR. Angiotensin II (AII) and endothelin-1 (ET-1) were assayed by ELISA. UA significantly increased [Ca{sup 2+}]i. Pre-incubation with Resv significantly reduced the change in [Ca{sup 2+}]i induced by UA. Incubation with UA for 6 or 12 h also increased AGT mRNA expression and AII protein synthesis. Resv blunted these increases in AGT mRNA expression and AII protein. Incubation with UA in the ihMCs increased ppET-1 expression and ET-1 protein synthesis at 6 and 12 h. When ihMCs were pre-incubated with Resv, UA had a significantly diminished effect on ppET-1 mRNA expression and ET-1 protein synthesis at 6 and 12 h, respectively. Our results suggested that UA triggers reactions including AII and ET-1 production in mesangial cells. The renin-angiotensin system may contribute to the pathogenesis of renal function and chronic kidney disease. Resv can minimize the impact of UA on AII, ET-1 and the increase of [Ca{sup 2+}]i in mesangial cells, suggesting that, at least in part, Resv can prevent the effects of soluble UA in mesangial cells.

  12. Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming.

    Science.gov (United States)

    Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T; Rose, James C; Diz, Debra I; Chappell, Mark C

    2014-02-01

    We previously identified angiotensin converting enzyme (ACE) and an endopeptidase activity that degraded angiotensin-(1-7) [Ang-(1-7)] to Ang-(1-5) and Ang-(1-4), respectively, in the cerebrospinal fluid (CSF) of 6-month old male sheep. The present study undertook a more comprehensive analysis of the CSF peptidase that converts Ang-(1-7) to Ang-(1-4) in control and in utero betamethasone-exposed sheep (BMX). Characterization of the Ang-(1-7) peptidase revealed that the thiol agents 4-aminophenylmercuric acetate (APMA) and p-chloromercuribenzoic acid (PCMB), as well as the metallo-chelators o-phenanthroline and EDTA essentially abolished the enzyme activity. Additional inhibitors for serine, aspartyl, and cysteine proteases, as well as selective inhibitors against the endopeptidases neprilysin, neurolysin, prolyl and thimet oligopeptidases did not attenuate enzymatic activity. Competition studies against the peptidase revealed similar IC50s for Ang-(1-7) (5μM) and Ang II (3μM), but lower values for Ala(1)-Ang-(1-7) and Ang-(2-7) of 1.8 and 2.0μM, respectively. In contrast, bradykinin exhibited a 6-fold higher IC50 (32μM) than Ang-(1-7) while neurotensin was a poor competitor. Mean arterial pressure (78±1 vs. 94±2mmHg, N=4-5, Pfetal programming. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Renal intramedullary infusion of tempol normalizes the blood pressure response to intrarenal blockade of heme oxygenase-1 in angiotensin II-dependent hypertension.

    Science.gov (United States)

    Stec, David E; Juncos, Luis A; Granger, Joey P

    2016-04-01

    Previous studies have demonstrated that intramedullary inhibition of heme oxygenase-1 (HO-1) increases the blood pressure and superoxide production response to angiotensin II (Ang II) infusion. The present study was designed to test the hypothesis that increased renal medullary superoxide production contributes to the increase in blood pressure in response to blockade of renal medullary HO-1 in Ang II-induced hypertension. Male C57BL/6J mice (16-24 weeks of age) were implanted with chronic intrarenal medullary interstitial (IRMI) and infused with: saline, tempol (6 mM), the HO-1 inhibitor QC-13 (25 μM), or a combination of tempol + QC-13. Tempol treatment was started 2 days before infusion of QC-13. After 2 days, Ang II was infused subcutaneously at a rate of 1 μg/kg/min for 10 days. Blood pressures on days 7-10 of Ang II infusion alone averaged 150 ± 3 mm Hg in mice receiving IRMI infusion of saline. IRMI infusion of QC-13 increased blood pressure in Ang II-treated mice to 164 ± 2 (P tempol had a blood pressure of 136 ± 3 mm Hg. Ang II-treated mice receiving IRMI infusion of tempol and QC-13 had a significantly lower blood pressure (142 ± 2 mm Hg, P tempol alone or in combination with QC-13. These results demonstrate that renal medullary interstitial blockade of HO-1 exacerbates Ang II-induced hypertension via a mechanism that is dependent on enhanced superoxide generation and highlight the important antioxidant function of HO-1 in the renal medulla. Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  14. 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.

  15. 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.

  16. 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

  17. N-3 PUFAs protect against aortic inflammation and oxidative stress in angiotensin II-infused apolipoprotein E-/- mice.

    Directory of Open Access Journals (Sweden)

    Kathryn M Wales

    Full Text Available Abdominal aortic aneurysm is associated with infiltration of inflammatory cells into the aortic wall. The inflammatory response is also evident in animal models, such as apolipoprotein E-deficient (ApoE-/- mice that have been infused with angiotensin II, prior to development of aortic aneurysm. Since omega-3 polyunsaturated fatty acids (n-3 PUFAs and their metabolites have anti-inflammatory and pro-resolving activity, we hypothesised that dietary supplementation with n-3 PUFAs would protect against inflammatory processes in this mouse model. Twenty C57 and 20 ApoE-/- 3-4 week old male mice were supplemented with a low (0.14%, n = 10/group or high (0.70%, n = 10/group n-3 PUFA diet for 8 weeks before 2-day infusion with 0.9% saline or angiotensin II (1000 ng/kg/min. Four ApoE-/- mice on the low n-3 PUFA diet and none of the ApoE-/- mice on the high n-3 PUFA diet showed morphological evidence of abdominal aortic dissection. The plasma concentration of the n-3 PUFA metabolite, resolvin D1 was higher in angiotensin II-infused ApoE-/- mice fed the high, compared to the low n-3 PUFA diet. The number of neutrophils and macrophages infiltrating the abdominal aorta was elevated in ApoE-/- mice on the low n-3 PUFA diet, and this was significantly attenuated in mice that were fed the high n-3 PUFA diet. Most neutrophils and macrophages were associated with dissected aortas. Immunoreactivity of the catalytic subunit of nicotinamide-adenine dinucleotide phosphate (NADPH oxidase, Nox2, and superoxide were elevated in ApoE-/- mice that were fed the low n-3 PUFA diet, and this was also significantly attenuated in mice that were fed the high n-3 PUFA diet. Together, the findings indicate that supplementation of ApoE-/- mice with a diet high in n-3 PUFA content protected the mice against pro-inflammatory and oxidative stress responses following short-term infusion with angiotensin II.

  18. 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.

  19. Ursodeoxycholic Acid Attenuates Acute Aortic Dissection Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice Associated with Reduced ROS and Increased Nrf2 Levels

    Directory of Open Access Journals (Sweden)

    Wanjun Liu

    2016-03-01

    Full Text Available Background/Aims: Acute aortic dissection (AAD is characterized by excessive smooth muscle cell (SMC loss, extracellular matrix (ECM degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA attenuates AAD formation. Methods: Angiotensin II (Ang II was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days. Results: Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37 and UDCA markedly reduced the incidence of AAD to 16% (6/37, accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS and apoptosis of vascular smooth muscle cells (VSMCs both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91 in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT, thereby inhibiting apoptosis of VSMCs. Conclusion: These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation.

  20. 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.

  1. Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men

    Directory of Open Access Journals (Sweden)

    Karim Zouaoui Boudjeltia

    2013-01-01

    Full Text Available The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO, an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels.

  2. 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 ...

  3. Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Lifang Wang

    2015-05-01

    Full Text Available Background: Local renin-angiotensin system (RAS activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF. It has been reported that angiotensin-converting enzyme 2 (ACE2 could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. Methods: Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC staining and western blot (WB testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA and pulmonary surfactant-associated protein A (SP-A IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-β1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. Results: Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-β1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. Conclusion: ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF.

  4. Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice.

    Science.gov (United States)

    Wang, Lifang; Wang, Yuxiang; Yang, Tuo; Guo, Yanfei; Sun, Tieying

    2015-01-01

    Local renin-angiotensin system (RAS) activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been reported that angiotensin-converting enzyme 2 (ACE2) could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC) staining and western blot (WB) testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA) and pulmonary surfactant-associated protein A (SP-A) IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-β1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-β1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF. © 2015 S. Karger AG, Basel.

  5. 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

  6. 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...

  7. Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-α, and MAP kinase signaling

    Science.gov (United States)

    Wei, Shun-Guang; Zhang, Zhi-Hua; Yu, Yang

    2014-01-01

    The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptors are expressed by neurons and glial cells in cardiovascular autonomic regions of the brain, including the hypothalamic paraventricular nucleus (PVN), and contribute to neurohumoral excitation in rats with ischemia-induced heart failure. The present study examined factors regulating the expression of SDF-1 in the PVN and mechanisms mediating its sympatho-excitatory effects. In urethane anesthetized rats, a 4-h intracerebroventricular (ICV) infusion of angiotensin II (ANG II) or tumor necrosis factor-α (TNF-α) in doses that increase mean blood pressure (MBP) and sympathetic drive increased the expression of SDF-1 in PVN. ICV administration of SDF-1 increased the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), JNK, and p38 MAPK in PVN, along with MBP, heart rate (HR), and renal sympathetic nerve activity (RSNA), but did not affect total p44/42 MAPK, JNK, and p38 MAPK levels. ICV pretreatment with the selective p44/42 MAPK inhibitor PD98059 prevented the SDF-1-induced increases in MBP, HR, and RSNA; ICV pretreatment with the selective JNK and p38 MAPK inhibitors attenuated but did not block these SDF-1-induced excitatory responses. ICV PD98059 also prevented the sympatho-excitatory response to bilateral PVN microinjections of SDF-1. ICV pretreatment with SDF-1 short-hairpin RNA significantly reduced ANG II- and TNF-α-induced phosphorylation of p44/42 MAPK in PVN. These findings identify TNF-α and ANG II as drivers of SDF-1 expression in PVN and suggest that the full expression of their cardiovascular and sympathetic effects depends upon SDF-1-mediated activation of p44/42 MAPK signaling. PMID:25260613

  8. 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.

  9. Relative Atrial Natriuretic Peptide Deficiency and Inadequate Renin and Angiotensin II Suppression in Obese Hypertensive Men

    DEFF Research Database (Denmark)

    Asferg, Camilla L; Nielsen, Søren J; Andersen, Ulrik B

    2013-01-01

    Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese ...... hypertensive men (obeseHT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure,......Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese...

  10. General approaches to structure-activity relationships illustrated by recent data on angiotensin II

    International Nuclear Information System (INIS)

    Fromageot, P.; Fermandjian, S.; Greff, D.; Meyer, P.

    1975-01-01

    Molecular conformations of angiotensin in trifluoroethanol and hexafluoroisopropanol solutions were studied by circular dichroism. The molecule is organized by intramolecular forces, which implies doubling-up of the molecule onto itself. Hence the definition cross-beta proposed for this model. Examination of the peptide fragments of the hormone shows that those belonging to the C-terminal series play a capital part in the establishment of the beta conformation of angiotensin. The ratio of the intramolecular forces varies with any disturbance of the medium, leading to conformational changes. Increasing the polarity of the solvent, and/or its acidity modifies the balance of forces. The C-terminal fragments of the molecule is that containing the functional groups essential to the biological activity [fr