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Sample records for decreased angiotensin ii

  1. ACE2 Decreases Formation and Severity of Angiotensin II-induced Abdominal Aortic Aneurysms

    PubMed Central

    Thatcher, Sean E.; Zhang, Xuan; Howatt, Deborah A.; Yiannikouris, Frederique; Gurley, Susan B.; Ennis, Terri; Curci, John A.; Daugherty, Alan; Cassis, Lisa A.

    2014-01-01

    Objective Angiotensin converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, while ACE2 activation suppresses aneurysm formation. Approach and Results ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Since ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined if ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazine aceturate (DIZE, 30 mg/kg/day) to Ldlr−/− mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of DIZE significantly reduced total sera cholesterol and VLDL-cholesterol concentrations. Notably, DIZE significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73 to 29%). None of these effects of DIZE were observed in the Ace2−/y mice. Conclusions These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system. PMID:25301841

  2. Lead exposure, begun in utero, decreases renin and angiotensin II in adult rats

    SciTech Connect

    Victery, W.; Vander, A.J.; Markel, H.; Katzman, L.; Shulak, J.M.; Germain, C.

    1982-05-01

    Male rats were exposed continously to Pb in utero and after birth by giving their mothers, during pregnancy and lactation, drinking water containing 0, 5, or 25 ppm Pb (as Pb acetate) and then continuing this regimen after weaning for approximately 5 months. At the time of sacrifice (5 months) the 5- and 25-ppm groups had mean blood Pb concentrations of 5.6 and 18.2 ..mu..g/dl, respectively. No differences in systolic blood pressure occurred between groups. Rats exposed to 25 ppm manifested a significant decrease in basal plasma renin activity (PRA) but a significant increase in PRA during stimulation of renin release by acute volume depletion. In this latter state, the ratio of angiotensin II to PRA was significantly reduced in the 25-ppm group. Groups exposed to 5 and 25 ppm both had significant decreases in renal renin concentration. We conclude that chronic exposure of rats to doses of Pb which produce blood Pb concentrations similar to those generally present in urban human populations does not induce hypertension but does inhibit renin synthesis and release, as well as reducing plasma angiotension II concentration at any given PRA, either by inhibiting conversion of AI to AII or by enhancing AII catabolism.

  3. Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum.

    PubMed

    Mertens, Birgit; Vanderheyden, Patrick; Michotte, Yvette; Sarre, Sophie

    2010-06-01

    A relationship between the central renin angiotensin system and the dopaminergic system has been described in the striatum. However, the role of the angiotensin II type 2 (AT(2)) receptor in this interaction has not yet been established. The present study examined the outcome of direct AT(2) receptor stimulation on dopamine (DA) release and synthesis by means of the recently developed nonpeptide AT(2) receptor agonist, compound 21 (C21). The effects of AT(2) receptor agonism on the release of DA and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine biosynthesis, were investigated using in vivo microdialysis. Local administration of C21 (0.1 and 1 microM) resulted in a decrease of the extracellular DOPAC levels, whereas extracellular DA concentrations remained unaltered, suggesting a reduced synthesis of DA. This effect was mediated by the AT(2) receptor since it could be blocked by the AT(2) receptor antagonist PD123319 (1 microM). A similar effect was observed after local striatal (10 nM) as well as systemic (0.3 and 3 mg/kg i.p.) administration of the AT(1) receptor antagonist, candesartan. TH activity as assessed by accumulation of extracellular levels of L-DOPA after inhibition of amino acid decarboxylase with NSD1015, was also reduced after local administration of C21 (0.1 and 1 microM) and candesartan (10 nM). Together, these data suggest that AT(1) and AT(2) receptors in the striatum exert an opposite effect on the modulation of DA synthesis rather than DA release. PMID:20097214

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

    SciTech Connect

    Zhao, Zhuo; Wang, Hao; Lin, Marina; Groban, Leanne

    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.

  5. Alkaloids of Nitraria sibirica Pall. decrease hypertension and albuminuria in angiotensin II-salt hypertension.

    PubMed

    Bakri, Mahinur; Yi, Yang; Chen, Ling-Dan; Aisa, Haji Akber; Wang, Mong-Heng

    2014-04-01

    In traditional Chinese medicine, Nitraria sibirica Pall. (Nitrariaceae) is used to treat hypertension. This study determined the effects of the total alkaloids of the leaves of Nitraria sibirica (NSTA) on blood pressure and albuminuria in mice treated with angiotensin II and a high-salt diet (ANG/HS). Adult mice were divided into three groups: control; infused with angiotensin II and fed a diet containing 4% NaCl (ANG/HS; and ANG/HS plus injection of NSTA (1 mg·kg(-1)·d(-1), i.p.). After treatment of these regimens, daily water and food intake, kidney weight, blood pressure, urinary albumin excretion, renal concentrations of inflammatory markers, including soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1), and the expression of renal fibrosis markers were determined. Compared to the control group, the ANG/HS group had higher blood pressure and urinary albumin excretion. Treatment with NSTA in ANG/HS mice for three weeks significantly reduced blood pressure and urinary albumin excretion. ANG/HS treatment caused elevated levels of sICAM-1 and MCP-1, as well as increased fibrosis markers. Concurrent treatment with ANG/HS and NSTA attenuated the levels and expression of renal inflammatory and fibrosis markers. Treatment with NSTA effectively reduces hypertension-induced albuminuria through the reduction of renal inflammatory and fibrosis markers. PMID:24863351

  6. Angiotensin II receptor blockers decrease serum concentration of fatty acid-binding protein 4 in patients with hypertension.

    PubMed

    Furuhashi, Masato; Mita, Tomohiro; Moniwa, Norihito; Hoshina, Kyoko; Ishimura, Shutaro; Fuseya, Takahiro; Watanabe, Yuki; Yoshida, Hideaki; Shimamoto, Kazuaki; Miura, Tetsuji

    2015-04-01

    Elevated circulating fatty acid-binding protein 4 (FABP4/A-FABP/aP2), an adipokine, is associated with obesity, insulin resistance, hypertension and cardiovascular events. However, how circulating FABP4 level is modified by pharmacological agents remains unclear. We here examined the effects of angiotensin II receptor blockers (ARBs) on serum FABP4 level. First, essential hypertensives were treated with ARBs: candesartan (8 mg day(-1); n=7) for 2 weeks, olmesartan (20 mg day(-1); n=9) for 12 weeks, and valsartan (80 mg day(-1); n=94) or telmisartan (40 mg day(-1); n=91) for 8 weeks added to amlodipine (5 mg day(-1)). Treatment with ARBs significantly decreased blood pressure and serum FABP4 concentrations by 8-20% without significant changes in adiposity or lipid variables, though the M value determined by hyperinsulinemic-euglycemic glucose clamp, a sensitive index of insulin sensitivity, was significantly increased by candesartan. Next, alterations in FABP4 secretion from 3T3-L1 adipocytes were examined under several agents. Lipolytic stimulation of the β-adrenoceptor in 3T3-L1 adipocytes by isoproterenol increased FABP4 secretion, and conversely, insulin suppressed FABP4 secretion. However, treatment of 3T3-L1 adipocytes with angiotensin II or ARBs for 2 h had no effect on gene expression or secretion of FABP4 regardless of β-adrenoceptor stimulation. In conclusion, treatment with structurally different ARBs similarly decreases circulating FABP4 concentrations in hypertensive patients as a class effect of ARBs, which is not attributable to blockade of the angiotensin II receptor in adipocytes. Reduction of FABP4 levels by ARBs might be involved in suppression of cardiovascular events. PMID:25672659

  7. Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II.

    PubMed

    Patel, Dhara; Alhawaj, Raed; Kelly, Melissa R; Accarino, John J O; Lakhkar, Anand; Gupte, Sachin A; Sun, Dong; Wolin, Michael S

    2016-06-01

    Oxidation of the soluble guanylate cyclase (sGC) heme promotes loss of regulation by nitric oxide (NO) and depletion of sGC. We hypothesized that angiotensin II (ANG II) stimulation of mitochondrial superoxide by its type 1 receptor could function as a potential inhibitor of heme biosynthesis by ferrochelatase, and this could decrease vascular responsiveness to NO by depleting sGC. These processes were investigated in a 24-h organoid culture model of bovine coronary arteries (BCA) with 0.1 μM ANG II. Treatment of BCA with ANG II increased mitochondrial superoxide, depleted mitochondrial superoxide dismutase (SOD2), ferrochelatase, and cytochrome oxidase subunit 4, and sGC, associated with impairment of relaxation to NO. These processes were attenuated by organoid culture with 8-bromo-cGMP and/or δ-aminolevulinic acid (a stimulator of sGC by protoporphyrin IX generation and heme biosynthesis). Organoid culture with Mito-TEMPOL, a scavenger of mitochondrial matrix superoxide, also attenuated ANG II-elicited ferrochelatase depletion and loss of relaxation to NO, whereas organoid culture with Tempol, an extramitochondrial scavenger of superoxide, attenuated the loss of relaxation to NO by ANG II, but not ferrochelatase depletion, suggesting cytosolic superoxide could be an initiating factor in the loss of sGC regulation by NO. The depletion of cytochrome oxidase subunit 4 and sGC (but not catalase) suggests that sGC expression may be very sensitive to depletion of heme caused by ANG II disrupting ferrochelatase activity by increasing mitochondrial superoxide. In addition, cGMP-dependent activation of protein kinase G appears to attenuate these ANG II-stimulated processes through both preventing SOD2 depletion and increases in mitochondrial and extramitochondrial superoxide. PMID:27037373

  8. Angiotensin II receptor heterogeneity

    SciTech Connect

    Herblin, W.F.; Chiu, A.T.; McCall, D.E.; Ardecky, R.J.; Carini, D.J.; Duncia, J.V.; Pease, L.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L. )

    1991-04-01

    The possibility of receptor heterogeneity in the angiotensin II (AII) system has been suggested previously, based on differences in Kd values or sensitivity to thiol reagents. One of the authors earliest indications was the frequent observation of incomplete inhibition of the binding of AII to adrenal cortical membranes. Autoradiographic studies demonstrated that all of the labeling of the rat adrenal was blocked by unlabeled AII or saralasin, but not by DuP 753. The predominant receptor in the rat adrenal cortex (80%) is sensitive to dithiothreitol (DTT) and DuP 753, and is designated AII-1. The residual sites in the adrenal cortex and almost all of the sites in the rat adrenal medulla are insensitive to both DTT and DuP 753, but were blocked by EXP655. These sites have been confirmed by ligand binding studies and are designated AII-2. The rabbit adrenal cortex is unique in yielding a nonuniform distribution of AII-2 sites around the outer layer of glomerulosa cells. In the rabbit kidney, the sites on the glomeruli are AII-1, but the sites on the kidney capsule are AII-2. Angiotensin III appears to have a higher affinity for AII-2 sites since it inhibits the binding to the rabbit kidney capsule but not the glomeruli. Elucidation of the distribution and function of these diverse sites should permit the development of more selective and specific therapeutic strategies.

  9. Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma

    PubMed Central

    Arrieta, O; Guevara, P; Escobar, E; García-Navarrete, R; Pineda, B; Sotelo, J

    2005-01-01

    Angiotensin II (Ang II) is a main effector peptide in the renin–angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT1 receptor of angiotensin inhibites tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT1 receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg−1 to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of cultured C6 cells which decreased by the administration of losartan. Our results suggest that the selective blockage of AT1 diminishes tumoral growth through inhibition of growth factors and promotion of apoptosis. PMID:15785746

  10. Dietary peptides from the non-digestible fraction of Phaseolus vulgaris L. decrease angiotensin II-dependent proliferation in HCT116 human colorectal cancer cells through the blockade of the renin-angiotensin system.

    PubMed

    Luna-Vital, Diego A; Liang, Katie; González de Mejía, Elvira; Loarca-Piña, Guadalupe

    2016-05-18

    This study aimed to determine the ability of peptides present in the non-digestible fraction (NDF) of common beans to decrease angiotensin II (AngII) through the blockade of RAS and its effect on the proliferation of HCT116 human colorectal cancer cells. Pure synthesized peptides GLTSK and GEGSGA and the peptide fractions (PF) of cultivars Azufrado Higuera and Bayo Madero were used. The cells were pretreated with pure peptides, PF or AGT at their IC50 or IC25 values, in comparison with the simultaneous treatment of peptides and AGT. For western blot and microscopy analysis, 100 μM and 0.5 mg mL(-1) were used for pure peptides and PF treatments, respectively. According to the ELISA tests, GLTSK and GEGSGA decreased (p < 0.05) the conversion rate of AGT to angiotensin I (AngI) by 38 and 28%, respectively. All the peptides tested reduced (p < 0.05) the conversion rate of AngI to AngII from 38 to 50%. When the cells were pretreated with both pure peptides and PF before exposure to AGT, the effectiveness inhibiting cell proliferation was higher than the simultaneous treatment suggesting their preventive effects. GLTSK and GEGSGA interacted with the catalytic site of renin, the angiotensin-I converting enzyme, and the AngII receptor, mainly through hydrogen bonds, polar, hydrophobic and cation-π interactions according to molecular docking. Through confocal microscopy, it was determined that GLTSK and GEGSGA caused the decrease (p < 0.05) of AngII-dependent STAT3 nuclear activation in HCT116 cells by 66 and 23%, respectively. The results suggest that peptides present in the common bean NDF could potentially ameliorate the effects of RAS overexpression in colorectal cancer. PMID:27156533

  11. Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins

    PubMed Central

    Chen, Yi-Jen; Chen, Yao-Chang; Tai, Ching-Tai; Yeh, Hung-I; Lin, Cheng-I; Chen, Shih-Ann

    2005-01-01

    Angiotensin II receptor blockers (AIIRBs) have been shown to prevent atrial fibrillation. The pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The aim of this study was to evaluate whether angiotensin II or AIIRB may change the arrhythmogenic activity of the PVs. Conventional microelectrodes and whole-cell patch clamps were used to investigate the action potentials (APs) and ionic currents in isolated rabbit PV tissue and single cardiomyocytes before and after administering angiotensin II or losartan (AIIRB). In the tissue preparations, angiotensin II induced delayed after-depolarizations (1, 10, and 100 nM) and accelerated the automatic rhythm (10 and 100 nM). Angiotensin II (100 nM) prolonged the AP duration and increased the contractile force (10 and 100 nM). Losartan (1 and 10 μM) inhibited the automatic rhythm. Losartan (10 μM) prolonged the AP duration and reduced the contractile force (1 and 10 μM). Angiotensin II reduced the transient outward potassium current (Ito) but increased the L-type calcium, delayed rectifier potassium (IK), transient inward (Iti), pacemaker, and Na+–Ca2+ exchanger (NCX) currents in the PV cardiomyocytes. Losartan decreased the Ito, IK, Iti, and NCX currents. In conclusion, angiotensin II and AIIRB modulate the PV electrical activity, which may play a role in the pathophysiology of atrial fibrillation. PMID:16273119

  12. Angiotensin II receptors in testes

    SciTech Connect

    Millan, M.A.; Aguilera, G.

    1988-05-01

    Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled (Sar1,Ile8)AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration of 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.

  13. Angiotensin II Type 2 Receptor Decreases Transforming Growth Factor-β Type II Receptor Expression and Function in Human Renal Proximal Tubule Cells

    PubMed Central

    Guo, Hui-Lin; Liao, Xiao-Hui; Liu, Qi; Zhang, Ling

    2016-01-01

    Transforming growth factor-β (TGF-β), via its receptors, induces epithelial-mesenchymal transition (EMT) and plays an important role in the development of renal tubulointersitial fibrosis. Angiotensin II type 2 receptor (AT2R), which mediates beneficial renal physiological functions, has received attention as a prospective therapeutic target for renoprotection. In this study, we investigated the effect and underlying mechanism of AT2R on the TGF-β receptor II (TGF-βRII) expression and function in human proximal tubular cells (HK-2). Here, we show that the AT2R agonist CGP42112A decreased TGF-βRII protein expression in a concentration- and time-dependent manner in HK-2 cells. The inhibitory effect of the AT2R on TGF-βRII expression was blocked by the AT2R antagonists PD123319 or PD123177. Stimulation with TGF-β1 enhanced EMT in HK-2 cells, which was prevented by pre-treatment with CGP42112A. One of mechanisms in this regulation is associated with the increased TGF-βRII degradation after activation of AT2R. Furthermore, laser confocal immunofluorescence microscopy showed that AT2R and TGF-βRII colocalized in HK-2 cells. AT2R and TGF-βRII coimmunoprecipitated and this interaction was increased after AT2R agonist stimulation for 30 min. The inhibitory effect of the AT2R on TGF-βRII expression was also blocked by the nitric oxide synthase inhibitor L-NAME, indicating that nitric oxide is involved in the signaling pathway. Taken together, our study indicates that the renal AT2R regulates TGF-βRII expression and function via the nitric oxide pathway, which may be important in the control of renal tubulointerstitial fibrosis. PMID:26867007

  14. The mechanism of the decrease in cytosolic Ca2+ concentrations induced by angiotensin II in the high K(+)-depolarized rabbit femoral artery.

    PubMed

    Ushio-Fukai, M; Yamamoto, H; Nishimura, J; Hirano, K; Kanaide, H

    2000-02-01

    1. Using front-surface fluorometry of fura-2-loaded strips, and measuring the transmembrane 45Ca2+ fluxes of ring preparations of the rabbit femoral artery, the mechanism underlying a sustained decrease in the cytosolic Ca2+ concentration ([Ca2+]i) induced by angiotensin II (AT-II) was investigated. 2. The application of AT-II during steady-state 118 mM K(+)-induced contractions caused a sustained decrease in [Ca2+]i following a rapid and transient increase in [Ca2+]i, while the tension was transiently enhanced. 3. When the intracellular Ca2+ stores were depleted by thapsigargin, the initial rapid and transient increase in [Ca2+]i was abolished, however, neither the sustained decrease in [Ca2+]i nor the enhancement of tension were affected. 4. Depolarization with 118 mM K+ physiological salt solution containing 1.25 mM Ba2+ induced a sustained increase in both the cytosolic Ba2+ concentration ([Ba2+]i) level and tension. However, the application of 10(-6) M AT-II during sustained Ba(2+)-contractions was found to have no effect on [Ba2+]i, but it did enhance tension. 5. After thapsigargin treatment, AT-II neither decreased nor increased the enhanced Ca2+ efflux rate induced by 118 mM K(+)-depolarization, whereas AT-II did increase the enhanced 45Ca2+ influx and the 45Ca2+ net uptake induced by 118 mM K(+)-depolarization. 6. Pretreatment with calphostin-C, partially, but significantly inhibited the decrease in [Ca2+]i induced by AT-II. 7. These findings therefore suggest that AT-II stimulates Ca2+ sequestration into the thapsigargin-insensitive Ca2+ stores, and thus induces a decrease in [Ca2+]i in the high external K(+)-stimulated rabbit femoral artery. PMID:10711341

  15. Documentation of angiotensin II receptors in glomerular epithelial cells

    NASA Technical Reports Server (NTRS)

    Sharma, M.; Sharma, R.; Greene, A. S.; McCarthy, E. T.; Savin, V. J.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    Angiotensin II decreases glomerular filtration rate, renal plasma flow, and glomerular capillary hydraulic conductivity. Although angiotensin II receptors have been demonstrated in mesangial cells and proximal tubule cells, the presence of angiotensin II receptors in glomerular epithelial cells has not previously been shown. Previously, we have reported that angiotensin II caused an accumulation of cAMP and a reorganization of the actin cytoskeleton in cultured glomerular epithelial cells. Current studies were conducted to verify the presence of angiotensin II receptors by immunological and non-peptide receptor ligand binding techniques and to ascertain the activation of intracellular signal transduction in glomerular epithelial cells in response to angiotensin II. Confluent monolayer cultures of glomerular epithelial cells were incubated with angiotensin II, with or without losartan and/or PD-123,319 in the medium. Membrane vesicle preparations were obtained by homogenization of washed cells followed by centrifugation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membrane proteins followed by multiscreen immunoblotting was used to determine the presence of angiotensin II receptor type 1 (AT1) or type 2 (AT2). Angiotensin II-mediated signal transduction in glomerular epithelial cells was studied by measuring the levels of cAMP, using radioimmunoassay. Results obtained in these experiments showed the presence of both AT1 and AT2 receptor types in glomerular epithelial cells. Angiotensin II was found to cause an accumulation of cAMP in glomerular epithelial cells, which could be prevented only by simultaneous use of losartan and PD-123,319, antagonists for AT1 and AT2, respectively. The presence of both AT1 and AT2 receptors and an increase in cAMP indicate that glomerular epithelial cells respond to angiotensin II in a manner distinct from that of mesangial cells or proximal tubular epithelial cells. Our results suggest that glomerular epithelial

  16. Angiotensin II and gene expression in the kidney.

    PubMed

    Klahr, S; Morrissey, J

    1998-01-01

    Angiotensin II, a potent vasoconstrictor, has a key role in renal injury and in the progression of chronic renal disease of diverse causes. In vascular smooth muscle cells, angiotensin II modulates growth, which may lead to hypertrophy and also may inhibit mitogen-stimulated DNA synthesis. The effects of angiotensin II on responsive cells are mediated by two classes of receptors, AT-1 and AT-2. Information obtained in the last decade indicates that angiotensin II increases the production of several autocrine factors, including transforming growth factor beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), and platelet-derived growth factor A chain (PDGF). Angiotensin also increases the release of other growth factors such as endothelin, platelet-activating factor (PAF), and interleukin 6. In addition, it increases the "activity" of nuclear factor-kappaB (NF-kappaB) and the synthesis of angiotensinogen. The emerging picture indicates that the actions of angiotensin II may be related to factors that are released or upregulated by angiotensin II, possibly through NF-kappaB activation. It appears likely that many of the effects of angiotensin II on renal disease may be mediated by TGF-beta1, TNF-alpha, and changes in the activity of NF-kappaB. The use of ACE inhibitors or antagonists of AT-1 or AT-2 receptors in experimental animals decreases the levels of angiotensin II or limits its action, thereby interfering with the production and effects of the factors described. PMID:9428470

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

    PubMed Central

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

    2012-01-01

    Abstract Connective tissue growth factor (CTGF/CCN-2) is mainly involved in the induction of extracellular matrix (ECM) proteins. The levels of CTGF correlate with the degree and severity of fibrosis in many tissues, including dystrophic skeletal muscle. The CTGF overexpression in tibialis anterior skeletal muscle using an adenoviral vector reproduced many of the features observed in dystrophic muscles including muscle damage and regeneration, fibrotic response and decrease in the skeletal muscle strength. The renin–angiotensin system is involved in the genesis and progression of fibrotic diseases through its main fibrotic components angiotensin-II and its transducer receptor AT-1. The use of AT-1 receptor blockers (ARB) has been shown to decrease fibrosis. In this paper, we show the effect of AT-1 receptor blockade on CTGF-dependent biological activity in skeletal muscle cells as well as the response to CTGF overexpression in normal skeletal muscle. Our results show that in myoblasts ARB decreased CTGF-mediated increase of ECM protein levels, extracellular signal regulated kinases 1/2 (ERK-1/2) phosphorylation and stress fibres formation. In tibialis anterior muscle overexpressing CTGF using an adenovirus, ARB treatment decreased CTGF-mediated increase of ECM molecules, α-SMA and ERK-1/2 phosphorylation levels. Quite remarkable, ARB was able to prevent the loss of contractile force of tibialis anterior muscles overexpressing CTGF. Finally, we show that ARB decreased the levels of fibrotic proteins, CTGF and ERK-1/2 phosphorylation augmented in a dystrophic skeletal muscle from mdx mice. We propose that ARB is a novel pharmacological tool that can be used to decrease the fibrosis induced by CTGF in skeletal muscle associated with muscular dystrophies. PMID:21645240

  18. Upregulation of ERK1/2-eNOS via AT2 Receptors Decreases the Contractile Response to Angiotensin II in Resistance Mesenteric Arteries from Obese Rats

    PubMed Central

    Hagihara, Graziela N.; Lobato, Nubia S.; Filgueira, Fernando P.; Akamine, Eliana H.; Aragão, Danielle S.; Casarini, Dulce E.; Carvalho, Maria Helena C.; Fortes, Zuleica B.

    2014-01-01

    It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats. PMID:25170617

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

    PubMed

    Hagihara, Graziela N; Lobato, Nubia S; Filgueira, Fernando P; Akamine, Eliana H; Aragão, Danielle S; Casarini, Dulce E; Carvalho, Maria Helena C; Fortes, Zuleica B

    2014-01-01

    It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats. PMID:25170617

  20. N- and C-terminal structure-activity study of angiotensin II on the angiotensin AT2 receptor.

    PubMed

    Bouley, R; Pérodin, J; Plante, H; Rihakova, L; Bernier, S G; Maletínská, L; Guillemette, G; Escher, E

    1998-02-19

    ]angiotensin II. Aliphatic residues, especially those of reduced size, caused a significant decrease in affinity especially [Sarcosine1, Gly8]angiotensin II who showed a 30-fold decrease. Introduction of a positive charge (Lys) at position 8 reduced the affinity even further. Stereoisomers in position 8 (L-->D configuration) also induced lower affinities. The angiotensin AT2 receptor display a structure-activity relationship similar to that observed on the AT1 receptor for the C-terminal position of the peptide hormone. Position 1 structure-activity relationships are however fundamentally different between the angiotensin AT1 and AT2 receptor. PMID:9570482

  1. Aldosterone response to angiotensin II during hypoxemia

    SciTech Connect

    Colice, G.L.; Ramirez, G.

    1986-07-01

    Exercise stimulates the renin-angiotensin-aldosterone system (RAAS). However, increases in plasma aldosterone concentrations (PAC) are suppressed when exercise is performed at high altitude or under hypoxemic conditions. As the angiotensin-II response to high-altitude exercise is normal, it is speculated that an inhibitor, discharged during hypoxemia, acted to suppress angiotensin-II-mediated aldosterone release. A study was conducted to test this hypothesis, taking into account the measurement of the aldosterone response to exogenous angiotensin II during normoxemia and hypoxemia. It was found that the dose-response curve of PAC to angiotensin II was not significantly inhibited by the considered model of hypoxemia. The hypoxemia-mediated release of an angiotensin II inhibitor does, therefore, not explain the previous observations of PAC suppression during hypoxemic exercise. 28 references.

  2. Sanguinarine inhibits angiotensin II-induced apoptosis in H9c2 cardiac cells via restoring reactive oxygen species-mediated decreases in the mitochondrial membrane potential

    PubMed Central

    LIU, YUAN; JIAO, RONG; MA, ZHEN-GUO; LIU, WEI; WU, QING-QING; YANG, ZHENG; LI, FANG-FANG; YUAN, YUAN; BIAN, ZHOU-YAN; TANG, QI-ZHU

    2015-01-01

    Cell apoptosis induced by Angiotensin II (Ang II) has a critical role in the development of cardiovascular diseases. The aim of the present study was to investigate whether sanguinarine (SAN), a drug which was proved to have anti-oxidant, anti-proliferative and immune enhancing effects, can abolish cell apoptosis induced by Ang II. In the present study, H9c2 cardiac cells were stimulated with 10 µM Ang II with or without SAN. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydrofluorescein diacetate, and changes of the mitochondrial membrane potential (MMP) were assessed using JC-1 staining. Furthermore, mRNA expression of NOX2 was determined by reverse transcription quantitative polymerase chain reaction, and apoptosis was detected by Annexin V/propidium iodide staining and flow cytometry. The expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) as well as cleaved (c)-caspase 3 and -9 were detected by western blot analysis, and the activity of caspase 3 and -9 was detected using an ELISA. The results of the present study showed that NOX2 expression and ROS generation induced by Ang II were inhibited by SAN, and the Ang 2-induced MMP loss was also ameliorated. Furthermore, Ang II-induced H9c2 cardiac cell apoptosis as well as c-caspase 3 and -9 levels were significantly reduced by SAN. Investigation of the possible pathway involved in the anti-apoptotic effect of SAN showed that the expression of Bcl-2 was decreased, while that of Bax was increased following stimulation with Ang II, which was reversed following treatment with SAN. In addition, Ang II enhanced the activity of caspase 9 and cleaved downstream caspases such as caspase-3, initiating the caspase cascade, while pre-treatment of H9c2 cardiac cells with SAN blocked these effects. In conclusion, the findings of the present study indicated that SAN inhibits the apoptosis of H9c2 cardiac cells induced by Ang II, most likely via restoring

  3. NADPH Oxidases and Angiotensin II Receptor Signaling

    PubMed Central

    Garrido, Abel Martin; Griendling, Kathy K.

    2010-01-01

    Over the last decade many studies have demonstrated the importance of reactive oxygen species (ROS) production by NADPH oxidases in angiotensin II (Ang II) signaling, as well as a role for ROS in the development of different diseases in which Ang II is a central component. In this review, we summarize the mechanism of activation of NADPH oxidases by Ang II and describe the molecular targets of ROS in Ang II signaling in the vasculature, kidney and brain. We also discuss the effects of genetic manipulation of NADPH oxidase function on the physiology and pathophysiology of the renin angiotensin system. PMID:19059306

  4. Glial high-affinity binding site with specificity for angiotensin II not angiotensin III: a possible N-terminal-specific converting enzyme

    SciTech Connect

    Printz, M.P.; Jennings, C.; Healy, D.P.; Kalter, V.

    1986-01-01

    Anomalous binding properties of angiotensin II to fetal rat brain primary cultures suggested a possible contribution from contaminating glia. To investigate this possibility, cultures of C6 glioma, a clonal rat cell line, were examined for the presence of angiotensin II receptors. A specific high-affinity site for (/sup 125/I)angiotensin II was measured both by traditional methodology using whole cells and by autoradiography. This site shared properties similar to that found with the brain cells, namely low ligand internalization and markedly decreased affinity for N-terminal sarcosine or arginine-angiotensin analogs. The competition rank order was angiotensin II much greater than (Sar1,Ile8)angiotensin II greater than or equal to des(Asp1,Arg2)angiotensin II. Angiotensin III did not compete for binding to the site. High-pressure liquid chromatography analysis indicated that the ligand either in the incubation or bound to the site was stable at 15 degrees C, but there was very rapid and extensive degradation by the C6 glioma cells at 37 degrees C. It is concluded that the site exhibits unusual N-terminal specificity for angiotensin with nanomolar affinity for angiotensin II. If angiotensin III is an active ligand in the brain, the site may have a converting enzyme function. Alternatively, it may form the des-Asp derivatives of angiotensin for subsequent degradation by other enzymatic pathways. Either way, it is proposed that the site may modulate the brain-angiotensin system.

  5. Angiotensin II reduces calcium uptake into bone.

    PubMed

    Schurman, Scott J; Bergstrom, William H; Shoemaker, Lawrence R; Welch, Thomas R

    2004-01-01

    Children with neonatal Bartter syndrome (NBS) have hypercalciuria, nephrocalcinosis, and osteopenia. A complex of basic-fibroblast growth factor (b-FGF) and a naturally occurring glycosaminoglycan has been identified in the serum and urine of NBS patients. This complex increases bone resorption in a bone disc bioassay system. Angiotensin II (AT II), which is increased in Bartter syndrome, increases the synthesis of b-FGF by cultured endothelial cells. Addition of 10(-8) M AT II to the bioassay, a concentration reported in Bartter syndrome patients, significantly decreased calcium uptake into bone discs [E/C 0.60 (0.04), P < 0.001 compared with buffer, normal E/C >0.90]. Adding b-FGF monoclonal antibody at 10 microg/ml [E/C 0.90 (0.06), P=NS] or indomethacin [E/C 1.00 (0.03), P=NS] to 10(-8 )M AT II neutralized this effect. In separate experiments, newborn rats were given intraperitoneal injections of AT II. Bone discs from these animals were used in the bioassay system and calcium uptake was markedly reduced compared with discs from rats injected with phosphate-buffered saline [AT II 6.6 x 10(-9), E/C 0.10 (0.04), P<0.001, AT II 3.3 x 10(-8), E/C 0.10 (0.05), P<0.001]. AT II decreases calcium uptake in the bone disc bioassay system. This effect can be abrogated by antibody to b-FGF or prostaglandin synthetase inhibition. These results support the hypothesis that in children with NBS, elevated levels of AT II stimulate local skeletal b-FGF synthesis, with a resultant increase in bone resorption via a prostaglandin-dependent pathway. PMID:14648327

  6. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures.

    PubMed

    Gowrisankar, Yugandhar V; Clark, Michelle A

    2016-07-01

    Angiotensin (Ang) II plays a critical role in cardiovascular and blood pressure regulation. Ang II is produced by angiotensin-converting enzyme (ACE) and it interacts with the Ang AT1 receptor to cause much of its well-known cardiovascular effects. Ang-(1-7) is another active peptide produced by the rennin-angiotensin system. This peptide is produced from Ang I or Ang II by the catalytic activity of ACE2. Ang-(1-7) interacts with the Mas receptor to counteract many of the effects of Ang II. Thus, the ACE2/Ang-(1-7)/Mas axis acts opposite of the ACE/Ang II/AT1 axis. In this study we investigated how Ang II regulates the key enzymes of these axes, ACE and its homolog ACE2, and determined whether they are dysregulated in the hypertensive condition. Brainstem and cerebellum astrocytes isolated from the spontaneously hypertensive rat (SHR) were used in these studies. Ang II effect on the enzymes' mRNA and protein levels was measured using quantitative PCR and western blotting techniques, respectively. Results from this study showed that Ang II up-regulated ACE protein levels, but down-regulated ACE mRNA levels in brainstem and cerebellum astrocytes in both models. Ang II also reduced ACE2 mRNA expression in SHR and Wistar astrocytes isolated from both brain regions. Ang II effects on ACE2 protein were biphasic. In SHR astrocytes, Ang II-mediated ACE2 protein initially increased then decreased at later time points. In contrast, in Wistar astrocytes, Ang II initially decreased ACE2 protein expression, but up-regulated the protein at later time points. The findings of these studies suggest that Ang II has a differential effect on ACE and ACE2 expression. Furthermore, in the SHR model there may be alteration in the ACE/ACE2 balance in a manner that favors increased Ang II generation and decreased Ang-(1-7) production contributing to the hypertensive phenotype observed in this model. The levels of angiotensin (Ang) II depend on the actions of angiotensin-converting enzyme

  7. Unexpected binding of an octapeptide to the angiotensin II receptor

    SciTech Connect

    Soffer, R.L.; Bandyopadhyay, S.; Rosenberg, E.; Hoeprich, P.; Teitelbaum, A.; Brunck, T.; Colby, C.B.; Gloff, C.

    1987-12-01

    An octapeptide, TBI-22 (Lys-Gly-Val-Tyr-Ile, His-Ala-Leu), inhibited binding of angiotensin II by a solubilized angiotensin receptor partially purified from rabbit liver. This inhibition appears to result from competition for binding to the same receptor. Radioiodinated TBI-22, like angiotensin II, bound to the solubilized receptor with an affinity such that the binding was inhibited 50% by unlabeled TBI-22 or angiotensin II at nanomolar concentrations. The binding reaction, like that for angiotensin II, required p-chloromercuriphenylsulfonic acid and was reversed in the presence of dithiothreitol. TBI-22 and angiotensin II share the sequence Val-Tyr-Ile-His; this tetrapeptide alone, however, did not inhibit binding of angiotensin II. Replacement of the tyrosine residue by aspartic acid in TBI-22 greatly reduced the ability of the peptide to compete with angiotensin II for binding, suggesting an important contribution of this residue to the configuration required for recognition by the receptor.

  8. Angiotensin II during Experimentally Simulated Central Hypovolemia

    PubMed Central

    Jensen, Theo Walther; Olsen, Niels Vidiendal

    2016-01-01

    Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, such as the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory, and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use 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 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 PubMed/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 support the possible organ-protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue. PMID:26973842

  9. Identification of the angiotensin II receptor in rat mesenteric artery.

    PubMed Central

    McQueen, J; Murray, G D; Semple, P F

    1984-01-01

    Specific binding sites of high affinity and low capacity for 125I-angiotensin II have been identified in a membrane fraction derived from arterial arcades of the rat mesentery. Heterogeneity of binding sites and extensive tracer degradation necessitated the use of nonlinear regression methods for the analysis of radioligand binding data. Forward and reverse rate constants for the high affinity sites obtained by three experimental approaches were in good agreement and gave a dissociation equilibrium constant (Kd) of 19-74 pM (95% confidence interval). Affinities for a number of angiotensin-related peptides calculated from competitive binding curves were in the order 125I-angiotensin II = angiotensin II greater than angiotensin III greater than [Sar1,Ile8]angiotensin II greater than [Sar1,Gly8]angiotensin II. Angiotensin I and biochemically unrelated peptides had virtually no effect on binding of tracer angiotensin II. The divalent cations Mn2+, Mg2+ and Ca2+ stimulated 125I-angiotensin II binding at concentrations of 2-10 mM, as did Na+ at 50-100 mM. In the presence of Na+ or Li+, K+ had a biphasic effect. The chelating agents EDTA and EGTA were inhibitory, as were the thiol reagents dithiothreitol and cysteine. This study defined angiotensin II binding sites in a vascular target tissue of sufficiently high affinity to interact rapidly with plasma angiotensin II at physiological concentrations. PMID:6095806

  10. Lack of protein kinase C-α leads to impaired urine concentrating ability and decreased aquaporin-2 in angiotensin II-induced hypertension.

    PubMed

    Thai, Tiffany L; Blount, Mitsi A; Klein, Janet D; Sands, Jeff M

    2012-07-01

    Regulation of water and urea transport in the inner medullary collecting duct is essential for urine concentration. Aquaporin (AQP)2 water channels and urea transporter (UT)-A1 are inserted into the apical membrane upon phosphorylation of the channels to allow the transcellular movement of water and urea. Since ANG II activates PKC in many cell types, we tested the hypothesis that ANG II-induced regulation of water and urea transport is mediated by PKC. Osmotic minipumps delivered ANG II to wild-type (WT) or PKC-α(-/-) mice for 7 days. Inner medullas were harvested, and protein abundance was determined by immunoblot. ANG II increased systolic blood pressure to a similar degree in WT and PKC-α(-/-) mice. ANG II had no effect on the urine output of WT mice but increased that of PKC-α(-/-) mice. In accordance with observed differences in urine output, AQP2 abundance was unchanged in ANG II-treated WT animals but was decreased in PKC-α(-/-) mice. No change in membrane accumulation was seen. Phosphorylation of the cAMP-induced transcription factor CREB was decreased in PKC-α(-/-) mice in response to ANG II with no change in overall CREB abundance. ANG II did not alter the abundance of UT-A1 protein in WT or PKC-α(-/-) mice. Phosphorylation and overall abundance of tonicity-responsive enhancer-binding protein, a transcription factor that regulates UT-A1, were also unaltered by ANG II in either group. We conclude that PKC-α protects against ANG II-induced decreases in urine concentrating ability by maintaining AQP2 levels through CREB phosphorylation. PMID:22492943

  11. Angiotensin II receptors in the gonads

    SciTech Connect

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

    1989-05-01

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

  12. Baicalin attenuates angiotensin II-induced endothelial dysfunction.

    PubMed

    Wei, Xiling; Zhu, Xingyu; Hu, Nan; Zhang, Xiuqin; Sun, Tianjiao; Xu, Jiyang; Bian, Xiaohong

    2015-09-11

    Angiotensin II (Ang II) has been shown to activate multiple downstream pathways resulting in endothelial dysfunction and oxidative stress. Baicalin, a natural flavone, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. In the present study, we hypothesized that baicalin has beneficial effects in Ang II-induced endothelial cells injury. Here, we shown that baicalin improved endothelial fuction impaired by Ang II through promoting endothelial-dependent vasodilation and suppressing the apoptosis of HUVECs in which baicalin decreased the expression of bax and cleaved caspase-3, and increased bcl-2 expression. Additionally, baicalin significantly conversed Ang II to angiotensin-1-7 [Ang-(1-7)] by activating angiotensin-converting enzyme 2 (ACE2) and Mas receptor mRNA expression and protein expression. Moreover, treatment with baicalin significantly reduced cell oxidative damage induced by Ang II through MDA/ROS decrease and NO/T-AOC increase. This antioxidant capacity was related to the increases of PI3K, phosphor-AKT (Ser-473) and phosphor-eNOS (Ser-1177). In conclusion, our results implicate that baicalin could protect endothelial cells from Ang II-induced endothelial dysfunction and oxidative stress via modulating the expression of bax, bcl-2 and cleaved caspase-3, activating ACE2/Ang-(1-7)/Mas axis and up-regulating PI3K/AKT/eNOS pathway. PMID:26239661

  13. Pre-transplant angiotensin II type 1receptor antibodies: a risk factor for decreased kidney graft function in the early post-transplant period?

    PubMed

    Hernández-Méndez, Erick Alejandro; Arreola-Guerra, José Manuel; Morales-Buenrostro, Luis E; Ramírez, Julia B; Calleja, Said; Castelán, Natalia; Salcedo, Isaac; Vilatobá, Mario; Contreras, Alan G; Gabilondo, Bernardo; Granados, Julio; Alberú, Josefina

    2014-01-01

    Angiotensin II type 1 receptor antibodies (AT1Rab) are associated to a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and BPAR during the 1st year post-transplant (PT) in adult kidney transplant recipients (KTR), between 03/2009 and 08/2012. Pre-KT sera were screened for AT1Rab (ELISA) and HLA-DSA (Luminex). Three groups were analyzed: AT1Rab only (n = 13); HLA-DSA only (n = 8); and no AT1Rab or HLA-DSA (n = 90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. KTR with AT1Rab had a lower mean eGFR (20 mL/min/1.73m2) when compared to KTR with no Abs at 12 months. The significant difference in eGFR was observed since the 1st month PT. Multivariate analysis showed 4 factors independently and significantly associated with eGFR at 12mos PT: BPAR (-18.7 95%, CI -28.2 to -9.26, p<0.001), AT1Rab (-10.51, CI -20.9 to -0.095, p = 0.048), donor age (-0.42, CI -0.75 to -0.103 p = 0.010), and recipient age (-0.36, CI -0.67 to -0.048, p = 0.024). In this study AT1Rab in pre-transplant sera from KTR, was an independent and significant risk factor contributing to a lower eGFR 12 months. PT. This finding deserves to be confirmed in a larger KTR population. PMID:25695237

  14. Oxidative DNA Damage in Kidneys and Heart of Hypertensive Mice Is Prevented by Blocking Angiotensin II and Aldosterone Receptors

    PubMed Central

    Brand, Susanne; Amann, Kerstin; Mandel, Philipp; Zimnol, Anna; Schupp, Nicole

    2014-01-01

    Introduction Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied. Methods In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis. Results Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone. Conclusion Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore

  15. Angiotensin II promotes endometrial cancer cell survival.

    PubMed

    Nowakowska, Magdalena; Matysiak-Burzyńska, Zuzanna; Kowalska, Karolina; Płuciennik, Elżbieta; Domińska, Kamila; Piastowska-Ciesielska, Agnieszka W

    2016-08-01

    Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation. PMID:27349856

  16. Knocking out Angiotensin II in the Heart

    PubMed Central

    Zablocki, Daniela; Sadoshima, Junichi

    2011-01-01

    Despite ongoing medical advances, cardiovascular disease continues to be a leading health concern. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular function, and is, therefore, the subject of extensive study. Several of the drugs currently used to treat hypertension and heart failure are designed to target Ang II synthesis and function, but none have been able to completely block the effects of RAS signaling thus far. This review discusses current and emerging approaches towards inhibiting cardiac RAS function in order to further improve cardiovascular disease outcomes. PMID:21234717

  17. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

    PubMed Central

    Chhabra, Kavaljit H.; Xia, Huijing; Pedersen, Kim Brint; Speth, Robert C.

    2013-01-01

    An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7–8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS. PMID:23462816

  18. Gender differences in response to acute and chronic angiotensin II infusion: a translational approach

    PubMed Central

    Toering, Tsjitske J; van der Graaf, Anne Marijn; Visser, Folkert W; Buikema, Hendrik; Navis, Gerjan; Faas, Marijke M; Lely, A Titia

    2015-01-01

    Women with renal disease progress at a slower rate to end stage renal disease than men. As angiotensin II has both hemodynamic and direct renal effects, we hypothesized that the female protection may result from gender differences in responses to angiotensin II. Therefore, we studied gender differences in response to angiotensin II, during acute (human) and chronic (rats) angiotensin II administration. In young healthy men (n = 18) and women (n = 18) we studied the responses of renal hemodynamics (125I-iothalamate and 131I-Hippuran) and blood pressure to graded angiotensin II infusion (0.3, 1.0, and 3.0 ng/kg/min for 1 h). Men had increased responses of diastolic blood pressure (P = 0.01), mean arterial pressure (P = 0.05), and a more pronounced decrease in effective renal plasma flow (P = 0.009) than women. We measured the changes in proteinuria and blood pressure in response to chronic administration (200 ng/kg/min for 3 weeks) of angiotensin II in rats. Male rats had an increased response of proteinuria compared with females (GEE analysis, P = 0.001). Male, but not female, angiotensin II-treated rats had increased numbers of renal interstitial macrophages compared to sham-treated rats (P < 0.001). In conclusion, gender differences are present in the response to acute and chronic infusion of angiotensin II. Difference in angiotensin II sensitivity could play a role in gender differences in progression of renal disease. PMID:26149279

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

    SciTech Connect

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

    1986-11-01

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

  20. Identification of angiotensin II receptor subtypes

    SciTech Connect

    Chiu, A.T.; Herblin, W.F.; McCall, D.E.; Ardecky, R.J.; Carini, D.J.; Duncia, J.V.; Pease, L.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; )

    1989-11-30

    We have demonstrated the existence of two distinct subtypes of the angiotensin II receptor in the rat adrenal gland using radioligand binding and tissue section autoradiography. The identification of the subtypes was made possible by the discovery of two structurally dissimilar, nonpeptide compounds, DuP 753 and EXP655, that show reciprocal selectivity for the two subtypes. In the rat adrenal cortex, DuP 753 inhibited 80% of the total AII binding with an IC50 value on the sensitive sites of 2 x 10(-8) M, while EXP655 displaced only 20%. In the rat adrenal medulla, EXP655 gave 90% inhibition of AII binding with an IC50 value of 3.0 x 10(-8) M, while DuP 753 was essentially inactive. The combination of the two compounds completely inhibited AII binding in both tissues.

  1. ACE2: Angiotensin II/Angiotensin-(1-7) balance in cardiorenal injury

    PubMed Central

    Varagic, Jasmina; Ahmad, Sarfaraz; Nagata, Sayaka; Ferrario, Carlos M.

    2014-01-01

    Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent to this interactive biochemical cascade. Over the last decade angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses a considerable advancement in research on the role of tissue ACE2 in development and progression of hypertension and cardiorenal injury. We also summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. Recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis are also reviewed. PMID:24510672

  2. DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

    PubMed Central

    Jurado-López, Raquel; Martínez-Martínez, Ernesto; Gómez-Hurtado, Nieves; Delgado, Carmen; Visitación Bartolomé, Maria; San Román, José Alberto; Cordova, Claudia; Lahera, Vicente; Nieto, Maria Luisa; Cachofeiro, Victoria

    2012-01-01

    Background The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. Methodology/Principal Findings The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. Conclusions/Significance Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac

  3. Angiotensin II Stimulates Sympathetic Neurotransmission to Adipose Tissue.

    PubMed

    King, Victoria L; English, Victoria L; Bharadwaj, Kalyani; Cassis, Lisa A

    2013-08-01

    Angiotensin II (AngII) facilitates sympathetic neurotransmission by regulating norepinephrine (NE) synthesis, release and uptake. These effects of AngII contribute to cardiovascular control. Previous studies in our laboratory demonstrated that chronic AngII infusion decreased body weight of rats. We hypothesized that AngII facilitates sympathetic neurotransmission to adipose tissue and may thereby decrease body weight. The effect of chronic AngII infusion on the NE uptake transporter and NE turnover was examined in metabolic (interscapular brown adipose tissue, ISBAT; epididymal fat, EF) and cardiovascular tissues (left ventricle, LV; kidney) of rats. To examine the uptake transporter saturation isotherms were performed using [(3)H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [(3)H]NIS binding density. To quantify NE turnover, alpha-methyl-para-tyrosine (AMPT) was injected in saline-infused, AngII-infused, or saline-infused rats that were pair-fed to food intake of AngII-infused rats. AngII significantly increased the rate of NE decline in all tissues compared to saline. The rate of NE decline in EF was increased to a similar extent by AngII and by pair-feeding. In rats administered AngII and propranolol, reductions in food and water intake and body weight were eliminated. These data support the hypothesis that AngII facilitates sympathetic neurotransmission to adipose tissue. Increased sympathetic neurotransmission to adipose tissue following AngII exposure is suggested to contribute to reductions in body weight. PMID:24224084

  4. Csk regulates angiotensin II-induced podocyte apoptosis.

    PubMed

    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. PMID:27225249

  5. The Role of Angiotensin II and Cyclic AMP in Alveolar Active Sodium Transport

    PubMed Central

    Ismael-Badarneh, Reem; Guetta, Julia; Klorin, Geula; Berger, Gidon; Abu-saleh, Niroz; Abassi, Zaid; Azzam, Zaher S.

    2015-01-01

    Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT1 and AT2. The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% ± 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10-10 M, 10-9 M, 10-8 M, 10-7 M or 10-6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT1 specific antagonist, pretreated rats, indicating an AT1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema. PMID:26230832

  6. Angiotensin II binding to cultured bovine adrenal chromaffin cells: identification of angiotensin II receptors

    SciTech Connect

    Boyd, V.L.; Printz, M.P.

    1986-03-05

    Physiological experiments have provided evidence that angiotensin II stimulates catecholamine secretion from the adrenal gland. Their laboratory and others have now shown by receptor autoradiography the presence of angiotensin II receptors (AIIR) in bovine and rat adrenal medulla. In order to extend these studies they have undertaken to define AIIR on cultured bovine adrenal chromaffin cells. Cells were isolated using the method of Levitt including cell enrichment with Percoll gradient centrifugation. Primary cultures of bovine adrenal medullary cells were maintained in DME/F12 medium containing 10% FCS. Cells were characterized by immunocytochemistry for Met- and Leu-enkephalin, PNMT, DBH and Chromagranin A. Cultured cells bind with high affinity and specificity (/sup 125/I)-ANG II yielding a K/sub D/ of 0.74 nM and B/sub max/ of 24,350 sites/cell. After Percoll treatment values of .77 nm and 34,500 sites/cell are obtained. K/sub D/ values are in close agreement with that obtained in adrenal slices by Healy. Competition studies identify a rank order of binding by this receptor similar to that of other tissues. They conclude that cultured chromaffin cells provide a suitable model system for the investigation and characterization of the ANG II receptor and for cellular studies of its functional significance.

  7. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  8. 6β-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice.

    PubMed

    Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet; Brand, David D; Katsurada, Akemi; Majid, Dewan S A; Navar, L Gabriel; Gonzalez, Frank J; Malik, Kafait U

    2016-05-01

    6β-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in maleCyp1b1(+/+)andCyp1b1(-/-)mice. Castration ofCyp1b1(+/+)mice orCyp1b1(-/-)gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality inCyp1b1(+/+)mice, but restored these effects of angiotensin II inCyp1b1(-/-)or castratedCyp1b1(+/+)mice.Cyp1b1gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin-converting enzyme inCyp1b1(+/+)mice. However, inCyp1b1(-/-)or castratedCyp1b1(+/+)mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice. PMID:26928804

  9. Effect of chronic intracerebroventricular angiotensin II infusion on vasopressin release in rats

    NASA Technical Reports Server (NTRS)

    Sterling, G. H.; Chee, O.; Riggs, R. V.; Keil, L. C.

    1980-01-01

    The effects of the chronic infusion of angiotensin II into the lateral cerebral ventricle on the release of arginine vasopressin in rats are investigated. Rats were subjected to a continuous infusion of angiotensin at a rate of 1 microgram/h for five days, during which they were offered water, isotonic saline or hypertonic saline ad libitum or 40 ml water/day, and fluid intake, changes in body weight, plasma sodium ion concentrations and plasma and pituitary arginine vasopressin levels were measured. Angiotensin II is found to increase the fluid intake of rats given isotonic saline and decrease plasma sodium ion levels with no changes in plasma or pituitary arginine vasopressin in those given water or isotonic saline. However, in rats given hypertonic saline, plasma sodium concentrations remained at control levels while plasma vasopressin increased, and in water-restricted rats the effects of angiotensin II were intermediate. Results thus demonstrate that angiotensin II-stimulated arginine vasopressin release is reduced under conditions in which plasma sodium ion concentration becomes dilute, compatible with a central role of angiotensin in the regulation of salt and water balance.

  10. Angiotensin II Receptor Blockers and Cancer Risk

    PubMed Central

    Zhao, Yun-Tao; Li, Peng-Yang; Zhang, Jian-Qiang; Wang, Lei; Yi, Zhong

    2016-01-01

    Abstract Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI). We investigated the risk of cancer associated with ARB at different background ACEI levels. Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction. Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included. Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently. Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00–1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94–1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90–1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79–1.24, P = 0.95). Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens. ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI. PMID:27149494

  11. Angiotensin II directly impairs adipogenic differentiation of human preadipose cells.

    PubMed

    Palominos, Marisol M; Dünner, Natalia H; Wabitsch, Martin; Rojas, Cecilia V

    2015-10-01

    Angiotensin II reduces adipogenic differentiation of preadipose cells present in the stroma-vascular fraction of human adipose tissue, which also includes several cell types. Because of the ability of non-adipose lineage cells in the stroma-vascular fraction to respond to angiotensin II, it is not possible to unequivocally ascribe the anti-adipogenic response to a direct effect of this hormone on preadipose cells. Therefore, we used the human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain to investigate the consequences of angiotensin II treatment on adipogenic differentiation under serum-free conditions, by assessing expression of typical adipocyte markers perilipin and fatty acid-binding protein 4 (FABP4), at the transcript and protein level. Reverse transcription-polymerase chain reaction showed that perilipin and FABP4 transcripts were, respectively, reduced to 0.33 ± 0.07 (P < 0.05) and 0.41 ± 0.19-fold (P < 0.05) in SGBS cells induced to adipogenic differentiation in the presence of angiotensin II. Western Blot analysis corroborated reduction of the corresponding proteins to 0.23 ± 0.21 (P < 0.01) and 0.46 ± 0.30-fold (P < 0.01) the respective controls without angiotensin II. Angiotensin II also impaired morphological changes associated with early adipogenesis. Hence, we demonstrated that angiotensin II is able to directly reduce adipogenic differentiation of SGBS preadipose cells. PMID:26112903

  12. Control of aldosterone secretion during sodium restriction: Adrenal receptor regulation and increased adrenal sensitivity to angiotensin II

    PubMed Central

    Aguilera, G.; Hauger, R. L.; Catt, K. J.

    1978-01-01

    The mechanism of increased adrenal sensitivity to angiotensin II during the aldosterone response to sodium restriction was investigated in the rat. Sodium restriction for 36 hr markedly increased the aldosterone-stimulating effect of low-dose (1 ng/min) infusion of angiotensin II and caused enhanced binding of 125I-labeled angiotensin II to the zona glomerulosa in vivo. Conversely, in vivo binding of 125I-labeled angiotensin II was significantly decreased after 36 hr of high-sodium intake. In isolated glomerulosa cells, the increased binding of angiotensin II after sodium restriction was shown to result from a significant increase in receptor affinity (+80%) and a smaller increase in receptor concentration (+25%). The corresponding aldosterone responses in dispersed cells showed an increase in sensitivity to angiotensin II, commensurate with the increased receptor affinity. More prolonged sodium restriction (4 days) caused a further increase in angiotensin receptor concentration (+70%) and maximal aldosterone response (+50%), whereas the binding affinity of adrenal receptors and the sensitivity of the in vitro aldosterone response had returned to normal. During sodium loading for 36 hr and 4 days, the converse effects on adrenal angiotensin II receptors and aldosterone production were observed. Also, in contrast to the consistent increase in angiotensin II receptors in the adrenal glands of sodium-restricted animals, the angiotensin II binding capacity of uterine smooth muscle was decreased by 40% after 7 days of sodium restriction. The rapid regulation of receptor affinity and concentration during changes in sodium intake provides a basis for the dynamic modulation of aldosterone responses by dietary sodium content. During sodium restriction, the sequential changes in receptor affinity and concentration account for the enhanced binding and steroidogenic actions of angiotensin II in vivo and in vitro. These receptor changes, and the converse effects of sodium

  13. Angiotensin II-induced angiotensin II type I receptor lysosomal degradation studied by fluorescence lifetime imaging microscopy

    NASA Astrophysics Data System (ADS)

    Li, Hewang; Yu, Peiying; Felder, Robin A.; Periasamy, Ammasi; Jose, Pedro A.

    2009-02-01

    Upon activation, the angiotensin (Ang) II type 1 receptor (AT1Rs) rapidly undergoes endocytosis. After a series of intracellular processes, the internalized AT1Rs recycle back to the plasma membrane or are trafficked to proteasomes or lysosomes for degradation. We recently reported that AT1Rs degrades in proteasomes upon stimulation of the D5 dopamine receptor (D5R) in human renal proximal tubule and HEK-293 cells. This is in contrast to the degradation of AT1R in lysosomes upon binding Ang II. However, the dynamic regulation of the AT1Rs in lysosomes is not well understood. Here we investigated the AT1Rs lysosomal degradation using FRET-FLIM in HEK 293 cells heterologously expressing the human AT1R tagged with EGFP as the donor fluorophore. Compared to its basal state, the lifetime of AT1Rs decreased after a 5-minute treatment with Ang II treatment and colocalized with Rab5 but not Rab7 and LAMP1. With longer Ang II treatment (30 min), the AT1Rs lifetime decreased and co-localized with Rab5, as well as Rab7 and LAMP1. The FLIM data are corroborated with morphological and biochemical co-immunoprecipitation studies. These data demonstrate that Ang II induces the internalization of AT1Rs into early sorting endosomes prior to trafficking to late endosomes and subsequent degradation in lysosomes.

  14. The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.

    PubMed Central

    Cockcroft, J R; Chowienczyk, P J; Brett, S E; Mant, T G; Durnin, C; Lynn, F; Stevenson, P; Ritter, J M

    1995-01-01

    We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels. PMID:8703667

  15. Renovascular remodeling and renal injury after extended angiotensin II infusion.

    PubMed

    Casare, Fernando Augusto Malavazzi; Thieme, Karina; Costa-Pessoa, Juliana Martins; Rossoni, Luciana Venturini; Couto, Gisele Kruger; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Oliveira-Souza, Maria

    2016-06-01

    Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor. PMID:26962104

  16. Immunosuppressive treatment protects against angiotensin II-induced renal damage.

    PubMed

    Muller, Dominik N; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C

    2002-11-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  17. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage

    PubMed Central

    Muller, Dominik N.; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C.

    2002-01-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-α on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-α receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-κB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-α is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  18. Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor

    PubMed Central

    Murugan, Dharmani; Lau, Yeh Siang; Lau, Wai Chi; Mustafa, Mohd Rais; Huang, Yu

    2015-01-01

    Angiotensin 1–7 (Ang 1–7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1–7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1–7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1–7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1–7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1–7. In addition, Ang 1–7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1–7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function. PMID:26709511

  19. Platelet activation during angiotensin II infusion in healthy volunteers.

    PubMed

    Larsson, P T; Schwieler, J H; Wallén, N H

    2000-01-01

    The present study was undertaken to evaluate the effects of an intravenous infusion of angiotensin II (10 ng/kg per min) on platelet function and coagulation in vivo in 18 healthy males. The infusion increased mean arterial pressure by 23+/-2 mm Hg. Plasma beta-thromboglobulin levels, reflecting platelet secretion, increased by 66+/-24% during the infusion, as did also platelet surface expression of P-selectin as measured by flow cytometry. Platelet fibrinogen binding increased, whereas platelet aggregability, assessed by ex vivo filtragometry, was unaltered. Angiotensin II caused mild activation of the coagulation cascade with increases in plasma levels of thrombin-antithrombin complex and prothrombin fragment F1 + 2. In conclusion, angiotensin II has mild platelet-activating effects in vivo and also enhances coagulation. Markers of platelet secretion are significantly increased, whereas markers of platelet aggregability are less affected. The clinical relevance of these findings remains to be clarified. PMID:10691100

  20. Angiotensin II inhibitor facilitates epidermal wound regeneration in diabetic mice

    PubMed Central

    Kamber, Maria; Papalazarou, Vasileios; Rouni, Georgia; Papageorgopoulou, Evagelia; Papalois, Apostolos; Kostourou, Vassiliki

    2015-01-01

    Tissue regeneration and wound healing are severely impaired in diabetes and are associated with poor circulation and dysfunctional blood vessels. Angiotensin II inhibitors are anti-hypertensive drugs used in clinical practice to regulate blood pressure and could affect tissue remodeling. We hypothesize that blocking angiotensin II, using Losartan, could facilitate tissue regeneration in diabetic mice. To this end, we established an experimental model of wound healing in streptozotocin-induced diabetic mice. Our data demonstrated that Losartan accelerates wound repair and normalizes wound stromal responses, having a beneficial role in wounds of diabetic individuals. Our findings highlight a potential therapeutic use of Losartan in improving wound repair in diabetic conditions. PMID:26106332

  1. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes

    PubMed Central

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-01-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin-like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t-test or one-way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  2. Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

    PubMed Central

    Lyons, D; Stewart, D; Webster, J; Benjamin, N

    1994-01-01

    Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects. PMID:7893582

  3. The Effects of Angiotensin II on Renal Water and Electrolyte Excretion in Normal and Caval Dogs*

    PubMed Central

    Porush, Jerome G.; Kaloyanides, George J.; Cacciaguida, Roy J.; Rosen, Stanley M.

    1967-01-01

    The effects of intravenous administration of angiotensin II on renal water and electrolyte excretion were examined during hydropenia, water diuresis, and hypotonic saline diuresis in anesthetized normal dogs and dogs with thoracic inferior vena cava constriction and ascites (caval dogs). The effects of unilateral renal artery infusion of a subpressor dose were also examined. During hydropenia angiotensin produced a decrease in tubular sodium reabsorption, with a considerably greater natriuresis in caval dogs, and associated with a decrease in free water reabsorption (TcH2O). Water and hypotonic saline diuresis resulted in an augmented angiotensin natriuresis, with a greater effect still observed in caval dogs. In these experiments free water excretion (CH2O) was limited to 8-10% of the glomerular filtration rate (GFR), although distal sodium load increased in every instance. In the renal artery infusion experiments a significant ipsilateral decrease in tubular sodium reabsorption was induced, particularly in caval dogs. These findings indicate that angiotensin has a direct effect on renal sodium reabsorption unrelated to a systemic circulatory alteration. The attenuation or prevention of the falls in GFR and effective renal plasma flow (ERPF) usually induced by angiotensin may partially account for the greater natriuretic response in caval dogs and the augmentation during water or hypotonic saline diuresis. However, a correlation between renal hemodynamics and the degree of natriuresis induced was not always present and, furthermore, GFR and ERPF decreased significantly during the intrarenal artery infusion experiments. Therefore, the present experiments indicate that another mechanism is operative in the control of the angiotensin natriuresis and suggest that alterations in intrarenal hemodynamics may play a role. The decrease in TcH2O and the apparent limitation of CH2O associated with an increase in distal sodium load localize the site of action of angiotensin

  4. Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension.

    PubMed

    Li, Xiao C; Zhuo, Jia L

    2016-08-01

    It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na(+) reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor- and/or megalin-mediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na(+)/H(+) exchanger 3, may provide a powerful feedforward mechanism for promoting Na(+) retention and the development of ANG II-induced hypertension. PMID:27372447

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

    PubMed

    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. PMID:27001297

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

    PubMed Central

    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.

    2014-01-01

    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 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute 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 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) 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 to transgenic and non-transgenic mice after the 10 minute 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. PMID:25469849

  7. Gynura procumbens causes vasodilation by inhibiting angiotensin II and enhancing bradykinin actions.

    PubMed

    Poh, Ting-Fung; Ng, Hien-Kun; Hoe, See-Ziau; Lam, Sau-Kuen

    2013-05-01

    Previous studies showed that Gynura procumbens reduced blood pressure by blocking calcium channels and inhibiting the angiotensin-converting enzyme activity. The present experiments were to further explore the effects and mechanisms of a purer aqueous fraction (FA-I) of G. procumbens on angiotensin I (Ang I)-induced and angiotensin II (Ang II)-induced contraction of aortic rings and also on the bradykinin (BK) effect on cardiovascular system. Rat aortic rings suspended in organ chambers were used to investigate the vascular reactivity of FA-I. Effect of FA-I on BK was studied by in vitro and in vivo methods. Results show that FA-I significantly (P < 0.05) decreased the contraction evoked by Ang I and Ang II. In the presence of indomethacin (10 µM) or N-nitro-L-arginine methyl ester (0.1 µM), the inhibitory effect of FA-I on Ang II-induced contraction of aortic rings was reduced. Besides, FA-I potentiated the vasorelaxant effect and enhanced the blood pressure-lowering effect of BK. In conclusion, FA-I reduced the contraction evoked by Ang II probably via the endothelium-dependent pathways, which involve activation of the release of nitric oxide and prostaglandins. The inhibition of angiotensin-converting enzyme activity by FA-I may contribute to the potentiation of the effects of BK on cardiovascular system. PMID:23328388

  8. Expression of Angiotensin II Receptor-1 in Human Articular Chondrocytes

    PubMed Central

    Kawakami, Yuki; Matsuo, Kosuke; Murata, Minako; Yudoh, Kazuo; Nakamura, Hiroshi; Shimizu, Hiroyuki; Beppu, Moroe; Inaba, Yutaka; Saito, Tomoyuki; Kato, Tomohiro; Masuko, Kayo

    2012-01-01

    Background. Besides its involvement in the cardiovascular system, the renin-angiotensin-aldosterone (RAS) system has also been suggested to play an important role in inflammation. To explore the role of this system in cartilage damage in arthritis, we investigated the expression of angiotensin II receptors in chondrocytes. Methods. Articular cartilage was obtained from patients with osteoarthritis, rheumatoid arthritis, and traumatic fractures who were undergoing arthroplasty. Chondrocytes were isolated and cultured in vitro with or without interleukin (IL-1). The expression of angiotensin II receptor types 1 (AT1R) and 2 (AT2R) mRNA by the chondrocytes was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). AT1R expression in cartilage tissue was analyzed using immunohistochemistry. The effect of IL-1 on AT1R/AT2R expression in the chondrocytes was analyzed by quantitative PCR and flow cytometry. Results. Chondrocytes from all patient types expressed AT1R/AT2R mRNA, though considerable variation was found between samples. Immunohistochemical analysis confirmed AT1R expression at the protein level. Stimulation with IL-1 enhanced the expression of AT1R/AT2R mRNA in OA and RA chondrocytes. Conclusions. Human articular chondrocytes, at least partially, express angiotensin II receptors, and IL-1 stimulation induced AT1R/AT2R mRNA expression significantly. PMID:23346400

  9. CYP4A2-Induced Hypertension is 20-HETE and Angiotensin II-Dependent

    PubMed Central

    Sodhi, Komal; Wu, Cheng-Chia; Cheng, Jennifer; Gotlinger, Katherine; Inoue, Kazuyoshi; Goli, Mohan; Falck, John R.; Abraham, Nader G.; Schwartzman, Michal L.

    2010-01-01

    We have previously shown that increased vascular endothelial expression of CYP4A2 leads to 20-HETE-dependent hypertension. The renin-angiotensin system (RAS) is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and RAS. In normotensive (110±3 mmHg) Sprague Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3 and 150±2 mmHg at 3, 5 and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mmHg. Treatment with lisinopril, losartan or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid (20-HEDE) decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) and increased levels of plasma and tissue Angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-HEDE. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression and increases Angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction. PMID:20837888

  10. Angiotensin II modulates salty and sweet taste sensitivities.

    PubMed

    Shigemura, Noriatsu; Iwata, Shusuke; Yasumatsu, Keiko; Ohkuri, Tadahiro; Horio, Nao; Sanematsu, Keisuke; Yoshida, Ryusuke; Margolskee, Robert F; Ninomiya, Yuzo

    2013-04-10

    Understanding the mechanisms underlying gustatory detection of dietary sodium is important for the prevention and treatment of hypertension. Here, we show that Angiotensin II (AngII), a major mediator of body fluid and sodium homeostasis, modulates salty and sweet taste sensitivities, and that this modulation critically influences ingestive behaviors in mice. Gustatory nerve recording demonstrated that AngII suppressed amiloride-sensitive taste responses to NaCl. Surprisingly, AngII also enhanced nerve responses to sweeteners, but had no effect on responses to KCl, sour, bitter, or umami tastants. These effects of AngII on nerve responses were blocked by the angiotensin II type 1 receptor (AT1) antagonist CV11974. In behavioral tests, CV11974 treatment reduced the stimulated high licking rate to NaCl and sweeteners in water-restricted mice with elevated plasma AngII levels. In taste cells AT1 proteins were coexpressed with αENaC (epithelial sodium channel α-subunit, an amiloride-sensitive salt taste receptor) or T1r3 (a sweet taste receptor component). These results suggest that the taste organ is a peripheral target of AngII. The specific reduction of amiloride-sensitive salt taste sensitivity by AngII may contribute to increased sodium intake. Furthermore, AngII may contribute to increased energy intake by enhancing sweet responses. The linkage between salty and sweet preferences via AngII signaling may optimize sodium and calorie intakes. PMID:23575826

  11. Role of α1D -adrenoceptors in vascular wall hypertrophy during angiotensin II-induced hypertension.

    PubMed

    Gallardo-Ortíz, I A; Rodríguez-Hernández, S N; López-Guerrero, J J; Del Valle-Mondragón, L; López-Sánchez, P; Touyz, R M; Villalobos-Molina, R

    2015-09-01

    The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1 -adrenoceptors (α1 -ARs) expression was explored. Alzet(®) minipumps filled with Ang II (200 ng kg(-1)  min(-1) ) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1 R antagonist, or with BMY 7378, a selective α1D -AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups. Angiotensin II decreased α1D -ARs without modifying the other α1 -ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1 Rs and α1D -ARs. Angiotensin II-induced α1D -AR-mediated vascular remodeling occurs independently of hypertension. Findings identify a α1D -AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation. PMID:26845248

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

    SciTech Connect

    Zhang, Feng; Ren, Jingyi; Chan, Kenneth; Chen, Hong

    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.

  13. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

    PubMed

    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. PMID:27063446

  14. The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle

    PubMed Central

    Lastra, Guido; Santos, Fernando R.; Hooshmand, Payam; Hooshmand, Paria; Mugerfeld, Irina; Aroor, Annayya R.; DeMarco, Vincent G.; Sowers, James R.; Henriksen, Erik J.

    2013-01-01

    Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation. PMID:23922555

  15. Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture

    NASA Technical Reports Server (NTRS)

    Wada, H.; Zile, M. R.; Ivester, C. T.; Cooper, G. 4th; McDermott, P. J.

    1996-01-01

    The purposes of this study were 1) to determine whether angiotensin II causes growth of adult feline cardiocytes in long-term culture, 2) to compare the growth effects of angiotensin II with those resulting from electrically stimulated contraction, and 3) to determine whether the anabolic effects of contraction are exerted via the angiotensin type 1 receptor. Adult feline cardiocytes were cultured on laminin-coated trays in a serum-free medium. Cardiocytes were either electrically stimulated to contract (1 Hz, 5-ms pulse duration, alternating polarity) or were nonstimulated and quiescent. Quiescent cells were studied as controls and after treatment with angiotensin II (10(-8) M), losartan (10(-6) M; an angiotensin type 1-receptor antagonist), or angiotensin II plus losartan. Contracting cells were studied in the presence and absence of angiotensin II or losartan. In quiescent cardiocytes, angiotensin II treatment on day 7 significantly increased protein synthesis rates by 22% and protein content per cell by 17%. The effects of angiotensin II were completely blocked by losartan. Electrically stimulated contraction on days 4 and 7 in culture significantly increased protein synthesis rate by 18 and 38% and protein content per cell by 19 and 46%, respectively. Angiotensin II treatment did not further increase protein synthesis rate or protein content in contracting cardiocytes. Furthermore, losartan did not block the anabolic effects of contraction on protein synthesis rates or protein content. In conclusion, angiotensin II can exert a modest anabolic effect on adult feline cardiocytes in culture. In contracting feline cardiocytes, angiotensin II has no effect on growth. Growth caused by electrically stimulated contraction occurs more rapidly and is greater in magnitude than that caused by angiotensin II. Growth of contracting adult feline cardiocytes is not dependent on activation of the angiotensin receptor.

  16. Local actions of angiotensin II: quantitative in vitro autoradiographic localization of angiotensin II receptor binding and angiotensin converting enzyme in target tissues

    SciTech Connect

    Chai, S.Y.; Allen, A.M.; Adam, W.R.; Mendelsohn, F.A.

    1986-01-01

    In order to gain insight into the local actions of angiotensin II (ANG II) we have determined the distribution of a component of the effector system for the peptide, the ANG II receptor, and that of an enzyme-catalysing ANG II formation, angiotensin converting enzyme (ACE), by in vitro autoradiography in several target tissues. The superagonist ANG II analog, /sup 125/I(Sar1)ANG II, or the antagonist analog, /sup 125/I(Sar1,Ile8)ANG II, were used as specific radioligands for ANG II receptors. A derivative of the specific ACE inhibitor, lysinopril, called /sup 125/I-351A, was used to label ACE in tissues. In the adrenal, a high density of ANG II receptors occurs in the glomerulosa zone of the cortex and in the medulla. ACE is also localized in these two zones, indicating that local production of ANG II may occur close to its sites of action in the zona glomerulosa and adrenal medulla. In the kidney, a high density of ANG II receptors is associated with glomeruli in the cortex and also with vasa recta bundles in the inner stripe of the outer medulla. ACE is found in very high concentration in deep proximal convoluted tubules of the cortex, while much lower concentrations of the enzyme occur in the vascular endothelium throughout the kidney. In the central nervous system three classes of relationships between ANG II receptors and ACE are observed: In the circumventricular organs, including the subfornical organ and organum vasculosum of the lamina terminalis, a high concentration of both components occurs. Since these structures have a deficient blood-brain barrier, local conversion of circulating angiotensin I (ANG I) to ANG II may contribute to the action of ANG II at these sites.

  17. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.

    PubMed

    Burke, Suzanne D; Zsengellér, Zsuzsanna K; Khankin, Eliyahu V; Lo, Agnes S; Rajakumar, Augustine; DuPont, Jennifer J; McCurley, Amy; Moss, Mary E; Zhang, Dongsheng; Clark, Christopher D; Wang, Alice; Seely, Ellen W; Kang, Peter M; Stillman, Isaac E; Jaffe, Iris Z; Karumanchi, S Ananth

    2016-07-01

    Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes. PMID:27270170

  18. Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats.

    PubMed

    Minas, Jacqueline N; Thorwald, Max A; Conte, Debra; Vázquez-Medina, Jose-Pablo; Nishiyama, Akira; Ortiz, Rudy M

    2015-11-01

    Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension. PMID:26234762

  19. The inhibitory effect of angiotensin II on BKCa channels in podocytes via oxidative stress.

    PubMed

    Gao, Na; Wang, Hui; Zhang, Xiaochen; Yang, Zhuo

    2015-01-01

    Angiotensin II (Ang II) is an important active substance of the renin-angiotensin system (RAS). The present study has confirmed that abnormalities of Ang II may be related with cerebrovascular diseases, endocrine diseases, cardiovascular diseases, liver diseases, such as: cerebral hypoxia, diabetes, obesity, atrial fibrillation, and liver cirrhosis. However, understanding effects of Ang II on podocytes is not enough. This study was to investigate the effects of oxidative stress on the large conductance, Ca(2+)-activated K(+) channels (BKCa). Results from the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death in a concentration-dependent manner. The measurement of superoxide dismutase (SOD) generation demonstrated that Ang II decreased the total SOD of cellular levels. Meaningfully, pretreatment of a type of ROS scavenger formulations named N-(mercaptopropionyl)-glycine (N-MPG) could inhibit podocyte apoptosis induced by Ang II. Meanwhile, patch-clamp technique was used in this study to detect the effects of Ang II on currents of BKCa channel in podocytes. The results indicated that Ang II inhibited the current amplitude of BKCa channel and decreased the slope of I-V curve. Ang II also made the activation curves of BKCa channel shift to the left. These results may provide a theoretical basis for potential treatment of chronic glomerular disease in the future. PMID:25234195

  20. Angiotensin-II blockage, muscle strength, and exercise capacity in physically independent older adults

    PubMed Central

    Coelho, Vinícius A.; Probst, Vanessa S.; Nogari, Bruna M.; Teixeira, Denilson C.; Felcar, Josiane M.; Santos, Denis C.; Gomes, Marcus Vinícius M.; Andraus, Rodrigo A. C.; Fernandes, Karen B. P.

    2016-01-01

    [Purpose] This study aimed to assess the exercise capacity and muscle strength in elderly people using drugs for angiotensin-II blockage. [Subjects and Methods] Four hundred and seven older adults were recruited for this study. Data about comorbidities and medication use were recorded and the individuals were divided into three groups: control group- elderly people with normal exercise capacity (n=235); angiotensin-converting enzyme inhibitor group − individuals using angiotensin-converting enzyme inhibitors (n=140); and angiotensin-II receptor blocker group- patients using angiotensin-II receptor blockers (n= 32). Exercise capacity was evaluated by a 6-minute walking test and muscle strength was measured using a handgrip dynamometer. [Results] Patients from the angiotensin-converting enzyme inhibitor group (mean: 99 ± 12%) and the angiotensin-II receptor blocker group (mean: 101 ± 14%) showed higher predicted values in the 6-minute walking test than the control group patients (mean: 96 ± 10%). Patients from the angiotensin-converting enzyme inhibitor group (mean: 105 ± 19%) and the angiotensin-II receptor blocker group (mean: 105.1 ± 18.73%) showed higher predicted values of muscle strength than control group patients (mean: 98.15 ± 18.77%). [Conclusion] Older adults using angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers have better functional exercise capacity and muscle strength. PMID:27065543

  1. Angiotensin II receptors and peritoneal dialysis-induced peritoneal fibrosis.

    PubMed

    Morinelli, Thomas A; Luttrell, Louis M; Strungs, Erik G; Ullian, Michael E

    2016-08-01

    The vasoactive hormone angiotensin II initiates its major hemodynamic effects through interaction with AT1 receptors, a member of the class of G protein-coupled receptors. Acting through its AT1R, angiotensin II regulates blood pressure and renal salt and water balance. Recent evidence points to additional pathological influences of activation of AT1R, in particular inflammation, fibrosis and atherosclerosis. The transcription factor nuclear factor κB, a key mediator in inflammation and atherosclerosis, can be activated by angiotensin II through a mechanism that may involve arrestin-dependent AT1 receptor internalization. Peritoneal dialysis is a therapeutic modality for treating patients with end-stage kidney disease. The effectiveness of peritoneal dialysis at removing waste from the circulation is compromised over time as a consequence of peritoneal dialysis-induced peritoneal fibrosis. The non-physiological dialysis solution used in peritoneal dialysis, i.e. highly concentrated, hyperosmotic glucose, acidic pH as well as large volumes infused into the peritoneal cavity, contributes to the development of fibrosis. Numerous trials have been conducted altering certain components of the peritoneal dialysis fluid in hopes of preventing or delaying the fibrotic response with limited success. We hypothesize that structural activation of AT1R by hyperosmotic peritoneal dialysis fluid activates the internalization process and subsequent signaling through the transcription factor nuclear factor κB, resulting in the generation of pro-fibrotic/pro-inflammatory mediators producing peritoneal fibrosis. PMID:27167177

  2. Apoptosis after reperfused myocardial infarction: Role of angiotensin II

    PubMed Central

    Jugdutt, Bodh I

    2004-01-01

    Angiotensin II (Ang II) plays a significant role in apoptosis after myocardial infarction (MI) and reperfused MI. Cumulative evidence suggests that Ang II is a major contributor to cardiomyocyte (CM) apoptosis and left ventricular (LV) dysfunction after acute reperfused MI and that apoptosis mediates a major portion of early LV dysfunction. Importantly, blockade of the Ang II type 1 receptor (AT1R) limits CM apoptosis and LV dysfunction after acute reperfused MI. Ang II type 2 receptor activation during AT1R blockade contributes to these beneficial effects. The role of Ang II and apoptosis in chronic LV remodelling, healing and post-MI heart failure is more complex and involves effects on the CMs, fibroblasts and vascular cells. The long-term effects of agents targeting apoptosis after reperfused MI, including AT1R blockade, on apoptosis in different cell types, windows of enhanced apoptosis and the appropriate timing of therapy need to be considered. PMID:19641712

  3. Angiotensin II in inflammation, immunity and rheumatoid arthritis

    PubMed Central

    Chang, Y; Wei, W

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. Although classically known for its role in the regulation of circulatory homeostasis, angiotensin II (Ang II) is recognized to act as a powerful proinflammatory mediator. Some research has showed that Ang II plays important roles in autoimmune diseases, including RA, systemic lupus erythematosus and multiple sclerosis. Ang II blockers prove effective in reducing inflammation and autoimmunity in rheumatic diseases and their relative safety, together with their effects for reducing the cardiovascular disease risk, suggest that Ang II blockers may at least act as effective adjunctive therapy for disease control in patients with RA. The present review focuses systematically on the potential impact of Ang II and its receptors on inflammation and immunomodulation in patients with RA. PMID:25302847

  4. Photoreleasable ligands to study intracrine angiotensin II signalling

    PubMed Central

    Tadevosyan, Artavazd; Létourneau, Myriam; Folch, Benjamin; Doucet, Nicolas; Villeneuve, Louis R; Mamarbachi, Aida M; Pétrin, Darlaine; Hébert, Terence E; Fournier, Alain; Chatenet, David; Allen, Bruce G; Nattel, Stanley

    2015-01-01

    Several lines of evidence suggest that intracellular angiotensin II (Ang-II) contributes to the regulation of cardiac contractility, renal salt reabsorption, vascular tone and metabolism; however, work on intracrine Ang-II signalling has been limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we aimed to synthesize and characterize cell-permeant Ang-II analogues that are inactive without uncaging, but release active Ang-II upon exposure to a flash of UV-light, and act as novel tools for use in the study of intracrine Ang-II physiology. We prepared three novel caged Ang-II analogues, [Tyr(DMNB)4]Ang-II, Ang-II-ODMNB and [Tyr(DMNB)4]Ang-II-ODMNB, based upon the incorporation of the photolabile moiety 4,5-dimethoxy-2-nitrobenzyl (DMNB). Compared to Ang-II, the caged Ang-II analogues showed 2–3 orders of magnitude reduced affinity toward both angiotensin type-1 (AT1R) and type-2 (AT2R) receptors in competition binding assays, and greatly-reduced potency in contraction assays of rat thoracic aorta. After receiving UV-irradiation, all three caged Ang-II analogues released Ang-II and potently induced the contraction of rat thoracic aorta. [Tyr(DMNB)4]Ang-II showed the most rapid photolysis upon UV-irradiation and was the focus of subsequent characterization. Whereas Ang-II and photolysed [Tyr(DMNB)4]Ang-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R), caged [Tyr(DMNB)4]Ang-II did not. Cellular uptake of [Tyr(DMNB)4]Ang-II was 4-fold greater than that of Ang-II and significantly greater than uptake driven by the positive-control HIV TAT(48–60) peptide. Intracellular photolysis of [Tyr(DMNB)4]Ang-II induced an increase in nucleoplasmic Ca2+ ([Ca2+]n), and initiated 18S rRNA and nuclear factor kappa B mRNA synthesis in adult cardiac cells. We conclude that caged Ang-II analogues represent powerful new tools for use in the selective study of intracrine signalling via Ang-II. PMID:25433071

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

    SciTech Connect

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

    1988-03-01

    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.

  6. Angiotensin II modulates respiratory and acid-base responses to prolonged hypoxia in conscious dogs.

    PubMed

    Heitman, S J; Jennings, D B

    1998-08-01

    We tested the hypothesis that angiotensin II (ANG II) contributes to ventilatory and acid-base adaptations during 3-4 h of hypoxia (partial pressure of O2 in arterial blood approximately 43 Torr) in the conscious dog. Three protocols were carried out over 3-4 h in five dogs: 1) air control, 2) 12% O2 breathing, and 3) 12% O2 breathing with ANG II receptors blocked by infusion of saralasin (0. 5 microg . kg-1 . min-1). After 2 h of hypoxia, expired ventilation and alveolar ventilation progressively increased, and the partial pressure of CO2 in arterial blood and the difference between the arterial concentrations of strong cations and strong anions ([SID]) decreased. When the hypoxic chemoreceptor drive to breathe was abolished transiently for 30 s with 100% O2, the resultant central apneic time decreased between 0.5 and 2.5 h of hypoxia. All these adaptive responses to hypoxia were abolished by ANG II receptor block. Because plasma ANG II levels were lower during hypoxia and hypoxic release of arginine vasopressin from the pituitary into the plasma was prevented by ANG II receptor block, the brain renin-angiotensin system was likely involved. It is possible that ANG II mediates ventilatory and acid-base adaptive responses to prolonged hypoxia via alterations in ion transport to decrease [SID] in brain extracellular fluid rather than acting by a direct neural mechanism. PMID:9688673

  7. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage.

    PubMed

    Villapol, Sonia; Balarezo, María G; Affram, Kwame; Saavedra, Juan M; Symes, Aviva J

    2015-11-01

    See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and

  8. The Cooperative Effect of Local Angiotensin-II in Liver with Adriamycin Hepatotoxicity on Mitochondria

    PubMed Central

    Taskin, Eylem; Guven, Celal; Sahin, Leyla; Dursun, Nurcan

    2016-01-01

    Background Adriamycin (ADR) is a drug used clinically for anticancer treatment; however, it causes adverse effects in the liver. The mechanism by which these adverse effects occur remains unclear, impeding efforts to enhance the therapeutic effects of ADR. Its hepatotoxicity might be related to increasing reactive oxygen species (ROS) and mitochondrial dysfunction. The interaction between ADR and the local renin-angiotensin system (RAS) in the liver is unclear. ADR might activate the RAS. Angiotensin-II (Ang-II) leads to ROS production and mitochondrial dysfunction. In the present study we investigated whether ADR’s hepatotoxicity interacts with local RAS in causing oxidative stress resulting from mitochondrial dysfunction in the rat liver. Material/Methods Rats were divided into 5 groups: control, ADR, co-treated ADR with captopril, co-treated ADR with Aliskiren, and co-treated ADR with both captopril and Aliskiren. Mitochondria and cytosol were separated from the liver, then biochemical measurements were made from them. Mitochondrial membrane potential (MMP) and ATP levels were evaluated. Results ADR remarkably decreased MMP and ATP in liver mitochondria (p<0.05). Co-administration with ADR and Aliskiren and captopril improved the dissipation of MMP (p<0.05). The decreased ATP level was restored by treatment with inhibitors of ACE and renin. Conclusions Angiotensin-II may contribute to hepatotoxicity of in the ADR via mitochondrial oxidative production, resulting in the attenuation of MMP and ATP production. PMID:27019222

  9. Angiotensin II Signaling in Human Preadipose Cells: Participation of ERK1,2-Dependent Modulation of Akt

    PubMed Central

    Dünner, Natalia; Quezada, Carolina; Berndt, F. Andrés; Cánovas, José; Rojas, Cecilia V.

    2013-01-01

    The renin-angiotensin system expressed in adipose tissue has been implicated in the modulation of adipocyte formation, glucose metabolism, triglyceride accumulation, lipolysis, and the onset of the adverse metabolic consequences of obesity. As we investigated angiotensin II signal transduction mechanisms in human preadipose cells, an interplay of extracellular-signal-regulated kinases 1 and 2 (ERK1,2) and Akt/PKB became evident. Angiotensin II caused attenuation of phosphorylated Akt (p-Akt), at serine 473; the p-Akt/Akt ratio decreased to 0.5±0.2-fold the control value without angiotensin II (p<0.001). Here we report that the reduction of phosphorylated Akt associates with ERK1,2 activities. In the absence of angiotensin II, inhibition of ERK1,2 activation with U0126 or PD98059 resulted in a 2.1±0.5 (p<0.001) and 1.4±0.2-fold (p<0.05) increase in the p-Akt/Akt ratio, respectively. In addition, partial knockdown of ERK1 protein expression by the short hairpin RNA technique also raised phosphorylated Akt in these cells (the p-Akt/Akt ratio was 1.5±0.1-fold the corresponding control; p<0.05). Furthermore, inhibition of ERK1,2 activation with U0126 prevented the reduction of p-Akt/Akt by angiotensin II. An analogous effect was found on the phosphorylation status of Akt downstream effectors, the forkhead box (Fox) proteins O1 and O4. Altogether, these results indicate that angiotensin II signaling in human preadipose cells involves an ERK1,2-dependent attenuation of Akt activity, whose impact on the biological functions under its regulation is not fully understood. PMID:24098385

  10. Angiotensin II centrally induces frequent detrusor contractility of the bladder by acting on brain angiotensin II type 1 receptors in rats

    PubMed Central

    Kawamoto, Bunya; Shimizu, Shogo; Shimizu, Takahiro; Higashi, Youichirou; Honda, Masashi; Sejima, Takehiro; Saito, Motoaki; Takenaka, Atsushi

    2016-01-01

    Angiotensin (Ang) II plays an important role in the brain as a neurotransmitter and is involved in psychological stress reactions, for example through activation of the sympatho-adrenomedullary system. We investigated the effects of centrally administered Ang II on the micturition reflex, which is potentially affected by the sympatho-adrenomedullary system, and brain Ang II receptors in urethane-anesthetized (1.0 g/kg, intraperitoneally) male rats. Central administration of Ang II (0.01, 0.02, and 0.07 nmol per rat, intracerebroventricularly, icv) but not vehicle rapidly and dose-dependently decreased the urinary bladder intercontraction interval, without altering the bladder detrusor pressure. Central administration of antagonists of Ang II type 1 but not type 2 receptors inhibited the Ang II-induced shortening of intercontraction intervals. Administration of the highest dose of Ang II (0.07 nmol per rat, icv) but not lower doses (0.01 and 0.02 nmol per rat, icv) elevated the plasma concentration of adrenaline. Bilateral adrenalectomy reduced Ang II-induced elevation in adrenaline, but had no effect on the Ang II-induced shortening of the intercontraction interval. These data suggest that central administration of Ang II increases urinary frequency by acting on brain Ang II type 1 receptors, independent of activation of the sympatho-adrenomedullary system. PMID:26908391

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

    PubMed

    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. PMID:25469849

  12. Angiotensin II-related hypertension and eye diseases

    PubMed Central

    Marin Garcia, Pablo Jesus; Marin-Castaño, Maria Encarna

    2014-01-01

    Systemic vascular disease, especially hypertension, has been suspected as a risk factor for some eye diseases including, diabetic retinopathy and age-related macular degeneration. Hypertension can contribute to chronic diseases by hemodynamic injury and/or cellular actions induced by hypertension-related hormones or growth factors. Among the most important is Angiotensin II (Ang II), which controls blood pressure and induces different cellular functions that may be dependent or independent of its effect on blood pressure. Importantly, as is true for heart, kidney and other organs, the renin-angiotensin system (RAS) is present in the eye. So, even in the absence of hypertension, local production of Ang II could be involved in eye diseases. The goal of this manuscript is to review the most relevant scientific evidence supporting the role of the RAS activation, in the development of age-related macular degeneration and diabetic retinopathy, and highlight the importance of Ang II in the etiology of these diseases. PMID:25276298

  13. Angiotensin II revisited: new roles in inflammation, immunology and aging

    PubMed Central

    Benigni, Ariela; Cassis, Paola; Remuzzi, Giuseppe

    2010-01-01

    That the renin–angiotensin system (RAS) is involved in regulation of blood pressure, vasoconstriction, sodium intake and potassium excretion is well established. Studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease. Binding of Ang II to its receptors (in particular AT1) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents. Altogether these findings open the unanticipated perspective for exploring Ang II signalling in therapeutic interventions in inflammatory diseases and aging-related tissue injury. This review extends from the discovery of Ang II and its implications in renal and cardiovascular physiology to cover the roles of the system in inflammation, tissue injury, autoimmunity, oxidative stress and aging. PMID:20597104

  14. A Low-Protein Diet Enhances Angiotensin II Production in the Lung of Pregnant Rats but Not Nonpregnant Rats

    PubMed Central

    Gao, Haijun; Tanchico, Daren Tubianosa; Yallampalli, Uma; Yallampalli, Chandrasekhar

    2016-01-01

    Pulmonary angiotensin II production is enhanced in pregnant rats fed a low-protein (LP) diet. Here we assessed if LP diet induces elevations in angiotensin II production in nonpregnant rats and whether Ace expression and ACE activity in lungs are increased. Nonpregnant rats were fed a normal (CT) or LP diet for 8, 12, or 17 days and timed pregnant rats fed for 17 days from Day 3 of pregnancy. Plasma angiotensin II, expressions of Ace and Ace2, and activities of these proteins in lungs, kidneys, and plasma were measured. These parameters were compared among nonpregnant rats or between nonpregnant and pregnant rats fed different diets. Major findings are as follows: (1) plasma angiotensin II levels were slightly higher in the LP than CT group on Days 8 and 12 in nonpregnant rats; (2) expression of Ace and Ace2 and abundance and activities of ACE and ACE2 in lungs, kidneys, and plasma of nonpregnant rats were unchanged by LP diet except for minor changes; (3) the abundance and activities of ACE in lungs of pregnant rats fed LP diet were greater than nonpregnant rats, while those of ACE2 were decreased. These results indicate that LP diet-induced increase in pulmonary angiotensin II production depends on pregnancy. PMID:27195150

  15. Ethanol alters angiotensin II stimulated mitogen activated protein kinase in hepatocytes: agonist selectivity and ethanol metabolic independence.

    PubMed

    Weng, Y; Shukla, S D

    2000-06-23

    Angiotensin II activated mitogen-activated protein kinase (MAPK) (p42 and p44) in rat hepatocytes exposed to ethanol and the relevance of ethanol metabolism on this activation was investigated. Hepatocytes, isolated from rat liver, were treated with or without ethanol for 24 h. Angiotensin II, vasopressin, insulin, serum and epinephrine significantly increased hepatocyte MAPK activity. Platelet activating factor (PAF), tumor necrosis factor-alpha (TNF-alpha), and insulin-like growth factor-1 (IGF-1) had little effect on MAPK activation. Interestingly, among the above agonists, which activated hepatocyte MAPK, ethanol exposure potentiated only angiotensin II and epinephrine-stimulated MAPK. Thus, potentiation of MAPK by ethanol exhibited agonist selectivity. In contrast to several other cells, there was prevalence of p42 over p44 MAPK band in hepatocytes. Angiotensin II treatment caused a rapid activation (peak 5 min) of MAPK followed by a decrease to basal levels in 30 min. Exposure with 100 mM ethanol potentiated the angiotensin II stimulated MAPK activity. This potentiation was partially blocked by pertussis toxin suggesting it to be a G-protein-dependent event. Treatment of the hepatocytes with pyrazole (an inhibitor of ethanol metabolism) or acetaldehyde (an ethanol metabolite) had no effect on potentiation. Thus, ethanol potentiation of hepatocyte MAPK is agonist-selective and independent of ethanol metabolism. PMID:10862821

  16. Mineralocorticoid and angiotensin II type 1 receptors in the subfornical organ mediate angiotensin II - induced hypothalamic reactive oxygen species and hypertension.

    PubMed

    Wang, Hong-Wei; Huang, Bing S; White, Roselyn A; Chen, Aidong; Ahmad, Monir; Leenen, Frans H H

    2016-08-01

    Activation of angiotensinergic pathways by central aldosterone (Aldo)-mineralocorticoid receptor (MR) pathway plays a critical role in angiotensin II (Ang II)-induced hypertension. The subfornical organ (SFO) contains both MR and angiotensin II type 1 receptors (AT1R) and can relay the signals of circulating Ang II to downstream nuclei such as the paraventricular nucleus (PVN), supraoptic nucleus (SON) and rostral ventrolateral medulla (RVLM). In Wistar rats, subcutaneous (sc) infusion of Ang II at 500ng/min/kg for 1 or 2weeks increased reactive oxygen species (ROS) as measured by dihydroethidium (DHE) staining in a nucleus - specific pattern. Intra-SFO infusion of AAV-MR- or AT1aR-siRNA prevented the Ang II-induced increase in AT1R mRNA expression in the SFO and decreased MR mRNA. Both MR- and AT1aR-siRNA prevented increases in ROS in the PVN and RVLM. MR- but not AT1aR-siRNA in the SFO prevented the Ang II-induced ROS in the SON. Both MR- and AT1aR-siRNA in the SFO prevented most of the Ang II-induced hypertension as assessed by telemetry. These results indicate that Aldo-MR signaling in the SFO is needed for the activation of Ang II-AT1R-ROS signaling from the SFO to the PVN and RVLM. Activation of Aldo-MR signaling from the SFO to the SON may enhance AT1R dependent activation of pre-sympathetic neurons in the PVN. PMID:27163380

  17. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    PubMed Central

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2014-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

  18. Role of angiotensin II in renal wrap hypertension.

    PubMed

    Denton, K M; Anderson, W P

    1985-01-01

    The role of angiotensin II in the development of renal wrap hypertension was studied in rabbits that underwent either bilateral renal cellophane wrap or sham operation. In half the rabbits, angiotensin II production was blocked by continuous administration of enalapril. Four weeks after renal wrapping, mean arterial pressure had risen by 48 +/- 5 mm Hg in untreated rabbits, but by only 25 +/- 4 mm Hg in enalapril-treated rabbits (p less than 0.01). Similar differences were also measured 6 weeks after wrapping. In untreated rabbits, plasma renin activity had increased fourfold 4 and 6 weeks after renal wrapping. There were no significant changes in blood pressure or plasma renin activity following sham operation. Compared with that in sham-operated rabbits, renal blood flow was reduced by 60% in the untreated rabbits 4 weeks after wrapping but by only 30% in the enalapril-treated wrapped rabbits (p less than 0.05). Renal vascular resistances were 5.5 +/- 1.7 mm Hg . ml-1 . min-1 and 1.2 +/- 0.1 mm Hg . min . ml-1 in the untreated wrapped and sham-operated rabbits respectively and 1.9 +/- 0.4 mm Hg . min . ml-1 and 0.8 +/- 1 mm Hg . min . ml-1 in the enalapril-treated wrapped and sham-operated rabbits. Renal wrapping did not alter filtration fraction in untreated rabbits, but markedly reduced it in enalapril-treated rabbits. These results suggest that angiotensin II had two major effects in rabbits after bilateral renal wrapping: it contributed substantially to the increase in blood pressure and caused renal vasoconstriction, primarily at a postglomerular site. PMID:3000937

  19. Localized accumulation of angiotensin II and production of angiotensin-(1-7) in rat luteal cells and effects on steroidogenesis.

    PubMed

    Pepperell, John R; Nemeth, Gabor; Yamada, Yuji; Naftolin, Frederick; Merino, Maricruz

    2006-08-01

    These studies aim to investigate subcellular distribution of angiotensin II (ANG II) in rat luteal cells, identify other bioactive angiotensin peptides, and investigate a role for angiotensin peptides in luteal steroidogenesis. Confocal microscopy showed ANG II distributed within the cytoplasm and nuclei of luteal cells. HPLC analysis showed peaks that eluted with the same retention times as ANG-(1-7), ANG II, and ANG III. Their relative concentrations were ANG II >or= ANG-(1-7) > ANG III, and accumulation was modulated by quinapril, an inhibitor of angiotensin-converting enzyme (ACE), Z-proprolinal (ZPP), an inhibitor of prolyl endopeptidase (PEP), and parachloromercurylsulfonic acid (PCMS), an inhibitor of sulfhydryl protease. Phenylmethylsulfonyl fluoride (PMSF), a serine protease inhibitor, did not affect peptide accumulation. Quinapril, ZPP, PCMS, and PMSF, as well as losartan and PD-123319, the angiotensin receptor type 1 (AT1) and type 2 (AT2) receptor antagonists, were used in progesterone production studies. ZPP significantly reduced luteinizing hormone (LH)-dependent progesterone production (P < 0.05). Quinapril plus ZPP had a greater inhibitory effect on LH-stimulated progesterone than either inhibitor alone, but this was not reversed by exogenous ANG II or ANG-(1-7). Both PCMS and PMSF acutely blocked LH-stimulated progesterone, and PCMS blocked LH-sensitive cAMP accumulation. Losartan inhibited progesterone production in permeabilized but not intact luteal cells and was reversed by ANG II. PD-123319 had no significant effect on luteal progesterone production in either intact or permeabilized cells. These data suggest that steroidogenesis may be modulated by angiotensin peptides that act in part through intracellular AT1 receptors. PMID:16478781

  20. A Study of Angiotensin II Pressor Response throughout Primigravid Pregnancy

    PubMed Central

    Gant, Norman F.; Daley, Gilroy L.; Chand, Santosh; Whalley, Peggy J.; MacDonald, Paul C.

    1973-01-01

    The present study was designed to ascertain sequentially the pressor response to angiotensin II in young primigravid patients throughout pregnancy in order a) to define when in pregnancy resistance to the pressor effects of angiotensin II develops; b) to define the physiologic sequence of events leading to this resistance; and c) to ascertain whether sensitivity to infused angiotensin II could be detected before the onset of clinical signs of pregnancy-induced hypertension. With this prospective approach, two separate groups of patients were defined. The first group of patients remained normal throughout pregnancy. The second group consisted of those patients who, while clinically normotensive during the initial phase of the study, ultimately developed hypertension of pregnancy. 192 patients were studied; of these, 120 patients remained normotensive and 72 developed pregnancy-induced hypertension. In both groups, vascular resistance to infused angiotensin II (more than 8 ng/kg/min required to elicit a pressor response of 20 mm Hg in diastolic pressure) was demonstrated as early as the 10th wk of pregnancy. In the group that remained normotensive, maximum mean vascular resistance occurred at 18-30 wk of pregnancy, (mean pressor dose required being 13.5 to 14.9 ng/kg/min). In those subjects who developed pregnancy-induced hypertension, the mean maximum dose required was 12.9 ng/kg/min, which was observed at the 18th wk of pregnancy. By the 22nd wk there was a clear separation of the two groups, with the mean dose requirement of the subjects destined to develop hypertension being progressively less than that of those who remained normal. The difference between the two groups became significant (P < 0.01) by 23-26 wk of pregnancy. Among patients requiring more than 8 ng/kg/min on one or more tests done between wk 28-32, 91% remained normotensive. Conversely, during the same time period among patients requiring less than 8 ng/kg/min, on at least one occasion, 90

  1. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes.

    PubMed

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-09-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin‑like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription‑quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t‑test or one‑way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  2. Angiotensin II and Oxidative Stress in the Failing Heart

    PubMed Central

    Zablocki, Daniela

    2013-01-01

    Abstract Significance: Despite recent medical advances, cardiovascular disease and heart failure (HF) continue to be major health concerns, and related mortality remains high. As a result, investigation of the mechanisms involved in the development of HF continues to be an active field of study. Recent Advances: The renin–angiotensin system (RAS) and its effector molecule, angiotensin (Ang) II, affect cardiac function through both systemic and local actions, and have been shown to play a major role in cardiac remodeling and dysfunction in the failing heart. Many of the downstream effects of AngII signaling are mediated by elevated levels of reactive oxygen species (ROS) and oxidative stress, which have also been implicated in the pathology of HF. Critical Issues: Inhibitors of the RAS have proven beneficial in the treatment of patients at risk for and suffering from HF, but remain only partially effective. ROS can be generated from several different sources, and the oxidative state is normally tightly regulated in the heart. How AngII increases ROS levels and causes dysregulation of the cardiac oxidative state has been the subject of considerable interest in recent years. Future Directions: A better understanding of this process and the mechanisms involved should lead to the development of more effective HF therapies and improved outcomes. Antioxid. Redox Signal. 19, 1095–1109. PMID:22429089

  3. Angiotensin II stimulates melanogenesis via the protein kinase C pathway

    PubMed Central

    LIU, LI-HONG; FAN, XIN; XIA, ZHI-KUAN; AN, XU-XI; YANG, RONG-YA

    2015-01-01

    Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which serve a crucial function in hyperpigmentation. The aim of the present study was to determine the effects of angiotensin II (Ang II) on melanogenesis and to elucidate the molecular events of Ang II-induced melanogenesis. Experiments were performed on human melanocytes to elucidate the pigmenting effect of Ang II and the underlying mechanisms. The elements involved in melanogenesis, including melanin content, tyrosinase (TYR) activity, and microphthalmia-associated transcription factor (MITF) and TYR expression at the mRNA and protein levels were evaluated. Melanin content and TYR activity increased in response to Ang II treatment in a concentration-dependent manner. MITF and TYR mRNA and protein expression levels were increased significantly in response to Ang II in a concentration-dependent manner. The Ang II-induced increase in melanin synthesis was reduced significantly in response to co-treatment with Ro-32-0432, a protein kinase C (PKC) inhibitor, whereas co-treatment with H-89, a PKA inhibitor, did not attenuate the Ang II-induced increase in melanin levels. These results suggest that PKC is required for Ang II-induced pigmentation in human melanocytes and that the mechanism involves the PKC pathway and MITF upregulation. PMID:26622519

  4. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    SciTech Connect

    Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

    1987-06-01

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 ..mu..M) stimulates increased neuronal (/sup 3/H)NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal (/sup 3/H)DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism.

  5. Tumor necrosis factor-induced contraction of cultured rat mesangial cells: interaction with angiotensin II.

    PubMed

    Medina, J; Baud, L; Garcia Escribano, C; Gila, J A; Rodriguez Puyol, D; Rodriguez Puyol, M

    1993-08-01

    The role of tumor necrosis factor alpha in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically--by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli--and biochemically--by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor alpha significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor alpha was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction > 10%) was analyzed. Tumor necrosis factor alpha also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8340701

  6. [Polyamines antagonizing angiotensin II contractile effects in isolated rat aorta].

    PubMed

    Costuleanu, Natalia; Foia, Liliana; Slătineanu, Simona Mihaela; Indrei, L L; Costuleanu, M; Petrescu, Gh

    2003-01-01

    Our study showed that the administration in pre-treatment of some polyamines (especially spermine and spermidine and almost null agmatine, putrescine and cadaverine) reduced the contractile effects of angiotensin II (Ang II) in isolated rat aorta. These effects might not be associated to the interference of clathrin coated vesicles (coated pits) formation or caveolae interaction (and thus to Ang II internalization through AT1 receptors). In contrast, these effects seem to be due to the interaction with voltage-gated membrane Ca2+ channels. Therefore, the alteration of transmembrane Ca2+ fluxes does not exclude the involvement of internalization process through coated pits or caveolae, since the endocytosis mediated by these phenomena essentially needs Ca2+. In addition, the inhibitory effects are dependent on the number of positive charges of the polyamine molecules. PMID:14755941

  7. Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro

    PubMed Central

    Liu, Jin-Jun; Huang, Ning; Lu, Yi; Zhao, Mei; Yu, Xiao-Jiang; Yang, Yang; Yang, Yong-hua; Zang, Wei-Jin

    2015-01-01

    Cardiac remodeling is characterized by overactivity of the renin–angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10−7 M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10−6 M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-β1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment. PMID:26596640

  8. Cilostazol suppresses angiotensin II-induced apoptosis in endothelial cells

    PubMed Central

    SHI, MIAO-QIAN; SU, FEI-FEI; XU, XUAN; LIU, XIONG-TAO; WANG, HONG-TAO; ZHANG, WEI; LI, XUE; LIAN, CHENG; ZHENG, QIANG-SUN; FENG, ZHI-CHUN

    2016-01-01

    Patients with essential hypertension undergo endothelial dysfunction, particularly in the conduit arteries. Cilostazol, a type III phosphodiesterase inhibitor, serves a role in the inhibition of platelet aggregation and it is widely used in the treatment of peripheral vascular diseases. Previous studies have suggested that cilostazol suppresses endothelial dysfunction; however, it remains unknown whether cilostazol protects the endothelial function in essential hypertension. The aim of the present study was to investigate whether, and how, cilostazol suppresses angiotensin II (angII)-induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) and Sprague Dawley rats were exposed to angII and treated with cilostazol. Endothelial cell apoptosis and function, nitric oxide and superoxide production, phosphorylation (p) of Akt, and caspase-3 protein expression levels were investigated. AngII exposure resulted in the apoptosis of endothelial cells in vitro and in vivo. In vitro, cilostazol significantly suppressed the angII-induced apoptosis of HUVECs; however, this effect was reduced in the presence of LY294002, a phosphoinositide 3 kinase (PI3K) inhibitor. Furthermore, cilostazol suppressed the angII-induced p-Akt downregulation and cleaved caspase-3 upregulation. These effects were also alleviated by LY294002. In vivo, cilostazol suppressed the angII-induced endothelial cell apoptosis and dysfunction. Cilostazol was also demonstrated to partially reduced the angII-induced increase in superoxide production. The results of the present study suggested that cilostazol suppresses endothelial apoptosis and dysfunction by modulating the PI3K/Akt pathway. PMID:26862035

  9. Cardiac steatosis potentiates angiotensin II effects in the heart.

    PubMed

    Glenn, Denis J; Cardema, Michelle C; Ni, Wei; Zhang, Yan; Yeghiazarians, Yerem; Grapov, Dmitry; Fiehn, Oliver; Gardner, David G

    2015-02-15

    Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis. Treatment with ANG II resulted in a similar increase in blood pressure in both nontransgenic and DGAT1 transgenic mice. However, ANG II in DGAT1 transgenic mice resulted in a marked increase in interstitial fibrosis and a reduction in systolic function compared with nontransgenic littermates. Lipidomic analysis revealed that >20% of lipid species were significantly altered between nontransgenic and DGAT1 transgenic animals, whereas 3% were responsive to ANG II administration. ROS were also increased by ANG II in DGAT1 transgenic hearts. ANG II treatment resulted in increased expression of transforming growth factor (TGF)-β2 and the type I TGF-β receptor as well as increased phosphorylation of Smad2 in DGAT1 transgenic hearts. Injection of neutralizing antibodies to TGF-β resulted in a reduction in fibrosis in DGAT1 transgenic hearts treated with ANG II. These results suggest that myocyte steatosis amplifies the fibrotic effects of ANG II through mechanisms that involve activation of TGF-β signaling and increased production of ROS. PMID:25485904

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

    PubMed

    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. PMID:26781276

  11. Purification of an angiotensin II binding protein by using antibodies to a peptide encoded by angiotensin II complementary RNA

    SciTech Connect

    Elton, T.S.; Dion, L.D.; Bost, K.L.; Oparil, S.; Blalock, J.E.

    1988-04-01

    The authors have generated a monospecific antibody to a synthetic peptide encoded by an RNA complementary to the mRNA for angiotensin II (AII) and determined whether this antibody recognizes the AII receptor. They demonstrate that the antibody competes specifically with /sup 125/I-labeled AII for the same binding site on rat adrenal membranes. Furthermore, they show this antibody inhibits the secretion of aldosterone from cultured rat adrenal cells, suggesting that the antibody recognizes the biologically relevant AII receptor. Finally, they demonstrate that antibody to the complementary peptide can be used to immunoaffinity-purify a protein of M/sub r/ 66,000 that specifically binds radiolabeled AII.

  12. Identification and characterization of an angiotensin II receptor on cultured bovine adrenal chromaffin cells

    SciTech Connect

    Boyd, V.L.

    1987-01-01

    The presence of an angiotensin II receptor on cultured bovine adrenal chromaffin cells was demonstrated by radioligand binding. A single class of finding sites with a K/sub D/ of 0.7 nM was characterized. The use of radioligands also allows the localization of receptors by autoradiography. Autoradiography demonstrated that approximately 50% of the isolated cells bound angiotensin II. It was of interest to see if angiotensin II bound to a cell that possessed a certain phenotype. In order to evaluate this possibility a technique was developed that combined autoradiography and immunocytochemistry. Results indicated that angiotensin II binding sites were not localized preferentially to either norepinephrine or epinephrine cells. Binding of angiotensin II was associated with the release of intracellular catecholamine stores. Cells were pre-loaded with /sup 3/H-norepinephrine and secretion was monitored by following radioactivity released into the supernatant. Alternatively, release of endogenous catecholamines was determined by fluorometric assay.

  13. Cytoplasmic translocation of HuR contributes to angiotensin II induced cardiac fibrosis.

    PubMed

    Bai, Danna; Ge, Lan; Gao, Yan; Lu, Xiaozhao; Wang, Haichang; Yang, Guodong

    2015-08-01

    Cardiac fibrosis is one of the key structural changes of the hypertrophied left ventricle in hypertensive heart disease. Increased angiotensin II was found to be important in the hypertension related fibrosis, while the underlying mechanism is unknown. In this study, we found that angiotensin II dose-dependently increased the expression of Col1a1, Col3a1 and α-smooth muscle actin, which were blocked by ROS (reactive oxygen species) scavenger N-acetyl cysteine (NAC). Mechanistically, angiotensin II induced robust ROS generation, which in turn induced cytoplasmic translocation of RNA binding protein HuR. Cytoplasmic translocated HuR increased TGFβ pathway activity and subsequent collagen synthesis. In contrast, knockdown of HuR nearly blocked angiotensin II induced TGFβ activation and collagen synthesis. Taken together, we here identified that angiotensin II promotes collagen synthesis in cardiac fibroblast through ROS-HuR-TGFβ pathway. PMID:26093296

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

    SciTech Connect

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

    1985-01-01

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

  15. Angiotensin II regulates growth of the developing papillas ex vivo

    PubMed Central

    Song, Renfang; Preston, Graeme; Khalili, Ali; El-Dahr, Samir S.

    2012-01-01

    We tested the hypothesis that lack of angiotensin (ANG) II production in angiotensinogen (AGT)-deficient mice or pharmacologic antagonism of ANG II AT1 receptor (AT1R) impairs growth of the developing papillas ex vivo, thus contributing to the hypoplastic renal medulla phenotype observed in AGT- or AT1R-null mice. Papillas were dissected from Hoxb7GFP+ or AGT+/+, +/−, −/− mouse metanephroi on postnatal day P3 and grown in three-dimentional collagen matrix gels in the presence of media (control), ANG II (10−5 M), or the specific AT1R antagonist candesartan (10−6 M) for 24 h. Percent reduction in papillary length was attenuated in AGT+/+ and in AGT+/− compared with AGT−/− (−18.4 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, −22.8 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, respectively). ANG II blunted the decrease in papilla length observed in respective media-treated controls in Hoxb7GFP+ (−1.5 ± 0.3 vs. −10.0 ± 1.4%, P < 0.05) or AGT+/+, +/−, and −/− papillas (−12.8 ± 0.7 vs. −18.4 ± 1.3%, P < 0.05, −16.8 ± 1.1 vs. −23 ± 1.2%, P < 0.05; −26.2 ± 1.6 vs. −32.2 ± 1.6%, P < 0.05, respectively). In contrast, percent decrease in the length of Hoxb7GFP+ papillas in the presence of the AT1R antagonist candesartan was higher compared with control (−24.3 ± 2.1 vs. −10.5 ± 1.8%, P < 0.05). The number of proliferating phospho-histone H3 (pH3)-positive collecting duct cells was lower, whereas the number of caspase 3-positive cells undergoing apoptosis was higher in candesartan- vs. media-treated papillas (pH3: 12 ± 1.4 vs. 21 ± 2.1, P < 0.01; caspase 3: 3.8 ± 0.5 vs. 1.7 ± 0.2, P < 0.01). Using quantitative RT-PCR, we demonstrate that AT1R signaling regulates the expression of genes implicated in morphogenesis of the renal medulla. We conclude that AT1R prevents shrinkage of the developing papillas observed ex vivo via control of Wnt7b, FGF7, β-catenin, calcineurin B1, and α3 integrin gene expression, collecting duct cell

  16. Metabolic Actions of Angiotensin II and Insulin: A Microvascular Endothelial Balancing Act

    PubMed Central

    Muniyappa, Ranganath; Yavuz, Shazene

    2012-01-01

    Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT2 receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT1 receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT1 receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT1 and AT2 receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature. PMID:22684034

  17. Effect of angiotensin-(1-7) and angiotensin II on the proliferation and activation of human endometrial stromal cells in vitro

    PubMed Central

    Shan, Tieying; Shang, Wei; Zhang, Lei; Zhao, Chunfang; Chen, Wei; Zhang, Yanan; Li, Guiying

    2015-01-01

    Recent studies have shown that angiotensin II (Ang II) or angiotensin-(1-7) [Ang-(1-7)] has effect on the proliferation and activation of a variety of cells, however, the exact mechanisms that the role of Ang II or Ang-(1-7) in human endometrial stromal cell (ESCs) remains elusive. Here we demonstrated that Ang II could promote proliferation and activation of ESCs, up-regulated the expression of a-SMA, TGF-β1 and IGF-I, increased the secretion of extracellular matrix [Type I collagen (Col I) and fibronectin (FN)] of ESCs; Ang-(1-7) could inhibit Ang II induced the proliferation and activation of ESCs, down-regulated the expression of a-SMA, TGF-β1 and IGF-I, decreased the secretion of extracellular matrix (Col I and FN) of ESCs. These findings suggest that Ang-(1-7) can inhibits Ang II induced the proliferation of ESCs, Ang-(1-7) can inhibits the Ang II induced activation of ESCs and decreases secretion of Col I and FN by suppressing TGF-β1 and IGF-I expression. PMID:26464636

  18. Angiotensin II Induced Cardiac Dysfunction on a Chip

    PubMed Central

    Horton, Renita E.; Yadid, Moran; McCain, Megan L.; Sheehy, Sean P.; Pasqualini, Francesco S.; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics. PMID:26808388

  19. Angiotensin II activates different calcium signaling pathways in adipocytes.

    PubMed

    Dolgacheva, Lyudmila P; Turovskaya, Maria V; Dynnik, Vladimir V; Zinchenko, Valery P; Goncharov, Nikolay V; Davletov, Bazbek; Turovsky, Egor A

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades: 1) Ang II → Gq → PLC → IP3 → IP3Rs → Ca(2+) 2) Gβγ → PI3Kγ → PKB 3) PKB → eNOS → NO → PKG 4) CD38 → cADPR → RyRs → Ca(2+) In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2 diabetes. PMID:26850364

  20. Mechanism of pulmonary conversion of angiotensin I to angiotensin II in the dog.

    NASA Technical Reports Server (NTRS)

    Oparil, S.; Tregear, G. W.; Koerner, T.; Barnes, B. A.; Haber, E.

    1971-01-01

    The conversion mechanism was studied in vivo in the pulmonary circulation of the intact anesthetized dog and in vitro in plasma by using L-Leu-angiotensin I, D-Leu-angiotensin I, and des-Leu-angiotensin I which had been synthesized by the solid-phase technique. The results obtained indicate that pulmonary conversion in vivo and plasma conversion in vitro occur via a dipeptidylcarboxypeptidase and that a D-amino acid at the C-terminus prevents conversion.

  1. Reduced proximal tubule angiotensin II receptor expression in streptozotocin-induced diabetes mellitus.

    PubMed

    Cheng, H F; Burns, K D; Harris, R C

    1994-12-01

    Diabetes mellitus is characterized by alterations in the intrarenal renin-angiotensin system, including decreases in glomerular angiotensin II (Ang II) receptor density. Since Ang II regulates proximal tubule transport function, the present studies examined whether diabetes altered expression of proximal tubule receptors. In basolateral membranes from 14 day streptozotocin-induced diabetic rats, specific binding of 125I Ang II was decreased to 53 +/- 8% of control (3.2 +/- 0.5 vs. 1.5 +/- 0.2 fmol/mg protein; N = 7; P < 0.02). Similarly, in proximal tubule brush border membranes from diabetic animals, specific binding was decreased to 63 +/- 11% of control (1.1 +/- 0.2 vs 0.6 +/- 0.1 fmol/mg protein; N = 9; P < 0.05). Concomitant insulin treatment reversed the decrease in specific binding of 125I Ang II to basolateral membranes (109 +/- 26% of control; N = 3) and to brush border membranes (85 +/- 17% of control; N = 6). In order to determine if changes in expression of type-1 Ang II receptors (AT1R) accompanied the changes in binding, quantitative polymerase chain reaction of AT1R mRNA was performed and expressed as the ratio of the amplified AT1R to that of an Msc1/Msc1 internal deletion mutant and normalized to that of beta-actin. In total RNA from proximal tubule suspensions of diabetic animals, AT1R mRNA expression decreased by 38% (21 +/- 3 vs. 13 +/- 2 cpm AT1R/cpm deletion mutant/cpm beta actin/10(6); N = 4; P < 0.0025). Insulin treatment reverted AT1R mRNA expression to control levels (22 +/- 3 cpm AT1R/cpm deletion mutant/cpm beta actin/10(6); P < 0.001 compared to the untreated group).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7700017

  2. Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat.

    PubMed

    Stepp, David W; Boesen, Erika I; Sullivan, Jennifer C; Mintz, James D; Hair, Clark D; Pollock, David M

    2007-10-01

    Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease. PMID:17693541

  3. Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep.

    PubMed Central

    Naden, R P; Rosenfeld, C R

    1981-01-01

    The response of uteroplacental blood flow (UBF) to angiotensin II is controversial. Moreover, the relationship of the uterine and systemic responses to infused angiotensin II is not well understood. Thus, in eight chronically instrumented, near-term pregnant sheep, we have determined the relationships between the dose and duration of constant systemic infusions of angiotensin II ([Val5] ANG II) and changes in UBF, uterine vascular resistance (UVR), mean arterial pressure (MAP), and systemic vascular resistance (SVR). [Val5] ANG II caused dose-dependent increases in UVR and MAP at all doses studied (P less than 0.05). The response in UBF was bidirectional, with increases at doses less than or equal to 1.15 microgram/min and decreases at greater than or equal to 2.29 micrograms/min (P less than 0.05). Increases in UBP occurred when the relative rise (delta) in MAP greater than delta UVR, whereas UBF was unchanged when delta MAP = delta UVR and decreased when delta MAP less than delta UVR. SVR also rose in a dose-dependent fashion (P less than 0.05); delta SVR was greater than delta UVR at doses less than or equal to 2.29 micrograms [Val5] ANG II/min (P less than 0.01). In studies of the effect of duration of [Val5] ANG II infusions, UBF increased at all doses during the 1st min, followed by stabilization at 4--5 min, with eventual decreases at doses greater than or equal to 2.29 micrograms/min and increases at doses less than 2.29 micrograms/min. The relationship between the changes in MAP and UVR to the response of UBF was as noted above. It is evident that (a) [Val5] NAG II is uterine vasoconstrictor, (b) changes in UBF are dependent upon relative changes in perfusion pressure and UVR, which in turn are dependent upon both the dose and duration of a [Val5] ANG II infusion, and (c) the uteroplacental vasculature is relatively refractory to the vasoconstricting effects of low doses of [Val5] ANG II. PMID:7263862

  4. Angiotensin II induced release of prostaglandins from rat uterus.

    PubMed

    Campos, G A; Guerra, F A; Israel, E J

    1983-08-01

    The effect of Angiotensin II (A-II) on 6-keto-prostaglandin F1 (6-keto-PGF1 alpha) and prostaglandin F (PGF) production by the rat uterus was studied using a novel superfusion technique. The method of superfusion used allows prostaglandin synthesis in the myometrium and endometrium to be measured independently while their anatomical relationship is undisturbed. Prostaglandins were measured by radioimmunoassay. In uterine horns from castrated, estrogen treated rats, A-II (10(-6)M) stimulated the production rate of 6-keto-PGF1 alpha in the myometrium nd PGF in the endometrium. Sterile horns and pregnant horns coexisting in the same animals showed different responses when superfused with culture medium containing A-II (10(-6)M). In the sterile horns A-II failed to stimulate prostaglandin synthesis whereas in the pregnant horns there was a significant increase in the production rate of both 6-keto-PGF1 alpha and PGF in the decidua (endometrium) and of 6-keto-PGF1 alpha in the myometrium. Our results suggests that the effect of A-II on prostaglandin synthesis by the rat uterus appears to be dependent of the hormonal milieu of the experimental animal. Estrogen stimulated A-II induced PG synthesis. Progesterone inhibited the synthesis of PGs caused by A-II in non-decidualized uterus but stimulated the release of PG in the decidualized uterus. The apparent differential effect of A-II in stimulating prostaglandin synthesis in the whole uterus indicates that there are different pathways for prostaglandin production in both the endometrium and myometrium. PMID:6689628

  5. Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma.

    PubMed

    Zorad, Stefan; Dou, Jing-tao; Benicky, Julius; Hutanu, Daniel; Tybitanclova, Katarina; Zhou, Jin; Saavedra, Juan M

    2006-12-15

    To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties. PMID:17064684

  6. L-type calcium channel β subunit modulates angiotensin II responses in cardiomyocytes.

    PubMed

    Hermosilla, Tamara; Moreno, Cristian; Itfinca, Mircea; Altier, Christophe; Armisén, Ricardo; Stutzin, Andres; Zamponi, Gerald W; Varela, Diego

    2011-01-01

    Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca(v)β subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca(v)β subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca(v)β subunit isoform, with Ca(v)β(1b) containing channels being more strongly regulated. Ca(v)β(2a) containing channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca(v)β subunit-dependent manner. These data demonstrate that Ca(v)β subunits alter the magnitude of inhibition of L-type current by Angiotensin II. PMID:21525790

  7. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

    PubMed Central

    Vilas-Boas, Walkíria Wingester; Ribeiro-Oliveira Jr, Antônio; Pereira, Regina Maria; da Cunha Ribeiro, Renata; Almeida, Jerusa; Nadu, Ana Paula; Simões e Silva, Ana Cristina; dos Santos, Robson Augusto Souza

    2009-01-01

    AIM: To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes. METHODS: Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS: PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05). In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 ± 0.08 vs 0.38 ± 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 ± 0.02 vs 0.13 ± 0.02, P < 0.04). Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70). CONCLUSION: Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis. PMID:19469002

  8. [Effect of safflor yellow B on vascular endothelial cells injury induced by angiotensin-II].

    PubMed

    Wang, Chao-Yun; Zhang, Shu-Ping; Xu, Yong; Yang, Ming; Jiang, Wen-Guo; Luan, Hai-Yun

    2012-06-01

    This study is to investigate protective effect of safflor yellow B (SYB) against vascular endothelial cells (VECs) injury induced by angiotensin-II (Ang-II). VECs were cultured and divided into six groups: control group, Ang-II group, Ang-II + SYB (1 micromolL(-1)) group, Ang-II + SYB (10 micromolL(-1)) group, Ang-II + SYB (100 micromolL(-1)) group and Ang- II + verapamil (10 micromolL(-1)) group. Except control group, all of VECs in other groups were treated with Ang- II at the final concentration of 0.1 micromolL(-1). Mitochondria membrane potential (MMP) and free calcium concentration ([Ca2+]i) were measured by laser scanning confocal microscopy, and mitochondria complex IV activity was detected by BCA method. The levels of reactive oxygen species (ROS) in VECs were analyzed by fluorescence detector and apoptosis of VECs was observed by flow cytometer. Caspase 3 was determined by Western blotting method. Comparing with control group, Ang-II was able to increase [Ca2+]i and ROS level, decrease MMP level, inhibit complex IV activity and enhance caspase 3 activity in VECs, as a result, enhance apoptosis of VECs. But SYB could significantly reduce the result induced by Ang- II relying on different dosages (P < 0.05 or P < 0.01). SYB was able to eliminate the effect of Ang-II on VECs via regulating [Ca2+]i, mitochondrial structure and function and inhibiting apoptosis. PMID:22919732

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

    PubMed Central

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

    2014-01-01

    Previous studies show that the angiotensin type 1 receptor (AT1R) is susceptible to rapid desensitization, but that more chronic treatments that stimulate ANG II lead to sensitization of several responses. It is unclear, however, if the processes of desensitization and sensitization interact. To test for differences in AT1R expression associated with single or repeated injections of ANG II, we measured AT1R mRNA in nuclei that control fluid intake of rats given ANG II either in a single injection or divided into three injections spaced 20 min apart. Rats given a single injection of ANG II had more AT1R mRNA in the subfornical organ (SFO) and the periventricular tissue surrounding the anteroventral third ventricle (AV3V) than did controls. The effect was not observed, however, when the same cumulative dose of ANG II was divided into multiple injections. Behavioral tests found that single daily injections of ANG II sensitized the dipsogenic response to ANG II, but a daily regimen of four injections did not cause sensitization. Analysis of 125I-Sar1-ANG II binding revealed a paradoxical decrease in binding in the caudal AV3V and dorsal median preoptic nucleus after 5 days of single daily injections of ANG II; however, this effect was absent in rats treated for 5 days with four daily ANG II injections. Taken together, these data suggest that a desensitizing treatment regimen prevents behavior- and receptor-level effects of repeated daily ANG II. PMID:25354729

  10. The effect of angiotensin II receptor blockers on hyperuricemia

    PubMed Central

    Wolff, Marissa L.; Cruz, Jennifer L.; Vanderman, Adam J.; Brown, Jamie N.

    2015-01-01

    The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ⩾7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: ‘uric acid’, ‘urate transporter’, ‘gout’, ‘angiotensin II receptor blockers’, ‘hyperuricemia’ and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. PMID:26568810

  11. Norepinephrine uptake by rat jejunum: Modulation by angiotensin II

    SciTech Connect

    Suvannapura, A.; Levens, N.R. )

    1988-02-01

    Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibition norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (K{sub m}) of 1.72 {mu}M and a maximum velocity (V{sub max}) of 1.19 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. The low-affinity component (uptake 2) exhibited a K{sub m} of 111.1 {mu}M and a V{sub max} of 37.1 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of ({sup 3}H)NE uptake into rat jejunum. ANG II inhibited intracellular ({sup 3}H)NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular ({sup 3}H)NE accumulation by 60%. Cocaine failed to potentiate the inhibition of ({sup 3}H)NE uptake produced by ANG II. Thus ANG II appears to prevent ({sup 3}H)NE accumulation within rat jejunum by inhibiting neuronal uptake.

  12. Quantitative autoradiography of angiotensin II receptors in the brain and kidney

    SciTech Connect

    Gehlert, D.R.

    1985-01-01

    The renin-angiotensin system is an important component in the regulation of systemic blood pressure. Angiotensin II is the principal effector peptide of this system. Interaction of angiotensin II with specific receptors can produce in several organic systems. When administered into the brain this octa-peptide produces a variety of responses including a stimulation of drinking, increased systemic blood pressure and several neuroendocrine responses. Its effects on the kidney include alterations in arteriolar resistance, mesangial cell contraction and a feedback inhibition of the release of renin. Since this peptide produces profound effects on homeostatis by an interaction with specific receptors, the quantitative technique of in vitro autoradiography was applied to localize receptor populations for angiotensin II. Specific binding sites for a radiolabeled form of angiotensin II were localized in various brain and kidney regions. In the rat brain high densities of angiotensin II receptors were observed in the paraventricular and suprachiasmatic nuclei of the hypothalamus, supraoptic nucleus and the posterior lobe of the pituitary, brain areas in which angiotensin II modified neuroendocrine functions.

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

    PubMed

    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. PMID:27233763

  14. Nitric oxide mediates the inhibitory action of platelet-activating factor on angiotensin II-induced renal vasoconstriction, in vivo.

    PubMed

    Handa, R K; Strandhoy, J W

    1996-06-01

    The objective of our study was to determine the mechanism(s) involved in the inhibitory effect of platelet-activating factor on renal vascular reactivity, in vivo. Bolus injections of vasoconstrictor agonists were administered into the renal circulation of pentobarbital anesthetized male Wistar rats at a dose to cause a transient 45 to 50% decrease in renal blood flow. Intrarenal infusion of platelet-activating factor (PAF) at 2.5 ng/min/kg attenuated the vasoconstrictor response to angiotensin II by 66%, a significantly smaller reduction of 35% for norepinephrine-mediated vasoconstriction, 22% for vasopressin-mediated vasoconstriction and no alteration of KCl-mediated vasoconstriction. The preferential inhibitory effect of platelet-activating factor on angiotensin II-mediated renal vasoconstriction was mimicked by the intrarenal infusion of either 0.2 to 5 micrograms/min/kg methacholine (endothelium-dependent vasodilator) or 2 micrograms/min/kg sodium nitroprusside (nitric oxide donor). After inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine, intrarenal infusion of PAF or methacholine reduced angiotensin II-mediated renal vasoconstriction significantly less than that observed in the absence of NG-monomethyl-L-arginine. Therefore, this study provides evidence that the shared ability of platelet-activating factor and methacholine to selectively reduce angiotensin II-mediated renal vasoconstriction involves endothelium-derived nitric oxide. PMID:8667214

  15. Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans.

    PubMed

    Matsukawa, Toshiyoshi; Miyamoto, Takenori

    2011-03-01

    We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II. PMID:21123762

  16. Effects of β(3)-adrenoceptor activation on expression of pancreatic adrenoceptors and angiotensin II receptors in ApoE(-/-) mice.

    PubMed

    Song, Jun-Ying; Li, Yan-Fang; Jiang, Zhi-Li; Guo, Yan-Qing

    2015-10-01

    Hyperlipidemia can be harmful to the pancreas and β3-adrenoceptor agonist can improve lipid metabolism disorder. We aimed to study the effects of β3-adrenoceptor activation on glucose, insulin and the expression of pancreatic adrenoceptors and angiotensin II receptors. Ten C57BL/6J mice at the age of 10 weeks served as normal control, and forty age-matched apolipoprotein E knockout (ApoE(-/-)) mice were randomly divided into hyperlipidaemia model group, low-dose and high-dose β3-adrenoceptor agonist group and β3-adrenoceptor antagonist group. After 26 weeks of high-fat diet, treatments were given for 12 weeks. Serum glucose and insulin levels in 48 weeks old mice were measured using an automatic biochemical detector. Quantitative rt-PCR and Western blot were used to analyze the mRNA and protein expression of α1A-, α2A-, β2-, β3-adrenoceptors and angiotensin II type 1 and type 2 receptors in pancreas. We found that β3-adrenoceptor agonist could decrease serum glucose and insulin levels in aged ApoE(-/-) mice (P<0.01) and down-regulate the expression of α1A-adrenoceptor and angiotensin II type 1 receptor which were significantly increased in model mice (P<0.05, P<0.01). Compared with the model mice, α2A-, β2-, β3-adrenoceptor and angiotensin II type 2 receptor expression were up-regulated in β3-adrenoceptor agonist treat mice (P<0.05, P<0.01). These results suggest that chronic β3-adrenoceptor activation regulated the expression of adrenoceptors and angiontensin II receptors towards contrary direction, which indicates that there are interactions between β3-adrenoceptor and subtypes of adrenoceptor and angiotensin II receptor, and these interactions may play a protective role in pancreas and improve glucose metabolism disorders. PMID:26102566

  17. Changes in angiotensin II receptor bindings in the hen neurohypophysis before and after oviposition.

    PubMed

    Takahashi, T; Nozaki, Y; Nakagawa-Mizuyachi, K; Nakayama, H; Kawashima, M

    2011-11-01

    The present study was performed to elucidate whether the angiotensin II (ANG II) receptor exists in the plasma membrane fraction of the neurohypophysis in hens, to estimate the time of action of ANG II on the neurohypophysis before and after oviposition, and to examine relationships between the action of ANG II on the neurohypophysis and those of estrogen and prostaglandin F(2α) (PGF(2α)) in relation to arginine vasotocin (AVT) release. The specific binding had a binding specificity to chicken ANG II (cANG II), reversibility, and saturation in the [(125)I]cANG II binding assay. Scatchard analysis revealed that the binding sites are of a single class. The equilibrium dissociation constant (K(d)) obtained by kinetic analysis and Scatchard analysis suggested a high affinity, and the maximum binding capacity (B(max)) obtained by Scatchard analysis suggested a limited capacity. These results suggest that an ANG II receptor exists in the neurohypophysis of hens. The K(d) and the B(max) value was significantly smaller in laying hens than in nonlaying hens, which suggests that bindings of the cANG II receptor change, depending on the difference in laying condition. Values of the K(d) and the B(max) decreased approximately 15 min before oviposition in laying hens, and decreased 1 h after an intramuscular injection of estradiol-17β and 5 min after an intravenous injection of cANG II in nonlaying hens. The amount of specific binding of PGF(2α) receptor in the neurohypophysis also decreased and AVT concentration in blood increased after the cANG II injection. It seems likely that the action of cANG II in the neurohypophysis increases due to the effect of estrogen approximately 15 min before oviposition, and the cANG II action stimulates AVT release through the increase in the PGF(2α) action in this tissue. PMID:22010242

  18. Caveolae regulate vasoconstriction of conduit arteries to angiotensin II in hindlimb unweighted rats.

    PubMed

    Wang, Zhongchao; Bai, Yungang; Yu, Jinwen; Liu, Huan; Cheng, Yaoping; Liu, Yonghong; Xie, Xiaoping; Ma, Jin; Bao, Junxiang

    2015-10-15

    Weightlessness induces the functional remodelling of arteries, but the changes to angiotensin II (Ang II)-elicited vasoconstriction and the underlying mechanism have never been reported. Caveolae are invaginations of the cell membrane crucial for the contraction of vascular smooth muscle cells, so we investigated the adaptation of Ang II-elicited vasoconstriction to simulated weightlessness and the role of caveolae in it. The 4 week hindlimb unweighted (HU) rat was used to simulate the effects of weightlessness. Ang II-elicited vasoconstriction was measured by isometric force recording. The morphology of caveolae was examined by transmission electron microscope. The binding of the angiotensin II type 1 receptor (AT1 ) and caveolin-1 (cav-1) was examined by coimmunoprecipitation and Western blot. We found that the maximal developing force (E(max)) of Ang II-elicited vasoconstriction was decreased in abdominal aorta by 30.6%, unchanged in thoracic aorta and increased in carotid artery by 17.9% after HU, while EC50 of the response was increased in all three arteries (P < 0.05). AT1 desensitization upon activation was significantly reduced by HU in all three arteries, as was the number of caveolae (P < 0.05). Furthermore, Ang II promoted the binding of AT1 and cav-1 significantly in control but not HU arteries. Both the number of caveolae and the binding of AT1 and cav-1 in HU arteries were restored by cholesterol pretreatment which also reinstated the change in EC50 as well as the level of AT1 desensitization. These results indicate that modified caveolae in vascular smooth muscle cells could interfere with the binding of AT1 and cav-1 mediating the adaptation of Ang II-elicited vasoconstriction to HU. PMID:26260249

  19. Assessment of angiotensin II receptor blockade in humans using a standardized angiotensin II receptor-binding assay.

    PubMed

    Maillard, M P; Mazzolai, L; Daven, V; Centeno, C; Nussberger, J; Brunner, H R; Burnier, M

    1999-12-01

    An in vitro angiotensin II (AngII) receptor-binding assay was developed to monitor the degree of receptor blockade in standardized conditions. This in vitro method was validated by comparing its results with those obtained in vivo with the injection of exogenous AngII and the measurement of the AngII-induced changes in systolic blood pressure. For this purpose, 12 normotensive subjects were enrolled in a double-blind, four-way cross-over study comparing the AngII receptor blockade induced by a single oral dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and placebo. A significant linear relationship between the two methods was found (r = 0.723, n = 191, P<.001). However, there exists a wide scatter of the in vivo data in the absence of active AngII receptor blockade. Thus, the relationship between the two methods is markedly improved (r = 0.87, n = 47, P<.001) when only measurements done 4 h after administration of the drugs are considered (maximal antagonist activity observed in vivo) suggesting that the two methods are equally effective in assessing the degree of AT-1 receptor blockade, but with a greatly reduced variability in the in vitro assay. In addition, the pharmacokinetic/pharmacodynamic analysis performed with the three antagonists suggest that the AT-1 receptor-binding assay works as a bioassay that integrates the antagonistic property of all active drug components of the plasma. This standardized in vitro-binding assay represents a simple, reproducible, and precise tool to characterize the pharmacodynamic profile of AngII receptor antagonists in humans. PMID:10619583

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

    PubMed Central

    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

  1. Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

    PubMed

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

    2015-08-01

    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 the 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 per minute) 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

  2. Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.

    PubMed

    Müller, D N; Mervaala, E M; Dechend, R; Fiebeler, A; Park, J K; Schmidt, F; Theuer, J; Breu, V; Mackman, N; Luther, T; Schneider, W; Gulba, D; Ganten, D; Haller, H; Luft, F C

    2000-07-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and

  3. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy

    PubMed Central

    Müller, Dominik N.; Mervaala, Eero M. A.; Dechend, Ralf; Fiebeler, Anette; Park, Joon-Keun; Schmidt, Folke; Theuer, Jürgen; Breu, Volker; Mackman, Nigel; Luther, Thomas; Schneider, Wolfgang; Gulba, Dietrich; Ganten, Detlev; Haller, Hermann; Luft, Friedrich C.

    2000-01-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT1 receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-κB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT1 receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT1 receptor blockade. Deletion of both AP-1 and NF-κB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT1 receptor blockade in this model are mediated via the inhibition of NF-κB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions. PMID

  4. Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

    PubMed

    Fujii, Naoto; Meade, Robert D; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah; Kenny, Glen P

    2015-05-01

    It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise. PMID:25767030

  5. Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

    PubMed Central

    Fujii, Naoto; Meade, Robert D.; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah

    2015-01-01

    It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise. PMID:25767030

  6. Effects of Angiotensin II Receptor Signaling during Skin Wound Healing

    PubMed Central

    Takeda, Hikaru; Katagata, Yohtaro; Hozumi, Yutaka; Kondo, Shigeo

    2004-01-01

    The tissue angiotensin (Ang) system, which acts independently of the circulating renin Ang system, is supposed to play an important role in tissue repair in the heart and kidney. In the skin, the role of the system for wound healing has remained to be ascertained. Our study demonstrated that oral administration of selective AngII type-1 receptor (AT1) blocker suppressed keratinocyte re-epithelization and angiogenesis during skin wound healing in rats. Immunoprecipitation and Western blot analysis indicated the existence of AT1 and AngII type-2 receptor (AT2) in cultured keratinocytes and myofibroblasts. In a bromodeoxyuridine incorporation study, induction of AT1 signaling enhanced the incorporation into keratinocytes and myofibroblasts. Wound healing migration assays revealed that induction of AT1 signaling accelerated keratinocyte re-epithelization and myofibroblasts recovering. In these experiments, induction of AT2 signaling acted vice versa. Taken together, our study suggests that skin wound healing is regulated by balance of opposing signals between AT1 and AT2. PMID:15509535

  7. Quantitative distribution of angiotensin II binding sites in rat brain by autoradiography

    SciTech Connect

    Saavedra, J.M.; Israel, A.; Plunkett, L.M.; Kurihara, M.; Shigematsu, K.; Correa, F.M.

    1986-07-01

    Angiotensin II binding sites were localized and quantified in individual brain nuclei from single rats by incubation of tissue sections with 1 nM /sup 125/I-(Sar1)-angiotensin II, (/sup 3/H)-Ultrofilm autoradiography, computerized microdensitometry and comparison with /sup 125/I-standards. High angiotensin II binding was present in the circumventricular organs (organon vasculosum laminae terminalis, organon subfornicalis and area postrema), in selected hypothalamic nuclei (nuclei suprachiasmatis, periventricularis and paraventricularis) and in the nucleus tractus olfactorii lateralis, the nucleus preopticus medianus, the dorsal motor nucleus of the vagus and the nucleus tractus solitarii. High affinity (KA from 0.3 to 1.5 X 10(9) M-1) angiotensin II binding sites were demonstrated in the organon subfornicalis, the nucleus tractus solitarii and the area postrema after incubation of consecutive sections from single rat brains with /sup 125/I-(Sar1)-angiotensin II in concentrations from 100 pM to 5 nM. These results demonstrate and characterize brain binding sites for angiotensin II of variable high affinity binding both inside and outside the blood-brain barrier.

  8. Angiotensin II type 1 receptor antibodies in childhood kidney transplantation.

    PubMed

    Bjerre, Anna; Tangeraas, Trine; Heidecke, Harald; Dragun, Duska; Dechend, Ralf; Staff, Anne Cathrine

    2016-08-01

    Angiotensin II type 1 receptor antibodies (AT1 RAb) have emerged as non-HLA Ab present in patients with acute AMR and risk of graft loss. Furthermore, AT1 RAb have been shown to increase angiotensin II sensitivity which may play a role in the development of CVD and hypertension. Data on AT1 RAb in stable transplant recipients are lacking. The aim of this study was to analyze the levels of AT1 RAb in a cohort of stable patients after kidney transplantation (tx) in childhood. A cross-sectional study of 30 children (median age 14, range 3-19 yr, median time since tx five yr) and 28 adults who were transplanted in childhood (median age 26, range 20-40 yr, median time since tx 18 yr) transplanted between 1993-2006 and 1983-2002, respectively, was performed. Healthy controls were 51 healthy children (5-8 yr) and 199 healthy donors (median age 56.5 yr, range 42-83 yr). Plasma AT1 RAb were analyzed by immunoassay. Median total AT1 RAb IgG concentration was significantly higher in the pediatric-tx group as compared to the adult-tx group (40.0 and 10.95 U/mL, p < 0.0001). For both groups, the tx group showed higher levels: the pediatric-tx group vs. control group (40.0 vs. 13.3 U/mL, p = 0.0006) and the adult-tx group vs. adult control group (10.95 vs. 6.5 U/mL, p < 0.0001). Age was the strongest indicator of high levels of AT1 RAb IgG (p = 0.0003). AT1 RAb total IgG levels are significantly higher in a stable pediatric-tx cohort as compared to adult-tx patients and healthy controls of comparable age groups. The relevance of our findings in relation to age, time since tx, previous or future rejection, and CVD risk merits future studies. PMID:27251358

  9. The role of hydrogen peroxide in the contractile response to angiotensin II.

    PubMed

    Torrecillas, G; Boyano-Adánez, M C; Medina, J; Parra, T; Griera, M; López-Ongil, S; Arilla, E; Rodríguez-Puyol, M; Rodríguez-Puyol, D

    2001-01-01

    In the last years, reactive oxygen species (ROS) have been proposed as mediators of proliferative/hypertrophic responses to angiotensin II (Ang II), both in vivo and in vitro. However, the hypothesis that the Ang II-dependent cell contraction could be mediated by ROS, particularly H2O2, has not been tested. Present experiments were devoted to test this hypothesis and to analyze the possible mechanisms involved. Catalase (CAT) prevented the increased myosin light chain phosphorylation and the decreased planar cell surface area (PCSA) induced by 1 microM Ang II in cultured rat vascular smooth muscle cells (VSMC). This preventive effect of CAT was also detected when 1 microM platelet-activating factor (PAF) was used as a contractile agonist instead of Ang II. Similar results were found when using horseradish peroxidase as an H2O2 scavenger or cultured rat mesangial cells. In vascular smooth muscle cells, CAT modified neither the binding of labeled Ang II nor the Ang II-induced inositol 1,4,5-trisphosphate (IP3) synthesis. However, it completely abolished the Ang II-dependent calcium peak, in a dose-dependent fashion. CAT-loaded cells (increased intracellular CAT concentration over 3-fold) did not show either a decreased PCSA or an increased intracellular calcium concentration after Ang II treatment. Ang II stimulated the H2O2 synthesis by cultured cells, and the presence of CAT in the extracellular compartment significantly diminished the Ang II-dependent increased intracellular H2O2 concentration. The physiological importance of these findings was tested in rat thoracic aortic rings: CAT prevented the contraction elicited by Ang II. In summary, present experiments point to H2O2 as a critical intracellular metabolite in the regulation of cell contraction. PMID:11125030

  10. Mechanisms underlying angiotensin II-induced calcium oscillations

    PubMed Central

    Edwards, Aurélie; Pallone, Thomas L.

    2008-01-01

    To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca2+ concentration ([Ca]cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP3) production and imposing a 90% blockade of K+ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP3 receptors (IP3R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca2+ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca2+-induced Ca2+ release (CICR) threshold of RyR is exceeded, the ensuing Ca2+ release is limited by Ca2+ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca2+ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP3R and RyR stores are separate because, in that case, Ca2+ released by RyR during CICR can enhance filling of adjacent IP3 stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes. PMID:18562632

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

    PubMed

    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. PMID:26612192

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

    PubMed

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

    2016-06-01

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

  13. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice.

    PubMed

    Dai, Hai-Long; Hu, Wei-Yuan; Jiang, Li-Hong; Li, Le; Gaung, Xue-Feng; Xiao, Zhi-Cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38(KI/+)) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38(KI/+) hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  14. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice

    PubMed Central

    Dai, Hai-long; Hu, Wei-yuan; Jiang, Li-hong; Li, Le; Gaung, Xue-feng; Xiao, Zhi-cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  15. Chromatographic resolution of angiotensin II receptor antagonists (sartans).

    PubMed

    Tahir, Muhammad Saqlain; Adnan, Ahmad; Syed, Quratulain

    2016-08-01

    First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5μm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations. PMID:27258943

  16. Autoradiographic localization of angiotensin II receptors in rat brain

    SciTech Connect

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

    1984-03-01

    The /sup 125/I-labeled agonist analog (1-sarcosine)-angiotensin II ((Sar/sup 1/)AII) bound with high specificity and affinity (K/sub a/ = 2 x 10/sup 9/ M/sup -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.

  17. Autoradiographic localization of angiotensin II receptors in rat brain.

    PubMed Central

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

    1984-01-01

    The 125I-labeled agonist analog [1-sarcosine]-angiotensin II ( [Sar1]AII) bound with high specificity and affinity (Ka = 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. Images PMID:6324205

  18. Cardiorespiratory effects of prolonged angiotensin II block in resting conscious dogs.

    PubMed

    Jennings, D B

    2001-09-01

    Intravenous (iv) infusion of the angiotensin II (ANG II) receptor blocker saralasin in resting conscious dogs during physiological pertubations, such as hypotension and prolonged hypoxia, indicates the presence of an ANG II drive to increase respiration and decrease the arterial partial pressure of CO2 (PaCO2). In contrast, in eupneic resting dogs on a regular chow diet, iv infusion of saralasin for short periods (up to 30 min) provides no evidence of a tonic effect of circulating levels of ANG II on acid-base balance, respiration, metabolism, or circulation. However, ANG II influences physiological processes involving salt, water, and acid-base balances, which are potentially expressed beyond a 30 min time period, and could secondarily affect respiration. Therefore, we tested the hypothesis that blocking ANG II with iv saralasin would affect respiration and circulation over a 4-h period. Contrary to the hypothesis, iv infusion of saralasin in resting conscious eupneic dogs on a regular chow diet over a 4-h period had no effects on plasma strong ions, osmolality, acid-base balance, respiration, metabolism, or circulation when compared with similar control studies in the same animals. Thus, ANG II does not play a tonic modulatory role in respiratory control under "normal" physiological conditions. PMID:11599785

  19. Deletion of the angiotensin II type 1 receptor–associated protein enhances renal sodium reabsorption and exacerbates angiotensin II–mediated hypertension

    PubMed Central

    Ohsawa, Masato; Tamura, Kouichi; Wakui, Hiromichi; Maeda, Akinobu; Dejima, Toru; Kanaoka, Tomohiko; Azushima, Kengo; Uneda, Kazushi; Tsurumi-Ikeya, Yuko; Kobayashi, Ryu; Matsuda, Miyuki; Uchida, Shinichi; Toya, Yoshiyuki; Kobori, Hiroyuki; Nishiyama, Akira; Yamashita, Akio; Ishikawa, Yoshihiro; Umemura, Satoshi

    2014-01-01

    Angiotensin II type 1 receptor (AT1R)–associated protein (ATRAP) promotes AT1R internalization along with suppression of pathological activation of tissue AT1R signaling. However, the functional significance of ATRAP in renal sodium handling and blood pressure regulation under pathological stimuli is not fully resolved. Here we show the blood pressure of mice with a gene-targeted disruption of ATRAP was comparable to that of wild-type mice at baseline. However, in ATRAP-knockout mice, angiotensin II–induced hypertension was exacerbated and the extent of positive sodium balance was increased by angiotensin II. Renal expression of the sodium-proton antiporter 3, a major sodium transporter in the proximal tubules, urinary pH, renal angiotensinogen production, and angiotensin II content was unaffected. Stimulation of the renal expression and activity of the epithelial sodium channel (ENaC), a major sodium transporter in the distal tubules, was significantly enhanced by chronic angiotensin II infusion. The circulating and urinary aldosterone levels were comparable. The blood pressure response and renal ENaC expression by aldosterone were not affected. Thus, ATRAP deficiency exacerbated angiotensin II–mediated hypertension by pathological activation of renal tubular AT1R by angiotensin II. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner. PMID:24694992

  20. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion

    PubMed Central

    Ma, Chun-ye; Yin, Lin

    2016-01-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury.

  1. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.

    PubMed

    Yoshida, Tadashi; Tabony, A Michael; Galvez, Sarah; Mitch, William E; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-10-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23769949

  2. Sirtuin3 Dysfunction Is the Key Determinant of Skeletal Muscle Insulin Resistance by Angiotensin II

    PubMed Central

    Macconi, Daniela; Perico, Luca; Longaretti, Lorena; Morigi, Marina; Cassis, Paola; Buelli, Simona; Perico, Norberto; Remuzzi, Giuseppe; Benigni, Ariela

    2015-01-01

    Background Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3. Objective Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection. Study Design Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as over-expressing cells. Results Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA. Conclusions Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in

  3. [Leu]enkephalin stimulates carbohydrate metabolism in isolated hepatocytes and kidney tubule fragments by interaction with angiotensin II receptors.

    PubMed Central

    Hothi, S K; Randall, D P; Titheradge, M A

    1989-01-01

    The possibility that the effects of [Leu]enkephalin in vitro on hepatic carbohydrate metabolism are mediated by interaction with angiotensin II receptors has been examined. Preincubation of hepatocytes with either the angiotensin II receptor antagonist [Sar1,Ile8]angiotensin II or 10 mM-dithiothreitol abolished the ability of both angiotensin II and [Leu]enkephalin to increase phosphorylase a in hepatocytes prepared from fed rats. Dithiothreitol had no effect on the stimulation of phosphorylase in the presence of glucagon or phenylephrine, although it also inhibited the response to vasopressin. [Leu]enkephalin displaced specifically bound 125I-labelled angiotensin II from hepatic plasma membranes over a concentration range of 10(-7)-10(-5) M. This correlated with the dose-response required to stimulate phosphorylase activity in intact hepatocytes and suggests that the effects of the opioid peptides on carbohydrate metabolism in liver are the result of cross-reactivity of the peptides with angiotensin II receptors. Addition of 10(-5) M-[Leu]enkephalin to isolated kidney tubule fragments stimulated gluconeogenesis from 5 mM-pyruvate, the magnitude of stimulation being comparable to that by either angiotensin II or adrenaline. This effect of the opioid peptide was also abolished by pretreatment of the tubules with [Sar1,Ile8]angiotensin II, suggesting that the ability of [Leu]enkephalin to interact with angiotensin II receptors is not restricted to the liver, but may occur in other tissues where both receptors occur together. PMID:2930480

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

    PubMed

    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. PMID:27246933

  5. Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension.

    PubMed

    Veiras, Luciana C; Han, Jiyang; Ralph, Donna L; McDonough, Alicia A

    2016-10-01

    Angiotensin II (AngII) hypertension increases distal tubule Na-Cl cotransporter (NCC) abundance and phosphorylation (NCCp), as well as epithelial Na(+) channel abundance and activating cleavage. Acutely raising plasma [K(+)] by infusion or ingestion provokes a rapid decrease in NCCp that drives a compensatory kaliuresis. The first aim tested whether acutely raising plasma [K(+)] with a single 3-hour 2% potassium meal would lower NCCp in Sprague-Dawley rats after 14 days of AngII (400 ng/kg per minute). The potassium-rich meal neither decreased NCCp nor increased K(+) excretion. AngII-infused rats exhibited lower plasma [K(+)] versus controls (3.6±0.2 versus 4.5±0.1 mmol/L; P<0.05), suggesting that AngII-mediated epithelial Na(+) channel activation provokes K(+) depletion. The second aim tested whether doubling dietary potassium intake from 1% (A1K) to 2% (A2K) would prevent K(+) depletion during AngII infusion and, thus, prevent NCC accumulation. A2K-fed rats exhibited normal plasma [K(+)] and 2-fold higher K(+) excretion and plasma [aldosterone] versus A1K. In A1K rats, NCC, NCCpS71, and NCCpT53 abundance increased 1.5- to 3-fold versus controls (P<0.05). The rise in NCC and NCCp abundance was prevented in the A2K rats, yet blood pressure did not significantly decrease. Epithelial Na(+) channel subunit abundance and cleavage increased 1.5- to 3-fold in both A1K and A2K; ROMK (renal outer medulla K(+) channel abundance) abundance was unaffected by AngII or dietary K(+) In summary, the accumulation and phosphorylation of NCC seen during chronic AngII infusion hypertension is likely secondary to potassium deficiency driven by epithelial Na(+) channel stimulation. PMID:27600183

  6. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules.

    PubMed

    Aroor, Annayya; Zuberek, Marcin; Duta, Cornel; Meuth, Alex; Sowers, James R; Whaley-Connell, Adam; Nistala, Ravi

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10(-8) M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. PMID:27213360

  7. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  8. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

    PubMed Central

    Aroor, Annayya; Zuberek, Marcin; Duta, Cornel; Meuth, Alex; Sowers, James R.; Whaley-Connell, Adam; Nistala, Ravi

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT1R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10−8 M) treatment of T35OK-AT1R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT1R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. PMID:27213360

  9. Direct positive chronotropic action by angiotensin II in the isolated mouse atrium.

    PubMed

    Mori, Toyoki; Hashimoto, Ayako

    2006-07-10

    We observed the direct positive chronotropic effect of angiotensin II in mouse atria and characterized its pharmacological property. C57BL/6J mice were anesthetized with pentobarbital and hearts were quickly excised. Atrial preparations including right and left atrium were isolated and suspended in the organ bath filled with Krebs-Henseleit solution gassed with 95% O2 and 5% CO2. Angiotensin II at concentrations of 10(-10) to 10(-6) M caused concentration-dependent increase in heart rate, and the maximal response was about 13% of that by isoproterenol. The effect was blocked by the selective AT1-receptor antagonist, losartan at concentrations of 10(-6) M, but not by the selective beta-blocker, nadolol at concentration of 10(-5) M. Furthermore, angiotensin I also caused concentration-dependent increase in heart rate, and the effect was blocked by angiotensin converting enzyme (ACE) inhibitor, captopril at concentrations of 10(-6) M. These results suggested that angiotensin I is converted to angiotensin II via ACE system in mice atria, and regulate heart rate through AT1-receptor stimulation, not by beta-adrenergic receptor. PMID:16564555

  10. Characterization of angiotensin II binding sites in African Green monkey uterus

    SciTech Connect

    Petersen, E.P.; Wright, J.W.; Harding, J.W.

    1985-01-14

    The observation that there are significant differences in the concentration, affinity, and specificity of both central nervous system (CNS) and peripheral angiotensin receptors among several different mammalian species, including the African Green monkey, led to the detailed analysis of /sup 125/I-angiotensin II binding in the uterus of the African Green monkey. The B/sub max/ for angiotensin receptors in uterine tissue from this species is 56.6 +/- 8.7 fmole per mg protein. The K/sub d/ for angiotensin II is .601 +/- .108 mM. The specificity of the receptor is similar to that reported for the uterus of the rat and dog. These results indicate that the angiotensin II receptors, although nearly absent from the CNS of the African Green monkey, are found in the uterus and are very similar to uterine receptors previously characterized in the rat and dog and support the use of these species as appropriate models for studying the biochemistry of angiotensin binding in the uterus. 25 references, 1 figure, 2 tables.

  11. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    PubMed

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  12. BLOCKADE OF BRAIN ANGIOTENSIN II AT1 RECEPTORS AMELIORATES STRESS, ANXIETY, BRAIN INFLAMMATION AND ISCHEMIA: THERAPEUTIC IMPLICATIONS

    PubMed Central

    SAAVEDRA, Juan M.; SÁNCHEZ-LEMUS, Enrique; BENICKY, Julius

    2010-01-01

    SUMMARY Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT1 receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT1 receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT1 receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT1 receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT1 receptors in humans is also neuroprotective

  13. Endothelial metabolism of angiotensin II to angiotensin III, not angiotensin (1-7), augments the vasorelaxation response in adrenal cortical arteries.

    PubMed

    Kopf, Phillip G; Campbell, William B

    2013-12-01

    Hyperaldosteronism is linked to the development and progression of several different cardiovascular diseases. Angiotensin (Ang) II increases aldosterone secretion and adrenal blood flow. Ang II peptide fragments are produced by various peptidases, and these Angs have diverse and vital physiologic roles. Due to the uncharacteristic vasorelaxation of adrenal arteries by Ang II, we tested the hypothesis that Ang II metabolism contributes to its relaxant activity in adrenal arteries. Metabolism of Angs by bovine adrenal cortical arteries and isolated bovine adrenal vascular cells was measured by liquid chromatography-mass spectrometry. The primary Ang metabolites of adrenal arteries are Ang III and Ang (1-7), with Ang IV produced to a lesser extent. Bovine microvascular endothelial cells produced a similar metabolic profile to adrenal arteries, whereas bovine adrenal artery smooth muscle cells exhibited less metabolism. In preconstricted adrenal arteries, Ang II caused relaxation in picomolar concentrations and constrictions at 10nM. Ang-converting enzyme 2 inhibition augmented this relaxation response, whereas aminopeptidase inhibition did not. Ang III was equipotent to Ang II in relaxing adrenal arteries. Ang IV did not cause relaxation. Nitric oxide synthase inhibition enhanced Ang II-induced constriction of adrenal arteries. Aminopeptidase inhibition increased the concentration range for Ang II-induced constriction of adrenal arteries. Ang III and Ang IV did not change the basal tone but caused constriction of adrenal arteries with nitric oxide synthase inhibition. These data indicate that Ang II metabolism modulates the vascular effects of Ang II in the adrenal vasculature. PMID:24092640

  14. Hydrosmotic effect of angiotensin II in the toad skin: role of cyclic AMP.

    PubMed

    Coviello, A; Brauckmann, E S; de Atenor, M S; Apud, J A; Causarano, J

    1975-01-01

    The mechanism of action of the hydrosmotic response of the isolated skin of the toad Bufo arenarum Hensel to angiotensin II was studied by means of an indirect pharmacological approach. Angiotensin II (2.10(-10) M), vasopressin (2.10(-13) M) and theophylline (10(-4) and 10(-3) M) in subliminal doses produced a significant increase on water permeability when added in different paired combinations. Angiotensin II (2.10(-7) M) and vasopressin (2.10(-8) M) in doses producing significant effects on water permeability increased the response to submaximal doses of epinephrine (10(-6) M) but not to higher doses (10(-5) M). Acid pH (6.4) and prostaglandin E1 (2.10(-7) M) reduced significantly the hydrosmotic response to angiotensin II, but in contrast with the toad bladder, the effect was not completely abolished. Present results support the view that the hydrosmotic effect of angiotensin II in toad skin is mediated by the adenylate cyclase - cyclic AMP system. PMID:189568

  15. Nerve-mediated antidiuresis and antinatriuresis after air-jet stress is modulated by angiotensin II.

    PubMed

    Veelken, R; Hilgers, K F; Stetter, A; Siebert, H G; Schmieder, R E; Mann, J F

    1996-11-01

    A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98 +/- 4% (n = 6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31 +/- 3 to 8 +/- 4 microL/min per gram kidney weight, P < .05, n = 12) and sodium excretion (from 4.3 +/- 0.9 to 1.2 +/- 0.3 mumol/min per gram kidney weight, P < .05, n = 12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 micrograms ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve-mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats. PMID:8901830

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

    SciTech Connect

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

    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.

  17. Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa

    SciTech Connect

    Urata, H.; Khosla, M.C.; Bumpus, M.; Husain, A. )

    1988-11-01

    Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, the authors examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. In ZG lysomal fractions {sup 125}I-labeled Ang II was degraded to {sup 125}I-labeled des-(Phe{sup 8})Ang II. Since Ang II antibodies do not recognize des-(Phe{sup 8})Ang II, these finding explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments.

  18. Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs.

    PubMed

    Bao, Xiaolu; Zhu, Weibo; Zhang, Ruijing; Wen, Caihong; Wang, Li; Yan, Yijia; Tang, Hesheng; Chen, Zhilong

    2016-05-01

    Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation. PMID:27004954

  19. Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels.

    PubMed

    Yue, Peng; Sun, Peng; Lin, Dao-Hong; Pan, Chunyang; Xing, Wenming; Wang, WenHui

    2011-02-01

    ROMK1 channels are located in the apical membrane of the connecting tubule and cortical collecting duct and mediate the potassium secretion during normal dietary intake. We used a perforated whole-cell patch clamp to explore the effect of angiotensin II on these channels in HEK293 cells transfected with green fluorescent protein (GFP)-ROMK1. Angiotensin II inhibited ROMK1 channels in a dose-dependent manner, an effect abolished by losartan or by inhibition of protein kinase C. Furthermore, angiotensin II stimulated a protein kinase C-sensitive phosphorylation of tyrosine 416 within c-Src. Inhibition of protein tyrosine kinase attenuated the effect of angiotensin II. Western blot studies suggested that angiotensin II inhibited ROMK1 channels by enhancing its tyrosine phosphorylation, a notion supported by angiotensin II's failure to inhibit potassium channels in cells transfected with the ROMK1 tyrosine mutant (R1Y337A). However, angiotensin II restored the with-no-lysine kinase-4 (WNK4)-induced inhibition of R1Y337A in the presence of serum-glucocorticoids-induced kinase 1 (SGK1), which reversed the inhibitory effect of WNK4 on ROMK1. Moreover, protein tyrosine kinase inhibition abolished the angiotensin II-induced restoration of WNK4-mediated inhibition of ROMK1. Angiotensin II inhibited ROMK channels in the cortical collecting duct of rats on a low sodium diet, an effect blocked by protein tyrosine kinase inhibition. Thus, angiotensin II inhibits ROMK channels by two mechanisms: increasing tyrosine phosphorylation of the channel and synergizing the WNK4-induced inhibition. Hence, angiotensin II may have an important role in suppressing potassium secretion during volume depletion. PMID:20927043

  20. Class A scavenger receptor deficiency augments angiotensin II-induced vascular remodeling.

    PubMed

    Qian, Lingling; Li, Xiaoyu; Fang, Ru; Wang, Zhuoyun; Xu, Yiming; Zhang, Hanwen; Bai, Hui; Yang, Qing; Zhu, Xudong; Ben, Jingjing; Xu, Yong; Chen, Qi

    2014-08-01

    Class A scavenger receptor (SR-A) is a multifunctional molecule that participates in macrophage-mediated inflammation. Here we evaluated the role of SR-A in angiotensin II (Ang II)-induced hypertensive vascular remodeling. Chronic infusion of Ang II leads to an increased systolic blood pressure both in SR-A knockout (SR-A(-/-)) and wild type (SR-A(+/+)) mice with no significant difference between these two groups. SR-A(-/-) hypertensive mice, however, exhibited a marked augmentation of arterial wall thickening and vascular cell proliferation compared with SR-A(+/+) hypertensive mice. M1 macrophage markers were increased whereas M2 macrophage markers were decreased in vascular tissues of SR-A(-/-) mice. Co-culture experiments revealed that more pro-inflammatory cytokines like TNF-α were produced by SR-A(-/-) peritoneal macrophages leading to a stronger proliferation of primary vascular smooth muscle cells in vitro. In addition, SR-A(-/-) macrophages were more prone to lipopolysaccharide-induced M1 differentiation while resisting interleukin-4-induced M2 differentiation. Importantly, transplantation of SR-A(-/-) bone marrow into SR-A(+/+) mice significantly augmented Ang II-induced vascular remodeling. These results show that SR-A is critical for Ang II-induced vascular remodeling by regulating macrophage polarization. Therefore, SR-A may be a useful therapeutic target for the intervention of hypertensive vascular remodeling. PMID:24875449

  1. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system

    PubMed Central

    Wen, Hairuo; Gwathmey, Judith K; Xie, Lai-Hua

    2014-01-01

    Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca2+/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions. PMID:24587981

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

    SciTech Connect

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

    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

  3. Association of the Serum Angiotensin II Level with Disease Severity in Severe Fever with Thrombocytopenia Syndrome Patients.

    PubMed

    Cheng, Jiamei; Li, Huiyu; Jie, Shenghua

    2016-01-01

    Objective Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel Bunyavirus. Recent data suggest that the physiological balance of multiple proinflammatory cytokines is substantially changed in cases of severe fever with thrombocytopenia syndrome virus (SFTSV) infection, and the inflammatory response probably plays an important role in disease progression. Angiotensin II is an important active substance of the renin-angiotensin system, and studies have demonstrated that angiotensin II is involved in key events in the inflammatory process and can regulate inflammatory cell responses. Methods In order to elucidate the role of angiotensin II in the pathogenesis of SFTS, we collected serum samples from SFTS patients in the acute or convalescent phase and tested the angiotensin II levels using an enzyme-linked immunosorbent assay as well as SFTSV viral RNA with real-time reverse-transcriptase polymerase chain reaction. Furthermore, we explored possible correlations between the angiotensin II levels and clinical parameters in SFTS patients. Results Our data showed that the serum level of angiotensin II was significantly increased in the acute phase compared with that seen in the convalescent phase and the healthy controls, while there were no significant differences between the convalescent cases and healthy controls (p>0.05). A correlation analysis demonstrated that the level of angiotensin II positively correlated with the SFTS viral RNA load. The angiotensin II levels were also found to be correlated with clinical parameters indicating impairments in organ functions. Moreover, we also found that the angiotensin II levels were significantly increased in the severe cases versus the non-severe cases (p<0.001). Conclusion The serum angiotensin II levels in SFTS patients may be used to stratify the disease severity and are possibly predictive of disease outcomes. PMID:27086801

  4. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.

    PubMed

    Norlander, Allison E; Saleh, Mohamed A; Kamat, Nikhil V; Ko, Benjamin; Gnecco, Juan; Zhu, Linjue; Dale, Bethany L; Iwakura, Yoichiro; Hoover, Robert S; McDonough, Alicia A; Madhur, Meena S

    2016-07-01

    Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders. PMID:27141060

  5. The Notch pathway mediates the angiotensin II-induced synthesis of extracellular matrix components in podocytes.

    PubMed

    Yao, Min; Wang, Xiaomei; Wang, Xiaomeng; Zhang, Tao; Chi, Yanqing; Gao, Feng

    2015-07-01

    The Notch pathway is known to contribute to the development of glomerular disease. Angiotensin II (Ang II), an important member of the renin-angiotensin system, stimulates the accumulation of extracellular matrix components in glomerular disease; however, the exact mechanisms involved remain to be elucidated. In the present study, we aimed to investigate the effects of the Notch pathway on the synthesis of extracellular matrix components in Ang II-stimulated podocytes. Mouse podocytes were stimulated with Ang II (10-6 mol/l). The activation of the Notch pathway was inhibited by a vector carrying short hairpin RNA (shRNA) targeting Notch1 (sh-Notch1) or by γ-secretase inhibitor (GSI). The protein levels of Notch1, Notch intracellular domain 1 (NICD1), hairy and enhancer of split-1 (Hes1), matrix metalloproteinase (MMP)-2, MMP-9, transforming growth factor-β1 (TGF-β1), type IV collagen and laminin were determined by western blot analysis. The Notch1, Hes1, MMP-2, MMP-9, TGF-β1, type IV collagen and laminin mRNA levels were detected by RT-PCR. The MMP-2 and MMP-9 activity was measured using a cell active fluorescence assay kit. The levels of TGF-β1, type IV collagen and laminin were determined in the culture medium of the podocytes by enzyme-linked immunosorbent assay (ELISA). Our results revealed that Ang II upregulated Notch1, NICD1, Hes1, TGF-β1, type IV collagen and laminin expression and downregulated MMP-2 and MMP-9 expression in the cultured podocytes. The inhibition of the Notch pathway by sh-Notch1 or GSI increased MMP-2 and MMP-9 expression, decreased the TGF-β1 level and suppressed type IV collagen and laminin expression. The inhibition of the Notch pathway by sh-Notch1 or GSI also increased MMP-2 and MMP-9 activity, and decreased TGF-β1 levels, type IV collagen levels and laminin secretion. These findings indicate that the Notch pathway potentially mediates the Ang II-induced synthesis of extracellular matrix components in podocytes through the

  6. Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms.

    PubMed

    Chen, Xiaofeng; Lu, Hong; Rateri, Debra L; Cassis, Lisa A; Daugherty, Alan

    2013-04-01

    Angiotensin II (AngII) has been invoked as a principal mediator for the development and progression of both thoracic and abdominal aortic aneurysms. While there is consistency in experimental and clinical studies that overactivation of the renin angiotensin system promotes aortic aneurysm development, there are many unknowns regarding the mechanistic basis underlying AngII-induced aneurysms. Interactions of AngII with TGF-β in both thoracic and abdominal aortic aneurysms have been the focus of recent studies. While these studies have demonstrated profound effects of manipulating TGF-β activity on AngII-induced aortic aneurysms, they have also led to more questions regarding the interactions between AngII and this multifunctional cytokine. This review compiled the recent literature to provide insights into understanding the potentially complex interactions between AngII and TGF-β in the development of aortic aneurysms. PMID:23395156

  7. The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer.

    PubMed

    Okazaki, Mitsuyoshi; Fushida, Sachio; Harada, Shinichi; Tsukada, Tomoya; Kinoshita, Jun; Oyama, Katsunobu; Tajima, Hidehiro; Ninomiya, Itasu; Fujimura, Takashi; Ohta, Tetsuo

    2014-12-01

    Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis. PMID:25224569

  8. Angiotensin II and vasopressin are involved in the defense system against anaphylactic hypotension in anesthetized rats.

    PubMed

    Wang, Mofei; Shibamoto, Toshishige; Kuda, Yuhichi; Sun, Lingling; Tanida, Mamoru; Kurata, Yasutaka

    2014-05-15

    Anaphylactic shock is sometimes life-threatening, but the defense system against this circulatory failure was not fully understood. Ameliorating roles of angiotensin (ANG) II and vasopressin in anaphylactic hypotension were investigated in anesthetized ovalbumin-sensitized Sprague-Dawley rats. The sensitized rats were randomly allocated to the following pretreatment groups (n=7/group): (1) control (non-pretreatment), (2) ANG II synthesis inhibitor captopril, (3) ANG II receptor antagonist losartan, and (4) V1a vasopressin receptor antagonist. Anaphylactic shock was induced by an intravenous injection of the antigen. The systemic arterial pressure (SAP), central venous pressure (CVP), portal venous pressure (PVP) and portal venous blood flow (PBF) were measured, and splanchnic vascular resistance (Rspl: (SAP-PVP)/PBF) was determined. In the control group, SAP markedly decreased, followed by a gradual recovery toward baseline. Rspl transiently decreased immediately after antigen, and then increased 1.5-fold at 15 min and thereafter. The pretreatment with either losartan, captopril or V1a receptor antagonist augmented the initial fall of SAP and attenuated the SAP recovery along with augmentation of the late increase in Rspl. The 2-h survival rate was significantly smaller in either pretreatment group than in the control group (100%). Plasma levels of ANG II and vasopressin increased to 3.8- and 9.8-fold, respectively, at 30 min after antigen in the control group, whereas captopril pretreatment inhibited the increase in ANG II. In conclusion, inhibition of ANG II or vasopressin exacerbates anaphylaxis-induced hypotension in anesthetized rats. PMID:24650734

  9. Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: Role of the angiotensin-(1-7)/Mas receptor axis.

    PubMed

    Souza, Luan Kelves M; Nicolau, Lucas A D; Sousa, Nayara A; Araújo, Thiago S L; Sousa, Francisca Beatriz M; Costa, Douglas S; Souza, Fabiana M; Pacífico, Dvison M; Martins, Conceição S; Silva, Renan O; Souza, Marcellus H L P; Cerqueira, Gilberto S; Medeiros, Jand Venes R

    2016-07-15

    The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent. PMID:27241079

  10. Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling.

    PubMed

    Wang, Fang; Chen, Houzao; Yan, Yunfei; Liu, Yue; Zhang, Shuyang; Liu, Depei

    2016-09-01

    An abdominal aortic aneurysm (AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein (BAI), the main component of the Chinese traditional drug "Huang Qin", attenuates the incidence and severity of AAA in Apoe (-/-) mice infused with angiotensin II (AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species (ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor (AT1R) and inhibiting mitogen-activated protein kinases (MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention. PMID:27333787

  11. Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress.

    PubMed

    Loh, Wei Mee; Ling, Wei Chih; Murugan, Dharmani D; Lau, Yeh Siang; Achike, Francis I; Vanhoutte, Paul M; Mustafa, Mohd Rais

    2015-08-01

    Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1μM) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10μM) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress. PMID:25869508

  12. Rapid, dynamic changes in glomerular permeability to macromolecules during systemic angiotensin II (ANG II) infusion in rats.

    PubMed

    Axelsson, Josefin; Rippe, Anna; Oberg, Carl M; Rippe, Bengt

    2012-09-15

    The actions of systemic angiotensin II (ANG II) infusions on glomerular permeability were investigated in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were continuously infused intravenously with either of four doses of ANG II ranging from 16 ng·kg(-1)·min(-1) (Lo-ANG II) to 1.82 μg·kg(-1)·min(-1) (Hi-ANG II), and in separate experiments with aldosterone (Aldo; 0.22 mg·kg(-1)·min(-1)), or with the calcium channel blocker nimodipine, or with the Aldo antagonist spironolactone together with a high ANG II dose (910 ng·kg(-1)·min(-1); Hi-Int-ANG II), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 10-80 Å) and (51)Cr-EDTA. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min and analyzed by high performance size-exclusion chromatography for determination of glomerular sieving coefficients (θ) to Ficoll. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were also assessed. For ANG II, there was a rapid, marked, partly reversible increase in glomerular permeability (θ) for Ficoll molecules >34 Å in radius, peaking at 5-15 min, which was completely abrogated by the ANG II blocker candesartan but not affected by spironolactone at 15 and 30 min. For Aldo, the response was similar to that found for the lowest dose of ANG II infused. For the two highest ANG II doses given (Hi-Int-ANG II and Hi-ANG II), GFR decreased transiently, concomitant with marked, sustained increases in MAP. Nimodipine completely blocked all hemodynamic ANG II actions, whereas the glomerular permeability response remained unchanged. Thus ANG II directly increased glomerular permeability independently of its hemodynamic actions and largely independently of the concomitant Aldo response. The ANG II-induced increases in glomerular permeability were, according to a two-pore and a log-normal distributed pore model, compatible with an

  13. Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms

    PubMed Central

    Zhang, Xuan; Thatcher, Sean; Wu, Congqing; Daugherty, Alan; Cassis, Lisa A.

    2014-01-01

    Objective Male sex is a non-modifiable risk factor for abdominal aortic aneurysm (AAA) development. Similar to humans, male mice are more susceptible to angiotensin II (AngII)-induced AAAs than females. Previous studies demonstrated that castration of males markedly reduced the formation of AngII-induced AAAs. Progression of AAA size is associated with increased risk of aneurysm rupture. In this study, we hypothesized that castration of male mice would reduce the progression of established AngII-induced AAAs. Methods Male apolipoprotein E (ApoE)-/- mice were infused with AngII for 1 month to induce AAA formation. Aortic diameters were measured by ultrasound and mice were stratified into 2 groups that were either sham-operated or castrated. AngII infusions were continued for a further 2 months. Ultrasound was used to quantify lumen diameters, and excised aortas were processed for quantification of AAA size, volume, and tissue characteristics. Results Sham-operated mice exhibited progressive dilation of suprarenal aortic lumen diameters during continued AngII infusion. Castration significantly decreased aortic lumen diameters (study endpoint: 1.88 ± 0.05 mm vs 1.63 ± 0.04 mm; P<.05; sham-operated [n = 15] vs castration [n = 17], respectively). However, maximal external AAA diameters were not significantly different between sham-operated and castrated mice. The vascular volume/lumen volume ratio of excised AAAs imaged by ultrasound was significantly increased by castration (sham-operated, 4.8 ± 0.9; castration, 9.5 ± 2.0 %; n = 11/group; P<.05). Moreover, compared to thin walled AAAs of sham-operated mice, aneurysm sections from castrated mice exhibited increased smooth muscle -actin and collagen. Conclusions Removal of endogenous male hormones by castration selectively reduces aortic lumen expansion while not altering the external AAA dimensions. PMID:24439319

  14. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts.

    PubMed

    Campbell, S E; Katwa, L C

    1997-07-01

    Angiotensin II (Ang II) stimulates pathologic myocardial fibrosis. Cardiac fibroblasts (CFb) and myofibroblasts mediate this response, perhaps in part by indirect production of specific cytokines. We sought to determine if Ang II could stimulate transforming growth factor-beta1 (TGF-beta1) gene expression and protein production in adult rat CFb and two cardiac myofibroblast cell types, scar myofibroblasts (MyoFb) and valvular interstitial cells (VIC). Confluent CFb, MyoFb, and VIC in serum-deprived (0.4% FCS) media were treated with Ang II (10(-7) m for CFb; 10(-9) m for MyoFb, VIC) for 24 h. Untreated cells served as controls. Culture media was collected and TGF-beta1 levels determined in triplicate using a sandwich ELISA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to determine TGF-beta1 mRNA expression. Ang II increased CFb (P<0.02) and VIC (P<0.04) TGF-beta1 mRNA expression, while the increase in MyoFb was not statistically significant. MyoFb produced the highest TGF-beta1 levels under control conditions compared to VIC and CFb. Ang II stimulated further TGF-beta1 secretion in VIC and CFb, but not MyoFb. The AT1 receptor antagonist Losartan (10(-7) m) greatly attenuated Ang II-stimulated TGF-B1 secretion and decreased TGF-beta1 immunostaining in VIC. The AT2 receptor antagonist PD123177 (10(-7) m) also decreased secretion and immunostaining of TGF-beta1 in VIC, but to a lesser extent than Losartan. TGF-beta1 secretion by MyoFb was unaffected by Losartan and PD123177, although TGF-B1 immunostaining was absent or greatly decreased, respectively, compared to Ang II-treated MyoFb. Ang II stimulates TGF-beta1 gene expression and/or protein production in cardiac fibroblast-like cells which may act as an autocrine/paracrine stimulus to collagen formation. Furthermore, TGF-beta1 production and secretion in these cells can be modulated by specific Ang II receptor antagonists, suggesting a potential benefit in preventing

  15. [Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?].

    PubMed

    Fournier, A; Ghitu, A; Darabont, R; Mazouz, H; Makdassi, R; Canaple, S; Rosa, A; Fernandez, L A

    Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities. PMID:10360191

  16. Angiotensin II Levels in Gingival Tissues from Healthy Individuals, Patients with Nifedipine Induced Gingival Overgrowth and Non Responders on Nifedipine

    PubMed Central

    Balaji, Anitha; Balaji, Thodur Madapusi

    2015-01-01

    Context The Renin Angiotensin system has been implicated in the pathogenesis of Drug Induced Gingival Overgrowth (DIGO), a fibrotic condition, caused by Phenytoin, Nifedipine and Cyclosporine. Aim This study quantified Angiotensin II levels in gingival tissue samples obtained from healthy individuals, patients on Nifedipine manifesting/not manifesting drug induced gingival overgrowth. Materials and Methods Gingival tissue samples were obtained from healthy individuals (n=24), patients on nifidipine manifesting gingival overgrowth (n= 18) and patients on nifidipine not manifesting gingival overgrowth (n=8). Angiotensin II levels were estimated in the samples using a commercially available ELISA kit. Results Angiotensin II levels were significantly elevated in patients on Nifedipine manifesting gingival overgrowth compared to the other 2 groups (p<0.01). Conclusion The results of the study give an insight into the role played by Angiotensin II in the pathogenesis of drug induced gingival overgrowth. PMID:26436057

  17. Region-specific changes in sympathetic nerve activity in angiotensin II-salt hypertension in the rat.

    PubMed

    Osborn, John W; Fink, Gregory D

    2010-01-01

    It is now well accepted that many forms of experimental hypertension and human essential hypertension are caused by increased activity of the sympathetic nervous system. However, the role of region-specific changes in sympathetic nerve activity (SNA) in the pathogenesis of hypertension has been difficult to determine because methods for chronic measurement of SNA in conscious animals have not been available. We have recently combined indirect, and continuous and chronic direct, assessment of region-specific SNA to characterize hypertension produced by administration of angiotensin II (Ang II) to rats consuming a high-salt diet (Ang II-salt hypertension). Angiotensin II increases whole-body noradrenaline (NA) spillover and depressor responses to ganglionic blockade in rats consuming a high-salt diet, but not in rats on a normal-salt diet. Despite this evidence for increased 'whole-body SNA' in Ang II-salt hypertensive rats, renal SNA is decreased in this model and renal denervation does not attenuate the steady-state level of arterial pressure. In addition, neither lumbar SNA, which largely targets skeletal muscle, nor hindlimb NA spillover is changed from control levels in Ang II-salt hypertensive rats. However, surgical denervation of the splanchnic vascular bed attenuates/abolishes the increase in arterial pressure and total peripheral resistance, as well as the decrease in vascular capacitance, observed in Ang II-salt hypertensive rats. We hypothesize that the 'sympathetic signature' of Ang II-salt hypertension is characterized by increased splanchnic SNA, no change in skeletal muscle SNA and decreased renal SNA, and this sympathetic signature creates unique haemodynamic changes capable of producing sustained hypertension. PMID:19717492

  18. Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

    PubMed

    Cui, Mingli; Cai, Zhaohua; Chu, Shichun; Sun, Zhe; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2016-01-01

    Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. PMID:26597820

  19. Hormonal stimulation of mitochondrial glutaminase. Effects of vasopressin, angiotensin II, adrenaline and glucagon.

    PubMed Central

    Corvera, S; García-Sáinz, J A

    1983-01-01

    Adrenaline (through alpha 1-adrenoceptors), vasopressin and angiotensin II stimulate mitochondrial glutaminase activity. This stimulation probably contributes to the ureogenic effect of these hormones. The activity of the enzyme is sensitive to Ca2+ depletion. A role of Ca2+ in hormonal modulation of glutaminase activity is suggested. PMID:6870814

  20. Mitochondrial oxidative stress mediates induction of autophagy and hypertrophy in angiotensin-II treated mouse hearts.

    PubMed

    Dai, Dao-Fu; Rabinovitch, Peter

    2011-08-01

    Autophagy is characterized by recycling of cellular organelles and can be induced by several stimuli, including nutrient deprivation and oxidative stress. As a major site of free radical production during oxidative phosphorylation, mitochondria are believed to be primary targets of oxidative damage during stress. Our recent study demonstrated that angiotensin II increases cardiac mitochondrial reactive oxygen species (ROS) production, causes a decline of mitochondrial membrane potential in cardiomyocytes and increases cardiac mitochondrial protein oxidative damage and mitochondrial DNA deletions. The deleterious effects of angiotensin II on mitochondria are associated with an increase in autophagosomes and increased signaling of mitochondrial biogenesis, interpreted as an attempt to replenish the damaged mitochondria and restore energy production. Direct evidence for the central role of mitochondrial ROS was investigated by comparing the effect on mice overexpressing catalase targeted to mitochondria (mCAT) and mice overexpressing peroxisomal targeted catalase (pCAT, the natural site of catalase) challenged by angiotensin II or Gαq overexpression. The mCAT, but not pCAT, mice are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage, biogenesis and autophagy induced by angiotensin II, as well as heart failure induced by overexpression of Gαq. PMID:21505274

  1. Subpressor doses of angiotensin II do not increase albumin excretion in humans.

    PubMed

    Erley, C M; Grau, C; Furian, T C; Wolf, S; Braun, N; Risler, T

    1996-11-01

    The objective of our study was to evaluate the effects of subpressor doses of angiotensin II and mild physical stress on renal hemodynamics and urinary albumin excretion (UAE) in a group of young patients with essential hypertension compared to normotensive subjects. Eleven patients (26 +/- 6 years) and ten healthy control persons (25 +/- 2 years) were enrolled in the study. Secondary forms of hypertension had been excluded. Angiotensin II was infused at a dose of 0.3 and 1.0 ng/kg/min and physical stress testing was done with a cycle ergometer (50 W at 10 min for hypertensives, 100 W at 10 min for normotensives). Renal hemodynamics were assessed by clearance techniques (continuous insulin and p-aminohippurate clearance). Mean arterial pressure (MAP) and UAE were significantly higher in the hypertensive group than in normotensive control persons at any time of measurement. There was no significant increase in MAP or UAE under angiotensin II infusion either in the hypertensive group or in the normotensive group. MAP increased significantly under physical stress in the normotensive group only (83 +/- 7 mmHg baseline vs. 108 +/- mmHg during physical stress, p < 0.05). Angiotensin II infusion resulted in a significant change concerning renal hemodynamics in the hypertensive group only. The filtration fraction increased (18 +/- 3% baseline vs. 25 +/- 7% under infusion of 1.0 ng/kg/min angiotensin II, p < 0.05) due to a decline in ERPF and an increase in GFR in the hypertensive group. The amount of UAE correlated with the magnitude of the MAP in both groups. No correlation was found between renal hemodynamic parameters and the UAE. A significant correlation was found between the norepinephrine levels and the UAE in the control group. We could not demonstrate an albuminuric effect of subpressor doses of angiotensin II in normotensive or hypertensive subjects despite its well known effects on renal hemodynamics with an increase of the filtration fraction. These data

  2. Different reactivity to angiotensin II of peripheral and renal arteries in spontaneously hypertensive rats: effect of acute and chronic angiotensin converting enzyme inhibition

    NASA Technical Reports Server (NTRS)

    Guidi, E.; Hollenberg, N. K.

    1986-01-01

    We assessed renal blood flow and pressor responses to graded angiotensin II doses in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats ingesting a diet containing 1.6% sodium basally and after acute and chronic angiotensin converting enzyme (ACE) inhibition with captopril. In the basal state the pressor response to angiotensin II was enhanced (P<0.0005) and the renal vascular response was blunted (P<0.005) in SHR compared with WKY rats. After acute captopril administration the pressor response was enhanced in both strains, and the difference between them was maintained, while the renal vascular response was enhanced in both, but more in SHR, so that the renal vascular response in the SHR became larger than in WKY (P<0.0001). Chronic captopril treatment blunted both pressor and renal responses in WKY rats, but only the pressor response in SHR. The renal vessels of SHR seem to be different from those of WKY rats in reaction to exogenous angiotensin II, and in response to both acute administration of captopril (probably acting through blockade of angiotensin II production) and chronic administration of captopril (probably acting mainly through accumulation of kinin or production of prostaglandins).

  3. Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease.

    PubMed

    Michel, Martin C; Brunner, Hans R; Foster, Carolyn; Huo, Yong

    2016-08-01

    We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin-angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin-angiotensin system? 2. Are they shared by other inhibitors of the renin-angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined. PMID:27130806

  4. Angiotensin II stimulates superoxide production in the thick ascending limb by activating NOX4

    PubMed Central

    Hong, Nancy J.; Garvin, Jeffrey L.

    2012-01-01

    Angiotensin II (ANG II) stimulates production of superoxide (O2−) by NADPH oxidase (NOX) in medullary thick ascending limbs (TALs). There are three isoforms of the catalytic subunit (NOX1, 2, and 4) known to be expressed in the kidney. We hypothesized that NOX2 mediates ANG II-induced O2− production by TALs. To test this, we measured NOX1, 2, and 4 mRNA and protein by RT-PCR and Western blot in TAL suspensions from rats and found three catalytic subunits expressed in the TAL. We measured O2− production using a lucigenin-based assay. To assess the contribution of NOX2, we measured ANG II-induced O2− production in wild-type and NOX2 knockout mice (KO). ANG II increased O2− production by 346 relative light units (RLU)/mg protein in the wild-type mice (n = 9; P < 0.0007 vs. control). In the knockout mice, ANG II increased O2− production by 290 RLU/mg protein (n = 9; P < 0.007 vs. control). This suggests that NOX2 does not contribute to ANG II-induced O2− production (P < 0.6 WT vs. KO). To test whether NOX4 mediates the effect of ANG II, we selectively decreased NOX4 expression in rats using an adenovirus that expresses NOX4 short hairpin (sh)RNA. Six to seven days after in vivo transduction of the kidney outer medulla, NOX4 mRNA was reduced by 77%, while NOX1 and NOX2 mRNA was unaffected. In control TALs, ANG II stimulated O2− production by 96%. In TALs transduced with NOX4 shRNA, ANG II-stimulated O2− production was not significantly different from the baseline. We concluded that NOX4 is the main catalytic isoform of NADPH oxidase that contributes to ANG II-stimulated O2− production by TALs. PMID:22875785

  5. Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

    PubMed Central

    Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

    1998-01-01

    OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

  6. Perinatal Nicotine Exposure Increases Angiotensin II Receptor-Mediated Vascular Contractility in Adult Offspring

    PubMed Central

    Xiao, DaLiao; Dasgupta, Chiranjib; Li, Yong; Huang, Xiaohui; Zhang, Lubo

    2014-01-01

    Previous studies have reported that perinatal nicotine exposure causes development of hypertensive phenotype in adult offspring. Aims The present study was to determine whether perinatal nicotine exposure causes an epigenetic programming of vascular Angiotensin II receptors (ATRs) and their-mediated signaling pathway leading to heightened vascular contraction in adult offspring. Main methods Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps from day 4 of gestation to day 10 after birth. The experiments were conducted at 5 months of age of male offspring. Key Findings Nicotine treatment enhanced Angitension II (Ang II)-induced vasoconstriction and 20-kDa myosin light chain phosphorylation (MLC20-P) levels. In addition, the ratio of Ang II-induced tension/MLC-P was also significantly increased in nicotine-treated group compared with the saline group. Nicotine-mediated enhanced constrictions were not directly dependent on the changes of [Ca2+]i concentrations but dependent on Ca2+ sensitivity. Perinatal nicotine treatment significantly enhanced vascular ATR type 1a (AT1aR) but not AT1bR mRNA levels in adult rat offspring, which was associated with selective decreases in DNA methylation at AT1aR promoter. Contrast to the effect on AT1aR, nicotine decreased the mRNA levels of vascular AT2R gene, which was associated with selective increases in DNA methylation at AT2R promoter. Significance Our results indicated that perinatal nicotine exposure caused an epigenetic programming of vascular ATRs and their-mediated signaling pathways, and suggested that differential regulation of AT1R/AT2R gene expression through DNA methylation mechanism may be involved in nicotine-induced heightened vasoconstriction and development of hypertensive phenotype in adulthood. PMID:25265052

  7. Chronic resveratrol reverses a mild angiotensin II-induced pressor effect in a rat model.

    PubMed

    Gordish, Kevin L; Beierwaltes, William H

    2016-01-01

    Resveratrol is reported to reduce blood pressure in animal models of hypertension, but the mechanisms are unknown. We have shown that resveratrol infusion increases sodium excretion. We hypothesized that chronic ingestion of resveratrol would reduce angiotensin II (Ang II)-induced increases in blood pressure by decreasing oxidative stress and by also decreasing sodium reabsorption through a nitric oxide-dependent mechanism. We infused rats with vehicle or 80 μg Ang II/d over 4 weeks. Vehicle or Ang II-infused rats were individually housed, pair fed, and placed on a diet of normal chow or normal chow plus 146 mg resveratrol/d. Groups included 1) control, 2) resveratrol-fed, 3) Ang II-treated, and 4) Ang II plus resveratrol. Systolic blood pressure was measured by tail cuff. During the 4th week, rats were placed in metabolic caging for urine collection. NO2/NO3 and 8-isoprostane excretion were measured. Ang II increased systolic blood pressure in the 1st week by +14±5 mmHg (P<0.05) in Group 3 and +10±3 mmHg (P<0.05) in Group 4, respectively. Blood pressure was unchanged in Groups 1 and 2. After 4 weeks, blood pressure remained elevated in Group 3 rats with Ang II (+9±3 mmHg, P<0.05), but in Group 4, blood pressure was no longer elevated (+2±2 mmHg). We found no significant differences between the groups in sodium excretion or cumulative sodium balance (18.49±0.12, 17.75±0.16, 17.97±0.17, 18.46±0.18 μEq Na+/7 d in Groups 1-4, respectively). Urinary excretion of NO2/NO3 in the four groups was 1) 1631±207 μmol/24 h, 2) 1045±236 μmol/24 h, 3) 1490±161 μmol/24 h, and 4) 609±17 μmol/24 h. 8-Isoprostane excretion was 1) 63.85±19.39 nmol/24 h, 2) 73.57±22.02 nmol/24 h, 3) 100.69±37.62 nmol/24 h, and 4) 103.00±38.88 nmol/24 h. We conclude that chronic resveratrol supplementation does not blunt Ang II-increased blood pressure, and while resveratrol has mild depressor effects, these do not seem to be due to natriuresis or enhanced renal nitric oxide

  8. Angiotensin II--nitric oxide interactions in the control of sympathetic outflow in heart failure.

    PubMed

    Zucker, I H; Liu, J L

    2000-03-01

    Activation of the sympathetic nervous system is a compensatory mechanism which initially provides support for the circulation in the face of a falling cardiac output. It has been recognized for some time that chronic elevation of sympathetic outflow with the consequent increase in plasma norepinephrine, is counterproductive to improving cardiac function. Indeed, therapeutic targeting to block excessive sympathetic activation in heart failure is becoming a more accepted modality. The mechanism(s) by which sympathetic excitation occurs in the heart failure state are not completely understood. Components of abnormal cardiovascular reflex regulation most likely contribute to this sympatho-excitation. However, central mechanisms which relate to the elaboration of angiotensin II (Ang II) and nitric oxide (NO) may also play an important role. Ang II has been shown to be a sympatho-excitatory peptide in the central nervous system while NO is sympatho-inhibitory. Recent studies have demonstrated that blockade of Ang II receptors of the AT(1) subtype augments arterial baroreflex control of sympathetic nerve activity in the heart failure state, thereby predisposing to a reduction in sympathetic tone. Ang II and NO interact to regulate sympathetic outflow. Blockade of NO production in normal conscious rabbits was only capable of increasing sympathetic outflow when accompanied by a background infusion of Ang II. Conversely, providing a source of NO to rabbits with heart failure reduced sympathetic nerve activity when accompanied by blockade of AT(1) receptors. Chronic heart failure is also associated with a decrease in NO synthesis in the brain as indicated by a reduction in the mRNA for the neuronal isoform (nNOS). Chronic blockade of Ang II receptors can up regulate nNOS expression. In addition, exercise training of rabbits with developing heart failure has been shown to reduce sympathetic tone, decrease plasma Ang II, improve arterial baroreflex function and increase n

  9. Chronic resveratrol reverses a mild angiotensin II-induced pressor effect in a rat model

    PubMed Central

    Gordish, Kevin L; Beierwaltes, William H

    2016-01-01

    Resveratrol is reported to reduce blood pressure in animal models of hypertension, but the mechanisms are unknown. We have shown that resveratrol infusion increases sodium excretion. We hypothesized that chronic ingestion of resveratrol would reduce angiotensin II (Ang II)-induced increases in blood pressure by decreasing oxidative stress and by also decreasing sodium reabsorption through a nitric oxide-dependent mechanism. We infused rats with vehicle or 80 μg Ang II/d over 4 weeks. Vehicle or Ang II-infused rats were individually housed, pair fed, and placed on a diet of normal chow or normal chow plus 146 mg resveratrol/d. Groups included 1) control, 2) resveratrol-fed, 3) Ang II-treated, and 4) Ang II plus resveratrol. Systolic blood pressure was measured by tail cuff. During the 4th week, rats were placed in metabolic caging for urine collection. NO2/NO3 and 8-isoprostane excretion were measured. Ang II increased systolic blood pressure in the 1st week by +14±5 mmHg (P<0.05) in Group 3 and +10±3 mmHg (P<0.05) in Group 4, respectively. Blood pressure was unchanged in Groups 1 and 2. After 4 weeks, blood pressure remained elevated in Group 3 rats with Ang II (+9±3 mmHg, P<0.05), but in Group 4, blood pressure was no longer elevated (+2±2 mmHg). We found no significant differences between the groups in sodium excretion or cumulative sodium balance (18.49±0.12, 17.75±0.16, 17.97±0.17, 18.46±0.18 μEq Na+/7 d in Groups 1–4, respectively). Urinary excretion of NO2/NO3 in the four groups was 1) 1631±207 μmol/24 h, 2) 1045±236 μmol/24 h, 3) 1490±161 μmol/24 h, and 4) 609±17 μmol/24 h. 8-Isoprostane excretion was 1) 63.85±19.39 nmol/24 h, 2) 73.57±22.02 nmol/24 h, 3) 100.69±37.62 nmol/24 h, and 4) 103.00±38.88 nmol/24 h. We conclude that chronic resveratrol supplementation does not blunt Ang II-increased blood pressure, and while resveratrol has mild depressor effects, these do not seem to be due to natriuresis or enhanced renal nitric oxide

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

    NASA Technical Reports Server (NTRS)

    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.

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

    PubMed Central

    Han, Lin; Ma, Yan; Qin, Jian-guo; Li, Li-na; Gao, Yu-shan; Zhang, Xiao-yu; Guo, Yi; Song, Lin-mei; Luo, Yan-ni; Chi, Xiao-yi

    2015-01-01

    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. PMID:26557147

  12. Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts.

    PubMed

    George, Mereena; Vijayakumar, Anupama; Dhanesh, Sivadasan Bindu; James, Jackson; Shivakumar, K

    2016-01-01

    Delineation of mechanisms underlying the regulation of fibrosis-related genes in the heart is an important clinical goal as cardiac fibrosis is a major cause of myocardial dysfunction. This study probed the regulation of Discoidin Domain Receptor 2 (DDR2) gene expression and the regulatory links between Angiotensin II, DDR2 and collagen in Angiotensin II-stimulated cardiac fibroblasts. Real-time PCR and western blot analyses showed that Angiotensin II enhances DDR2 mRNA and protein expression in rat cardiac fibroblasts via NADPH oxidase-dependent reactive oxygen species induction. NF-κB activation, demonstrated by gel shift assay, abolition of DDR2 expression upon NF-κB inhibition, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of DDR2 by NF-κB in Angiotensin II-treated cells. Inhibitors of Phospholipase C and Protein kinase C prevented Angiotensin II-dependent p38 MAPK phosphorylation that in turn blocked NF-κB activation. Angiotensin II also enhanced collagen gene expression. Importantly, the stimulatory effects of Angiotensin II on DDR2 and collagen were inter-dependent as siRNA-mediated silencing of one abolished the other. Angiotensin II promoted ERK1/2 phosphorylation whose inhibition attenuated Angiotensin II-stimulation of collagen but not DDR2. Furthermore, DDR2 knockdown prevented Angiotensin II-induced ERK1/2 phosphorylation, indicating that DDR2-dependent ERK1/2 activation enhances collagen expression in cells exposed to Angiotensin II. DDR2 knockdown was also associated with compromised wound healing response to Angiotensin II. To conclude, Angiotensin II promotes NF-κB activation that up-regulates DDR2 transcription. A reciprocal regulatory relationship between DDR2 and collagen, involving cross-talk between the GPCR and RTK pathways, is central to Angiotensin II-induced increase in collagen expression in cardiac fibroblasts. PMID:26674152

  13. Heme oxygenase-1 gene expression modulates angiotensin II-induced increase in blood pressure.

    PubMed

    Yang, Liming; Quan, Shuo; Nasjletti, Alberto; Laniado-Schwartzman, Michal; Abraham, Nader G

    2004-06-01

    The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of approximately 5x10(9) cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16+/-3, 27+/-3, and 38+/-3 at 0.5, 2, and 10 ng) was surpassed (P<0.05) in LXSN rats (23+/-1, 37+/-2, and 52+/-2 at 0.5, 2, and 10 ng). Importantly, treating LSN-HHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli. PMID:15166181

  14. Investigation of long chain omega-3 PUFAs on arterial blood pressure, vascular reactivity and survival in angiotensin II-infused Apolipoprotein E-knockout mice.

    PubMed

    Bürgin-Maunder, Corinna S; Nataatmadja, Maria; Vella, Rebecca K; Fenning, Andrew S; Brooks, Peter R; Russell, Fraser D

    2016-02-01

    Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) decrease inflammation and oxidative stress in an angiotensin II-infused apolipoprotein E-knockout (ApoE(-/-)) mouse model of AAA. This study investigated the effects of LC n-3 PUFAs on blood pressure and vascular reactivity in fourteen angiotensin II-infused ApoE(-/-) male mice. Blood pressure was obtained using a non-invasive tail cuff method and whole blood was collected by cardiac puncture. Vascular reactivity of the thoracic aorta was assessed using wire myography and activation of endothelial nitric oxide synthase (eNOS) was determined by immunohistochemistry. A high LC n-3 PUFA diet increased the omega-3 index and reduced the n-6 to n-3 PUFA ratio. At day 10 post-infusion with angiotensin II, there was no difference in systolic blood pressure or diastolic blood pressure in mice fed the high or low n-3 PUFA diets. The high LC n-3 PUFA diet resulted in a non-significant trend for delay in time to death from abdominal aortic rupture. Vascular reactivity and eNOS activation remained unchanged in mice fed the high compared to the low LC n-3 PUFA diet. This study argues against direct improvement in vascular reactivity in ApoE(-/-) mice that were supplemented with n-3 PUFA for 8 weeks prior to infusion with angiotensin II. PMID:26638987

  15. Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.

    PubMed

    Lehman, Allison M B; Montford, John R; Horita, Henrick; Ostriker, Allison C; Weiser-Evans, Mary C M; Nemenoff, Raphael A; Furgeson, Seth B

    2014-11-01

    The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-α-actin) and protein synthesis ([(3)H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARα, PPARγ, PPARδ, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARγ knockout cells demonstrated blunted responses to bexarotene, indicating that PPARγ is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38. PMID:25169989

  16. Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats.

    PubMed

    Koriyama, Hiroshi; Nakagami, Hironori; Nakagami, Futoshi; Osako, Mariana Kiomy; Kyutoku, Mariko; Shimamura, Munehisa; Kurinami, Hitomi; Katsuya, Tomohiro; Rakugi, Hiromi; Morishita, Ryuichi

    2015-07-01

    Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, including Alzheimer disease, dyslipidemia, and hypertension. The aim of this study was to design DNA vaccines for high blood pressure and eventually develop human vaccine therapy to treat hypertension. Plasmid vector encoding hepatitis B core-angiotensin II (Ang II) fusion protein was injected into spontaneously hypertensive rats using needleless injection system. Anti-Ang II antibody was successfully produced in hepatitis B core-Ang II group, and antibody response against Ang II was sustained for at least 6 months. Systolic blood pressure was consistently lower in hepatitis B core-Ang II group after immunization, whereas blood pressure reduction was continued for at least 6 months. Perivascular fibrosis in heart tissue was also significantly decreased in hepatitis B core-Ang II group. Survival rate was significantly improved in hepatitis B core-Ang II group. This study demonstrated that Ang II DNA vaccine to spontaneously hypertensive rats significantly lowered high blood pressure for at least 6 months. In addition, Ang II DNA vaccines induced an adequate humoral immune response while avoiding the activation of self-reactive T cells, assessed by ELISPOT assay. Future development of DNA vaccine to treat hypertension may provide a new therapeutic option to treat hypertension. PMID:26015450

  17. Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II.

    PubMed

    Li, T-T; Jia, L-X; Zhang, W-M; Li, X-Y; Zhang, J; Li, Y-L; Li, H-H; Qi, Y-F; Du, J

    2016-01-01

    Inflammation plays an important role in hypertensive cardiac injury. The endoplasmic reticulum (ER) stress pathway is involved in the inflammatory response. However, the role of ER stress in elevated angiotensin II (Ang II)-induced cardiac injury remains unclear. In this study, we investigated the role of ER stress in Ang II-induced hypertensive cardiac injury. Transcriptome analysis and quantitative real-time PCR showed that Ang II infusion in mice increased ER stress-related genes expression in the heart. C/EBP homologous protein (CHOP) deficiency, a key mediator of ER stress, increased infiltration of inflammatory cells, especially neutrophils, the production of inflammatory cytokines, chemokines in Ang II-infused mouse hearts. CHOP deficiency increased Ang II-induced cardiac fibrotic injury: (1) Masson trichrome staining showed increased fibrotic areas, (2) immunohistochemistry staining showed increased expression of α-smooth muscle actin, transforming growth factor β1 and (3) quantitative real-time PCR showed increased expression of collagen in CHOP-deficient mouse heart. Bone marrow transplantation experiments indicated that CHOP deficiency in bone marrow cells was responsible for Ang II-induced cardiac fibrotic injury. Moreover, TUNEL staining and flow cytometry revealed that CHOP deficiency decreased neutrophil apoptosis in response to Ang II. Taken together, our study demonstrated that hypertension induced ER stress after Ang II infusion. ER stress in bone marrow-derived cells protected acute cardiac inflammation and injury in response to Ang II. PMID:27277680

  18. [Ca{sup 2+}]{sub i} and PKC-{alpha} are involved in the inhibitory effects of Ib, a novel nonpeptide AngiotensinII subtype AT{sub 1} receptor antagonist, on AngiotensinII-induced vascular contraction in vitro

    SciTech Connect

    Wang Yu; Wang Wei; Wang Qiujuan Wu Jinhui; Xu Jinyi; Wu Xiaoming

    2007-12-07

    The vasoactive peptide AngiotensinII (AngII) is an important factor in the cardiovascular system, exerting most of its effects through AngII receptor type 1 (AT{sub 1}). Ib, a new nonpeptide AT{sub 1} receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. In this study, the inhibitory effects of Ib on AngII-induced vascular contraction in vitro were investigated, and its molecular mechanisms were further explored. In endothelium-denuded aortic rings from rabbits, Ib produced a rightward shift in the concentration-response curve for AngII with a decrease in the maximal contractile response and the pD{sub 2}{sup '} was 7.29. In vascular smooth muscle cells (VSMCs), the specific binding of [{sup 125}I]AngII to AT{sub 1} receptors was inhibited by Ib in a concentration-dependent manner with IC{sub 50} value of 0.96 nM. Ib could inhibit both AngII-induced Ca{sup 2+} mobilization from internal stores and Ca{sup 2+} influx. Moreover, the translocation of PKC-{alpha} stimulated by AngII was inhibited by Ib. Thus, the inhibitory effects of Ib might be related with the depression on AngII-induced increase in [Ca{sup 2+}]{sub i} and translocation of PKC-{alpha} through blocking AT{sub 1} receptors.

  19. Potential effect of angiotensin II receptor blockade in adipose tissue and bone.

    PubMed

    Nakagami, Hironori; Osako, Mariana Kiomy; Morishita, Ryuichi

    2013-01-01

    Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, and also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Blockade of renin-angiotensin system (RAS) attenuates weight gain and adiposity by enhanced energy expenditure, and the favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. Similarly, bone metabolism is closely regulated by hormones and cytokines, which have effects on both bone resorption and deposition. It is known that the receptors of Ang II are expressed in culture osteoclasts and osteoblasts, and Ang II is postulated to be able to act upon the cells involved in bone metabolism. In in vitro system, Ang II induced the differentiation and activation of osteoclasts responsible for bone resorption. Importantly, it was demonstrated by the sub-analysis of a recent clinical study that the fracture risk was significantly reduced by the usage of angiotensin-converting enzyme inhibitors. To treat the subgroups of hypertensive patients with osteoporosis RAS can be considered a novel target. PMID:23176218

  20. Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness

    PubMed Central

    Agbor, Larry N.; Elased, Khalid M.; Walker, Mary K.

    2011-01-01

    Hypotension in aryl hydrocarbon receptor knockout mice (ahr−/−) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr−/− (ECahr−/−) mice would exhibit a similar phenotype. We generated ECahr−/− mice by crossing AHR floxed mice (ahrfx/fx) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior to and following an acute injection of Ang II or chronic treatment with an angiotensin converting enzyme inhibitor (ACEi). ECahr−/− mice were hypotensive (ECahr+/+: 116.1 ± 1.4; ECahr−/−: 107.4 ± 2.0 mmHg, n=11, p<0.05) and exhibited significantly different responses to Ang II and ACEi. While Ang II increased BP in both genotypes, the increase was sustained in ECahr+/+, whereas the increase in ECahr−/− mice steadily declined. Area under the curve analysis showed that Ang II-induced increase in diastolic BP (DBP) over 30 min was significantly lower in ECahr−/− mice (ECahr+/+ 1297 ± 223 mmHg/30 min; ECahr−/−AUC: 504 ± 138 mmHg/30 min, p<0.05). In contrast, while ACEi decreased BP in both genotypes, the subsequent rise in DBP after treatment was significantly delayed in the ECahr−/− mice. ECahr−/− mice also exhibited reduced vascular and adipose Ang II type 1 receptor (AT1R) expression, and reduced aortic Ang II-dependent vasoconstriction in the presence of vascular adipose. Taken together these data suggest that hypotension in ECahr−/− mice results from reduced vascular responsiveness to Ang II that is influenced by AT1R expression and adipose. PMID:21684261

  1. Effect of renal sympathetic nerve on adrenergically and angiotensin II-induced renal vasoconstriction in normal Wistar-Kyoto rats

    PubMed Central

    2011-01-01

    Background This study examined the effect of renal sympathetic innervation on adrenergically and angiotensin II (Ang II)-induced renal vasoconstriction in Wistar-Kyoto (WKY) rats. Methods Forty-eight WKY rats were treated with either losartan (10 mg/kg/day p.o.) or carvedilol (5 mg/kg/day p.o.) or a combination of them (10 mg/kg/day + 5 mg/kg/day p.o.) for 7 days. On day 8, the rats were anaesthetized, and renal vasoconstrictor experiments were carried out. A group of rats was subjected to acute unilateral renal denervation during the acute study. Changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by Ang II, noradrenaline (NA), and methoxamine (ME). Results In normal animals, losartan decreased (P < 0.05) the renal vasoconstrictor response to Ang II but not to NA or ME. Carvedilol treatment, however, blunted (P < 0.05) the renal vasoconstrictor responses to Ang II and adrenergic agonists. Combination of losartan and carvedilol blunted (P < 0.05) the renal vasoconstrictor response to Ang II but augmented the responses to NA and ME (all P < 0.05). Interestingly, when denervated rats were treated with the same combination, there was a reduction (P < 0.05) in the renal vasoconstrictor responses to Ang II and adrenergic agonists. Conclusions Data suggest that the renal sympathetic nerve contributes to adrenergic agonist-mediated renal vasoconstrictions in normal rats. The data further indicate an interactive relationship between renin-angiotensin and sympathetic nervous systems in modulating adrenergically and Ang II-induced renal vasoconstriction in WKY rats. PMID:21047287

  2. Cardiac oxidative stress and dysfunction by fine concentrated ambient particles (CAPs) are mediated by angiotensin-II.

    PubMed

    Ghelfi, Elisa; Wellenius, Gregory A; Lawrence, Joy; Millet, Emil; Gonzalez-Flecha, Beatriz

    2010-09-01

    Inhalation exposure to fine concentrated ambient particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine particulate matter (PM) exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin-converting enzyme (ACE) inhibitor (benazepril), or an angiotensin receptor blocker (ARB; valsartan) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard fine particle concentrator (fine PM mass concentration: 440 +/- 80 microg/m(3)). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, thiobarbituric acid reactive substances (TBARS) and for plasma levels of angiotensin-II. Also, continuous electrocardiogram (ECG) measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pre-treatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARS), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. PMID:20718632

  3. Cardiac Oxidative Stress and Dysfunction by Fine Concentrated Ambient Particles (CAPs) are Mediated by Angiotensin-II

    PubMed Central

    Ghelfi, Elisa; Wellenius, Gregory A.; Lawrence, Joy; Millet, Emil; Gonzalez-Flecha, Beatriz

    2013-01-01

    Inhalation exposure to fine Concentrated Ambient Particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine PM exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin converting enzyme (ACE) inhibitor (Benazepril ®), or an angiotensin receptor blocker (ARB, Valsartan ®) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard Fine Particle Concentrator (fine PM mass concentration: 440 ± 80 μg/m3). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, TBARS and for plasma levels of angiotensin-II. Also, continuous ECG measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pretreatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARs), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. PMID:20718632

  4. Foxp3+ regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice.

    PubMed

    Yodoi, Keiko; Yamashita, Tomoya; Sasaki, Naoto; Kasahara, Kazuyuki; Emoto, Takuo; Matsumoto, Takuya; Kita, Tomoyuki; Sasaki, Yoshihiro; Mizoguchi, Taiji; Sparwasser, Tim; Hirata, Ken-ichi

    2015-04-01

    Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3(+) Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3(+) Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E-deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II-infused mice received interleukin-2/anti-interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II-infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3(+) Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3(+) Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3(+) Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3(+) Tregs against AAA. Our findings suggest that Foxp3(+) Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA. PMID:25601931

  5. Effects of angiotensin II blockade on inflammation-induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers

    PubMed Central

    Hanafy, S; Dagenais, N J; Dryden, W F; Jamali, F

    2007-01-01

    Background and purpose: Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. Experimental approach: We used 4 groups of male Sprague–Dawley rats (220–280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg−1 oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg−1 verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Cav1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with 3H-nitrendipine. Key results: Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein. Conclusions and implications: Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan. PMID:17965735

  6. Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease.

    PubMed

    Chow, Bryna S M; Allen, Terri J

    2016-08-01

    Angiotensin II (Ang II) is well-considered to be the principal effector of the renin-angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water-electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system. PMID:27358027

  7. Chronic cyclosporin A nephrotoxicity, P-glycoprotein overexpression, and relationships with intrarenal angiotensin II deposits.

    PubMed Central

    del Moral, R. G.; Andujar, M.; Ramírez, C.; Gómez-Morales, M.; Masseroli, M.; Aguilar, M.; Olmo, A.; Arrebola, F.; Guillén, M.; García-Chicano, M. J.; Nogales, F. F.; O'Valle, F.

    1997-01-01

    P-glycoprotein (P-gp) expels hydrophobic substances from the cell, including chemotherapeutic agents and immunosuppressants such as cyclosporin A (CsA) and FK506. Exposure of cultured renal tubular cells to CsA induces P-gp overexpression in cell membranes. Angiotensin II has recently been implicated as the principal factor responsible for progression of interstitial fibrosis induced by CsA. To investigate the in vivo relationships between histological lesions, P-gp overexpression, and intrarenal angiotensin II deposits, we developed a model of chronic CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day CsA for 28 and 56 days and fed either a standard maintenance diet or a low-salt diet. Immunohistochemical methods were used to study the expression of P-gp in renal tubular cells and the appearance of intrarenal angiotensin II deposits. Rats treated with CsA developed chronic nephrotoxicity lesions that were more evident in the group fed the low-salt diet. Treatment with CsA induced overexpression of P-gp in tubular cells of the kidney that increased with time. We found that immunohistochemical expression of P-gp was slightly more severe in rats fed a low-salt diet. Intrarenal deposits of angiotensin II were more evident in rats treated with CsA; these deposits also increased with time. This finding was also more relevant in rats given the low-salt diet. The up-regulation of P-gp was inversely related to the incidence of hyaline arteriopathy (r = -0.65; P < 0.05), periglomerular (r = -0.58; P < 0.05) and peritubular fibrosis (r = -0.63; P < 0.05), and intrarenal angiotensin H deposits in animals with severe signs of nephrotoxicity (r = -0.65; P < 0.05). These results support the hypothesis that the role of P-gp as a detoxicant in renal cells may be related to mechanisms that control the cytoplasmic removal of both toxic metabolites from CsA and those originating from the catabolism of signal transduction proteins (methylcysteine esters), which are produced

  8. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats

    PubMed Central

    Phie, James; Haleagrahara, Nagaraja; Newton, Patricia; Constantinoiu, Constantin; Sarnyai, Zoltan; Chilton, Lisa; Kinobe, Robert

    2015-01-01

    Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension. PMID:26393919

  9. Diabetic state, high plasma insulin and angiotensin II combine to augment endothelin-1-induced vasoconstriction via ETA receptors and ERK

    PubMed Central

    Kobayashi, T; Nogami, T; Taguchi, K; Matsumoto, T; Kamata, K

    2008-01-01

    Background and purpose: Mechanisms associated with the enhanced contractile response to endothelin-1 in hyperinsulinaemic diabetes have been examined using the rat aorta. Functions for angiotensin II, endothelin-1 receptor expression and extracellular signal-regulated kinase (ERK) have been investigated. Experimental approach: Streptozotocin-induced diabetic rats were infused with angiotensin II or, following insulin treatment, were treated with losartan, an angiotensin II receptor antagonist. Contractions of aortic strips with or without endothelium, in response to endothelin-1 and angiotensin II, were examined in vitro. Aortic ETA receptors and ERK/MEK expression were measured by western blotting. Key results: Insulin-treated diabetic rats exhibited increases in plasma insulin, angiotensin II and endothelin-1. The systolic blood pressure and endothelin-1-induced contractile responses in aortae in vitro were enhanced in insulin-treated diabetic rats and blunted by chronic losartan administration. LY294002 (phosphatidylinositol 3-kinase inhibitor) and/or PD98059 (MEK inhibitor) diminished the enhanced contractile response to endothelin-1 in aortae from insulin-treated diabetic rats. ETA and ETB receptors, ERK-1/2 and MEK-1/2 protein expression and endothelin-1-stimulated ERK phosphorylation were all increased in aortae from insulin-treated diabetic rats. Such increases were blunted by chronic losartan administration. Endothelin-1-induced contraction was significantly higher in aortae from angiotensin II-infused diabetic rats. angiotensin II-infusion increased ERK phosphorylation, but the expression of endothelin receptors and ERK/MEK proteins remained unchanged. Conclusions and implications: These results suggest that the combination of high plasma angiotensin II and insulin with a diabetic state induced enhancement of endothelin-1-induced vasoconstriction, ETA receptor expression and ERK expression/activity in the aorta. Losartan improved both the diabetes

  10. Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.

    PubMed

    Mazzolai, L; Maillard, M; Rossat, J; Nussberger, J; Brunner, H R; Burnier, M

    1999-03-01

    Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects. PMID:10082498

  11. P-selectin increases angiotensin II-induced cardiac inflammation and fibrosis via platelet activation

    PubMed Central

    LIU, GAIZHEN; LIANG, BIN; SONG, XIAOSU; BAI, RUI; QIN, WEIWEI; SUN, XU; LU, YAN; BIAN, YUNFEI; XIAO, CHUANSHI

    2016-01-01

    Platelet activation is important in hypertension-induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P-selectin recruits leukocytes to sites of inflammation, the role of P-selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet-derived P-selectin promotes hypertensive cardiac inflammation and fibrosis. P-selectin knockout (P-sel KO) mice and wild-type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross-transplanted with platelets originating from either WT or P-sel KO mice. P-selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P-sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P-sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, α-smooth muscle actin and transforming growth factor β1 (TGF-β1) expression levels were decreased in the P-sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P-sel KO mice, the number of Mac-2 (galectin-3)- and TGF-β1-positive cells was increased in mice that received WT platelets compared with those that received P-sel KO platelets, and the mRNA expression levels of collagen I and TGF-β1 were also increased. The results from the present study suggest that activated platelets secrete P-selectin to promote cardiac inflammation and fibrosis in Ang II-induced hypertension. PMID:27121797

  12. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders.

    PubMed

    Saavedra, Juan M

    2012-11-01

    The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  13. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

    PubMed Central

    SAAVEDRA, Juan M.

    2012-01-01

    The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT1 receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT1 receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer’s disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer’s disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  14. Glycyl-histidyl-lysine interacts with the angiotensin II AT1 receptor.

    PubMed

    García-Sáinz, J A; Olivares-Reyes, J A

    1995-01-01

    Gly-His-Lys, a tripeptide isolated from human plasma that increases the growth rate of many cells, stimulated in dose-dependent fashion the activity of phosphorylase a in isolated rat hepatocytes. Such effect was associated to increases in both IP3 production and [Ca++]i. Interestingly, these effects of Gly-His-Lys were antagonized by losartan, a nonpeptide angiotensin II receptor antagonist (AT1 selective), which suggested that these receptors were involved in its effect. Binding competition experiments using the radioligand [125I][Sar1-Ile8]angiotensin II clearly indicated that Gly-His-Lys interacts with AT1 receptors. It was also observed that other histidine-containing tripeptides were also capable of interacting with these receptors. PMID:8545239

  15. Impact of Angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients.

    PubMed

    Kourilsky, Antoine; Bertrand, Guillaume; Ursu, Renata; Doridam, Jennifer; Barlog, Ciprian; Faillot, Thierry; Mandonnet, Emmanuel; Belin, Catherine; Levy, Christine; Carpentier, Antoine F

    2016-03-01

    Glioblastoma patients often require chronic administration of steroids due to peri-tumoral edema. Preliminary studies showed that treatment with Angiotensin-II Receptor Blockers (ARBs) for high blood pressure might be associated with reduced peri-tumoral edema. In this study, we aim to radiologically assess the effect of ARBs on peri-tumoral edema. We conducted a cross-sectional survey on patients with newly diagnosed GBM. Patients treated with ARBs for high blood pressure were paired to non ARB-treated patients based on similar age, tumor location and tumor size. Patients taking steroids at the time of pre-operative Magnetic Resonance Imaging were excluded from the study. In each pair of patients, we compared the volumes of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal and the Apparent Diffusion Coefficient (ADC) in the same area. Eleven (11) ARB-treated patients were selected and paired to 11 non ARB-treated controls. Volumes of peri-tumoral hyper T2-FLAIR signal were significantly lower in the ARB-treated group than in the non ARB-treated group (p = 0.02). Additionally, peri-tumoral ADCs were also significantly lower in the treated group (p = 0.02), suggesting that the peri-tumoral area in this group had less edematous features. These results suggest that ARBs may reduce the volume of peri-tumoral hyper T2-FLAIR signal by decreasing edema. PMID:26754004

  16. Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect.

    PubMed

    Nie, Yong-yan; Da, Ya-jing; Zheng, Hao; Yang, Xiao-xia; Jia, Lin; Wen, Cai-hong; Liang, Li-sha; Tian, Juan; Chen, Zhi-long

    2012-04-15

    A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation. PMID:22410249

  17. Platelet-activating factor mediates angiotensin II-induced proteinuria in isolated perfused rat kidney.

    PubMed

    Perico, N; Lapinski, R; Konopka, K; Aiello, S; Noris, M; Remuzzi, G

    1997-09-01

    Isolated kidney preparations (IPK) from male Sprague Dawley rats perfused at constant pressure were used to evaluate the effect of angiotensin II (AII) and platelet-activating factor (PAF) on renal function and urinary protein excretion. Compared with basal, intrarenal infusion of AII at 8 ng/min caused a progressive increase in protein excretion (11 +/- 6 versus 73 +/- 21 micrograms/min) in parallel with a decline in renal perfusate flow (RPF) (29 +/- 3 versus 18 +/- 3 ml/min). Addition to the perfusate of PAF at 50 nM final concentration also induced proteinuria (9 +/- 4 versus 55 +/- 14 micrograms/min) but did not change RPF (29 +/- 3 versus 30 +/- 3 ml/min). Preexposure of isolated kidneys to the PAF receptor antagonist WEB 2086 prevented the increase in urinary protein excretion induced by AII infusion (basal: 13 +/- 6; post-AII: 12 +/- 7 micrograms/min) but failed to prevent the vasoactive effect of AII (RPF, basal: 30 +/- 2; post-AII: 21 +/- 3 ml/min). In additional experiments, dexamethasone reduced the proteinuric effect of PAF remarkably. These results indicate that in isolated kidney preparation: (1) AII infusion induced proteinuria and decreased RPF; and (2) the effect of AII in enhancing urinary protein excretion was completely prevented by a specific PAF receptor antagonist, which, however, did not influence the AII-induced fall in RPF. It is suggested that PAF plays a major role in AII-induced changes in the permselective function of the glomerular capillary barrier. PMID:9294830

  18. The effect of altered sodium balance upon renal vascular reactivity to angiotensin II and norepinephrine in the dog. Mechanism of variation in angiotensin responses.

    PubMed Central

    Oliver, J A; Cannon, P J

    1978-01-01

    The mechanism whereby the vasoconstrictor response to angiotensin II (AII) is influenced by sodium balance or disease is unclear. To explore this question, the renal vascular responses (RVR) to intrarenal injections of subpressor doses of AII and norepinephrine were studied in dogs with an electromagnetic flowmeter. Acute and chronic sodium depletion increased plasma renin activity (PRA) and blunted the RVR to AII, while acute sodium repletion and chronic sodium excess plus desoxycorticosterone acetate decreased PRA and enhanced the RVR to AII. The magnitude of the RVR to AII was inversely related to PRA. The RVR to norepinephrine was unaffected by sodium balance and was not related to PRA. Inhibition of the conversion of angiotensin I to AII by SQ 20,881 during sodium depletion lowered mean arterial blood pressure (MABP), increased renal blood flow (RBF), and enhanced the RVR to AII but not to norepinephrine. Administration of bradykinin to chronically sodium-depleted dogs also lowered the MABP and increased RBF but had no effect on the RVR to AII. SQ 20,881 had no effect on MABP, RBF, or the RVR to AII in the dogs with chronic sodium excess and desoxycorticosterone acetate. Administration of indomethacin to chronically sodium-depleted dogs lowered RBF but did not influence the RVR to AII. The results indicate that the RVR to AII is selectively influenced by sodium balance and that the magnitude of the response is inversely related to the availability of endogenous AII. The data did not suggest that the variations in the RVR to AII were because of direct effects of sodium on vascular contraction, changes in the number of vascular AII receptors, or the renal prostaglandins. The results are consistent with the hypothesis that the vasoconstrictor effect of AII in the renal vasculature is primarily dependent upon the degree to which the AII vascular receptors are occupied by endogenous hormone. PMID:641142

  19. miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy

    PubMed Central

    Yang, Yong; Zhou, Yong; Cao, Zheng; Tong, Xin Zhu; Xie, Hua Qiang; Luo, Tao; Hua, Xian Ping; Wang, Han Qin

    2016-01-01

    Cardiac hypertrophy is characterized by maladaptive tissue remodeling that may lead to heart failure or sudden death. MicroRNAs (miRs) are negative regulators of angiotensin II and the angiotensin II receptor subtype 1 (AGTR1), which are two components involved in cardiac hypertrophy. In the present study, the interaction between angiotensin II receptor subtype 1 (AGTR1) signaling and miR-155 was investigated. Rat H9C2 (2–1) cardiomyocytes were transfected with miR-155 analogues or inhibitors, then stimulated with angiotensin II to induce cardiac hypertrophy. miR-155 expression was revealed to be altered following transfection with chemically-modified miR-155 analogues and inhibitors in rat cardiomyocytes. In cell cardiac hypertrophy models, the cell surface area, AGTR1, atrial natriuretic peptide and myosin heavy chain-β mRNA expression levels were revealed to be lower in cells stimulated with miR-155 analogue-transfected cells treated with angiotensin II compared with cells stimulated with angiotensin alone (P<0.05), as determined using reverse transcription-polymerase chain reaction (PCR), quantitative PCR and western blot analyses. Furthermore, calcineurin mRNA and protein, intracellular free calcium and nuclear factor of activated T-cells-4 proteins were downregulated in miR-155 analogue-transfected cells treated with angiotensin II, as compared with cells stimulated with angiotensin II alone (P<0.05). In conclusion, the current study indicates that miR-155 may improve cardiac hypertrophy by downregulating AGTR1 and suppressing the calcium signaling pathways activated by AGTR1. PMID:27588076

  20. Exploring new scaffolds for angiotensin II receptor antagonism.

    PubMed

    Kritsi, Eftichia; Matsoukas, Minos-Timotheos; Potamitis, Constantinos; Karageorgos, Vlasios; Detsi, Anastasia; Magafa, Vasilliki; Liapakis, George; Mavromoustakos, Thomas; Zoumpoulakis, Panagiotis

    2016-09-15

    Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities. PMID:27480029

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

    SciTech Connect

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

    1987-09-01

    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 /sup 125/I-AII and /sup 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 /sup 125/I-AIII metabolism was due to soluble peptidases, whereas that of /sup 125/I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of /sup 125/I-AII and /sup 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.

  2. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition.

    PubMed

    Gonzalez-Villalobos, Romer A; Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C; Katsurada, Akemi; Kim, Catherine; Upchurch, G M; Prieto, Minolfa C; Kobori, Hiroyuki; Navar, L Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT(1)R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9-12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng x kg(-1) x min(-1) for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 +/- 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 +/- 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 +/- 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 +/- 0.07, P < 0.05) or in combination with ANG II (0.80 +/- 0.07, P < 0.05). AT(1)R protein (by WB) was increased by ANG II (1.27 +/- 0.06, P < 0.05) and ACEi (1.17 +/- 0.06, P < 0.05) but not ANG II + ACEi [1.15 +/- 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 +/- 0.23, P < 0.05) and ACEi (1.57 +/- 0.15, P < 0.05), but not ANG II + ACEi (1.10 +/- 0.15, NS). No significant changes were observed in AGT, ACE, or AT(1)R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT(1)R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

  3. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition

    PubMed Central

    Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C.; Katsurada, Akemi; Kim, Catherine; Upchurch, G. M.; Prieto, Minolfa C.; Kobori, Hiroyuki; Navar, L. Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT1R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9–12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng·kg−1·min−1 for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 ± 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 ± 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 ± 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 ± 0.07, P < 0.05) or in combination with ANG II (0.80 ± 0.07, P < 0.05). AT1R protein (by WB) was increased by ANG II (1.27 ± 0.06, P < 0.05) and ACEi (1.17 ± 0.06, P < 0.05) but not ANG II + ACEi [1.15 ± 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 ± 0.23, P < 0.05) and ACEi (1.57 ± 0.15, P < 0.05), but not ANG II + ACEi (1.10 ± 0.15, NS). No significant changes were observed in AGT, ACE, or AT1R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT1R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

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

    SciTech Connect

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

    1987-07-01

    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 /sup 125/I-Ang-II to glial cultures was rapid, reversible, saturable, and specific for Ang-II. The rank order of potency of /sup 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 /sup 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 (/sup 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.

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

    SciTech Connect

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

    1986-02-01

    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.

  6. The Angiotensin II Type 2 Receptor in Brain Functions: An Update

    PubMed Central

    Guimond, Marie-Odile; Gallo-Payet, Nicole

    2012-01-01

    Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2 receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2 receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2 receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2 receptor in the brain must also consider the Ang IV/AT4 receptor. PMID:23320146

  7. Contribution of Chymase-Dependent Angiotensin II Formation to the Progression of Tubulointerstitial Fibrosis in Obstructed Kidneys in Hamsters

    PubMed Central

    Fan, Yu-Yan; Nishiyama, Akira; Fujisawa, Yoshihide; Kobori, Hiroyuki; Nakano, Daisuke; Matsuura, Junji; Hase, Naoki; Hitomi, Hirofumi; Kiyomoto, Hideyasu; Urata, Hidenori; Kohno, Masakazu

    2009-01-01

    Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl]-butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT1-receptor blocker olmesartan (10 mg/kg per day, p.o,) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of α-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-β. The UUO hamsters showed markedly higher AngII contents and increased AT1-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of α-SMA, type I collagen, and TGF-β and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT1-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters. PMID:19721329

  8. Review: Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model

    PubMed Central

    Re, Richard N.

    2012-01-01

    In the classical renin-angiotensin system, circulating ANG II mediates growth stimulatory and hemodynamic effects through the plasma membrane ANG II type I receptor, AT1. ANG II also exists in the intracellular space in some native cells, and tissues and can be upregulated in diseases, including hypertension and diabetes. Moreover, intracellular AT1 receptors can be found associated with endosomes, nuclei, and mitochondria. Intracellular ANG II can function in a canonical fashion through the native receptor and also in a noncanonical fashion through interaction with alternative proteins. Likewise, the receptor and proteolytic fragments of the receptor can function independently of ANG II. Participation of the receptor and ligand in alternative intracellular pathways may serve to amplify events that are initiated at the plasma membrane. We review historical and current literature relevant to ANG II, compared with other intracrines, in tissue culture and transgenic models. In particular, we describe a new transgenic mouse model, which demonstrates that intracellular ANG II is linked to high blood pressure. Appreciation of the diverse, pleiotropic intracellular effects of components of the renin-angiotensin system should lead to alternative disease treatment targets and new therapies. PMID:22170617

  9. Angiotensin II (de)sensitization: Fluid intake studies with implications for cardiovascular control.

    PubMed

    Daniels, Derek

    2016-08-01

    Cardiovascular disease is the leading cause of death worldwide and hypertension is the most common risk factor for death. Although many anti-hypertensive pharmacotherapies are approved for use in the United States, rates of hypertension have increased over the past decade. This review article summarizes a presentation given at the 2015 meeting of the Society for the Study of Ingestive Behavior. The presentation described work performed in our laboratory that uses angiotensin II-induced drinking as a model system to study behavioral and cardiovascular effects of the renin-angiotensin system, a key component of blood pressure regulation, and a common target of anti-hypertensives. Angiotensin II (AngII) is a potent dipsogen, but the drinking response shows a rapid desensitization after repeated injections of AngII. This desensitization appears to be dependent upon the timing of the injections, requires activation of the AngII type 1 (AT1) receptor, requires activation of mitogen-activated protein (MAP) kinase family members, and involves the anteroventral third ventricle (AV3V) region as a critical site of action. Moreover, the response does not appear to be the result of a more general suppression of behavior, a sensitized pressor response to AngII, or an aversive state generated by the treatment. More recent studies suggest that the treatment regimen used to produce desensitization in our laboratory also prevents the sensitization that occurs after daily bolus injections of AngII. Our hope is that these findings can be used to support future basic research on the topic that could lead to new developments in treatments for hypertension. PMID:26801390

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

    SciTech Connect

    Gu, Jun; Liu, Xu; Wang, Quan-xing; Tan, Hong-wei; Guo, Meng; Jiang, Wei-feng; Zhou, Li

    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. Differential regulation of angiotensin converting enzyme 2 and nuclear factor-κB by angiotensin II receptor subtypes in type 2 diabetic kidney.

    PubMed

    Pandey, Anuradha; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Gaikwad, Anil Bhanudas

    2015-11-01

    Angiotensin II (Ang II) acts through Angiotensin Converting Enzyme (ACE)/Ang II type 1 receptor (AT1R) axis to promote renal failure whereas the Ang II type 2 receptor (AT2R)/Angiotensin Converting Enzyme 2 (ACE2)/Ang1-7/Mas axis constitutes the protective arm of Renin Angiotensin System (RAS). Though Ang II has been known to activate the Nuclear Factor-κB (NF-κB) signalling pathway through different receptor subtype(s) in different tissues under various diseases, the subtype orchestrating this stimulation in type 2 diabetic kidney remains elusive. ACE2, a protective monocarboxypeptidase, responsible for conversion of Ang II to Ang1-7, opposes the deleterious effects of RAS pathway but how its expression is altered with blockade of AT1R and AT2R is not yet known. Hence, the present study was conceived to understand the regulation of NF-κB and ACE2 by using specific AT1 and AT2 receptor antagonists in non-genetic model of type 2 diabetic nephropathy. Our results show that the AT1R and AT2R antagonists lead to the repression and activation of NF-κB signalling pathway, respectively which suggests the role of AT1R in NF-κB activation. The blockade of AT2R led to an increase in ACE2 expression, which may be a compensatory response to the drastically increased inflammatory mediators and oxidative stress in the diabetic kidney. To the best of our knowledge, this is the first study showing the differential regulation of NF-κB and ACE2 by Ang II receptor subtypes and thus this study improves our understanding regarding regulation of inflammatory cascade and ACE2 by AT1R and AT2R in type 2 diabetic kidney, which may help in designing novel strategies to combat the disease in future. PMID:26271886

  12. [Respective roles of cortisol, aldosterone and angiotensin II during pathophysiology of atherosclerosis].

    PubMed

    Ayari, Hanène

    2013-01-01

    The involvement of angiotensin II, cortisol and aldosterone in increased cardiovascular risk is well known but their interactions within arterial wall and during atheroma formation are not established. In fact, mild cortisol excess is associated with a higher prevalence of cardiovascular events, increased intima media thickness, a higher frequency of atherosclerotic plaques and increased mortality. Conversely, remission from hypercortisolism is followed by improvement in cardiovascular risk markers as intima-media thickness or arterial distensibility, suggesting a strong link between cortisol excess and adverse vascular remodeling. On the other hand, implication of renin-angiotensin system (RAS) in atheromatous remodeling is well documented. The RAS also includes aldosterone, a mineralocorticoid which secretion is mainly and strongly stimulated by angiotensin II, and which receptor (MR) can also be activated by cortisol given that MR affinity is similar for both aldosterone and cortisol. The role of aldosterone in arterial remodeling is still very controversial. Aldosterone treatment associated with a high salt diet induced not only hypertension but also oxidative stress, collagen synthesis and vascular inflammation. However in models without salt loading or arterial hypertension, such as the treatment with deoxycorticosterone acetate in dogs, no alterations in aortic structure were observed and moreover, the MR blockade with eplerenone did not attenuate atherosclerosis in the aorta of diabetic Apo-E KO mice. It stems that among the different effects and mechanisms described in cell experiments, it is not known which are indeed operating in situ in human vessels and thus, if local cortisol is deleterious or beneficial and, if activation of MR by aldosterone or cortisol is important in vascular remodeling and atherogenesis. RAS blocker treatment would be particularly beneficial in essential hypertensive patients with low plasma renin, to attenuate both angiotensin

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

    PubMed

    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. PMID:27394920

  14. Angiotensin II-triggered kinase signaling cascade in the central nervous system.

    PubMed

    Bali, Anjana; Jaggi, Amteshwar Singh

    2016-04-01

    Recent studies have projected the renin-angiotensin system as a central component of the physiological and pathological processes of assorted neurological disorders. Its primary effector hormone, angiotensin II (Ang II), not only mediates the physiological effects of vasoconstriction and blood pressure regulation in cardiovascular disease but is also implicated in a much wider range of neuronal activities and diseases, including Alzheimer's disease, neuronal injury, and cognitive disorders. Ang II produces different actions by acting on its two subtypes of receptors (AT1 and AT2); however, the well-known physiological actions of Ang II are mainly mediated through AT1 receptors. Moreover, recent studies also suggest the important functional role of AT2 receptor in the brain. Ang II acts on AT1 receptors and conducts its functions via MAP kinases (ERK1/2, JNK, and p38MAPK), glycogen synthase kinase, Rho/ROCK kinase, receptor tyrosine kinases (PDGF and EGFR), and nonreceptor tyrosine kinases (Src, Pyk2, and JAK/STAT). AT1R-mediated NADPH oxidase activation also leads to the generation of reactive oxygen species, widely implicated in neuroinflammation. These signaling cascades lead to glutamate excitotoxicity, apoptosis, cerebral infarction, astrocyte proliferation, nociception, neuroinflammation, and progression of other neurological disorders. The present review focuses on the Ang II-triggered signal transduction pathways in central nervous system. PMID:26574890

  15. Angiotensin II Vascular Receptors: Their Avidity in Relationship to Sodium Balance, the Autonomic Nervous System, and Hypertension

    PubMed Central

    Brunner, Hans R.; Chang, Paul; Wallach, Ronald; Sealey, Jean E.; Laragh, John H.

    1972-01-01

    During intravenous administration of varying doses of angiotensin II antibody to anesthetized rats, apparently specific vascular receptors were characterized. These receptors compete with administered antibody to bind circulating angiotensin. This competitive phenomenon was used to evaluate the affinity of these receptors for angiotensin. Apparent vascular receptor affinity was defined by the amount of antibody required to block the blood pressure response to exogenous angiotensin. It was found that this receptor affinity varies directly with sodium intake so that the amount of antibody required to block was eightfold greater in normal animals on a high sodium intake, as compared with those on a low sodium intake. Sodium dependence of receptors was also demonstrated in nephrectomized animals, in desoxycorticosterone (DOC)-treated rats, and in chronic renal hypertension. Thus the observed changes in receptor affinity were usually inversely related to measured endogenous angiotensin II levels. Ganglionic blockade increased antibody requirement eightfold. All of these changes were consistent, with no overlap observed in response of individual animals from different groups. These results may explain the variation in pressor activity of angiotensin associated with changes in salt balance and ganglionic blockade. In general, when sufficient antibody was injected to block the effect of exogenous angiotensin a blood pressure lowering effect was also observed. Two exceptions were the nephrectomized and the one-kidney renal hypertensive animals, in both of which antibody administration had no effect on blood pressure. Additional results suggest that changes in receptor affinity are involved in the pathogenesis of various types of experimental hypertensions because the amount of antibody required to block angiotensin was enhanced in renal (twofold), DOC (fourfold), and genetic (fourfold) hypertension. Accordingly, changes in the affinity of these receptors could be critically

  16. Preventive effect of gomisin J from Schisandra chinensis on angiotensin II-induced hypertension via an increased nitric oxide bioavailability.

    PubMed

    Ye, Byeong Hyeok; Lee, Seung Jin; Choi, Young Whan; Park, So Youn; Kim, Chi Dae

    2015-03-01

    Gomisin J (GJ) is a small molecular weight lignan found in Schisandra chinensis and has been demonstrated to have vasodilatory activity. In this study, the authors investigated the effect of GJ on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. In addition, we determined the relative potencies of gomisin A (GA) and GJ with respect to vasodilatory activity and antihypertensive effects. C57/BL6 mice infused s.c. with Ang II (2 μg kg(-1) min(-1) for 2 weeks) showed an increase in BP and a decrease in plasma nitric oxide (NO) metabolites. In the thoracic aortas of Ang II-induced hypertensive mice, a decrease in vascular NO was accompanied by an increase in reactive oxygen species (ROS) production. Furthermore, these alterations in BP, plasma concentrations of NO metabolites and in the vascular productions of NO and ROS in Ang II-treated mice were reversed by the co-administration of GJ (1 and 3 μg kg(-1) min(-1)). In in vitro studies, Ang II decreased the cellular concentration of NO, which was accompanied by a reduction in phosphorylated endothelial nitric oxide synthase (eNOS) and an increase in ROS production. These eNOS phosphorylation and ROS production changes in Ang II-treated cells were also reversed by GJ pretreatment (0-3 μg ml(-1)). Interestingly, the vasodilatory and antihypertensive effects of GJ were more prominent than those of GA. Collectively, an increase in BP in mice treated with Ang II was markedly attenuated by GJ, which was attributed to the preservations of vascular NO bioavailability and eNOS function, and to the inhibition of ROS production in Ang II-induced hypertensive mice. PMID:25427681

  17. Impact of angiotensin II type 1 receptor gene polymorphism on insulin resistance in polycystic ovary syndrome.

    PubMed

    El-Mesallamy, H; El-Refaie, T; El-Razek, R A

    2013-04-01

    Insulin resistance is allegedly a target pathophysiological mechanism in the pathogenesis of polycystic ovary syndrome. Moreover, this metabolic alteration is possibly genetically determined. In view of the recent evidence implicating genetic variants of the renin-angiotensin system as candidates in several metabolic disorders, we investigated the allele and genotype frequencies of the A1166 C polymorphism of the angiotensin II type 1 receptor in relation with various metabolic and biochemical parameters in affected females trying to asses its role in the pathogenesis of this syndrome. The study was conducted on 83 females of which 39 females served as the control group. The participants were matched for age, body mass index and degree of obesity. For all subjects biochemical parameters were assayed including soluble CD40 ligand together with fasting glucose and insulin which were used for calculation of insulin resistance indices, Genotyping performed using real time polymerase chain reaction revealed that the C allele frequency and the AC genotype were less frequently observed in patients compared to controls, however this difference was not statistically significant (p=0.146). Lack of the C allele was associated with adverse metabolic parameters including higher rate of insulin resistance as well as solubes CD40 ligand in the patients group. Results of the current study support a causative role for the A1166 C polymorphism of the angiotensin II type 1 gene polymorphism in the pathogenesis or phenotypic expression of polycystic ovary syndrome. PMID:23564192

  18. Antidiuretic action of angiotensin II in the river lamprey Lampetra fluviatilis: evidence for endocrine control of kidney function in cyclostomes.

    PubMed

    Cobb, C S; Brown, J A; Rankin, J C

    2010-10-01

    Intravenous infusion of angiotensin II ([Asn¹ Val⁵]-Ang II) at 10⁻⁹ mol min⁻¹ kg⁻¹ body mass produced a significant antidiuresis in river lamprey Lampetra fluviatilis, captured during upstream migration and maintained in fresh water. Although the renin-angiotensin hormonal system (RAS) is now recognized in jawless fishes, until this study, the role of homologous Ang II in L. fluviatilis kidney function had not been examined. This study provides the first evidence for an antidiuretic action of Ang II in cyclostomes and, in evolutionary terms, suggests a renal function for the RAS in early vertebrates. PMID:21039513

  19. The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress

    PubMed Central

    Liu, Feng; Havens, Jennifer; Yu, Qi; Wang, Gang; Davisson, Robin L.; Pickel, Virginia M.; Iadecola, Costantino

    2012-01-01

    The renin-angiotensin system (RAS) and its active peptide angiotensin II (AngII) have major involvements not only in hypertension but also in mood and anxiety disorders. Substantial evidence supports the notion that AngII acts as a neuromodulator in the brain. In this review, we provide an overview of the link between the RAS and anxiety or mood disorders, and focus on recent advances in the understanding of AngII-linked, NADPH oxidase-derived oxidative stress in the central nervous system, which may underlie pathogenesis of mood and anxiety disorders. PMID:22461954

  20. Contractile effects of intracellularly administered angiotensin II are partially dependent on membrane receptors internalization in isolated rat aorta.

    PubMed

    Petrescu, G; Costuleanu, M; Slătineanu, S M; Foia, L; Costuleanu, N; Costuleanu, A

    2001-01-01

    In the present study we used the isolated rat aorta as a model to characterize the modulation of contractile effects of extra- and intracellularly administered angiotensin II by dithiothreitol (DTT) and hyperosmotic sucrose. DTT inactivation of AT1 receptor as well as disruption of the clathrin-coated pits by hyperosmotic sucrose significantly inhibited the contraction induced by intracellularly administered AII. We suggest that these intracellular effects of angiotensin peptides are associated with AT1 receptor activation/internalization and may thus be part of the mechanism of angiotensin peptides direct contractile effects in the vascular smooth muscle. PMID:12092224

  1. Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway.

    PubMed

    Yu, Liangzhu; Meng, Wei; Ding, Jieqiong; Cheng, Menglin

    2016-04-29

    Myocardial hypertrophy is an independent risk factor for cardiac morbidity and mortality. The antiaging protein klotho reportedly possesses a protective role in cardiac diseases. However, the precise mechanisms underlying the cardioprotective effects of klotho remain unknown. This study was aimed to determine the effects of klotho on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and the possible mechanism of actions. We found that klotho significantly inhibited Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by decreased [(3)H]-Leucine incorporation, cardiomyocyte surface area and β-myosin heavy chain (β-MHC) mRNA expression. Meanwhile, klotho inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway in cardiomyocytes, as evidenced by decreased protein expression of active β-catenin, downregulated protein and mRNA expression of the β-catenin target genes c-myc and cyclin D1, and increased β-catenin phosphorylation. Inhibition of the Wnt/β-catenin pathway by the specific inhibitor XAV939 markedly attenuated Ang II-induced cardiomyocyte hypertrophy. The further study revealed that klotho treatment significantly downregulated protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). The AT1R antagonist losartan inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway and cardiomyocyte hypertrophy. Our findings suggest that klotho inhibits Ang II-induced cardiomyocyte hypertrophy through suppression of the AT1R/β-catenin signaling pathway, which may provide new insights into the mechanism underlying the protective effects of klotho in heart diseases, and raise the possibility that klotho may act as an endogenous antihypertrophic factor by inhibiting the Ang II signaling pathway. PMID:26970306

  2. Maturation of the angiotensin II cardiovascular response in the embryonic White Leghorn chicken (Gallus gallus)

    PubMed Central

    Jonker, Sonnet S.; Hicks, James W.; Thornburg, Kent L.

    2010-01-01

    Angiotensin II (Ang II) is an important regulator of cardiovascular function in adult vertebrates. Although its role in regulating the adult system has been extensively investigated, the cardiovascular response to Ang II in embryonic vertebrates is relatively unknown. We investigated the potential of Ang II as a regulator of cardiovascular function in embryonic chickens, which lack central nervous system control of cardiovascular function throughout the majority of incubation. The cardiovascular response to Ang II in embryonic chickens was investigated over the final 50% of their development. Ang II produced a dose-dependent increase in arterial pressure on each day of development studied, and the response increased in intensity as development progressed. The Ang II type-1 receptor nonspecific competitive peptide antagonist [Sar1 ile8] Ang II blocked the cardiovascular response to subsequent injections of Ang II on day 21 only. The embryonic pressure response to Ang II (hypertension only) differed from that of adult chickens, in which initial hypotension is followed by hypertension. The constant level of gene expression for the Ang II receptor, in conjunction with an increasing pressure response to the peptide, suggests that two Ang II receptor subtypes are present during chicken development. Collectively, the data indicate that Ang II plays an important role in the cardiovascular development of chickens; however, its role in maintaining basal function requires further study. PMID:20495810

  3. Efficient transcription of the human angiotensin II type 2 receptor gene requires intronic sequence elements.

    PubMed Central

    Warnecke, C; Willich, T; Holzmeister, J; Bottari, S P; Fleck, E; Regitz-Zagrosek, V

    1999-01-01

    To investigate mechanisms of human angiotensin II type 2 receptor (hAT2) gene regulation we functionally characterized the promoter and downstream regions of the gene. 5'-Terminal deletion mutants from -1417/+100 to -46/+100 elicited significant but low functional activity in luciferase reporter gene assays with PC12W cells. Inclusion into the promoter constructs of intron 1 and the transcribed region of the hAT2 gene up to the translation start enhanced luciferase activity 6.7+/-1.6-fold and 11.6+/-1.7-fold (means+/-S.E.M.) respectively, whereas fusion of the promoter to the spliced 5' untranslated region of hAT2 cDNA did not, which indicated an enhancement caused by intronic sequence elements. Reverse transcriptase-mediated PCR confirmed that the chimaeric hAT2-luciferase mRNA was regularly spliced in PC12W cells. A Northern blot analysis of transfected cells showed levels of luciferase mRNA expression consistent with the respective enzyme activities. Mapping of intron 1 revealed that a 12 bp sequence in the centre of the intron was required for the increase in promoter activity, whereas the 5' adjacent intronic region mediated a decrease in luciferase activity. Mutation of the 12 bp region led to altered protein binding and markedly decreased luciferase activity. Cloned into a promoterless luciferase vector, a 123 bp intron 1 fragment was able to direct reporter gene expression to the same activity as occurred in conjunction with the 5' flanking region. These results indicate that sequence elements in intron 1 are necessary for efficient transcription of hAT2. In reporter gene assays, intron 1 might by itself function as a promoter and initiate transcription from an alternative start point. PMID:10229654

  4. Changes in glomerular hemodynamic response to angiotensin II after subacute renal denervation in rats.

    PubMed Central

    Tucker, B J; Mundy, C A; Maciejewski, A R; Printz, M P; Ziegler, M G; Pelayo, J C; Blantz, R C

    1986-01-01

    We examined the changes in glomerular hemodynamics produced by angiotensin II (AII) in both normal Munich-Wistar rats and rats which were unilaterally renal denervated (measured kidney) 4-6 d prior to the measurement periods. Measurements of glomerular dynamics were performed in a control period after plasma volume expansion and during infusion of 11 ng X 100 g body wt-1 X min-1 of AII. The glomerular hydrostatic pressure gradient increased from 38 +/- 1 to 49 +/- 1 mmHg in denervated rats compared with a lesser response in controls (from 39 +/- 1 to 45 +/- 1 mmHg, P less than 0.05). Single nephron plasma flow decreased from 213 +/- 17 to 87 +/- 4 nl X min-1 X g kidney wt (KW)-1 in denervated kidneys versus a more modest decrease in control kidneys (from 161 +/- 9 to 102 +/- 5 nl X min X gKW-1). These changes were due to a greater increase in both afferent and efferent arteriolar resistance after AII infusion in denervated compared with control kidneys. Glomerular AII receptor maximum binding was 1,196 +/- 267 fmol/mg protein in denervated kidneys compared with 612 +/- 89 fmol/mg protein (P less than 0.01) in controls with no change in receptor affinity. We conclude the subacute unilateral renal denervation results in renal vasodilation, denervation magnifies the vasoconstrictive effect of AII infusion on glomerular hemodynamics, and the observed increased response to AII after denervation is associated with increases in glomerular AII receptors. PMID:3745432

  5. PKC δ and βII regulate angiotensin II-mediated fibrosis through p38: a mechanism of RV fibrosis in pulmonary hypertension

    PubMed Central

    Chichger, Havovi; Vang, Alexander; O'Connell, Kelly A.; Zhang, Peng; Mende, Ulrike; Harrington, Elizabeth O.

    2015-01-01

    Pulmonary hypertension (PH) eventually leads to right ventricular (RV) fibrosis and dysfunction that is associated with increased morbidity and mortality. Although angiotensin II plays an important role in RV remodeling associated with hypoxic PH, the molecular mechanisms underlying RV fibrosis in PH largely remain unresolved. We hypothesized that PKC-p38 signaling is involved in RV collagen accumulation in PH and in response to angiotensin II stimulation. Adult male Sprague-Dawley rats were exposed to 3 wk of normoxia or hypoxia (10% FiO2) as a model of PH. Hypoxic rats developed RV hypertrophy and fibrosis associated with an increase in PKC βII and δ protein expression and p38 dephosphorylation in freshly isolated RV cardiac fibroblasts. Further mechanistic studies were performed in cultured primary cardiac fibroblasts stimulated with angiotensin II, a key activator of ventricular fibrosis in PH. Angiotensin II induced a reduction in p38 phosphorylation that was attenuated following chemical inhibition of PKC βII and δ. Molecular and chemical inhibition of PKC βII and δ abrogated angiotensin II-induced cardiac fibroblast proliferation and collagen deposition in vitro. The effects of PKC inhibition on proliferation and fibrosis were reversed by chemical inhibition of p38. Conversely, constitutive activation of p38 attenuated angiotensin II-induced increase of cardiac fibroblast proliferation and collagen accumulation. PKC βII- and δ-dependent inactivation of p38 regulates cardiac fibroblast proliferation and collagen deposition in response to angiotensin II, which suggests that the PKC-p38 signaling in cardiac fibroblasts may be involved and important in the pathophysiology of RV fibrosis in PH. PMID:25659900

  6. Angiotensin II Contributes to Diabetic Renal Dysfunction in Rodents and Humans via Notch1/Snail Pathway

    PubMed Central

    Gagliardini, Elena; Perico, Norberto; Rizzo, Paola; Buelli, Simona; Longaretti, Lorena; Perico, Luca; Tomasoni, Susanna; Zoja, Carla; Macconi, Daniela; Morigi, Marina; Remuzzi, Giuseppe; Benigni, Ariela

    2014-01-01

    In nondiabetic rat models of renal disease, angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. Herein, we wanted to explore the role of Ang II in diabetic nephropathy by a translational approach spanning from in vitro to in vivo rat and human studies, and to dissect the intracellular pathways involved. In isolated perfused rat kidneys and in cultured human podocytes, Ang II down-regulated nephrin expression via Notch1 activation and nuclear translocation of Snail. Hairy enhancer of split-1 was a Notch1-downstream gene effector that activated Snail in cultured podocytes. In vitro changes of the Snail/nephrin axis were similar to those in renal biopsy specimens of Zucker diabetic fatty rats and patients with advanced diabetic nephropathy, and were normalized by pharmacological inhibition of the renin-angiotensin system. Collectively, the present studies provide evidence that Ang II plays a relevant role in perpetuating glomerular injury in experimental and human diabetic nephropathy via persistent activation of Notch1 and Snail signaling in podocytes, eventually resulting in down-regulation of nephrin expression, the integrity of which is crucial for the glomerular filtration barrier. PMID:23707238

  7. Effects of probucol on angiotensin II-induced BMP-2 expression in human umbilical vein endothelial cells.

    PubMed

    Zhang, Ming; Wang, Jian; Liu, Jing-Hua; Chen, Shu-Juan; Zhen, Bin; Wang, Chang-Hua; He, Hua; Jiang, Chen-Xi

    2013-01-01

    Bone morphogenetic protein-2 (BMP-2) participates significantly in vascular development and pathophysiological processes. Angiotensin II (AngII) has been demonstrated to be critical in the initiation and progression of atherosclerosis. However, the effects of AngII on BMP-2 expression and of probucol on the AngII-induced BMP-2 expression in human umbilical vein endothelial cells (HUVECs) are unknown. The aim of our study was to investigate these effects. HUVECs were cultured and stimulated with various agents. The total superoxide dismutase (SOD) activity and the concentrations of malondialdehyde (MDA) and BMP-2 were measured by standard methods. Northern blotting was used to detect the expression of BMP-2 mRNA. The activation of NF-κB in the HUVECs was also determined. The AngII treatment significantly increased BMP-2 expression levels and activated NF-κB. These effects were suppressed by treatment with pyrrolidine dithiocarbamate (PDTC) or probucol. Furthermore, the increased levels of MDA in the conditioned medium and the decrease in the total SOD activity caused by the AngII treatment were reversed by treatment with probucol or PDTC. Probucol downregulated the AngII‑induced BMP-2 expression. These effects of probucol may be mediated by the inhibition of NF-κB activation. PMID:23128665

  8. Physiological regulation of extracellular matrix collagen and elastin in the arterial wall of rats by noradrenergic tone and angiotensin II.

    PubMed

    Dab, Houcine; Kacem, Kamel; Hachani, Rafik; Dhaouadi, Nadra; Hodroj, Wassim; Sakly, Mohsen; Randon, Jacques; Bricca, Giampiero

    2012-03-01

    The interactions between the effects of the sympathetic nervous system (SNS) and angiotensin II (ANG II) on vascular extracellular matrix (ECM) synthesis were determined in rats. The mRNA and protein content of collagen I, collagen III and elastin in the abdominal aorta (AA) and femoral artery (FA) was investigated in Wistar-Kyoto rats treated for 5 weeks with guanethidine, a sympathoplegic, losartan, an ANG II AT1 receptor (AT1R) blocker, or both. The effects of noradrenaline (NE) and ANG II on collagen III and elastin mRNA, and the receptor involved, were tested in cultured vascular smooth muscle cells (VSMCs) in vitro. Guanethidine increased collagen types I and III and decreased elastin, while losartan had an opposite effect, although without effect on collagen III. The combination of treatments abrogated changes induced by simple treatment with collagen I and elastin, but increased collagen III mRNA in AA and not in FA. NE stimulated collagen III mRNA via β receptors and elastin via α1 and α2 receptors. ANG II stimulated collagen III but inhibited elastin mRNA via AT1R. Overall, SNS and ANG II exert opposite and antagonistic effects on major components of ECM in the vascular wall. This may be of relevance for the choice of a therapeutic strategy in vascular diseases. PMID:21729992

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

    SciTech Connect

    Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

    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

  10. Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine.

    PubMed

    Baum, Michel

    2016-02-15

    Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10(-8) M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm(-1)·min(-1), P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10(-6) M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm(-1)·min(-1) (P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10(-3) M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10(-5) H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II. PMID:26661654

  11. [The experimental examination of the effect on the uterine blood flow of angiotensin II during pregnancy (author's transl)].

    PubMed

    Schmidt, A W

    1976-10-15

    In experiments with animals it was investigated the endurance of the myometrial and the blood flow of the renal cortex during endogenous pressure substances. At the same time it was tested, if treatment with sexual hormones or a pregnancy had the tested principles and changes through pressure substances, and that the changes were significant. The investigations were conducted on three groups of female rabbits. The blood changes in myometrial and in the uterine were measured and continually registered with the special heated thermistor, from the principle of the thermoclearance. The success of the blood pressure was intraarterial measured with an electric mechanism. Precisely the same doses (in relativity of the animals weight) of pressure substances were applied with an infusions pump intravenously. And pressure substances Angiotensin II, Norepinephrine and Epinephrine, and their actions on the blood pressure and blood flow through the myometrium and through the renal cortex were examined. Altogether 131 values were registered. The results of the study that were statistically secure were as follows: a) The uterine blood flow pro tissue volume unit stays constant also by pregnancy or pseudopregnancy. b) The blood flow of the kidney is perhaps twice as high as the myometrial. c) The myometrial blood flow is with the arterial systolic blood pressure tightly correlated. Blood pressure increases through Angiotensin-infusion and also recovery of the uterine blood flow. d) An autoregulation of the uterine blood flow is not observed. e) The decrease of the renal blood flow after the giving of pressure substances was not modified through pregnancy. f) In quality the behaviour of the organ blood flow is the same after applied infusion of the pressure substances. Quantity differences exist however between Angiotensin II, Norepinephrine and Epinephrine. The method of measuring the blood flow through the uterus and in the kidney was placed in one view there. The finding of

  12. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

    PubMed

    Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa-Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith

    2014-08-01

    Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors. PMID:24807206

  13. Angiotensin II receptor subtypes in rat renal preglomerular vessels.

    PubMed

    De León, H; Garcia, R

    1992-01-01

    A simple technique to isolate rat renal preglomerular vessels is described. Kidneys were pressed against a 0.3 mm stainless steel grid. The whole vascular tree, including the interlobar, arcuate, and interlobular arteries, as well as the afferent arterioles, remained on the grid surface from where they were recovered. Extensive washing yielded a highly pure preparation of renal microvessels. Radioligand binding experiments were performed to characterize 125I-[Sar1,Ile8]-ANG II binding sites in preglomerular microvessel membranes. Equilibrium saturation binding experiments revealed the presence of one group of high affinity receptors (Kd = 1.22 +/- 0.171 nM; Bmax = 209 +/- 14 fmol/mg protein). Competitive inhibition experiments with two highly specific nonpeptide ANG II antagonists, losartan (DuP 753), which is specific for the AT1 receptor subtype, and PD123319, which is specific for the AT2 subtype, demonstrated that the large majority of, if not all, ANG II receptors in rat renal preglomerular vessels correspond to the AT1 subtype. PMID:1299411

  14. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    SciTech Connect

    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

    2014-02-01

    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

  15. Reciprocal Influence of Salt Intake on Adrenal Glomerulosa and Renal Vascular Responses to Angiotensin II in Normal Man

    PubMed Central

    Hollenberg, Norman K.; Chenitz, William R.; Adams, Douglass F.; Williams, Gordon H.

    1974-01-01

    The adrenal glomerulosa cell and the renal vasculature respond to similar arterial angiotensin II (A II) levels. We have assessed the effect of decreased sodium intake on their responses to A II in man. Studies were performed in 42 normal subjects in balance on a daily intake of 100 meq potassium and either 200 or 10 meq sodium/day. Renal blood flow was measured with 133Xe and arterial A II, renin and aldosterone concentrations by radioimmunoassay. A II was infused intravenously (1, 3, or 10 ng/kg/min) for 40—60 min; 14 subjects received graded doses. The A II level increased linearly with dose and plateaued within 3 min; blood pressure and renal vascular resistance showed a similar time-course. Aldosterone rose within 10 and plateaued within 20 min. Dose-response relationships were established between the rate of A II infusion and the adrenal, the renal vascular, and pressor responses. Sodium restriction reduced the pressor (P < 0.01) and the renal vascular response (P < 0.01), but potentiated the adrenal response to A II (P < 0.01). An excellent correlation was found between the plasma A II and aldosterone levels, but the slope of their regression relationship on a high (y = 0.13x + 6) and low salt intake (y = 0.32x + 14) differed significantly (P < 0.0005). Thus, sodium intake reciprocally influences vascular and adrenal responses to A II: salt restriction blunts the vascular response and potentiates the adrenal's, a physiologically important influence in view of aldosterone's role in sodium conservation. PMID:4365595

  16. PGC-1α ameliorates AngiotensinII-induced eNOS dysfunction in human aortic endothelial cells.

    PubMed

    Li, Jie; Geng, Xiao-Yong; Cong, Xiao-Liang

    2016-08-01

    Increasing evidences support that PGC-1α participates in regulating endothelial homeostasis, in part by mediating endothelial nitric oxide (NO) synthase (eNOS) activity and NO production. However, the molecular mechanisms by which PGC-1α regulates eNOS activity are not completely understood. In the present study, we investigated the effects of PGC-1α on eNOS dysfunction and further explore the underlying mechanisms. The results showed that PGC-1α expression was downregulated after AngiotensinII (AngII) treatment and paralleled with the decreased NO generation in human aortic endothelial cells. Overexpression of PGC-1α with adenovirus or pharmacological agonist ameliorated AngII-induced the decrease of NO generation, evidenced by the restoration of cGMP and nitrite concentration. Rather than affecting eNOS expression and uncoupling, PGC-1α inhibited AngII-induced decrease of eNOS serine 1177 phosphorylation through activation of PI3K/Akt signaling. In addition, PGC-1α overexpression suppressed AngII-induced the increase of PP2A-A/eNOS interaction and PP2A phosphatase activity, with a concomitant decrease in PP2A phosphorylation, leading to eNOS serine 1177 phosphorylation. However, pharmacological inhibition of PI3K/Akt signaling blunted the observed effect of PGC-1α on PP2A activity. Taken together, our findings suggest that PGC-1α overexpression improves AngII-induced eNOS dysfunction and that improved eNOS dysfunction is associated with activated PI3K/Akt pathway, impaired PP2A activity and reduced PP2A-A/eNOS association. These date indicate that forced PGC-1α expression may be a novel therapeutic approach for endothelial dysfunction. PMID:27235860

  17. Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease.

    PubMed

    Saavedra, Juan M

    2016-03-01

    Alzheimer's disease is the most frequent type of dementia and diagnosed late in the progression of the illness when irreversible brain tissue loss has already occurred. For this reason, treatments have been ineffective. It is imperative to find novel therapies ameliorating modifiable risk factors (hypertension, stroke, diabetes, chronic kidney disease, and traumatic brain injury) and effective against early pathogenic mechanisms including alterations in cerebral blood flow leading to poor oxygenation and decreased access to nutrients, impaired glucose metabolism, chronic inflammation, and glutamate excitotoxicity. Angiotensin II receptor blockers (ARBs) fulfill these requirements. ARBs are directly neuroprotective against early injury factors in neuronal, astrocyte, microglia, and cerebrovascular endothelial cell cultures. ARBs protect cerebral blood flow and reduce injury to the blood brain barrier and neurological and cognitive loss in animal models of brain ischemia, traumatic brain injury, and Alzheimer's disease. These compounds are clinically effective against major risk factors for Alzheimer's disease: hypertension, stroke, chronic kidney disease, diabetes and metabolic syndrome, and ameliorate age-dependent cognitive loss. Controlled studies on hypertensive patients, open trials, case reports, and database meta-analysis indicate significant therapeutic effects of ARBs in Alzheimer's disease. ARBs are safe compounds, widely used to treat cardiovascular and metabolic disorders in humans, and although they reduce hypertension, they do not affect blood pressure in normotensive individuals. Overall, there is sufficient evidence to consider long-term controlled clinical studies with ARBs in patients suffering from established risk factors, in patients with early cognitive loss, or in normal individuals when reliable biomarkers of Alzheimer's disease risk are identified. PMID:26993513

  18. Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells.

    PubMed Central

    Senthil, D; Faulkner, J L; Choudhury, G G; Abboud, H E; Kasinath, B S

    2001-01-01

    Interaction between angiotensin II, which binds a G-protein-coupled receptor, and insulin, a ligand for receptor tyrosine kinase, was examined in renal proximal tubular epithelial cells. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) which follows the release of the factor from a heterodimeric complex by phosphorylation of its binding protein, 4E-BP1. Angiotensin II (1 nM) or insulin (1 nM) individually stimulated 4E-BP1 phosphorylation. However, pre-incubation with angiotensin II abrogated insulin-induced phosphorylation of 4E-BP1, resulting in persistent binding to eIF4E. Although angiotensin II and insulin individually activated phosphoinositide 3-kinase and extracellular signal-regulated kinase (ERK)-1/-2-type mitogen-activated protein (MAP) kinase, pre-incubation with angiotensin II abolished insulin-induced stimulation of these kinases, suggesting more proximal events in insulin signalling may be intercepted. Pretreatment with angiotensin II markedly inhibited insulin-stimulated tyrosine phosphorylation of insulin-receptor beta-chain and insulin-receptor substrate 1. Losartan prevented angiotensin II inhibition of insulin-induced ERK-1/-2-type MAP kinase activation and 4E-BP1 phosphorylation, suggesting mediation of the effect of angiotensin II by its type 1 receptor. Insulin-stimulated de novo protein synthesis was also abolished by pre-incubation with angiotensin II. These data show that angiotensin II inhibits 4E-BP1 phosphorylation and stimulation of protein synthesis induced by insulin by interfering with proximal events in insulin signalling. Our data provide a mechanistic basis for insulin insensitivity induced by angiotensin II. PMID:11695995

  19. Bletilla striata polysaccharide inhibits angiotensin II-induced ROS and inflammation via NOX4 and TLR2 pathways.

    PubMed

    Yue, Long; Wang, Wang; Wang, Yan; Du, Ting; Shen, Weiping; Tang, Huiling; Wang, Ying; Yin, Hongping

    2016-08-01

    In the current study, we analyzed the functions and mechanisms of Bletilla striata polysaccharide b (BSPb) against Angiotensin II (Ang II)-induced oxidative stress and inflammation in human mesangial cells (HMCs). It was found that BSPb could inhibit generation of Ang II-induced reactive oxygen species (ROS) and activation of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in a dose-dependent manner. Further studies revealed that BSPb effectively blocked upregulation of NADPH oxidase 4 (NOX4). Moreover, knockdown of NOX4 significantly impaired the anti-oxidative function of BSPb. In addition, BSPb decreased overexpression of Toll-like receptor 2 (TLR2) induced by Ang II. Blocking TLR2 expression impaired the anti-inflammatory effects of BSPb. In conclusion, BSPb was found to possess anti-oxidative stress and anti-inflammatory functions against Ang II-induced ROS generation and proinflammatory cytokines activation. The NOX4 and TLR2 pathways played important roles in the biological effects mediated by BSPb. PMID:27151672

  20. Angiotensin II type I receptor blockade attenuates reflex cutaneous vasoconstriction in aged but not young skin.

    PubMed

    Lang, James A; Kolb, Kelsey E

    2015-05-15

    Stimulation of angiotensin II type I receptors (AT1R) elicits vasoconstriction (VC) that may be occurring through the activation of a pathogenic vascular pathway such as Rho kinase (ROCK). We hypothesize that reflex cutaneous VC to whole body cooling (mean skin temperature = 30.5°C) in older humans relies in part on AT1R activation, which may explain greater ROCK activity attendant with aging. Two microdialysis (MD) fibers were placed in the forearm skin of 10 young (Y; 24 ± 1 yr) and 10 older (O; 70 ± 2 yr) individuals for infusion of 1) lactated Ringer's solution (switched to fasudil, a ROCK antagonist, after cooling); and 2) AT1R blockade with losartan. Laser Doppler flux (LDF) was measured over each MD site and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/mean arterial pressure) and expressed as percent change from baseline (%ΔCVCBASELINE). In older individuals the VC response to whole body cooling was blunted (Y = -34 ± 2, O = -17 ± 3%ΔCVC) and was further attenuated at the losartan site (Y = -34 ± 3, O = -9 ± 3%ΔCVC; P < 0.05). The VC response to an exogenous 10-μM dose of angiotensin II (Y = -27 ± 3, O = -42 ± 5%ΔCVC) was completely blocked in sites pretreated with losartan or with fasudil. These data suggest that AT1R activation contributes to the reflex VC response in aged but not young skin. Furthermore, the angiotensin II component of the VC response appears to occur primarily through a ROCK-mediated mechanism. PMID:25770238

  1. Reflex limb dilatation following norepinephrine and angiotensin II in conscious dogs

    NASA Technical Reports Server (NTRS)

    Vatner, S. F.; Mcritchie, R. J.

    1976-01-01

    The extent to which norepinephrine (NE) and angiotensin II (AN) constrict the mesenteric, renal, and iliac beds in conscious dogs is evaluated with a view to elicit opposing reflex actions tempering the vasoconstriction in the limb of the animals tested. The afferent and efferent mechanisms mediating this reflex are analyzed. It is shown that intravenous NE and AN cause striking reflex iliac dilatation in the limb of the conscious dog. The afferent arc of this reflex involves both arterial baroreceptor and vagal path-ways, whereas the efferent mechanism involves an interaction of alpha-adrenergic and histaminergic receptors.

  2. Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients.

    PubMed

    Huang, Fengming; Guo, Jing; Zou, Zhen; Liu, Jun; Cao, Bin; Zhang, Shuyang; Li, Hui; Wang, Wei; Sheng, Miaomiao; Liu, Song; Pan, Jingcao; Bao, Changjun; Zeng, Mei; Xiao, Haixia; Qian, Guirong; Hu, Xinjun; Chen, Yuanting; Chen, Yu; Zhao, Yan; Liu, Qiang; Zhou, Huandi; Zhu, Jindong; Gao, Hainv; Yang, Shigui; Liu, Xiaoli; Zheng, Shufa; Yang, Jiezuan; Diao, Hongyan; Cao, Hongcui; Wu, Ying; Zhao, Min; Tan, Shuguang; Guo, Dan; Zhao, Xiliang; Ye, Yicong; Wu, Wei; Xu, Yingchun; Penninger, Josef M; Li, Dangsheng; Gao, George F; Jiang, Chengyu; Li, Lanjuan

    2014-01-01

    A novel influenza A (H7N9) virus of avian origin emerged in eastern China in the spring of 2013. This virus causes severe disease in humans, including acute and often lethal respiratory failure. As of January 2014, 275 cases of H7N9-infected patients had been reported, highlighting the urgency of identifying biomarkers for predicting disease severity and fatal outcomes. Here, we show that plasma levels of angiotensin II, a major regulatory peptide of the renin-angiotensin system, are markedly elevated in H7N9 patients and are associated with disease progression. Moreover, the sustained high levels of angiotensin II in these patients are strongly correlated with mortality. The predictive value of angiotensin II is higher than that of C-reactive protein and some clinical parameters such as the PaO2/FiO2 ratio (partial pressure of arterial oxygen to the fraction of inspired oxygen). Our findings indicate that angiotensin II is a biomarker for lethality in flu infections. PMID:24800963

  3. Mechanisms underlying the cerebral microvascular responses to angiotensin II-induced hypertension.

    PubMed

    Vital, Shantel A; Terao, Satoshi; Nagai, Mutsumi; Granger, D Neil

    2010-11-01

    Angiotensin II (AngII) and AngII type-1 receptors (AT1r) have been implicated in the pathogenesis of hypertension and ischemic stroke. The objectives of this study was to determine if/how chronic AngII administration affects blood-brain barrier (BBB) function and blood cell adhesion in the cerebral microvasculature. AngII-loaded osmotic pumps were implanted in wild type (WT) and mutant mice. Leukocyte and platelet adhesion were monitored in cerebral venules by intravital microscopy and BBB permeability detected by Evans blue leakage. AngII (two week) infusion increased blood pressure in WT mice. This was accompanied by an increased BBB permeability and a high density of adherent leukocytes and platelets. AT1r (on the vessel wall, but not on blood cells) was largely responsible for the microvascular responses to AngII. Immunodeficient (Rag-1(-/-) ) mice exhibited blunted blood cell recruitment responses without a change in BBB permeability. A similar protection pattern was noted in RANTES(-/-) and P-selectin(-/-) mice, with bone marrow chimeras (blood cell deficiency only) yielding responses comparable to the respective knockouts. These findings implicate AT1r in the microvascular dysfunction associated with AngII-induced hypertension and suggest that immune cells and blood cell-associated RANTES and P-selectin contribute to the blood cell recruitment, but not the BBB failure, elicited by AngII. PMID:21044218

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

    SciTech Connect

    Sharma, Girish; Goalstone, Marc Lee; E-mail: Marc.Goalstone@uchsc.edu

    2007-03-23

    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 (<60 min) with insulin or A-II increased phosphorylation of ERK1/2 at 15 min and ERK5 at 5 min. Chronic treatment ({<=}8 h) with insulin increased ERK1/2 phosphorylation by 4 h and ERK5 by 8 h. A-II-stimulated phosphorylation of ERK1/2 by 8 h and ERK5 by 4 h. The EC{sub 50} for insulin treatment effecting ERK1/2 and ERK5 phosphorylation was 1.5 and 0.1 nM, whereas the EC{sub 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.

  5. Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain

    PubMed Central

    Chrissobolis, Sophocles; Banfi, Botond; Sobey, Christopher G.

    2012-01-01

    Angiotensin II (Ang II) promotes vascular disease through several mechanisms including by producing oxidative stress and endothelial dysfunction. Although multiple potential sources of reactive oxygen species exist, the relative importance of each is unclear, particularly in individual vascular beds. In these experiments, we examined the role of NADPH oxidase (Nox1 and Nox2) in Ang II-induced endothelial dysfunction in the cerebral circulation. Treatment with Ang II (1.4 mg·kg−1·day−1 for 7 days), but not vehicle, increased blood pressure in all groups. In wild-type (WT; C57Bl/6) mice, Ang II reduced dilation of the basilar artery to the endothelium-dependent agonist acetylcholine compared with vehicle but had no effect on responses in Nox2-deficient (Nox2−/y) mice. Ang II impaired responses to acetylcholine in Nox1 WT (Nox1+/y) and caused a small reduction in responses to acetylcholine in Nox1-deficient (Nox1−/y) mice. Ang II did not impair responses to the endothelium-independent agonists nitroprusside or papaverine in either group. In WT mice, Ang II increased basal and phorbol-dibutyrate-stimulated superoxide production in the cerebrovasculature, and these increases were abolished in Nox2−/y mice. Overall, these data suggest that Nox2 plays a relatively prominent role in mediating Ang II-induced oxidative stress and cerebral endothelial dysfunction, with a minor role for Nox1. PMID:22628375

  6. Physiological regulation of pro-inflammatory cytokines expression in rat cardiovascular tissues by sympathetic nervous system and angiotensin II.

    PubMed

    Dab, Houcine; Hachani, Rafik; Sakly, Mohsen; Bricca, Giampiero; Kacem, Kamel

    2013-12-01

    Pro-inflammatory cytokines regulation by sympathetic nervous system (SNS) and angiotensin II (ANG II) was widely described in cardiovascular system, but the role of such neuro-humoral interaction needs further investigation in this context. We tested SNS-ANG II interaction on IL-6 and TNF-α mRNA expression in left ventricle and aorta from normotensive rats by sympathectomy with guanethidine and blockade of the ANG II AT1 receptors (AT1R) antagonist with losartan. mRNA synthesis of IL-6 and TNF-α were performed by Q-RT-PCR. In the left ventricle, IL-6 mRNA increased by 63% (p < 0.01) after sympathectomy, still unchanged after losartan treatment and decreased by 38% (p < 0.05) after combined treatment. TNF-α mRNA decreased by 44% (p < 0.01), only after combined treatment. In the aorta, IL-6 mRNA increased equally by 65% (p < 0.05) after sympathectomy or losartan treatment. TNF-α mRNA decreased by 28, 41, and 42% (p < 0.05) after sympathectomy, losartan and combined treatments, respectively. Our data suggest that ANG II stimulates directly (via AT1R) and indirectly (via SNS) IL-6 mRNA synthesis in left ventricle and aorta and TNF-α mRNA in left ventricle. ANG II seems unable to influence directly TNF-α mRNA synthesis in the aorta but can stimulate this cytokine via SNS. The results are relevant to prevent or reduce proinflammatory cytokines overexpression seen in cardiovascular diseases. PMID:23846262

  7. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.

    PubMed

    Ogata, Yoshiki; Nemoto, Wataru; Nakagawasai, Osamu; Yamagata, Ryota; Tadano, Takeshi; Tan-No, Koichi

    2016-09-01

    Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors. PMID:27401876

  8. Autoradiographic localization of (/sup 125/I)-angiotensin II binding sites in the rat adrenal gland

    SciTech Connect

    Healy, D.P.; Maciejewski, A.R.; Printz, M.P.

    1985-03-01

    To gain greater insight into sites of action of circulating angiotensin II (Ang II) within the adrenal, we have localized the (/sup 125/I)-Ang II binding site using in vitro autoradiography. Autoradiograms were generated either by apposition of isotope-sensitive film or with emulsion-coated coverslips to slide-mounted adrenal sections labeled in vitro with 1.0 nM (/sup 125/I)-Ang II. Analysis of the autoradiograms showed that Ang II binding sites were concentrated in a thin band in the outer cortex (over the cells of the zona glomerulosa) and in the adrenal medulla, which at higher power was seen as dense patches. Few sites were evident in the inner cortex. The existence of Ang II binding sites in the adrenal medulla was confirmed by conventional homogenate binding techniques which revealed a single class of high affinity Ang II binding site (K/sub d/ . 0.7nM, B/sub max/ . 168.7 fmol/mg). These results suggest that the adrenal medulla may be a target for direct receptor-mediated actions of Ang II.

  9. Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms.

    PubMed

    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

    2014-09-01

    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

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

    SciTech Connect

    Chen, Xiao-Qing; Zhang, Dao-Liang; Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang; Jiang, Wei-Feng; Zhou, Li; Zhao, Liang; Wang, Quan-Xing; Liu, Xu

    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.

  11. Differentiation in the angiotensin II receptor 1 blocker class on autonomic function.

    PubMed

    Krum, H

    2001-09-01

    Autonomic function is disordered in cardiovascular disease states such as chronic heart failure (CHF) and hypertension. Interactions between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) may potentially occur at a number of sites. These include central sites (eg, rostral ventrolateral medulla), at the level of baroreflex control, and at the sympathetic prejunctional angiotensin II receptor 1 (AT(1)) receptor, which is facilitatory for norepinephrine release from the sympathetic nerve terminal. Therefore, drugs that block the RAAS may be expected to improve autonomic dysfunction in cardiovascular disease states. In order to test the hypothesis that RAAS inhibition directly reduces SNS activity, a pithed rat model of sympathetic stimulation has been established. In this model, an increase in frequency of stimulation results in a pressor response that is sympathetically mediated and highly reproducible. This pressor response is enhanced in the presence of angiotensin II and is reduced in the presence of nonselective AIIRAs that block both AT(1) and AT(2) receptor subtypes (eg, saralasin). AT(1)-selective antagonists have also been studied in this model, at pharmacologically relevant doses. In one such study, only the AT(1) blocker eprosartan reduced sympathetically stimulated increases in blood pressure, whereas comparable doses of losartan, valsartan, and irbesartan did not. The reason(s) for the differences between eprosartan and other agents of this class on sympathetic modulation are not clear, but may relate to the chemical structure of the drug (a non- biphenyl tetrazole structure that is chemically distinct from the structure of other AIIRAs), receptor binding characteristics (competitive), or unique effects on presynaptic AT(1) receptors. PMID:11580884

  12. Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

    PubMed Central

    Drummond, Heather A.; Gousette, Monette U.; Storm, Megan V.; Abraham, Nader G.; Csongradi, Eva

    2012-01-01

    Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (139±3 versus 153±2 mmHg in the transgenic and control mice, respectively; P<0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments,. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption. PMID:22323644

  13. Atorvastatin blocks increased l-type Ca2+ current and cell injury elicited by angiotensin II via inhibiting oxide stress.

    PubMed

    Ma, Yanzhuo; Kong, Lingfeng; Qi, Shuying; Wang, Dongmei

    2016-04-01

    Thel-type Ca(2+)current (ICa,l) plays a crucial role in shaping action potential and is involved in cardiac arrhythmia. Statins have been demonstrated to contribute to anti-apoptotic and anti-arrhythmic effects in the heart. Here, we examined whether atorvastatin regulates theICa,land cell injury induced by angiotensin II (AngII) as well as the putative intracellular cascade responsible for the effects. Cultured neonatal rat ventricular myocytes were incubated with AngII for 24 h, and then cell injury and expression levels of Nox2/gp91(phox), p47(phox) ,and Cav1.2 were analyzed. In addition,ICa,lwas recorded using the whole-cell patch-clamp technique, and mechanisms of atorvastatin actions were also investigated. It was found that the number of apoptotic cardiomyocytes was increased and cell viability was significantly decreased after AngII administration. AngII also augmented the expressions of Nox2/gp91(phox)and p47(phox)compared with control cardiomyocytes. Exposure to AngII evokedICa,lin a voltage-dependent manner without affecting theI-Vrelationship. In addition, AngII enhanced membrane Cav1.2 expression. These effects were abolished in the presence of the reactive oxygen species (ROS) scavenger, manganese (III)-tetrakis 4-benzoic acid porphyrin [Mn(III)TBAP], or the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin. These results suggested that atorvastatin mediates cardioprotection against arrhythmias and cell injury by controlling the AngII-ROS cascade. PMID:26940997

  14. Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats

    PubMed Central

    Li, Zhengqian; Mo, Na; Li, Lunxu; Cao, Yiyun; Wang, Wenming; Liang, Yaoxian; Deng, Hui; Xing, Rui; Yang, Lin; Ni, Cheng; Chui, Dehua; Guo, Xiangyang

    2016-01-01

    Reversible blood-brain barrier (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 of MMP (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 (PPARγ) 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. PMID:27199659

  15. Attenuated cardiovascular hypertrophy and oxidant generation in response to angiotensin II infusion in glutaredoxin-1 knockout mice

    PubMed Central

    Bachschmid, Markus M.; Xu, Shanqin; Maitland-Toolan, Karlene A.; Ho, Ye-Shih; Cohen, Richard A.; Matsui, Reiko

    2010-01-01

    Glutaredoxin-1 (Glrx) is a thioltransferase that regulates protein S-glutathiolation. To elucidate the role of endogenous Glrx in cardiovascular disease, Glrx knockout (KO) mice were infused with angiotensin II (Ang II) for 6 days. After Ang II infusion, body weight and blood pressure were similar between WT and Glrx KO mice. However, compared to WT mice, Glrx KO mice demonstrated (1) less cardiac and aortic medial hypertrophy, (2) less oxidant generation in aorta assessed by dihydroethidium staining and nitrotyrosine, (3) decreased phosphorylation of Akt in the heart, and (4) less expression of inducible NOS (iNOS) in aorta and heart. In cultured embryonic fibroblasts from Glrx KO mice, S-glutathiolation of actin was enhanced and actin depolymerization was impaired after hydrogen peroxide stimulation compared with WT cells. Furthermore, oxidant generation in phorbol ester-stimulated fibroblasts and RAW 264.7 macrophage-like cells was lower with Glrx siRNA knockdown. These data indicate that Ang II-induced oxidant production and hypertrophic responses were attenuated in Glrx KO mice, which may result from impaired NADPH oxidase activation. PMID:20638471

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

    PubMed

    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. PMID:7745246

  17. Synthesis and biological evaluation of a new angiotensin II receptor antagonist.

    PubMed

    Zheng, H-l; Zhu, W-b; Wu, D; Da, Y-j; Yan, Y-J; Bian, J; Chen, Z-l

    2014-12-01

    The design, synthesis, in vitro and in vivo evaluation of (2 R,6 S)-4-({1-[2-(1 H-tetrazol-5-yl)phenyl]-1 H-indol-4-yl}methyl)-2,6-dimethylmorpholine, compound 1, as a novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 1 displayed a high affinity for the angiotensin II type 1receptor with IC50 value of 0.82 nM. It acted as a potent anti-hypertensive derivative (maximal reduction of mean arterial pressure of 47 mm Hg at 10 mg/kg po in spontaneously hypertensive rat producing a dose-dependent fall in blood pressure following oral administration lasting beyond 10 h. Acute toxicity tests measured the LD50 of 1 value as 2431.7 mg/kg, which is higher than Losartan (LD50=2248 mg/kg). In addition further testing showed that 1 also demonstrated efficient anti-proliferative activity in vitro and anti-prostate cancer activity in vivo were also found. Taken together this compound could be considered as an effective and durable anti-hypertension drug candidate with additional anti-prostate cancer activity. These encouraging results are deserved of further investigation towards its use for therapeutic benefit. PMID:24573978

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

    PubMed Central

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

    2013-01-01

    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. PMID:24303148

  19. Serum activity of angiotensin converting enzyme 2 is decreased in patients with acute ischemic stroke.

    PubMed

    Bennion, Douglas M; Rosado, Christian A; Haltigan, Emily A; Regenhardt, Robert W; Sumners, Colin; Waters, Michael F

    2016-07-01

    Levels of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, are dynamically altered after stroke in preclinical models. We sought to characterize the previously unexplored changes in serum ACE2 activity of stroke patients and the mechanism of these changes. Serum samples were obtained from patients during acute ischemic stroke (n=39), conditions mimicking stroke (stroke-alert, n=23), or from control participants (n=20). Enzyme activity levels were analyzed by fluorometric assay and correlated with clinical variables by regression analyses. Serum ACE2 activity was significantly lower in acute ischemic stroke as compared to both control and stroke-alert patients, followed by an increase to control levels at three days. Serum ACE2 activity significantly correlated with the presence of ischemic stroke after controlling for other factors (P=0.01). Additional associations with ACE2 activity included a positive correlation with systolic blood pressure at presentation in stroke-alert (R(2)=0.24, P=0.03), while stroke levels showed no correlation (R(2)=0.01, P=0.50). ACE2 sheddase activity was unchanged between groups. These dynamic changes in serum ACE2 activity in stroke, which concur with preclinical studies, are not likely to be driven primarily by acute changes in blood pressure or sheddase activity. These findings provide new insight for developing therapies targeting this protective system in ischemic stroke. PMID:27488276

  20. Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

    PubMed Central

    Lu, Hong; Howatt, Deborah A.; Balakrishnan, Anju; Moorleghen, Jessica J.; Rateri, Debra L.; Cassis, Lisa A.; Daugherty, Alan

    2015-01-01

    Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5 - 10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms. PMID:26436287

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

    PubMed Central

    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

  2. Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice.

    PubMed

    Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju; Moorleghen, Jessica J; Rateri, Debra L; Cassis, Lisa A; Daugherty, Alan

    2015-01-01

    Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5-10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms. PMID:26436287

  3. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats.

    PubMed

    Muller, D N; Dechend, R; Mervaala, E M; Park, J K; Schmidt, F; Fiebeler, A; Theuer, J; Breu, V; Ganten, D; Haller, H; Luft, F C

    2000-01-01

    We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end

  4. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

    PubMed Central

    Safari, Tahereh; Nematbakhsh, Mehdi; Evans, Roger G.; Denton, Kate M.

    2015-01-01

    Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7 ± 1.9% in estradiol-treated rats but only by 27.3 ± 5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen. PMID:26681937

  5. Gender Difference in Renal Blood Flow Response to Angiotensin II Administration after Ischemia/Reperfusion in Rats: The Role of AT2 Receptor

    PubMed Central

    Maleki, Maryam

    2016-01-01

    Background. Renal ischemia/reperfusion (I/R) is one of the major causes of kidney failure, and it may interact with renin angiotensin system while angiotensin II (Ang II) type 2 receptor (AT2R) expression is gender dependent. We examined the role of AT2R blockade on vascular response to Ang II after I/R in rats. Methods. Male and female rats were subjected to 30 min renal ischemia followed by reperfusion. Two groups of rats received either vehicle or AT2R antagonist, PD123319. Mean arterial pressure (MAP), and renal blood flow (RBF) responses were assessed during graded Ang II (100, 300, and 1000 ng/kg/min, i.v.) infusion at controlled renal perfusion pressure (RPP). Results. Vehicle or antagonist did not alter MAP, RPP, and RBF levels significantly; however, 30 min after reperfusion, RBF decreased insignificantly in female treated with PD123319 (P = 0.07). Ang II reduced RBF and increased renal vascular resistance (RVR) in a dose-related fashion (Pdose < 0.0001), and PD123319 intensified the reduction of RBF response in female (Pgroup < 0.005), but not in male rats. Conclusion. The impact of the AT2R on vascular responses to Ang II in renal I/R injury appears to be sexually dimorphic. PD123319 infusion promotes these hemodynamic responses in female more than in male rats. PMID:27034657

  6. Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.

    PubMed

    Haudek, Sandra B; Cheng, Jizhong; Du, Jie; Wang, Yanlin; Hermosillo-Rodriguez, Jesus; Trial, JoAnn; Taffet, George E; Entman, Mark L

    2010-09-01

    Angiotensin-II (Ang-II) is an autacoid generated as part of the pathophysiology of cardiac hypertrophy and failure. In addition to its role in cardiac and smooth muscle contraction and salt retention, it was shown to play a major role in the cardiac interstitial inflammatory response and fibrosis accompanying cardiac failure. In this study, we examined a model of Ang-II infusion to clarify the early cellular mechanisms linking interstitial fibrosis with the onset of the tissue inflammatory response. Continuous infusion of Ang-II resulted in increased deposition of collagen in the heart. Ang-II infusion also resulted in the appearance of distinctive small, spindle-shaped, bone marrow-derived CD34(+)/CD45(+) fibroblasts that expressed collagen type I and the cardiac fibroblast marker DDR2 while structural fibroblasts were CD34(-)/CD45(-). Genetic deletion of monocyte chemoattractant protein (MCP)-1 (MCP-1-KO mice) prevented the Ang-II-induced cardiac fibrosis and the appearance of CD34(+)/CD45(+) fibroblasts. Real-time PCR in Ang-II-treated hearts revealed a striking induction of types I and III collagen, TGF-beta1, and TNF mRNA expression; this was obviated in Ang-II-infused MCP-1-KO hearts. In both wild-type and MCP-1-KO mice, Ang-II infusion resulted in cardiac hypertrophy, increased systolic function and hypertension which were not significantly different between the WT and MCP-1-KO mice over the 6-week course of infusion. In conclusion, the development of Ang-II-induced non-adaptive fibrosis in the heart required induction of MCP-1, which modulated the uptake and differentiation of a CD34(+)/CD45(+) fibroblast precursor population. In contrast to the inflammatory and fibrotic response, the hemodynamic response to Ang-II was not affected by MCP-1 in the first 6weeks. PMID:20488188

  7. Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors.

    PubMed

    Dao, Vu Thao-Vi; Medini, Sawsan; Bisha, Marion; Balz, Vera; Suvorava, Tatsiana; Bas, Murat; Kojda, Georg

    2016-07-15

    Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity. PMID:27235748

  8. Thymosin β4 Prevents Angiotensin II-Induced Cardiomyocyte Growth by Regulating Wnt/WISP Signaling.

    PubMed

    Li, Li; Guleria, Rakeshwar S; Thakur, Suresh; Zhang, Cheng-Lin; Pan, Jing; Baker, Kenneth M; Gupta, Sudhiranjan

    2016-08-01

    Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio-protective effect of Tβ4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tβ4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, β-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tβ4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tβ4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tβ4. This is the first report which demonstrates that Tβ4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. © 2015 Wiley Periodicals, Inc. PMID:26627308

  9. Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo.

    PubMed

    Alvarez, A; Sanz, M J

    2001-08-01

    Chronically elevated angiotensin II (Ang-II)-induced hypertension is partly mediated by superoxide production. In this study, we have investigated whether the leukocyte-endothelial cell interactions elicited by Ang-II involve reactive oxygen species (ROS) generation. Intravital microscopy within the rat mesenteric microvessels was used. Superfusion (60 min) with Ang-II (1 nM) induced significant increases in leukocyte rolling flux, adhesion, and emigration, which were inhibited by pretreatment with superoxide dismutase or catalase. Dihydrorhodamine-123 oxidation indicated that ROS are primarily produced by the vessel wall. Administration of dimethylthiourea, desferrioxamine, or N-acetylcysteine provoked significant reductions in Ang-II-induced leukocyte-endothelial cell interactions. In addition, a blockade of platelet-activating factor or leukotrienes also attenuated such responses significantly. The results presented indicate that in vivo Ang-II-induced leukocyte recruitment is dependent on the generation of intra- and extracellular ROS. Therefore, the use of anti-oxidants might constitute an alternative therapy for the control of the subendothelial leukocyte infiltration associated with hypertension and atherosclerosis. PMID:11493611

  10. AT1 Receptor Mediated Augmentation of Intrarenal Angiotensinogen in Angiotensin II-Dependent Hypertension

    PubMed Central

    Kobori, Hiroyuki; Prieto-Carrasquero, Minolfa C.; Ozawa, Yuri; Navar, L. Gabriel

    2009-01-01

    Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in association with increased intrarenal Ang II content. The present study was performed to determine if the augmentation of intrarenal angiotensinogen requires activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220 g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5 mg/d, n=12). Ang II infusion progressively increased systolic blood pressure (SBP) compared with sham (178±8 mm Hg versus119±4 at day 11). ARB treatment prevented hypertension (113±6 at day 11). Twenty-four-hour urine collections were taken at day 12, and plasma and tissue samples were harvested at day 13. The Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II and sham groups (365±46 fmol/mL versus 76±9 and 45±14, respectively). Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by Ang II infusion (65±17 fmol/g in sham, 606±147 in Ang II group, and 288±28 in Ang II+ARB group). Ang II infusion significantly increased kidney angiotensinogen compared with sham (1.69±0.21 densitometric units versus 1.00±0.17). This change was reflected by increased angiotensinogen immunostaining in proximal tubules. ARB treatment prevented this increase (1.14±0.12). Urinary angiotensinogen excretion rates were enhanced 4.7× in Ang II group (4.67±0.41 densitometric units versus 1.00±0.21) but ARB treatment prevented the augmentation of urinary angiotensinogen (0.96±0.23). These data demonstrate that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1-dependent and provide further evidence that urinary angiotensinogen is closely linked to intrarenal Ang II in Ang II-dependent hypertension. PMID:15037565

  11. Altered activities of kininase II, an angiotensin converting enzyme, prekallikrein, and nitric oxide in Kuwaiti patients with type 2 diabetes.

    PubMed

    Sharma, J N; Al-Shoumer, Kas; Matar, K M; Madathil, N V; Al-Moalem, Amk

    2015-06-01

    The current investigation was conducted to examine kininase II or angiotensin converting enzyme (ACE), plasma prekallikrein (PK), and nitric oxide (NO) concentrations in healthy Kuwaiti subjects and newly diagnosed Kuwaiti type 2 diabetic patients before and after treatment for 6 weeks with metformin hydrochloride 500 mg twice daily after meal. With the consent of volunteers, blood and urine samples were collected after an overnight fasting. Samples were collected from the diabetic patients before and after treatment for 6 weeks. Enzyme linked immunosorbent assay (ELISA) was carried out on the aliquoted samples to measure the concentration of kininase II. NO was detected via colorimetry. Plasma Kininase II or ACE levels were significantly (P <0.01) increased by 18% in untreated diabetics when compared with healthy volunteers. However, after treatment there was a significant decrease of 20% in their ACE levels. Plasma prekallikrein levels were raised significantly (P <0.01) by 28% in diabetic patients in contrast with the control subjects and the levels were significantly reduced (P <0.0001) by 44% after treatment with metformin hydrochloride. NO levels were found to be significantly decreased in plasma by 56% and in urine by 62% in untreated diabetic patients as compared with the healthy subjects. However, when the treated diabetic patients were compared with untreated diabetics, there was an increase of 50% in plasma and 37% in urine samples. The high levels of kininase II, prekallikrein, and reduced NO may be partly responsible for the induction of renal, cardiac, and hypertensive complications associated with type 2 diabetes. Reduced NO level is an indication of endothelial dysfunction resulting in increased blood pressure. Oral anti-diabetic treatment is associated with protective effects through the reduction of kininase II (ACE), prekallikrein, and elevation of NO levels. PMID:25964383

  12. TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis.

    PubMed

    Duerrschmid, Clemens; Crawford, Jeffrey R; Reineke, Erin; Taffet, George E; Trial, Joann; Entman, Mark L; Haudek, Sandra B

    2013-04-01

    Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart. PMID:23337087

  13. Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo.

    PubMed

    Estellés, Rossana; Milian, Lara; Nabah, Yafa Naim Abu; Mateo, Teresa; Cerdá-Nicolás, Miguel; Losada, Mercedes; Ivorra, María Dolores; Issekutz, Andrew C; Cortijo, Julio; Morcillo, Esteban J; Blázquez, María Amparo; Sanz, María-Jesús

    2005-09-01

    Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h. BM inhibited neutrophil infiltration into the peritoneal cavity at 4 h and 8 h by 73% and 77%, respectively, SB at 8 h by 55%, and B had no effect on this response. Although BM inhibited the release of cytokine-inducible neutrophil chemoattractant/keratinocyte-derived chemokine, macrophage inflammatory protein-2 (MIP-2), and platelet-activating factor (PAF) elicited by Ang-II, SB only reduced the release of MIP-2 after 4 h of its administration. Sixty-minute superfusion of the rat mesentery with 1 nM Ang-II induced a significant increase in the leukocyte-endothelial cell interactions and P-selectin up-regulation, which were inhibited by 1 microM BM and SB. The generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II was inhibited significantly by the three alkaloids tested. BM also diminished Ang-II-induced interleukin-8 release from endothelial cells and blocked the PAF receptor on human neutrophils (concentration of the compound needed to produce 50% inhibition value: 28.2 microM). Therefore, BM is a potent inhibitor of Ang-II-induced neutrophil accumulation in vivo. This effect appears to be mediated through inhibition of CXC chemokine and PAF release, ROS scavenging activity, and blockade of the PAF receptor. Thus, it may have potential therapeutic interest for the control of neutrophil recruitment that occurs in inflammation associated with elevated levels of Ang-II. PMID:15944212

  14. Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation

    PubMed Central

    Topchiy, Elena; Panzhinskiy, Evgeniy; Griffin, W. Sue T.; Barger, Steven W.; Das, Mita; Zawada, W. Michael

    2013-01-01

    Reactive oxygen species (ROS) have been reported to affect neural stem cell self-renewal and therefore may be important for normal development and may influence neurodegenerative processes when ROS activity is elevated. To determine if increasing production of superoxide, via activation of NADPH oxidase (Nox), increases neural stem cell proliferation, 100nM angiotensin II (Ang II) – a strong stimulator of Nox – was applied to cultures of a murine neural stem cell line C17.2. Twelve hours following a single treatment with Ang II there was a doubling of the number of neural stem cells. This increase in neural stem cell numbers was preceded by a gradual elevation of superoxide levels (detected by dihydroethidium, DHE, fluorescence) from the steady state at 0, 5, and 30 minutes and gradually increasing from one hour to the maximum at 12 h, and returning to baseline at 24 h. Ang II-dependent proliferation was blocked by the antioxidant N-acetyl-L-cysteine (NAC). Confocal microscopy revealed the presence of two sources of intracellular ROS in C17.2 cells: i) mitochondrial and ii) extramitochondrial; the latter indicative of involvement of one or more specific isoforms of Nox. Of the Nox family, mRNA expression for one member, Nox4, is abundant in neural stem cell cultures, and Ang II treatment resulted in elevation of the relative levels of Nox4 protein. SiRNA targeting of Nox4 mRNA reduced both the constitutive and Ang II-induced Nox4 protein levels and attenuated Ang II-driven increases in superoxide levels and stem cell proliferation. Our findings are consistent with our hypothesis that Ang II-induced proliferation of neural stem cells occurs via Nox4-generated superoxide, suggesting that an Ang II/Nox4 axis is an important regulator of neural stem cell self-renewal and as such may fine-tune normal or stress- or disease-modifying neurogenesis. PMID:23751520

  15. Angiotensin II-mediated posttranslational modification of nNOS in the PVN of rats with CHF: role for PIN

    PubMed Central

    Sharma, Neeru M.; Llewellyn, Tamra L.; Zheng, Hong

    2013-01-01

    An increased sympathetic drive is an adverse characteristic in chronic heart failure (CHF). The protein expression of neuronal nitric oxide synthase (nNOS)- and hence nitric oxide (NO)-mediated sympathoinhibition is reduced in the paraventricular nucleus (PVN) of rats with CHF. However, the molecular mechanism(s) of nNOS downregulation remain(s) unclear. The aim of the study was to reveal the underlying molecular mechanism for the downregulation of nNOS in the PVN of CHF rats. Sprague-Dawley rats with CHF (6–8 wk after coronary artery ligation) demonstrated decreased nNOS dimer/monomer ratio (42%), with a concomitant increase in the expression of PIN (a protein inhibitor of nNOS known to dissociate nNOS dimers into monomers) by 47% in the PVN. Similarly, PIN expression is increased in a neuronal cell line (NG108) treated with angiotensin II (ANG II). Furthermore, there is an increased accumulation of high-molecular-weight nNOS-ubiquitin (nNOS-Ub) conjugates in the PVN of CHF rats (29%). ANG II treatment in NG108 cells in the presence of a proteasome inhibitor, lactacystin, also leads to a 69% increase in accumulation of nNOS-Ub conjugates immunoprecipitated by an antiubiquitin antibody. There is an ANG II-driven, PIN-mediated decrease in the dimeric catalytically active nNOS in the PVN, due to ubiquitin-dependent proteolytic degradation in CHF. Our results show a novel intermediary mechanism that leads to decreased levels of active nNOS in the PVN, involved in subsequent reduction in sympathoinhibition during CHF, offering a new target for the treatment of CHF and other cardiovascular diseases. PMID:23832698

  16. Are polyamines involved in the contractile effects of angiotensin II in the rat aorta? (Polyamines and angiotensin II in rat aorta).

    PubMed

    Costuleanu, Natalia; Foia, Liliana; Slătineanu, Simona Mihaela; Costuleanu, M; Petrescu, G

    2004-01-01

    Angiotensin II (AII) is a central factor involved in the pathophysiology of arterial hypertension and atherosclerosis. On the other hand, polyamines represent a family of organic cations with low molecular weight, playing intracellular regulatory roles essential for the cellular growth and differentiation. The cellular contents, the synthesis and the transport of polyamines are increased following the actions of AII, as well as of other cellular growth factors. Our results show that the administration of polyamines as pre-treatment modulates the contractile effects of extracellular AII (80 nM). This modulation is concentration-dependent and dual: the lower concentrations amplify and the higher concentrations reduce the effects of AII in the isolated rat aorta rings without endothelium. Moreover, DL-alpha-Difluoromethylomithine (DFMO), a specific inhibitor of ornithine decarboxylase, does not significantly modify the contractile effects of AII. Thus, these data suggest that polyamines generated through this metabolic pathway are not involved in the contractile effects of AII in rat aortic vascular smooth muscle. PMID:15986523

  17. Abnormal Adrenal Responsiveness and Angiotensin II Dependency in High Renin Essential Hypertension

    PubMed Central

    Dluhy, Robert G.; Bavli, Sam Z.; Leung, Frank K.; Solomon, Harold S.; Moore, Thomas J.; Hollenberg, Norman K.; Williams, Gordon H.

    1979-01-01

    Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na+/100 meq K+ diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24±6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 ± 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 ± 1 ng/ml per h; plasma aldosterone = 87 ± 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 μg/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (−15 ± 3 mm Hg) was significantly greater than in the normal adrenal responsive group (−3 ± 2 mm Hg) (P < 0.02). It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes. PMID:500810

  18. Exogenous insulin augments in healthy volunteers the cardiovascular reactivity to noradrenaline but not to angiotensin II.

    PubMed Central

    Gans, R O; Bilo, H J; von Maarschalkerweerd, W W; Heine, R J; Nauta, J J; Donker, A J

    1991-01-01

    Hyperinsulinemia has been implicated in the pathogenesis of the blood pressure elevation in patients with noninsulin-dependent diabetes mellitus, obesity, but also essential hypertension. In these conditions an increased cardiovascular reactivity to noradrenaline (NA) and angiotensin II (AII) can be observed. Using the euglycemic clamp technique, we determined the cardiovascular reactivity to graded infusions of NA and AII in nine healthy males before (Bas), and 1 and 6 h after infusion of insulin (50 mU/kg per h) was started. On separate days control experiments were carried out to control for any circadian variation. Insulin led to a decrease of the amount of circulating NA necessary to increase the diastolic blood pressure (DBP) 20 mmHg (actual experiment [mean +/- SEM]: Bas, 23.1 +/- 5.0; 1 h, 14.8 +/- 3.0; and 6 h, 12.3 +/- 3.1; and control experiment: Bas, 20.7 +/- 5.0; 1 h, 18.6 +/- 3.5; and 6 h, 17.3 +/- 3.3 nmol/liter; Bas vs. 1 and 6 h: P less than 0.05). Although the amount of NA infused to raise DBP 20 mmHg showed a similar decline after 1 h of insulin infusion, no such change from baseline could be observed at 6 h. This appeared to be due to an increase in NA clearance with more prolonged insulin infusion. Insulin exerted no effect on the amount of AII infused to increase DBP 20 mmHg (actual experiment: Bas, 27.6 +/- 6.4; 1 h, 28.8 +/- 10.0; and 6 h, 21.2 +/- 5.3; and control experiment: Bas, 33.6 +/- 5.7; 1 h, 34.2 +/- 6.1; and 6 h, 23.4 +/- 4.7 ng/kg/min; NS). We did observe a circadian variation in AII reactivity. Whether the increase in cardiovascular responsiveness to NA after administration of insulin contributes to the elevation in blood pressure frequently observed in patients with insulin resistance remains to be proven. PMID:1864961

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

    PubMed Central

    Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Garner, Ron E; McKallip, Robert J; Zhao, Zhi-Qing

    2015-01-01

    Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin-converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02%) vs in the Ang II group (0.7±0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID:26648693

  20. A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

    PubMed Central

    George, Amee J.; Purdue, Brooke W.; Gould, Cathryn M.; Thomas, Daniel W.; Handoko, Yanny; Qian, Hongwei; Quaife-Ryan, Gregory A.; Morgan, Kylie A.; Simpson, Kaylene J.; Thomas, Walter G.; Hannan, Ross D.

    2013-01-01

    Summary The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R–EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R–EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R–EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR–EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer. PMID:24046455

  1. A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation.

    PubMed

    George, Amee J; Purdue, Brooke W; Gould, Cathryn M; Thomas, Daniel W; Handoko, Yanny; Qian, Hongwei; Quaife-Ryan, Gregory A; Morgan, Kylie A; Simpson, Kaylene J; Thomas, Walter G; Hannan, Ross D

    2013-12-01

    The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer. PMID:24046455

  2. Angiotensin II receptor blockers: a new possible treatment for chronic migraine?

    PubMed

    Disco, Caterina; Maggioni, Ferdinando; Zanchin, Giorgio

    2015-08-01

    The objective is to suggest a possible role of different angiotensin receptor blockers in the treatment of chronic migraine, especially in hypertensive subjects. Chronic migraine is a highly disabling disorder affecting between 1.4 and 2.2 % of the general population. Despite many pharmacological and non-pharmacological treatments proposed, the results are rather discouraging. Therefore, we believe that should be highlighted all the possible therapies that may lead to an improvement of the symptomatology. Particularly, data available on efficacy of ARBs in preventing chronic migraine are poor. Methods include case reports, literature review and discussion. We report three cases recently treated with angiotensin II receptor blockers that showed a significant improvement, never previously presented with more conventional treatments, including beta blockers. In all three cases, we obtained the reversibility from a chronic migraine to an episodic. Taking a cue from this observation, we consider desirable large controlled, randomized trials to assess the effectiveness of ARBs both in CM hypertensive patients and in patients who do not require anti-hypertensive therapy; furthermore are desirable comparative studies between the various ARB inhibitors to assay any intermolecular differences in efficacy. PMID:25917398

  3. Angiotensin II-inhibition: effect on Alzheimer’s pathology in the aged triple transgenic mouse

    PubMed Central

    Ferrington, Linda; Palmer, Laura E.; Love, Seth; Horsburgh, Karen J; Kelly, Paul AT; Kehoe, Patrick G

    2012-01-01

    Reducing excessive accumulation of amyloid-β (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies, and inhibition of angiotensin-converting enzyme (ACE) may delay onset or progression of AD. The effects of an ACE-inhibitor (ACE-I) and an angiotensin II receptor blocker (ARB) on Aβ and tau pathology in a triple transgenic (3xTGAD) mouse model of AD were investigated. 9-10month 3xTGAD mice were treated with ARB, ACE-I or vehicle for 6 months. Mean arterial blood pressure (MABP) was measured periodically and mice were assessed behaviourally. Aβ, phospho-tau, amyloid precursor protein (APP) and ACE activity were analysed. MABP was significantly reduced at 2 weeks and 3 months in the ACE-I group and at 3 months in the ARB group, compared to vehicle. Neither drug altered performance of 3xTGAD mice in Morris Water Maze or T-maze, nor were Aβ, tau immunolabelling or APP levels altered. ACE-I significantly reduced ACE activity in kidney. Prolonged treatment with ACE-I or ARB does not affect Aβ or phospho-tau accumulation in brains of aged 3xTGAD mice. PMID:22611468

  4. The effect of subfornical organ lesions and ventricular blockade on drinking induced by angiotensin II.

    PubMed

    Hoffman, W E; Phillips, M I

    1976-05-21

    The role of the subfornical organ (SFO) as the unique receptor site for the drinking behavior induced by intracranial injections of angiotensin II (AII) was investigated. It was found that: (1) drinking in response to intraventricular (IVT) injections of AII was reduced in 6 rats but was unchanged after 80-100% damage of the SFO in 4 cases; (2) reduction of drinking to lateral ventricular application of AII was seen with no apparent SFO damage in 4 rats; (3) recovery of the AII induced drinking deficit was consistently observed within a short time interval (14 days), even in those animals with complete SFO lesions: (4) the presence of ventricular debris was correlated with deficits in water intake to IVT angiotensin injections. In a second experiment artificial blockade of the ventricular space was produced by a plugging technique. Plugging the anterior third ventricle simulated the effects of SFO lesioning. It was concluded that the SFO is not a unique receptor area since the ventral anterior third ventricle is also sensitive for AII (IVT) induced drinking. If the SFO is a receptor site for AII circulating in the CSF it is probably not the only periventricular receptor site. Access of AII to the anterior ventral third ventricle appears to be essential for inducement of drinking. PMID:1276893

  5. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling

    PubMed Central

    Paradis, Pierre; Dali-Youcef, Nassim; Paradis, François W.; Thibault, Gaétan; Nemer, Mona

    2000-01-01

    Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse α-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases. PMID:10639182

  6. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling.

    PubMed

    Paradis, P; Dali-Youcef, N; Paradis, F W; Thibault, G; Nemer, M

    2000-01-18

    Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases. PMID:10639182

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

    SciTech Connect

    Marie, J.; Seyer, R.; Lombard, C.; Desarnaud, F.; Aumelas, A.; Jard, A.; Bonnafous, J.C. )

    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.

  8. Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling.

    PubMed

    Zhou, Chaoming; Ramaswamy, Swarna S; Johnson, Derrick E; Vitturi, Dario A; Schopfer, Franciso J; Freeman, Bruce A; Hudmon, Andy; Levitan, Edwin S

    2016-01-01

    Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO(-)) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO(-) oxidizes and modestly activates pure CaMKII in the absence of Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-independent CaMKII activity. The role of ONOO(-) in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO(-) and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO(-) participates in Ang II-CaMKII signaling. The requirement for ONOO(-) in transducing Ang II signaling identifies ONOO(-), which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling. PMID:27079272

  9. GLUTATHIONE PEROXIDASE-1 PLAYS A MAJOR ROLE IN PROTECTING AGAINST ANGIOTENSIN II-INDUCED VASCULAR DYSFUNCTION

    PubMed Central

    Chrissobolis, Sophocles; Didion, Sean P.; Kinzenbaw, Dale A.; Schrader, Laura I.; Dayal, Sanjana; Lentz, Steven R.; Faraci, Frank M.

    2011-01-01

    Levels of reactive oxygen species, including hydrogen peroxide (H2O2), increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases (GPx) are known to metabolize H2O2, the role of GPx during hypertension is poorly defined. We tested the hypothesis that GPx-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1 +/− and Gpx1 −/−) and Gpx1 transgenic (Tg) mice, and their respective littermate controls, were examined in vitro following overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh, an endothelium-dependent agonist) was similar in control, Gpx1 +/−, and Gpx1 Tg mice, whereas in Gpx1 −/− mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L Ang II. In contrast, relaxation to ACh in arteries from Gpx1 +/− mice was inhibited by ~60% following treatment with 1 nmol/L Ang II, indicating Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 Tg mice, or arteries from control mice treated with PEG-catalase (which degrades H2O2). Thus, genetic and pharmacological evidence suggests a major role for GPx-1 and H2O2 in Ang II-induced effects on vascular function. PMID:18299484

  10. Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling

    PubMed Central

    Zhou, Chaoming; Ramaswamy, Swarna S.; Johnson, Derrick E.; Vitturi, Dario A.; Schopfer, Franciso J.; Freeman, Bruce A.; Hudmon, Andy; Levitan, Edwin S.

    2016-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca2+-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca2+ independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO−) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO− oxidizes and modestly activates pure CaMKII in the absence of Ca2+/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca2+-independent CaMKII activity. The role of ONOO− in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO− and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO− participates in Ang II-CaMKII signaling. The requirement for ONOO− in transducing Ang II signaling identifies ONOO−, which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling. PMID:27079272

  11. Central angiotensin II induces thirst-related responses in an amphibian.

    PubMed

    Propper, C R; Hillyard, S D; Johnson, W E

    1995-03-01

    Angiotensin II (A-II), a potent inducer of thirst-related behavior in many vertebrate species, was injected into the third ventricle of the brain of the spadefoot toad, Scaphiopus couchii. Following injection of 10 ng A-II the animals demonstrated a significant increase in water absorption response (WR) behavior, in which toads press their ventral skin to a moist surface and absorb water by osmosis. This increase in the frequency of WR behavior was positively correlated with an increase in water gain during a 2-hr period indicating that centrally injected A-II stimulates water intake by this amphibian species. We have previously demonstrated that WR behavior is also induced by intraperitoneal (i.p.) injections of A-II in several anuran species, including S. couchii. Thus, amphibians, like other vertebrates, demonstrate an increase in water intake in response to either centrally administered or circulating A-II. A second series of experiments was conducted to determine whether the above response to A-II might be secondary to increases in the circulating levels of aldosterone (ALDO) or antidiuretic hormone because the release of both of these hormones has been shown by others to be stimulated by A-II. Scaphiopus couchii injected i.p. with either ALDO or arginine vasotocin in dosages of 1, 10, and 100 micrograms/100 g body weight showed no increase in WR behavior relative to toads injected with saline alone. These results suggest that A-II acts directly on the brain of S. couchii to induce WR behavior. PMID:7782064

  12. An Intact Median Preoptic Nucleus is Necessary for Chronic Angiotensin II-Induced Hypertension

    PubMed Central

    Ployngam, Trasida; Collister, John P.

    2007-01-01

    The median preoptic nucleus (MnPO) receives afferent input from the subfornical organ, a circumventricular organ that has been shown to be necessary in mediating the full chronic hypertensive response to angiotensin II (ANG II) administration. In addition, intravenous ANG II infusion has been shown to cause activation of a number of neurons in both the dorsal and ventral part of MnPO. Taken together, we hypothesized that the MnPO is necessary for the full hypertensive response observed during chronic ANG II-induced hypertension. To test this hypothesis, male Sprague Dawley rats were subjected to either sham (SHAM) or electrolytic lesion of both the dorsal and ventral part of the MnPO (MnPOx). During the same surgery, rats were instrumented with venous catheters, and radiotelemetric transducers for the intravenous administration of ANG II and the measurement of blood pressure and heart rate, respectively. Rats were then given a week recovery period. After 3 days of saline control infusion, ANG II was intravenously infused (10 ng ˙ kg−1˙ min−1) in both sham and MnPOx animals for 10 consecutive days, and followed by 3 recovery days. By day 7 of Ang II infusion, MAP had increased 38 ± 3 mmHg in sham lesion rats (n=6), but MAP of MnPOx rats (>90% MnPO ablated; n=5) had only increased 18 ± 2 mmHg. This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the MnPO is necessary for the chronic hypertensive response to ANG II administration. PMID:17618605

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

    NASA Technical Reports Server (NTRS)

    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).

  14. Angiotensin II modification by decomposition products of linoleic acid-derived lipid hydroperoxide.

    PubMed

    Takahashi, Ryo; Goto, Takaaki; Oe, Tomoyuki; Lee, Seon Hwa

    2015-09-01

    Polyunsaturated fatty acids are highly susceptible to oxidation induced by reactive oxygen species and enzymes, leading to the formation of lipid hydroperoxides. The linoleic acid (LA)-derived hydroperoxide, 13-hydroperoxyoctadecadienoic acid (HPODE) undergoes homolytic decomposition to reactive aldehydes, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal, trans-4,5-epoxy-2(E)-decenal (EDE), and 4-hydroperoxy-2(E)-nonenal (HPNE), which can covalently modify peptides and proteins. ONE and HNE have been shown to react with angiotensin (Ang) II (DRVYIHPF) and modify the N-terminus, Arg(2), and His(6). ONE-derived pyruvamide-Ang II (Ang P) alters the biological activities of Ang II considerably. The present study revealed that EDE and HPNE preferentially modified the N-terminus and His(6) of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His(6)(EDE)]-Ang II, hydrated forms were detected as major products, suggesting considerable involvement of the vicinal dihydrodiol (formed by epoxide hydration) in EDE-derived protein modification in vivo. Substantial amounts of [N-(EDE-H2O)]-Ang II isomers were also formed and their synthetic pathway might involve the tautomerization of a carbinolamine intermediate, followed by intramolecular cyclization and dehydration. The main HPNE-derived products were [His(6)(HPNE)]-Ang II and [N-(HPNE-H2O)]-Ang II. However, ONE, HNE, and malondialdehyde-derived modifications were dominant, because HPNE is a precursor of these aldehydes. A mixture of 13-HPODE and [(13)C18]-13-HPODE (1:1) was then used to determine the major modifications derived from LA peroxidation. The characteristic doublet (1:1) observed in the mass spectrum and the mass difference of the [M+H](+) doublet aided the identification of Ang P (N-terminal α-ketoamide), [N-ONE]-Ang II (4-ketoamide), [Arg(2)(ONE-H2O)]-Ang II, [His(6)(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole

  15. RAMP1 Augments Cerebrovascular Responses to CGRP And Inhibits Angiotensin II-Induced Vascular Dysfunction

    PubMed Central

    Chrissobolis, Sophocles; Zhang, Zhongming; Kinzenbaw, Dale A.; Lynch, Cynthia M.; Russo, Andrew F.; Faraci, Frank M.

    2010-01-01

    Background and Purpose Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1). Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in hRAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro following overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by ∼50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in hRAMP1 transgenic mice. Conclusions RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states where Ang II plays a major role. PMID:20814003

  16. Effects of Angiotensin-II Receptor Blocker on Inhibition of Thrombogenicity in a Canine Atrial Fibrillation Model

    PubMed Central

    Jung, Jae Seung; Kim, Min Kyung; Sim, Jaemin; Kim, Jin Seok; Lim, Hong Euy; Park, Sang Weon; Kim, Young-Hoon

    2016-01-01

    Background and Objectives Angiotensin-II receptor blockers (ARBs) are known to reduce the development of atrial fibrillation (AF) through reverse-remodeling. However, the effect of ARBs on thrombogenicity in AF remains unknown. Materials and Methods Twelve dogs were assigned to control (n=4), ARB (candesartan cilexitil 10 mg/kg/day p.o., 12 weeks; n=4), or sham (n=4) groups. Sustained AF was induced by rapid atrial pacing. Both arterial and venous serum levels of tissue inhibitor of matrix metalloproteinase-1, von Willebrand factor, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and during AF (0, 4, and 12 weeks) with enzyme-linked immunosorbent assay. Biopsies from both atria including the appendages were performed to semi-quantitatively assess endocardial and myocardial fibrosis after 12 weeks. Results The serum levels of bio-markers were not significantly different at baseline or during AF between the control and the candesartan groups. The levels were not significantly different over time, but there was a trend toward a decrease in arterial VCAM-1 from 4 to 12 weeks in the candesartan group compared to the control group. The grades of endocardial fibrosis after 12 weeks but not those of myocardial fibrosis were slightly reduced in the candesartan group compared to the control group. Conclusion This study did not show that the ARB candesartan significantly reverses thrombogenicity or fibrosis during AF. Future studies using a larger number of subjects are warranted to determine the therapeutic effect of renin-angiotensin-aldosterone system blockade on prothrombogenic processes in AF. PMID:27275170

  17. Changes in blood pressure and dipsogenic responsiveness to angiotensin II during chronic exposure of rats to cold

    SciTech Connect

    Fregly, M.J.; Shechtman, O.; van Bergen, P.; Reeber, C.; Papanek, P.E. )

    1991-03-11

    To assess the role of the renin-angiotensin (RA) system in the development of cold-induced hypertension in rats, systolic blood pressure (SBP), plasma renin activity (PRA), and the dipsogenic responsiveness to s.c. administration of angiotensin II (AII) were measured weekly for 4 weeks. SBP increased significantly during the third week of exposure to cold (5C), compared to warm-adapted controls. A significant increase in SBP occurred during the third week of cold. In contrast, (PRA) increased within the first week of cold, and declined thereafter to reach the level of the control by the third week. By the fourth week, PRA decreased to a level significantly below that of control. The dipsogenic responsiveness to acute administration of AII increased significantly by the third week of cold and remained significantly elevated during the fourth week. There was a significant direct relationship between dipsogenic responsiveness to AII and SBP in the cold-treated but not the control group. There was also a significant indirect linear relationship between PRA and dipsogenic responsiveness to AII. Cold-treated rats had significant increases in urinary norepinephrine output and weights of heart, kidneys, adrenals, and brown adipose tissue. Thus, the results suggest, but do not prove, either that the elevation of blood pressure under these conditions may be induced by changes in the RA system. The results suggest further that the reduction in the drinking response to AII accompanying increases in PRA may be related to changes in the regulation of central receptors for AII.

  18. Role of AMP-activated protein kinase α1 in angiotensin-II-induced renal Tgfß-activated kinase 1 activation.

    PubMed

    Mia, Sobuj; Castor, Tatsiana; Musculus, Katharina; Voelkl, Jakob; Alesutan, Ioana; Lang, Florian

    2016-08-01

    Angiotensin-II is a key factor in renal fibrosis. Obstructive nephropathy induces an isoform shift from catalytic Ampkα2 towards Ampkα1 which contributes to signaling involved in renal tissue injury. The present study explored whether the Ampkα1 isoform contributes to the renal effects of angiotensin-II. To this end, angiotensin-II was infused by subcutaneous implantation of osmotic minipumps in gene-targeted mice lacking functional Ampkα1 (Ampkα1(-/-)) and corresponding wild-type mice (Ampkα1(+/+)). Western blotting and qRT-PCR were employed to determine protein abundance and mRNA levels, respectively, in renal tissue. In Ampkα1(+/+) mice, angiotensin-II increased renal Ampkα1 protein expression without significantly modifying renal Ampkα2 protein expression. The renal phosphorylated Ampkα (Thr(172)) protein abundance was not affected by angiotensin-II in neither genotypes, but was significantly lower in Ampkα1(-/-) mice than Ampkα1(+/+) mice. Angiotensin-II increased the phosphorylation of Tak1 (Ser(412)) in renal tissue of Ampkα1(+/+) mice, an effect virtually absent in the Ampkα1(-/-) mice. Furthermore, angiotensin-II treatment significantly increased renal protein and mRNA expression of α-smooth muscle actin (αSma) as well as Tak1-target gene expression: Cox2, Il6 and Pai1 in Ampkα1(+/+) mice, all effects significantly less pronounced in Ampkα1(-/-) mice. In conclusion, angiotensin-II up-regulates the Ampkα1 isoform in renal tissue. Ampkα1 participates in renal Tak1 activation and Tak1-dependent signaling induced by angiotensin-II. PMID:27230958

  19. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats

    PubMed Central

    Snijder, P M; Frenay, A R; de Boer, R A; Pasch, A; Hillebrands, J L; Leuvenink, H G D; van Goor, H

    2015-01-01

    Background and Purpose Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. Experimental Approach Male Sprague Dawley rats were infused with Ang II (435 ng kg min−1) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). Key Results Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. Conclusions and Implications Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24962324

  20. Angiotensin II AT1 receptor constitutive activation: from molecular mechanisms to pathophysiology.

    PubMed

    Petrel, Christophe; Clauser, Eric

    2009-04-29

    Mutations activating the angiotensin II AT(1) receptor are important to identify and characterize because they give access to the activation mechanisms of this G protein coupled receptor and help to characterize the signaling pathways and the potential pathophysiology of this receptor. The different constitutively activated mutations of the AT(1) receptor are mostly localized in transmembrane domains (TM) and their characterization demonstrated that release of intramolecular constraints and movements among these TM are a necessary step for receptor activation. These mutations constitutively activate Gq linked signaling pathways, receptor internalization and maybe the G protein-independent signaling pathways. Expression of such mutations in mice is linked to hypertension and cardiovascular diseases, but such natural mutations have not been identified in human pathology. PMID:19061936

  1. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  2. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

    PubMed Central

    Toth, Peter; Tucsek, Zsuzsanna; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Tarantini, Stefano; Deak, Ferenc; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-01-01

    Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood–brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation. PMID:23942363

  3. Cisplatin-induced nephrotoxicity alters blood pressure response to angiotensin II administration in rats

    PubMed Central

    Dehghani, Aghdas; Saberi, Shadan; Nematbakhsh, Mehdi

    2016-01-01

    Background: Cisplatin (CP) is an effective chemotherapeutic drug used in the clinic, which is accompanied with nephrotoxicity. CP may also disturb hemodynamics of the circulation system. We have tested the role of CP in mean arterial pressure (MAP) response to graded angiotensin (Ang) II infusion in rats. Materials and Methods: Male and female rats were treated with CP (2.5 mg/kg/day) for a period of 1-week and compared with the vehicle-treated animals. The blood pressure response to Ang II (100–1000 ng/kg/min) was determined under the anesthesia condition. Endothelial permeability of aorta was measured according to the Evans blue uptake. The kidney tissue was also subjected to histological investigation. Results: Significant increase in serum levels of blood urea nitrogen and creatinine and pathological findings in CP-treated rats verified CP-induced nephrotoxicity. Significant difference in percentage of change in MAP response to Ang II between male and female rats was detected in vehicle-treated groups (P < 0.05) while in CP-treated animals this response difference was not observed. The groups were not significantly different with regard to the endothelial permeability of aorta while the serum level of nitrite in male rats increased significantly following administration of CP (P < 0.05). Conclusion: It seems the different response in percentage of change of MAP to graded Ang II infusion between male and female indicates the effect of CP on renin Ang system parameters. PMID:27110550

  4. Angiotensin II-superoxide-NFκB signaling and aortic baroreceptor dysfunction in chronic heart failure

    PubMed Central

    Zhang, Dongze; Muelleman, Robert L.; Li, Yu-Long

    2015-01-01

    Chronic heart failure (CHF) affects approximately 5.7 million people in the United States. Increasing evidence from both clinical and experimental studies indicates that the sensitivity of arterial baroreflex is blunted in the CHF state, which is a predictive risk factor for sudden cardiac death. Normally, the arterial baroreflex regulates blood pressure and heart rate through sensing mechanical alteration of arterial vascular walls by baroreceptor terminals in the aortic arch and carotid sinus. There are aortic baroreceptor neurons in the nodose ganglion (NG), which serve as the main afferent component of the arterial baroreflex. Functional changes of baroreceptor neurons are involved in the arterial baroreflex dysfunction in CHF. In the CHF state, circulating angiotensin II (Ang II) and local Ang II concentration in the NG are elevated, and AT1R mRNA and protein are overexpressed in the NG. Additionally, Ang II-superoxide-NFκB signaling pathway regulates the neuronal excitability of aortic baroreceptors through influencing the expression and activation of Nav channels in aortic baroreceptors, and subsequently causes the impairment of the arterial baroreflex in CHF. These new findings provide a basis for potential pharmacological interventions for the improvement of the arterial baroreflex sensitivity in the CHF state. This review summarizes the mechanisms responsible for the arterial baroreflex dysfunction in CHF. PMID:26528122

  5. Gene and MicroRNA Transcriptional Signatures of Angiotensin II in Endothelial Cells

    PubMed Central

    Mehta, Jawahar L.; Mercanti, Federico; Stone, Annjannette; Wang, Xianwei; Ding, Zufeng; Romeo, Francesco

    2015-01-01

    Abstract: Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P < 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II–dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II–mediated proangiogenic response in human endothelial cells. PMID:24853489

  6. TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II

    PubMed Central

    Schultz, Jo El J.; Witt, Sandra A.; Glascock, Betty J.; Nieman, Michelle L.; Reiser, Peter J.; Nix, Stacey L.; Kimball, Thomas R.; Doetschman, Thomas

    2002-01-01

    Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-β1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-β1–deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang IItreatment. In contrast, Ang II–treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II–treated wild-type mice but unchanged in Ang II–treated TGF-β1–deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II–treated mice. Atrial natriuretic factor expression was ∼6-fold elevated in Ang II–treated wild-type, but not TGF-β1–deficient mice. However, the α- to β-myosin heavy chain switch did not occur in Ang II–treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-β1. The Ang IIeffect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-β1 is an important mediator of the hypertrophic growth response of the heart to Ang II. PMID:11901187

  7. N-acetylcysteine alleviates angiotensin II-mediated renal fibrosis in mouse obstructed kidneys

    PubMed Central

    Shen, Yang; Miao, Nai-jun; Xu, Jin-lan; Gan, Xin-xin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Lu, Li-min

    2016-01-01

    Aim: To investigate the effects of ROS scavenger N-acetylcysteine (NAC) on angiotensin II (Ang II)-mediated renal fibrosis in vivo and in vitro. Methods: Mice were subjected to unilateral ureteral obstruction (UUO), and then treated with vehicle or NAC (250 mg/kg, ip) for 7 days. Histological changes of the obstructed kidneys were observed with Masson's trichrome staining. ROS levels were detected with DHE staining. The expression of relevant proteins in the obstructed kidneys was assessed using Western blotting assays. Cultured rat renal fibroblast NRK-49F cells were used for in vitro experiments. Results: In the obstructed kidneys, Ang II levels were significantly elevated, and collagen I was accumulated in the interstitial spaces. Furthermore, ROS production and the expression of p47 (a key subunit of NADPH oxidase complexes) were increased in a time-dependent manner; the expression of fibronectin, α-SMA and TGF-β were upregulated. Administration of NAC significantly alleviated the fibrotic responses in the obstructed kidneys. In cultured NRK-49F cells, treatment with Ang II (0.001–10 μmol/L) increased the expression of fibronectin, collagen I, α-SMA and TGF-β in dose-dependent and time-dependent manners. Ang II also increased ROS production and the phosphorylation of Smad3. Pretreatment with NAC (5 μmol/L) blocked Ang II-induced oxidative stress and ECM production in the cells. Conclusion: In mouse obstructed kidneys, the fibrotic responses result from Ang II upregulation can be alleviated by the ROS scavenger N-acetylcysteine. PMID:27041464

  8. Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron

    PubMed Central

    Nguyen, Mien T X; Han, Jiyang; Ralph, Donna L; Veiras, Luciana C; McDonough, Alicia A

    2015-01-01

    In Sprague Dawley rats, 2-week angiotensin II (AngII) infusion increases Na+ transporter abundance and activation from cortical thick ascending loop of Henle (TALH) to medullary collecting duct (CD) and raises blood pressure associated with a pressure natriuresis, accompanied by depressed Na+ transporter abundance and activation from proximal tubule (PT) through medullary TALH. This study tests the hypothesis that early during AngII infusion, before blood pressure raises, Na+ transporters’ abundance and activation increase all along the nephron. Male Sprague Dawley rats were infused via osmotic minipumps with a subpressor dose of AngII (200 ng/kg/min) or vehicle for 3 days. Overnight urine was collected in metabolic cages and sodium transporters’ abundance and phosphorylation were determined by immunoblotting homogenates of renal cortex and medulla. There were no significant differences in body weight gain, overnight urine volume, urinary Na+ and K+ excretion, or rate of excretion of a saline challenge between AngII and vehicle infused rats. The 3-day nonpressor AngII infusion significantly increased the abundance of PT Na+/H+ exchanger 3 (NHE3), cortical TALH Na-K-2Cl cotransporter 2 (NKCC2), distal convoluted tubule (DCT) Na-Cl cotransporter (NCC), and cortical CD ENaC subunits. Additionally, phosphorylation of cortical NKCC2, NCC, and STE20/SPS1-related proline–alanine-rich kinase (SPAK) were increased; medullary NKCC2 and SPAK were not altered. In conclusion, 3-day AngII infusion provokes PT NHE3 accumulation as well as NKCC2, NCC, and SPAK accumulation and activation in a prehypertensive phase before evidence for intrarenal angiotensinogen accumulation. PMID:26347505

  9. Aldosterone response to sodium deprivation and angiotensin II in patients with hypopituitarism.

    PubMed

    Seifert, C; Oelkers, W

    1981-03-01

    Unknown pituitary factor(s) apart from ACTH may participate in the regulation of aldosterone (aldo) secretion in man. We investigated whether the 'sensitization' of the zona glomerulosa against angiotensin II (A II) by sodium deficiency was mediated by the pituitary gland. A II was infused in stepwise increasing doses (2, 4, 8 ng/kg/min) into 5 normal subjects (N) and into 8 patients with hypopituitarism (H) before and after 4 days on low sodium diet. Mean cumulative sodium balance after the low sodium diet was -145mM in N and -165mM in H. Plasma-aldo and aldo-excretion rate on the normal sodium diet were slightly higher in H than in N but rose less than normal during sodium depletion in H. Plasma A II and renin activity on normal sodium were slightly higher in H than in N, but the increase on the low sodium diet was blunted in H. The stimulation of plasma-aldo by A II infusion was similar in both groups on the normal sodium diet. In both groups, the response of P-aldo to A II infusion was greater in the sodium deplete than in the replete state, although 'sensitization' was slightly less marked in H than in N. This may be due to the blunted rise of plasma-A II after sodium loss in H, which may also account for abnormalities in the blood pressure response in the H group. Altogether, the results speak against a direct involvement of the pituitary gland in 'sensitization', but an indirect influence through unexplained abnormalities in renin secretion is possible. PMID:7211097

  10. Expression of angiotensin II receptors in the caprine ovary and improvement of follicular viability in vitro.

    PubMed

    Bruno, J B; Lima-Verde, I B; Celestino, J J H; Lima, L F; Matos, M H T; Faustino, L R; Donato, M A M; Peixoto, C A; Campello, C C; Silva, J R V; Figueiredo, J R

    2016-08-01

    This study aimed to evaluate mRNA levels of angiotensin II (ANG II) receptors (AGTR1 and AGTR2) in caprine follicles and to investigate the influence of ANG II on the viability and in vitro growth of preantral follicles. Real-time polymerase chain reaction (PCR) was used to quantify AGTR1 and AGTR2 mRNA levels in the different follicular stages. For culture, caprine ovaries were collected, cut into 13 fragments and then either directly fixed for histological and ultrastructural analysis (fresh control) or placed in culture for 1 or 7 days in α-minumum essential medium plus (α-MEM+) with 0, 1, 5, 10, 50 or 100 ng/ml ANG II. Then, the fragments were destined to morphological, viability and ultrastructural analysis. The results showed that primordial follicles had higher levels of AGTR1 and AGTR2 mRNA than secondary follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA than their respective cumulus-oocyte complex (COCs). After 7 days of culture, ANG II (10 or 50 ng/ml) maintained the percentages of normal follicles compared with α-MEM+. Fluorescence and ultrastructural microscopy confirmed follicular integrity in ANG II (10 ng/ml). In conclusion, a high expression of AGTR1 and AGTR2 is observed in primordial follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA. Finally, 10 ng/ml ANG II maintained the viability of caprine preantral follicles after in vitro culture. PMID:26464313

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

    PubMed

    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. PMID:26351030

  12. Angiotensin II-Induced Arterial Thickening, Fibrosis and Stiffening Involves Elevated Arginase Function

    PubMed Central

    Bhatta, Anil; Yao, Lin; Toque, Haroldo A.; Shatanawi, Alia; Xu, Zhimin; Caldwell, Ruth B.; Caldwell, R. William

    2015-01-01

    Background Arterial stiffness (AS) is an independent risk factor for cardiovascular morbidity/mortality. Smooth muscle cell (SMC) proliferation and increased collagen synthesis are key features in development of AS. Arginase (ARG), an enzyme implicated in many cardiovascular diseases, can compete with nitric oxide (NO) synthase for their common substrate, L-arginine. Increased arginase can also provide ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to vascular cell proliferation and collagen formation, respectively. We hypothesized that elevated arginase activity is involved in Ang II-induced arterial thickening, fibrosis, and stiffness and that limiting its activity can prevent these changes. Methods and Results We tested this by studies in mice lacking one copy of the ARG1 gene that were treated with angiotensin II (Ang II, 4 weeks). Studies were also performed in rat aortic Ang II-treated SMC. In WT mice treated with Ang II, we observed aortic stiffening (pulse wave velocity) and aortic and coronary fibrosis and thickening that were associated with increases in ARG1 and ODC expression/activity, proliferating cell nuclear antigen, hydroxyproline levels, and collagen 1 protein expression. ARG1 deletion prevented each of these alterations. Furthermore, exposure of SMC to Ang II (1 μM, 48 hrs) increased ARG1 expression, ARG activity, ODC mRNA and activity, cell proliferation, collagen 1 protein expression and hydroxyproline content. Treatment with ABH prevented these changes. Conclusion Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target. PMID:25807386

  13. Pressure-Induced Renal Injury in Angiotensin II Versus Norepinephrine-Induced Hypertensive Rats

    PubMed Central

    Polichnowski, Aaron J.; Cowley, Allen W.

    2010-01-01

    The susceptibility to renal perfusion pressure (RPP)-induced renal injury was investigated in angiotensin II (AngII) versus norepinephrine (NE)-infused hypertensive rats. To determine the magnitude of RPP-induced injury, Sprague-Dawley rats fed a 4% salt diet were instrumented with a servocontrolled aortic balloon occluder positioned between the renal arteries to maintain RPP to the left kidney at baseline levels while the right kidney was exposed to elevated RPP during a 2 week infusion of: 1) AngII i.v. (25 ng/kg/min), 2) NE i.v. (0.5, 1, and 2 ug/kg/min on Days 1, 2, and 3-14, respectively), or saline i.v. (sham rats). Over the 14 days of AngII infusion, RPP averaged 161.5 ± 8 mmHg to uncontrolled kidneys and 121.9 ± 2 mmHg to servocontrolled kidneys. In NE-infused rats, RPP averaged 156.3 ± 3 mmHg to uncontrolled kidneys and 116.9 ± 2 mmHg to servocontrolled kidneys. RPP averaged 111.1 ± 1 mmHg to kidneys of sham rats. Interlobular arterial injury and juxtamedullary glomerulosclerosis were largely RPP-dependent in both models of hypertension. Superficial cortical glomerulosclerosis was greater and RPP-dependent in NE versus AngII-infused rats, which was primarily independent of RPP. Outer medullary tubular necrosis and interstitial fibrosis was also primarily RPP-dependent in both models of hypertension; however, the magnitude of injury was exacerbated in AngII-infused rats. We conclude that elevated RPP is the dominant cause of renal injury in both NE and AngII-induced hypertensive rats and that underlying neurohumoral factors in these models of hypertension alter the pattern and magnitude of RPP-induced renal injury. PMID:19858406

  14. Involvement of central angiotensin II type 1 receptors in LPS-induced systemic vasopressin release and blood pressure regulation in rats.

    PubMed

    Shimizu, Fumihiro; Kasai, Toshihiro; Takamata, Akira

    2009-06-01

    The purpose of this study was to evaluate the involvement of central angiotensin II (ANG II) and ANG II type 1 (AT(1)) receptors in systemic release of arginine vasopressin (AVP) and blood pressure regulation during endotoxemia. LPS (150 microg/kg) was injected intravenously 30 min after intracerebroventricular (icv) losartan (50 microg), an AT(1) receptor antagonist, or subcutaneous (sc) captopril (50 mg/kg), an angiotensin-converting enzyme inhibitor. Rats with icv and sc saline injections served as control. LPS administration increased plasma AVP concentration from 2.1 +/- 0.2 to 15.2 +/- 2.5 pg/ml (60 min after LPS injection) without significant changes in plasma osmolality or hematocrit. LPS-induced AVP secretion was significantly attenuated by pretreatment with icv losartan (2.3 +/- 0.5 to 3.7 +/- 0.5 pg/ml) but was not attenuated after peripheral captopril treatment (2.2 +/- 0.6 to 17.6 +/- 4.2 pg/ml). LPS administration significantly decreased systolic blood pressure (SBP) by 22.7 +/- 5.4 mmHg after intravenous LPS injection in icv losartan-treated rats, while SBP remained unchanged in vehicle-treated or sc captopril-treated rats by intravenous LPS. These results indicate that central AT(1) receptors, not responsive to peripheral ANG II, play an important role in systemic AVP secretion and maintenance of blood pressure during endotoxemia. PMID:19359612

  15. Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening.

    PubMed

    Majeed, Beenish; Tawinwung, Supannikar; Eberson, Lance S; Secomb, Timothy W; Larmonier, Nicolas; Larson, Douglas F

    2014-01-01

    Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Three-month-old male C57BL/6J mice were treated with IL-2/mAbCD25 concomitantly with continuous infusion of angiotensin type 1 receptor agonist, [Val(5)]angiotensin II. Our results indicate that the IL-2/mAbCD25 complex effectively induced Treg phenotype expansion by 5-fold in the spleens with minimal effects on total CD4(+) and CD8(+) T-lymphocyte numbers. The IL-2/mAbCD25 complex inhibited angiotensin II-mediated aortic collagen remodeling and the resulting stiffening, analyzed with in vivo pulse wave velocity and effective Young's modulus. Furthermore, the IL-2/mAbCD25 complex suppressed angiotensin II-mediated Th17 responses in the lymphoid organs and reduced gene expression of IL-17 as well as T cell and macrophage infiltrates in the aortic tissue. This study provides data that support the protective roles of Tregs in vascular stiffening and highlights the use of the IL-2/mAbCD25 complex as a new potential therapy in angiotensin II-related vascular diseases. PMID:25258681

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

    PubMed

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

    2015-09-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID:26121982

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

    PubMed

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

    2016-01-01

    This protocol describes receptor binding patterns for Angiotensin II (Ang II) in the rat brain using a radioligand specific for Ang II receptors to perform receptor autoradiographic mapping. Tissue specimens are harvested and stored at -80 °C. A cryostat is used to coronally section the tissue (brain) and thaw-mount the sections onto charged slides. The slide-mounted tissue sections are incubated in (125)I-SI-Ang II to radiolabel Ang II receptors. Adjacent slides are separated into two sets: 'non-specific binding' (NSP) in the presence of a receptor saturating concentration of non-radiolabeled Ang II, or an AT1 Ang II receptor subtype (AT1R) selective Ang II receptor antagonist, and 'total binding' with no AT1R antagonist. A saturating concentration of AT2 Ang II receptor subtype (AT2R) antagonist (PD123319, 10 µM) is also present in the incubation buffer to limit (125)I-SI-Ang II binding to the AT1R subtype. During a 30 min pre-incubation at ~22 °C, NSP slides are exposed to 10 µM PD123319 and losartan, while 'total binding' slides are exposed to 10 µM PD123319. Slides are then incubated with (125)I-SI-Ang II in the presence of PD123319 for 'total binding', and PD123319 and losartan for NSP in assay buffer, followed by several 'washes' in buffer, and water to remove salt and non-specifically bound radioligand. The slides are dried using blow-dryers, then exposed to autoradiography film using a specialized film and cassette. The film is developed and the images are scanned into a computer for visual and quantitative densitometry using a proprietary imaging system and a spreadsheet. An additional set of slides are thionin-stained for histological comparisons. The advantage of using receptor autoradiography is the ability to visualize Ang II receptors in situ, within a section of a tissue specimen, and anatomically identify the region of the tissue by comparing it to an adjacent histological reference section. PMID:27341008

  18. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

    SciTech Connect

    Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade; Xiang Qun; Gore, Elizabeth

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or

  19. Qiliqiangxin inhibits angiotensin II-induced transdifferentiation of rat cardiac fibroblasts through suppressing interleukin-6

    PubMed Central

    Zhou, Jingmin; Jiang, Kun; Ding, Xuefeng; Fu, Mingqiang; Wang, Shijun; Zhu, Lingti; He, Tao; Wang, Jingfeng; Sun, Aijun; Hu, Kai; Chen, Li; Zou, Yunzeng; Ge, Junbo

    2015-01-01

    Qiliqiangxin (QL), a traditional Chinese medicine, had long been used to treat chronic heart failure. Recent studies revealed that differentiation of cardiac fibroblasts (CFs) into myofibroblasts played an important role in cardiac remodelling and development of heart failure, however, little was known about the underlying mechanism and whether QL treatment being involved. This study aimed to investigate the effects of QL on angiotensin II (AngII)-induced CFs transdifferentiation. Study was performed on in vitro cultured CFs from Sprague–Dawley rats. CFs differentiation was induced by AngII, which was attenuated by QL through reducing transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA). Our data showed that AngII-induced IL-6 mRNA as well as typeI and typeIII collagens were reduced by QL. IL-6 deficiency could suppress TGF-β1 and α-SMA, and both IL-6 siRNA and QL-mediated such effect was reversed by foresed expression of recombined IL-6. Increase in actin stress fibres reflected the process of CFs differentiation, we found stress fibres were enhanced after AngII stimulation, which was attenuated by pre-treating CFs with QL or IL-6 siRNA, and re-enhanced after rIL-6 treatment. Importantly, we showed that calcineurin-dependent NFAT3 nuclear translocation was essential to AngII-mediated IL-6 transcription, QL mimicked the effect of FK506, the calcineurin inhibitor, on suppression of IL-6 expression and stress fibres formation. Collectively, our data demonstrated the negative regulation of CFs differentiation by QL through an IL-6 transcriptional mechanism that depends on inhibition of calcineurin/NFAT3 signalling. PMID:25752645

  20. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

    PubMed Central

    Siddiquee, K; Hampton, J; McAnally, D; May, LT; Smith, LH

    2013-01-01

    Background and Purpose The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. Experimental Approach The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. Key Results Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP1) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. Conclusions and Implications Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. Linked Article This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040 PMID:22935142

  1. Role of angiotensin II in experimental Venezuelan equine encephalitis in rats.

    PubMed

    Bermúdez, John; Valero, Nereida; Mosquera, Jesús; Vargas, Renata; Hernández-Fonseca, Juan P; Quiroz, Yasmir; Godoy, Rosario

    2015-10-01

    Venezuelan equine encephalitis (VEE) is a viral disease transmitted by mosquitoes. The inflammation induced by the VEE virus is associated with a high mortality rate in mice. Angiotensin II (Ang II), a pro-inflammatory molecule, is produced in the normal rat brain. There is no information about the role of this molecule in the inflammatory events occurring during VEE and the effect of inflammation on the mortality rate in VEE-virus-infected rats. This study was designed to determine the role of Ang II in VEE and to analyze the effect of inflammation on mortality in infected rats. Two groups of rats were studied: 1) Virus-infected animals and controls (n = 60) were treated with losartan (a blocker of the Ang II-AT1 receptor) or with pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB) or left untreated and analyzed for morbidity and mortality. 2) Animals treated using the same protocol (n = 30) were sacrificed at day 4 postinfection and analyzed by immunohistochemistry and histopathology and for cytokine production. Increased expression of Ang II, ICAM-1, ED-1 and cytokines (IL-1α, MCP-1, IL-6 and IL-10) in infected animals was observed. The main histopathology findings were dilated capillaries and capillaries with endothelial detachment. Losartan and PDTC reduced the expression of IL-1α, MCP-1, and IL-10, and the number of dilated capillaries and capillaries with endothelial detachment. Survival analysis showed that 100% mortality was reached earlier in infected rats treated with losartan (day 14) or PDTC (day 11) than in untreated animals (day 19). These findings suggest that Ang II plays a role in VEE and that brain inflammation is protective against viral infection. PMID:26156105

  2. Consequences of postnatal vascular smooth muscle EGFR deletion on acute angiotensin II action.

    PubMed

    Schreier, Barbara; Hünerberg, Mirja; Rabe, Sindy; Mildenberger, Sigrid; Bethmann, Daniel; Heise, Christian; Sibilia, Maria; Offermanns, Stefan; Gekle, Michael

    2016-01-01

    Epi dermal growth factor (EGF) receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II (Ang II). Vascular EGFR has been proposed to be involved in vascular tissue homoeostasis and remodelling. Thus, most studies have focused on its role during long-term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the postnatal role of VSMCs (vascular smooth muscle cells) EGFR in vivo and ex vivo, we generated a mouse model with cell-specific and inducible deletion of VSMC EGFR and studied the effect on basal blood pressure, acute pressure response to, among others, Ang II in vivo as well as ex vivo, cardiovascular tissue homoeostasis and vessel morphometry in male mice. In knockout (KO) animals, systolic, diastolic and mean blood pressures were reduced compared with wild-type (WT). Furthermore, Ang II-induced pressure load was lower in KO animals, as was Ang II-induced force development and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in aortic rings from KO animals. By contrast, we observed no difference in force development during application of serotonin, KCl, endothelin-1 or endothelin-1-induced pressure load in KO animals. In addition, nitric oxide (NO)-mediated vasodilation was not affected. Heart weight (HW) increase and up-regulation of aortic and cardiac expression of Ccl2 (chemoattractant protein-2) and serpinE1 (plasminogen activator inhibitor 1) during the transition from 4- to 10-months of age were prevented by VSMC EGFR KO. We conclude that VSMC EGFR is involved in basal blood pressure homoeostasis and acute pressure response to Ang II, and thereby contributes to maturation-related remodelling. PMID:26438881

  3. Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I.

    PubMed

    Brink, M; Price, S R; Chrast, J; Bailey, J L; Anwar, A; Mitch, W E; Delafontaine, P

    2001-04-01

    We previously showed that angiotensin II (ang II) infusion in the rat produces cachexia and decreases circulating insulin-like growth factor I (IGF-I). The weight loss derives from an anorexigenic response and a catabolic effect of ang II. In these experiments we assessed potential catabolic mechanisms and the involvement of the IGF-I system in these responses to ang II. Ang II infusion caused a significant decrease in body weight compared with that of pair-fed control rats. Kidney and left ventricular weights were significantly increased by ang II, whereas fat tissue was unchanged. Skeletal muscle mass was significantly decreased in the ang II-infused rats, and a reduction in lean muscle mass was a major reason for their overall loss of body weight. In skeletal muscles, ang II did not significantly decrease protein synthesis, but overall protein breakdown was accelerated; inhibiting lysosomal and calcium-activated proteases did not reduce the ang II-induced increase in muscle proteolysis. Circulating IGF-I levels were 33% lower in ang II rats vs. control rats, and this difference was reflected in lower IGF-I messenger RNA levels in the liver. Moreover, IGF-I, IGF-binding protein-3, and IGF-binding protein-5 messenger RNAs in the gastrocnemius were significantly reduced. To investigate whether the reduced circulating IGF-I accounts for the loss in muscle mass, we increased circulating IGF-I by coinfusing ang II and IGF-I, but this did not prevent muscle loss. Our data suggest that ang II causes a loss in skeletal muscle mass by enhancing protein degradation probably via its inhibitory effect on the autocrine IGF-I system. PMID:11250929

  4. Relaxin Does Not Improve Angiotensin II-Induced Target-Organ Damage

    PubMed Central

    Haase, Nadine; Rugor, Julianna; Przybyl, Lukasz; Qadri, Fatimunnisa; Müller, Dominik N.; Dechend, Ralf

    2014-01-01

    Relaxin is a corpus-luteum produced protein hormone with vasodilatatory, anti-fibrotic, and angiogenic properties that are opposite to angiotensin (Ang) II. We investigated whether or not relaxin ameliorates Ang II-induced target-organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGR) that develop severe hypertension, target-organ damage, and die untreated within 7–8 weeks. Recombinant relaxin at a low (26 μg/kg/d) and a high dose (240 μg/kg/d) was given to 4 week-old dTGR and age-matched Sprague-Dawley rats (SD). Systolic blood pressure increased progressively in untreated dTGRs from 162±3 mmHg at week 5 to 225±5 mmHg at week 7. Relaxin had no effect on blood pressure whereas SD rats were normotensive (106±1 mmHg). Untreated and relaxin-treated dTGR had similarly severe cardiac hypertrophy indices. Relaxin did not ameliorate albuminuria and did not prevent matrix-protein deposition in the heart and kidney in dTGR. Finally, relaxin treatment did not reduce mortality. These data suggest that pharmacological doses of relaxin do not reverse severe effects of Ang II. PMID:24710077

  5. Anti-Plasmodium Activity of Angiotensin II and Related Synthetic Peptides

    PubMed Central

    Maciel, Ceres; de Oliveira Junior, Vani Xavier; Fázio, Marcos Antonio; Nacif-Pimenta, Rafael; Miranda, Antonio; Pimenta, Paulo F. P.; Capurro, Margareth Lara

    2008-01-01

    Plasmodium species are the causative agents of malaria, the most devastating insect-borne parasite of human populations. Finding and developing new drugs for malaria treatment and prevention is the goal of much research. Angiotensins I and II (ang I and ang II) and six synthetic related peptides designated Vaniceres 1-6 (VC1-VC6) were assayed in vivo and in vitro for their effects on the development of the avian parasite, Plasmodium gallinaceum. Ang II and VC5 injected into the thoraces of the insects reduced mean intensities of infection in the mosquito salivary glands by 88% and 76%, respectively. Although the mechanism(s) of action is not completely understood, we have demonstrated that these peptides disrupt selectively the P.gallinaceum cell membrane. Additionally, incubation in vitro of sporozoites with VC5 reduced the infectivity of the parasites to their vertebrate host. VC5 has no observable agonist effects on vertebrates, and this makes it a promising drug for malaria prevention and chemotherapy. PMID:18820728

  6. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    PubMed

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Δkinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension

  7. Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling.

    PubMed

    Carneiro de Morais, Carla P; Polidoro, Juliano Z; Ralph, Donna L; Pessoa, Thaissa D; Oliveira-Souza, Maria; Barauna, Valério G; Rebouças, Nancy A; Malnic, Gerhard; McDonough, Alicia A; Girardi, Adriana C C

    2015-10-15

    Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na(+)/H(+) exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na(+)-dependent intracellular pH recovery. We found that 10(-7) M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization. PMID:26246427

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

    PubMed Central

    Gopal, Kaliappan; Nagarajan, Perumal; Jedy, Jose; Raj, Avinash T.; Gnanaselvi, S. Kalai; Jahan, Parveen; Sharma, Yogendra; Shankar, Esaki M.; Kumar, Jerald M.

    2013-01-01

    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. PMID:23826202

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

    SciTech Connect

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

    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.

  10. Beneficial effects of astragaloside IV against angiotensin II-induced mitochondrial dysfunction in rat vascular smooth muscle cells.

    PubMed

    Lu, Yao; Li, Su; Wu, Hengfang; Bian, Zhiping; Xu, Jindan; Gu, Chunrong; Chen, Xiangjian; Yang, Di

    2015-11-01

    Angiotensin II (Ang II)-induced mitochondrial dysfunction is a prominent characteristic of the majority of cardiovascular diseases. Astragaloside IV (As-IV), the major active ingredient of Astragalus membranaceus (Fisch.) Bge. (a traditional Chinese herbal medicine), possesses antioxidant properties. The present study was carried out to examine whether As-IV can reverse Ang II-induced mitochondrial dysfunction in vascular smooth muscle cells (VSMCs) and to elucidate the underlying molecular mechanisms. Cultured rat aortic VSMCs treated with Ang II (1 µM) for 24 h exhibited mitochondrial dysfunction, including a decrease in mitochondrial oxygen consumption rates (OCRs), adenosine triphosphate (ATP) production and mitochondrial DNA (mtDNA) levels, as well as the disruption of mitochondrial structural integrity. Following treatment with Ang II, As-IV (50 µg/ml) was added to the culture medium followed by incubation for a further 24 h. The administration of As-IV significantly increased the mitochondrial OCRs, ATP production and the mtDNA levels, and reversed the mitochondrial morphological changes which occurred in the VSMCs. Treatment with As-IV also reversed the Ang II-induced increase in the production of reactive oxygen species (ROS), the increase in NADPH oxidase and xanthine oxidase activity, as well as the decrease in mitochondrial membrane potential (ΔΨm) and manganese superoxide dismutase (Mn-SOD) activity. Furthermore, treatment with As-IV led to an increase in the mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and mitochondrial transcription factor A (Tfam), and in the protein expression of PGC-1α, parkin and dynamin 1-like protein 1 (Drp1) in the VSMCs. These results indicate that As-IV exerts beneficial effects on Ang II-induced mitochondrial dysfunction in rat VSMCs and that these effects are mediated through the inhibition of ROS overproduction, as well as the promotion of mitochondrial autophagy and

  11. Beneficial effects of astragaloside IV against angiotensin II-induced mitochondrial dysfunction in rat vascular smooth muscle cells

    PubMed Central

    LU, YAO; LI, SU; WU, HENGFANG; BIAN, ZHIPING; XU, JINDAN; GU, CHUNRONG; CHEN, XIANGJIAN; YANG, DI

    2015-01-01

    Angiotensin II (Ang II)-induced mitochondrial dysfunction is a prominent characteristic of the majority of cardiovascular diseases. Astragaloside IV (As-IV), the major active ingredient of Astragalus membranaceus (Fisch.) Bge. (a traditional Chinese herbal medicine), possesses antioxidant properties. The present study was carried out to examine whether As-IV can reverse Ang II-induced mitochondrial dysfunction in vascular smooth muscle cells (VSMCs) and to elucidate the underlying molecular mechanisms. Cultured rat aortic VSMCs treated with Ang II (1 µM) for 24 h exhibited mitochondrial dysfunction, including a decrease in mitochondrial oxygen consumption rates (OCRs), adenosine triphosphate (ATP) production and mitochondrial DNA (mtDNA) levels, as well as the disruption of mitochondrial structural integrity. Following treatment with Ang II, As-IV (50 µg/ml) was added to the culture medium followed by incubation for a further 24 h. The administration of As-IV significantly increased the mitochondrial OCRs, ATP production and the mtDNA levels, and reversed the mitochondrial morphological changes which occurred in the VSMCs. Treatment with As-IV also reversed the Ang II-induced increase in the production of reactive oxygen species (ROS), the increase in NADPH oxidase and xanthine oxidase activity, as well as the decrease in mitochondrial membrane potential (ΔΨm) and manganese superoxide dismutase (Mn-SOD) activity. Furthermore, treatment with As-IV led to an increase in the mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and mitochondrial transcription factor A (Tfam), and in the protein expression of PGC-1α, parkin and dynamin 1-like protein 1 (Drp1) in the VSMCs. These results indicate that As-IV exerts beneficial effects on Ang II-induced mitochondrial dysfunction in rat VSMCs and that these effects are mediated through the inhibition of ROS overproduction, as well as the promotion of mitochondrial autophagy and

  12. Angiotensin II regulates ACE and ACE2 in neurons through p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 signaling

    PubMed Central

    Xiao, Liang; Haack, Karla K. V.

    2013-01-01

    Brain ANG II plays an important role in modulating sympathetic function and homeostasis. The generation and degradation of ANG II are carried out, to a large extent, through the angiotensin-converting enzyme (ACE) and ACE2, respectively. In disease states, such as hypertension and chronic heart failure, central expression of ACE is upregulated and ACE2 is decreased in central sympathoregulatory neurons. In this study, we determined the expression of ACE and ACE2 in response to ANG II in a neuronal cell culture and the subsequent signaling mechanism(s) involved. A mouse catecholaminergic neuronal cell line (CATH.a) was treated with ANG II (30, 100, and 300 nM) for 24 h, and protein expression was determined by Western blot analysis. ANG II induced a significant dose-dependent increase in ACE and decrease in ACE2 mRNA and protein expression in CATH.a neurons. This effect was abolished by pretreatment of the cells with the p38 MAPK inhibitor SB-203580 (10 μM) 30 min before administration of ANG II or the ERK1/2 inhibitor U-0126 (10 μM). These data suggest that ANG II increases ACE and attenuates ACE2 expression in neurons via the ANG II type 1 receptor, p38 MAPK, and ERK1/2 signaling pathways. PMID:23535237

  13. Angiotensin II type 1 receptor blockers as a first choice in patients with acute myocardial infarction

    PubMed Central

    Lee, Jang Hoon; Bae, Myung Hwan; Yang, Dong Heon; Park, Hun Sik; Cho, Yongkeun; Lee, Won Kee; Jeong, Myung Ho; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jin; Chae, Shung Chull

    2016-01-01

    Background/Aims: Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI). Methods: Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI. Results: Seventy percent of the patients were Killip class 1 and had a LV ejection fraction ≥ 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051). Conclusions: Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI. PMID:26701233

  14. Angiotensin II Receptor Blockers and Cancer Risk: A Meta-Analysis of Randomized Controlled Trials.

    PubMed

    Zhao, Yun-Tao; Li, Peng-Yang; Zhang, Jian-Qiang; Wang, Lei; Yi, Zhong

    2016-05-01

    Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI).We investigated the risk of cancer associated with ARB at different background ACEI levels.Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction.Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included.Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently.Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00-1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94-1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90-1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79-1.24, P = 0.95).Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens.ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI. PMID:27149494

  15. Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

    PubMed Central

    Lee, Doug-Yoon; Wauquier, Fabien; Eid, Assaad A.; Roman, Linda J.; Ghosh-Choudhury, Goutam; Khazim, Khaled; Block, Karen; Gorin, Yves

    2013-01-01

    Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces endothelial nitric-oxide synthase (eNOS) uncoupling with enhanced generation of reactive oxygen species (ROS) and decreased production of NO. Ang II promotes a rapid increase in 3-nitrotyrosine formation, and uric acid attenuates Ang II-induced decrease in NO bioavailability, demonstrating that peroxynitrite mediates the effects of Ang II on eNOS dysfunction. Ang II rapidly up-regulates Nox4 protein. Inhibition of Nox4 abolishes the increase in ROS and peroxynitrite generation as well as eNOS uncoupling triggered by Ang II, indicating that Nox4 is upstream of eNOS. This pathway contributes to Ang II-mediated fibronectin accumulation in MCs. Ang II also elicits an increase in mitochondrial abundance of Nox4 protein, and the oxidase contributes to ROS production in mitochondria. Overexpression of mitochondrial manganese superoxide dismutase prevents the stimulatory effects of Ang II on mitochondrial ROS production, loss of NO availability, and MC fibronectin accumulation, whereas manganese superoxide dismutase depletion increases mitochondrial ROS, NO deficiency, and fibronectin synthesis basally and in cells exposed to Ang II. This work provides the first evidence that uncoupled eNOS is responsible for Ang II-induced MC fibronectin accumulation and identifies Nox4 and mitochondrial ROS as mediators of eNOS dysfunction. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal fibrosis. PMID:23940049

  16. The angiotensin II receptor antagonist, losartan, enhances regulator of G protein signaling 2 mRNA expression in vascular smooth muscle cells of Wistar rats.

    PubMed

    Wu, Yaqiong; Nakagawa, Suguru; Takahashi, Hidenori; Kawabata, Yukari; Suzuki, Etsu; Uehara, Yoshio

    2016-05-01

    Angiotensin II (Ang II) reportedly enhances regulator of G-protein signaling 2 (RGS2), thus making a negative feedback loop for Ang II signal transduction. However, few studies have reported whether Ang II receptor (ATR) antagonists influence RGS2 mRNA expression. We investigated RGS2 mRNA expression when Ang II binding to ATR was blocked with Ang II subtype-1 receptor (AT1R) blockers using vascular smooth muscle cells from the thoracic aorta of male Wistar rats. RGS2 mRNA expression significantly increased with Ang II stimulation, and this increase was almost completely abolished by olmesartan, a potent AT1R-specific blocker. Ang II subtype-2 receptor (AT2R) was not involved in Ang II-mediated RGS expression. In contrast, the AT1R blocker, losartan, partially decreased Ang II-mediated RGS2 mRNA expression because this antagonist directly stimulated RGS2 mRNA expression in Ang II-free medium. EXP3174, which is an active metabolite of losartan, almost completely blunted Ang II-mediated RGS2 mRNA expression without direct stimulation of RGS2 mRNA expression. Moreover, pretreatment with olmesartan abolished Ang II-mediated RGS2 mRNA expression. Treatment with a protein kinase C inhibitor partially decreased losartan-mediated RGS2 mRNA expression. These results suggest that AT1R blockers inhibit RGS2 mRNA expression in response to Ang II via an AT1R-mediated mechanism. However, the AT1R blocker, losartan, behaves as a direct agonist for RGS2 mRNA expression via AT1R through protein kinase C-dependent and -independent pathways. In conclusion, losartan exhibits dual effects on RGS2 mRNA expression, and the direct upregulation of RGS2 mRNA expression may provide a new strategy for the treatment of hypertension. PMID:26763849

  17. Differential Phenotypes of Tissue-Infiltrating T Cells during Angiotensin II-Induced Hypertension in Mice

    PubMed Central

    Wei, Zihui; Spizzo, Iresha; Diep, Henry; Drummond, Grant R.; Widdop, Robert E.; Vinh, Antony

    2014-01-01

    Hypertension remains the leading risk factor for cardiovascular disease (CVD). Experimental hypertension is associated with increased T cell infiltration into blood pressure-controlling organs, such as the aorta and kidney; importantly in absence of T cells of the adaptive immune system, experimental hypertension is significantly blunted. However, the function and phenotype of these T cell infiltrates remains speculative and undefined in the setting of hypertension. The current study compared T cell-derived cytokine and reactive oxygen species (ROS) production from normotensive and hypertensive mice. Splenic, blood, aortic, kidney and brain T cells were isolated from C57BL/6J mice following 14-day vehicle or angiotensin (Ang) II (0.7 mg/kg/day, s.c.) infusion. T cell infiltration was increased in aorta, kidney and brain from hypertensive mice. Cytokine analysis in stimulated T cells indicated an overall Th1 pro-inflammatory phenotype, but a similar proportion (flow cytometry) and quantity (cytometric bead array) of IFN-γ, TNF-α, IL-4 and IL-17 between vehicle- and Ang II- treated groups. Strikingly, elevated T cell-derived production of a chemokine, chemokine C-C motif ligand 2 (CCL2), was observed in aorta (∼6-fold) and kidney in response to Ang II, but not in brain, spleen or blood. Moreover, T cell-derived ROS production in aorta was elevated ∼3 -fold in Ang II-treated mice (n = 7; P<0.05). Ang II-induced hypertension does not affect the overall T cell cytokine profile, but enhanced T cell-derived ROS production and/or leukocyte recruitment due to elevated CCL2, and this effect may be further amplified with increased infiltration of T cells. We have identified a potential hypertension-specific T cell phenotype that may represent a functional contribution of T cells to the development of hypertension, and likely several other associated vascular disorders. PMID:25501574

  18. Estrogen Regulates Angiotensin II Receptor Expression Patterns and Protects the Heart from Ischemic Injury in Female Rats.

    PubMed

    Xue, Qin; Xiao, Daliao; Zhang, Lubo

    2015-07-01

    Previous studies have shown that female offspring are resistant to fetal stress-induced programming of ischemic-sensitive phenotype in the heart; however, the mechanisms responsible remain unclear. The present study tested the hypothesis that estrogen plays a role in protecting females in fetal programming of increased heart vulnerability. Pregnant rats were divided into normoxic and hypoxic (10.5% O2 from Day 15 to 21 of gestation) groups. Ovariectomy (OVX) and estrogen (E2) replacement were performed in 8-wk-old female offspring. Hearts of 4-mo-old females were subjected to ischemia and reperfusion injury in a Langendorff preparation. OVX significantly decreased postischemic recovery of left ventricular function and increased myocardial infarction, and no difference was observed between normoxic and hypoxic groups. The effect of OVX was rescued by E2 replacement. OVX decreased the binding of glucocorticoid receptor (GR) to glucocorticoid response elements at angiotensin II type 1 (Agtr1) and type 2 (Agtr2) receptor promoters, resulting in a decrease in Agtr1 and an increase in Agtr2 in the heart. Additionally, OVX decreased estrogen receptor (ER) expression in the heart and inhibited ER/GR interaction in binding to glucocorticoid response elements at the promoters. Consistent with the changes in Agtrs, OVX significantly decreased Prkce abundance in the heart. These OVX-induced changes were abrogated by E2 replacement. The results indicate that estrogen is not directly responsible for the sex dimorphism in fetal programming of heart ischemic vulnerability but suggest a novel mechanism of estrogen in regulating cardiac Agtr1/Agtr2 expression patterns and protecting female hearts against ischemia and reperfusion injury. PMID:25972014

  19. Estrogen Regulates Angiotensin II Receptor Expression Patterns and Protects the Heart from Ischemic Injury in Female Rats1

    PubMed Central

    Xue, Qin; Xiao, Daliao; Zhang, Lubo

    2015-01-01

    Previous studies have shown that female offspring are resistant to fetal stress-induced programming of ischemic-sensitive phenotype in the heart; however, the mechanisms responsible remain unclear. The present study tested the hypothesis that estrogen plays a role in protecting females in fetal programming of increased heart vulnerability. Pregnant rats were divided into normoxic and hypoxic (10.5% O2 from Day 15 to 21 of gestation) groups. Ovariectomy (OVX) and estrogen (E2) replacement were performed in 8-wk-old female offspring. Hearts of 4-mo-old females were subjected to ischemia and reperfusion injury in a Langendorff preparation. OVX significantly decreased postischemic recovery of left ventricular function and increased myocardial infarction, and no difference was observed between normoxic and hypoxic groups. The effect of OVX was rescued by E2 replacement. OVX decreased the binding of glucocorticoid receptor (GR) to glucocorticoid response elements at angiotensin II type 1 (Agtr1) and type 2 (Agtr2) receptor promoters, resulting in a decrease in Agtr1 and an increase in Agtr2 in the heart. Additionally, OVX decreased estrogen receptor (ER) expression in the heart and inhibited ER/GR interaction in binding to glucocorticoid response elements at the promoters. Consistent with the changes in Agtrs, OVX significantly decreased Prkce abundance in the heart. These OVX-induced changes were abrogated by E2 replacement. The results indicate that estrogen is not directly responsible for the sex dimorphism in fetal programming of heart ischemic vulnerability but suggest a novel mechanism of estrogen in regulating cardiac Agtr1/Agtr2 expression patterns and protecting female hearts against ischemia and reperfusion injury. PMID:25972014

  20. The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1-7) or carbachol.

    PubMed

    Mahon, J M; Allen, M; Herbert, J; Fitzsimons, J T

    1995-11-01

    The effect intracerebroventricular injections of angiotensin II (0.1 nm), angiotensin-(1-7) (1 or 100 nm) and carbachol (500 ng) on c-fos expression was examined in the forebrain of Lister hooded rats. Intense staining of the c-Fos protein was found in the median preoptic nucleus, organum vasculosum of the lamina terminalis, subfornical organ, paraventricular nucleus and supraoptic nucleus after angiotensin II and carbachol Angiotensin II caused significantly more c-fos expression in the ventral median preoptic nucleus and organum vasculosum of the lamina terminalis than carbachol, whereas in the paraventricular and supraoptic nuclei this was reversed, with carbachol having a greater effect on c-fos expression in these areas. Angiotensin-(1-7), however, only induced c-Fos protein in the organum vasculosum of the lamina terminalis and median preoptic nucleus with the number and the intensity of staining of the nuclei significantly less in both areas than after angiotensin II or carbachol. Separate groups of Lister rats were given i.c.v. injections of the same substances at the same doses, but excluding the lower dose of angiotensin-(1-7), and the intakes of water and 1.8% NaCl over 60 min were measured. Angiotensin II stimulated intakes of both water and NaCl. The effect on water intake was almost immediate (<1 min), whereas NaCl intake did not usually start until at least 5 min after injection. Over 60 min, water (12.4 +/- 1.0 ml) and NaCl (4.2 +/- 0.9 ml) intakes were significantly greater than water (1.1 +/- 0.2 ml) and NaCl (0.6 +/- 0.5 ml) intakes of the controls. Carbachol caused less drinking than angiotensin II, the water intake over 60 min being significantly less (4.8 +/- 0.7 ml) and the latency of response greater (>5 min). Carbachol, unlike angiotensin II, had little effect on NaCl intake (0.7 +/- 0.4 ml). Angiotensin-(1-7) had no effect on water (1.1 +/- 0.3 ml) or NaCl (0.3 +/- 0.3 ml) intakes. The plasma levels of vasopressin were measured after i

  1. A case of lithium intoxication induced by an antihypertensive angiotensin 1 subtype-specific angiotensin II receptor blocker in an elderly patient with bipolar disorder and hypertension.

    PubMed

    Hayashi, Yuichi; Nishida, Shohei; Takekoshi, Akira; Murakami, Muneharu; Yamada, Megumi; Kimura, Akio; Suzuki, Akio; Inuzuka, Takashi

    2016-01-01

    Lithium carbonate is considered to be a first-line treatment for bipolar disorder; however, this drug has a narrow therapeutic window, and lithium intoxication is commonly induced by various drugs interaction and situations. We herein report a case of lithium intoxication induced by the administration of an antihypertensive agent targeting the angiotensin 1 (AT1) subtype of the angiotensin II receptor in a 65-year-old woman with a 40-year history of bipolar disorder type 1, and 1-year history of essential hypertension. Her bipolar disorder had been well-controlled with 600 mg/day of lithium carbonate for more than 10 years. She was later diagnosed with hypertension and the AT1 receptor blocker, azilsartan was thereafter administrated on a daily basis. After 3 weeks of azilsartan administration, she presented with progressive action tremor and showed a gradual deterioration of her physical state. Four months after the start of azilsartan administration, she presented with alternating episodes of diarrhea and constipation. Two weeks before admission to our hospital, she presented with mild consciousness disturbances, myoclonus, truncal ataxia, and appetite loss. She was diagnosed to have lithium intoxication based on an elevated serum lithium concentration of 3.28 mEq/l.It is therefore important to evaluate the serum lithium concentration after the administration of antihypertensive agents, and consider lithium-antihypertensive agent interactions when selecting antihypertensive agents in elderly patients receiving long-term lithium carbonate treatment. PMID:27535187

  2. Increased contractile responses to 5-hydroxytryptamine and Angiotensin II in high fat diet fed rat thoracic aorta

    PubMed Central

    Ghatta, Srinivas; Ramarao, Poduri

    2004-01-01

    Background Feeding normal rats with high dietary levels of saturated fat leads to pathological conditions, which are quite similar to syndrome X in humans. These conditions such as hypertriglyceridemia, hypercholesterolemia, obesity, and hyperglycemia might induce hypertension through various mechanisms. Metabolic syndrome and the resulting NIDDM represent a major clinical challenge because implementation of treatment strategies is difficult. Vascular abnormalities probably contribute to the etiology of many diabetic complications including nephropathy, neuropathy, retinopathy, and cardiomyopathy. It has been shown that in Streptozotocin induced diabetic animals there is an increase in maximal responses to 5-Hydroxytryptamine and Angiotensin II. The purpose of this study was to evaluate High fat diet fed rats for the development of hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperglycemia and to assess their vascular responses to 5-Hydroxytryptamine and Angiotensin II. Methods Male Sprague Dawley rats were used for this study and were divided into two equal groups. One of the groups was fed with normal pellet diet and they served as the control group, whereas the other group was on a high fat diet for 4 weeks. Body weight, plasma triglycerides, plasma cholesterol, and plasma glucose were measured every week. Intraperitoneal glucose tolerance test was performed after 4 weeks of feeding. At the end of fourth week of high fat diet feeding, thoracic aortae were removed, and cut into helical strips for vascular reactivity studies. Dose-response curves of 5-Hydroxytryptamine and Angiotensin II were obtained. Results There was no significant difference in pD2, with 5-Hydroxytryptamine and Angiotensin II in both groups but Emax was increased. Conclusions These results suggest that hypertension in high fat diet rats is associated with increased in vitro vascular reactivity to 5-HT and Ang II. PMID:15287987

  3. Genotoxicity of Advanced Glycation End Products: Involvement of Oxidative Stress and of Angiotensin II Type 1 Receptors

    NASA Astrophysics Data System (ADS)

    Schupp, Nicole; Schinzel, Reinhard; Heidland, August; Stopper, Helga

    2005-06-01

    In patients with chronic renal failure, cancer incidence is increased. This may be related to an elevated level of genomic damage, which has been demonstrated by micronuclei formation as well as by comet assay analysis. Advanced glycation end products (AGEs) are markedly elevated in renal failure. In the comet assay, the model AGEs methylglyoxal- and carboxy(methyl)lysine-modified bovine serum albumin (BSA) induced significant DNA damage in colon, kidney, and liver cells. The addition of antioxidants prevented AGE-induced DNA damage, suggesting enhanced formation of reactive oxygen species (ROS). The coincubation with dimethylfumarate (DMF), an inhibitor of NF-κB translocation, reduced the genotoxic effect, thereby underscoring the key role of NF-κB in this process. One of the genes induced by NF-κB is angiotensinogen. The ensuing proteolytic activity yields angiotensin II, which evokes oxidative stress as well as proinflammatory responses. A modulator of the renin-angiotensin system (RAS), the angiotensin II (Ang II) receptor 1 antagonist, candesartan, yielded a reduction of the AGE-induced DNA damage, connecting the two signal pathways, RAS and AGE signaling. We were able to identify important participants in AGE-induced DNA damage: ROS, NF-κB, and Ang II, as well as modulators to prevent this DNA damage: antioxidants, DMF, and AT1 antagonists.

  4. Changes in plasma angiotensin II, aldosterone, arginine vasotocin, corticosterone, and electrolyte concentrations during acclimation to dry condition and seawater in the crab-eating frog.

    PubMed

    Uchiyama, Minoru; Maejima, Sho; Wong, Marty K S; Preyavichyapugdee, Narin; Wanichanon, Chaitip; Hyodo, Susumu; Takei, Yoshio; Matuda, Kouhei

    2014-01-01

    The crab-eating frog Fejervarya cancrivora inhabits mangrove swamps and marshes in Southeast Asia. In the present study, circulating angiotensin II (Ang II), aldosterone (Aldo), arginine vasotocin (AVT), and corticosterone (Cort) concentrations as well as various blood parameters were studied under osmotically stressful conditions. Following acclimation to hyperosmotic seawater and dry condition for 5days, body weight was significantly decreased. Under both conditions, plasma Na(+), Cl(-), and urea concentrations, hematocrit values (Ht; blood volume indicator), and osmolality were significantly increased. Dehydration associated with hypovolemic and hyperosmotic states of body fluids was induced during acclimation to hyperosmotic seawater and dry condition in the crab-eating frogs. Ang II, Aldo, AVT, and Cort were maintained within relatively narrow concentration ranges in the control frogs; however, in frogs under dry and hyperosmotic seawater conditions, large variations were observed among individuals in each group. Mean plasma Ang II and Aldo concentrations significantly increased in hyperosmotic seawater-acclimated and desiccated frogs. Although mean plasma AVT concentrations in dehydrated frogs of both the groups were approximately 2.0-3.5 times higher than those in the control frogs, the differences were not significant because of the variation. There was a significant correlation between plasma osmolality and AVT as well as Ang II but not Aldo. A significant correlation was also observed between Ht and AVT as well as Ang II. Plasma Ang II was significantly correlated with plasma Aldo. These results indicate that the crab-eating frogs may exhibit similar physiological responses to both seawater-acclimated and dry conditions. It appears that under dehydrated conditions, osmoregulatory mechanisms participate in stabilization of the situation. The renin-angiotensin system may have pivotal roles in body fluid regulation under volemic and osmotic stress in the

  5. Somatostatin analog (SMS 201-995) inhibits the basal and angiotensin II-stimulated sup 3 H-thymidine uptake by rat adrenal glands

    SciTech Connect

    Pawlikowski, M.; Lewinski, A.; Sewerynek, E.; Szkudlinski, M.; Kunert-Radek, J.; Wajs, E. )

    1990-02-14

    The effects of a long-acting somatostatin analog SMS 201-995 injections on the basal and angiotensin II-stimulated ({sup 3}H)-thymidine uptake by the rat adrenal glands incubated in vitro were examined. It was shown that SMS 201-995 significantly inhibited the ({sup 3}H)-thymidine uptake and, additionally, suppressed the stimulatory effect of a single angiotensin II injection.

  6. Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2

    PubMed Central

    Pellieux, Corinne; Foletti, Alessandro; Peduto, Giovanni; Aubert, Jean-François; Nussberger, Jürg; Beermann, Friedrich; Brunner, Hans-R.; Pedrazzini, Thierry

    2001-01-01

    FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II–induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II–dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2–deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells. PMID:11748268

  7. Carbon-11 labeling of nonpeptide angiotensin-II antogonists: MK-996 and analogs

    SciTech Connect

    Mathews, W.B.; Burns, H.D.; Hamill, T.D.

    1994-05-01

    Our goal was to develop a tracer that can be used for imaging of angiotensin-II (ANG-II), AT{sub 1} receptors in vivo via PET. MK-996 is a potent, nonpeptide, benzamide-based, AT{sub 1} selective antagonist (IC{sub 50}=0.15 nM) in clinical trials for the treatment of hypertension. (C-11)MK-996 was prepared using (C-11)benzoyl chloride synthesized in two steps from (C-11) carbon dioxide via (C-11)benzoic acid. The labeled acid chloride was made by reacting the (C-11)benzoic acid with either phthaloyl dichloride or thionyl chloride. After HPLC purification, the (C-11)MK-996 with an average synthesis time of 38 minutes from EOB, a non-decay corrected radiochemical yield of 3%, and a specific activity of 1162 Ci/mmol at EOS. Although this route provided the radiotracer in sufficient quantities for imaging studies, the synthesis was cumbersome. Thus, a labeled tracer that could be prepared more conveniently was sought.

  8. Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension.

    PubMed

    Sasser, Jennifer M; Cunningham, Mark W; Baylis, Chris

    2014-12-15

    Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects. PMID:25298524

  9. Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis

    PubMed Central

    2012-01-01

    Introduction Systemic sclerosis (SSc) is an autoimmune inflammatory disorder of unknown etiology characterized by fibrosis of the skin and internal organs. Ang II (angiotensin II), a vasoconstrictive peptide, is a well-known inducer of kidney, heart, and liver fibrosis. The goal of this study was to investigate the profibrotic potential of Ang II in the mouse skin. Methods Ang II was administered by subcutaneous osmotic mini pumps to C57BL/6 male mice. Collagen-content measurements were performed with Gomori Trichrome staining and hydroxyproline assay. The mRNA expression level of collagens, TGF-β1, TGF-β2, TGF-β3, CTGF, αSMA, CD3, Emr1, CD45/B220, MCP1, and FSP1 were quantified with real-time polymerase chain reaction (PCR). Immunostaining was performed for markers of inflammation and fibrosis, including, phospho-Smad2, αSMA, CD3, Mac3, CD45/B220, and CD163B. Fibrocytes were identified by double staining with CD45/FSP1 and CD45/PH4. Endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) were identified by double staining with VE-cadherin/FSP1. Results Ang II-infused mice develop prominent dermal fibrosis in the area proximal to the pump, as shown by increased collagen and CTGF mRNA levels, increased hydroxyproline content, and more tightly packed collagen fibers. In addition, elevated mRNA levels of TGF-β2 and TGF-β3 along with increased expression of pSmad2 were observed in the skin of Ang II-treated mice. Dermal fibrosis was accompanied by an increased number of infiltrating fibrocytes, and an increased number of αSMA-positive cells, as well as CD163B+ macrophages in the upper dermis. This correlated with significantly increased mRNA levels of αSMA, Emr1, and MCP1. Infiltration of CD3-, CD45/B220-, and Mac3-positive cells was observed mainly in the hypodermis. Furthermore, an increased number of double-positive VE-cadherin/FSP1 cells were detected in the hypodermis only. Conclusions This work demonstrates that Ang II induces both

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

    PubMed Central

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

    2016-01-01

    TGF-β1 is known to inhibit muscle regeneration after muscle injury. However, it is unknown if high systemic levels of TGF-β can affect the muscle regeneration process. In the present study, we demonstrated the effect of a CCl4 intra-peritoneal injection and losartan (an angiotensin II type 1 receptor antagonist) on skeletal muscle (gastrocnemius muscle) injury and regeneration. Male C57BL/6 mice were grouped randomly as follows: control (n = 7), CCl4-treatment group (n = 7), and CCl4 + losartan treatment group (n = 7). After CCl4 treatment for a 16-week period, the animals were sacrificed and analyzed. The expression of dystrophin significantly decreased in the muscle tissues of the control group, as compared with that of the CCl4 + losartan group (p < 0.01). p(phospho)-Smad2/3 expression significantly increased in the muscles of the control group compared to that in the CCl4 + losartan group (p < 0.01). The expressions of Pax7, MyoD, and myogenin increased in skeletal muscles of the CCl4 + losartan group compared to the corresponding levels in the control group (p < 0.01). We hypothesize that systemically elevated TGF-β1 as a result of CCl4-induced liver injury causes skeletal muscle injury, while losartan promotes muscle repair from injury via blockade of TGF-β1 signaling. PMID:26867195

  11. Effect of intracerebroventricular deuterium oxide on water intake and AVP release induced by intravenous infusion of angiotensin II in sheep.

    PubMed

    Hjelmqvist, H; Rundgren, M

    1990-02-01

    The effect of intracerebroventricular (i.c.v.) infusion (0.02 ml min-1) of deuterium oxide (D2O), with NaCl added to isotonicity, on the water intake and arginine vasopressin (AVP) release caused by intravenous (i.v.) infusion of angiotensin II (AII) (4.8 nmol min-1) was studied in euhydrated sheep. The i.c.v. infusion of D2O, which started 80 min before commencement of the AII infusion, induced a water diuresis in four out of six animals and a measurable decrease in plasma AVP concentration. The i.v. infusion of AII effectively stimulated the AVP release and the response was unaffected by prior and simultaneous i.c.v. administration of D2O. However, the water intake measured 2 min after cessation of the AII administration was reduced by 50% when D2O was infused i.c.v. compared to that seen after simply the AII infusion. The inhibitory effect of D2O on AII-induced drinking disappeared rapidly after discontinuation of D2O administration. Compensatory increased drinking was seen during the first post-infusion hour, resulting in an equivalent cumulative intake of water at 60 min post-infusion in the two types of experiments. The present results support the idea that at least some of the cerebral effects of circulating AII on fluid balance are medicated via targets which are simultaneously accessible to influences from the blood and the cerebrospinal fluid. PMID:2156405

  12. Vascular α1D-adrenoceptors are overexpressed in aorta of the aryl hydrocarbon receptor null mouse: role of increased angiotensin II

    PubMed Central

    Vázquez-Cuevas, F. G.; López-Guerrero, J. J.; Figueroa-García, M. C.; Gallardo-Ortiz, I. A.; Ibarra, M.; Rodríguez-Sosa, M.; Gonzalez, F. J.; Elizondo, G.

    2009-01-01

    Summary The hypothesis that α1D-adrenoceptors may mediate the pro-hypertensive actions of angiotensin II (Ang II) was tested in isolated aorta (α1D-adrenoceptor bearing tissue) of the aryl hydrocarbon receptor null mouse (AhR−/−), which shows increased levels of Ang II, cardiac hypertrophy and hypertension. The effect of captopril (an angiotensin converting enzyme inhibitor) on both blood pressure and aortic α1D-adrenoceptor expression and function in mice were determined. Basal blood pressure was higher in AhR−/− mice, while captopril therapy decreased it to wild-type (WT) values. Aortas of adult WT and AhR−/− mice were stimulated by phenylephrine or noradrenaline to induce contraction; the maximal effect was higher in AhR−/− mice, without a significant change in pEC50. PA2 values for the selective α1D-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazynil]ethyl]-8-azaspiro [4.5]decane-7,9-dione) were 9.19 and 8.94 for WT and AhR−/−, respectively; while Schild slopes were not different from 1. PCR experiments showed c. 77% increase in AhR−/− α1D-adrenoceptors cDNA compared with WT mice; while western blot analysis demonstrated c. 88% increase in α1D-adrenoceptor protein in AhR−/− mice. Captopril therapy decreased α1D-adrenoceptor-induced contraction and protein in AhR−/− mice to WT levels. These data support the hypothesis that under conditions where Ang II is elevated, vascular α1D-adrenoceptors are increased, and further suggest that both Ang II and vascular α1D-adrenoceptors could be related in the onset of hypertension. PMID:18598287

  13. Alpinate oxyphyllae fructus (Alpinia Oxyphylla Miq) extracts inhibit angiotensin-II induced cardiac apoptosis in H9c2 cardiomyoblast cells.

    PubMed

    Chang, Yung-Ming; Tsai, Chuan-Te; Wang, Chiun-Chuang Roger; Chen, Yueh-Sheng; Lin, Yueh-Min; Kuo, Chia-Hua; Tzang, Bor-Show; Chen, Ray-Jade; Tsai, Fuu-Jen; Huang, Chih-Yang

    2013-01-01

    Angiotensin II (Ang II) is a risk factor for cardiovascular disease. We used a traditional Chinese medicine, alpinate oxyphyllae fructus (AOF), to evaluate its effect on Ang II-induced cardiac apoptosis and mitochondrial dysfunction. Ang II-treated H9c2 cells were administered AOF of 20-100 µg/mL concentrations. Ang II significantly increased TUNEL-positive nuclei in the H9c2 cells, effect was inhibited by AOF administration in both pre-treated and post-treated H9c2 cells. Caspases 9 and 3 activities were increased by Ang II and downregulated by AOF administration, especially in pre-treatment. AOF treatment reversed Ang II-induced mitochondria membrane potential instability in H9c2 cells as observed by JC-1 stain assay. Furthermore, pro-apoptotic proteins Bad and cytochrome c increased and decreased respectively under AOF administration. The levels of p-Bad anti-apoptotic protein were significantly increased after AOF treatment. This study indicates that mitochondrial dependent apoptosis induced by Ang II. PMID:23391902

  14. Radiation injury in rat lung: II. Angiotensin-converting enzyme activity

    SciTech Connect

    Ward, W.F.; Solliday, N.H.; Molteni, A.; Port, C.D.

    1983-11-01

    To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of /sup 60/Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90 to 150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.

  15. Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B.

    PubMed

    Bhatt, Siddhartha R; Lokhandwala, Mustafa F; Banday, Anees Ahmad

    2014-01-01

    Abstract The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension. However, the mechanisms causing this upregulation are unknown. Oxidative stress is an important regulator of protein expression via activation of transcription factors such as nuclear factor kappa B (NFκB). The present study was carried out to test the hypothesis that oxidative stress contributes to vascular AT1R upregulation via NFκB in human aortic smooth muscle cells (HASMC) and spontaneously hypertensive rats (SHR). HASMC exposed to oxidative stress exhibited a robust increase in AT1R mRNA in HASMC. Furthermore, oxidative stress failed to upregulate AT1Rs in the presence of either an antioxidant catalase or siRNA against p65 subunit of NFκB. To test the role of oxidative stress and NFκB in hypertension, prehypertensive SHR were treated with NFκB inhibitor pyrrolidine dithiocarbamate from 5 weeks to 11-12 weeks of age. At 11-12 weeks of age, SHR exhibited increased NFκB expression, AT1R upregulation and exaggerated Ang II-induced vasoconstriction as compared to age-matched Wistar Kyoto (WKY) rats. PDTC treatment of SHR lowered NFκB expression, normalized AT1R expression and Ang II-induced vasoconstriction. More importantly, PDTC treatment significantly attenuated hypertension development in SHR. In conclusion, vascular oxidative can upregulate AT1R, via mechanisms involving NFκB, and contribute to the development of hypertension. PMID:25198883

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

    PubMed Central

    Zhou, Yi; Wu, Wenxue; Lindholt, Jes S.; Sukhova, Galina K.; Libby, Peter; Yu, Xueqing; Shi, Guo-Ping

    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 concentration in blood cell lysates from 485 AAA patients and 204 age- and sex-matched controls. AAA patients exhibited lower blood cell Foxp3 expression than controls (P < 0.0001). Pearson's correlation test demonstrated a significant but negative correlation between Foxp3 and AAA annual expansion rate before (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 < 0.0001). Adoptive transfer of Tregs from wild-type (WT) and IL10-deficient (Il10–/–) mice increased AAA lesion Treg content, but only WT mice Tregs reduced AAA size, AAA incidence, blood pressure, lesion macrophage and CD4+ and CD8+ T-cell accumulation, and angiogenesis with concurrent increase of lesion collagen content. Both AAA lesion immunostaining and plasma ELISA demonstrated that adoptive transfer of WT Tregs, but not Il10–/– Tregs, reduced the expression of MCP-1. In vitro cell culture and aortic ring assay demonstrated that only Tregs from WT mice, but not those from Il10–/– mice, reduced macrophage MCP-1 secretion, macrophage and vascular cell protease expression and activity, and aortic ring microvessel formation. Conclusion This study supports a protective role of Tregs in human and experimental AAA by releasing IL10 to suppress inflammatory cell chemotaxis, arterial wall remodelling, and angiogenesis. PMID:25824145

  17. Angiotensin-(1–7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1

    PubMed Central

    McCollum, LaTronya T.; Gallagher, Patricia E.

    2012-01-01

    Chronic hypertension induces cardiac remodeling, including left ventricular hypertrophy and fibrosis, through a combination of both hemodynamic and humoral factors. In previous studies, we showed that the heptapeptide ANG-(1–7) prevented mitogen-stimulated growth of cardiac myocytes in vitro, through a reduction in the activity of the MAPKs ERK1 and ERK2. In this study, saline- or ANG II-infused rats were treated with ANG-(1–7) to determine whether the heptapeptide reduces myocyte hypertrophy in vivo and to identify the signaling pathways involved in the process. ANG II infusion into normotensive rats elevated systolic blood pressure >50 mmHg, in association with increased myocyte cross-sectional area, ventricular atrial natriuretic peptide mRNA, and ventricular brain natriuretric peptide mRNA. Although infusion with ANG-(1–7) had no effect on the ANG II-stimulated elevation in blood pressure, the heptapeptide hormone significantly reduced the ANG II-mediated increase in myocyte cross-sectional area, interstitial fibrosis, and natriuretic peptide mRNAs. ANG II increased phospho-ERK1 and phospho-ERK2, whereas cotreatment with ANG-(1–7) reduced the phosphorylation of both MAPKs. Neither ANG II nor ANG-(1–7) altered the ERK1/2 MAPK kinase MEK1/2. However, ANG-(1–7) infusion, with or without ANG II, increased the MAPK phosphatase dual-specificity phosphatase (DUSP)-1; in contrast, treatment with ANG II had no effect on DUSP-1, suggesting that ANG-(1–7) upregulates DUSP-1 to reduce ANG II-stimulated ERK activation. These results indicate that ANG-(1–7) attenuates cardiac remodeling associated with a chronic elevation in blood pressure and upregulation of a MAPK phosphatase and may be cardioprotective in patients with hypertension. PMID:22140049

  18. Effects of angiotensin II on intracellular Ca2+ and pH in isolated beating rabbit hearts and myocytes loaded with the indicator indo-1.

    PubMed Central

    Ikenouchi, H; Barry, W H; Bridge, J H; Weinberg, E O; Apstein, C S; Lorell, B H

    1994-01-01

    1. Angiotensin II increases myocardial contractility in several species, including the rabbit and man. However, it is controversial whether the predominant mechanism is an increase in free cytosolic [Ca2+]i or a change in myofilament Ca2+ sensitivity. To address this question, we infused angiotensin II in isolated perfused rabbit hearts loaded with the Ca2+ indicator indo-1 AM and measured changes in beat-to-beat surface transients of the Ca2+i-sensitive 400:500 nm ratio and left ventricular contractility. The effects of angiotensin II were compared with the response to a Ca(2+)-dependent increase in the inotropic state produced by a change in the perfusate [Ca2+] from 0.9 to 3.6 nM. 2. In the isolated beating heart, an increase in perfusate [Ca2+] caused an increase in left ventricular pressure +dP/dt in association with an increase in peak systolic [Ca2+]i. Angiotensin II perfusion caused a similar increase in left ventricular +dP/dt in the absence of any increase in peak systolic [Ca2+]i. 3. To exclude any contribution of non-myocyte sources of Ca(2+)-sensitive fluorescence which may be present in the intact heart, we also compared the effects of angiotensin II and a change in superfusate [Ca2+] in collagenase-dissociated paced adult rabbit ventricular myocytes loaded with indo-1 AM. In the isolated rabbit myocytes a change in perfusate [Ca2+] from 0.9 to 3.6 mM caused an increase in peak systolic cell shortening coincident with an increase in peak systolic [Ca2+]i. In contrast, angiotensin II caused a similar increase in peak systolic cell shortening whereas there was no increase in peak systolic [Ca2+]i. There was also no change in inward Ca2+ current (ICa) in response to angiotensin II. 4. To investigate further the mechanism of the positive inotropic action of angiotensin II, its effects on intracellular pH were studied in isolated rabbit myocytes loaded with the fluorescent H+ probe SNARF 1. These experiments demonstrated that angiotensin II induced a 0.2 p

  19. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis.

    PubMed

    Chow, Bryna S Man; Kocan, Martina; Bosnyak, Sanja; Sarwar, Mohsin; Wigg, Belinda; Jones, Emma S; Widdop, Robert E; Summers, Roger J; Bathgate, Ross A D; Hewitson, Tim D; Samuel, Chrishan S

    2014-07-01

    Fibrosis is a hallmark of chronic kidney disease, for which there is currently no effective cure. The hormone relaxin is emerging as an effective antifibrotic therapy; however, its mechanism of action is poorly understood. Recent studies have shown that relaxin disrupts the profibrotic actions of transforming growth factor-β1 (TGF-β1) by its cognate receptor, relaxin family peptide receptor 1 (RXFP1), extracellular signal-regulated kinase phosphorylation, and a neuronal nitric oxide synthase-dependent pathway to abrogate Smad2 phosphorylation. Since angiotensin II also inhibits TGF-β1 activity through its AT2 receptor (AT2R), we investigated the extent to which relaxin interacts with the AT2R. The effects of the AT2R antagonist, PD123319, on relaxin activity were examined in primary rat kidney myofibroblasts, and in kidney tissue from relaxin-treated male wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction. Relaxin's antifibrotic actions were significantly blocked by PD123319 in vitro and in vivo, or when relaxin was administered to AT2R-knockout mice. While heterodimer complexes were formed between RXFP1 and AT2Rs independent of ligand binding, relaxin did not directly bind to AT2Rs but signaled through RXFP1-AT2R heterodimers to induce its antifibrotic actions. These findings highlight a hitherto unrecognized interaction that may be targeted to control fibrosis progression. PMID:24429402

  20. Comparison of the hypertrophic effect of phorbol ester, norepinephrine, angiotensin II and contraction on cultured cardiomyocytes

    SciTech Connect

    Allo, S.N.; Carl, L.L.; Morgan, H.E. )

    1991-03-15

    Phorbol 12-myristate 13-acetate (PMA), norepinephrine (NE), angiotensin II (AII) and contraction stimulate cardiomyocyte growth. Differences exist in the time course and extent of protein and RNA accumulation. Cells plated at 4 {times} 10{sup 6} cells/60mm dish and arrested with 50 mM KCl demonstrated no significant growth. Treatment with PMA stimulated growth to a maximum of 17% at 48 h. In contrast, maximal stimulation of growth was 36% at 48 h and 31% at 72 h for contracting and NE treated cells, respectively. Maximal stimulation of the capacity for protein synthesis was 32% for PMA treated cells at 24 h as compared to 59% and 77% for NE treated and contracting cells respectively at 72 h. In support of a primary role for altered capacity in the regulation of protein synthesis, there was a significant correlation between RNA and protein content independent of the stimulus used. AII increased RNA content by 28% at 48h, but had no effect on growth up to 72h. Treatment with staurosporine blocked the stimulation of growth, suggestive of a role for protein kinase C (PKC). However, the inhibition of contraction-induced growth was due in part to a reduction in the rate of contraction. It was concluded that: significant differences existed in the time course of growth stimulation and RNA accumulation, depending on the stimulus; and growth inhibition by staurosporine is suggestive of an important role of PKC in hypertrophic growth induced by these stimuli.

  1. Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification.

    PubMed

    Krovat, Eva M; Langer, Thierry

    2003-02-27

    Chemical feature based pharmacophore models were elaborated for angiotensin II receptor subtype 1 (AT(1)) antagonists using both a quantitative and a qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The training sets for quantitative model generation consisted of 25 selective AT(1) antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM. Additionally, a qualitative pharmacophore hypothesis was derived from multiconformational structure models of the two highly active AT(1) antagonists 4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative model, the best pharmacophore hypothesis consisted of a five-features model (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a hydrogen bond acceptor, a negative ionizable function, and an aromatic plane function). The best qualitative model consisted of seven features (Hypo2: 11 points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable function, and two hydrophobic functions). The obtained pharmacophore models were validated on a wide set of test molecules. They were shown to be able to identify a range of highly potent AT(1) antagonists, among those a number of recently launched drugs and some candidates presently undergoing clinical tests and/or development phases. The results of our study provide confidence for the utility of the selected chemical feature based pharmacophore models to retrieve structurally diverse compounds with desired biological activity by virtual screening. PMID:12593652

  2. Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

    PubMed

    Senda, Asuna; Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Yamashita, Miki; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-01-01

    Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID:26632190

  3. Detection of angiotensin II binding to single adrenal zona glomerulosa cells by confocal Raman microspectroscopy

    NASA Astrophysics Data System (ADS)

    McCoy, Michael J.; Habermann, Timothy J.; Hanke, Craig J.; Adar, Fran; Campbell, William B.; Nithipatikom, Kasem

    1999-04-01

    We developed a confocal Raman microspectroscopic technique to study ligand-receptor bindings in single cells using Raman-labeled ligands and surface-enhanced Raman scattering (SERS). The adrenal zona glomerulosa (ZG) cells were used as a model in this study. ZG cells have a high density of angiotensin II (AII) receptors on the cellular membrane. There are two identified subtypes of AII receptors,namely AT1 and AT2 receptors. AII is a peptidic hormone, which upon binding to its receptors, stimulates the release of aldosterone from ZG cells. The cellular localization of these receptors subtypes was detected in single ZG cells by using immunocomplexation of receptors with specific antibodies and confocal Raman microspectroscopy. In the binding study, we used biotin-labeled AII to bind to its receptors in ZG cells. Then, avidin and Raman-labeled AII. The binding was measure directly on the single ZG cells. The results showed that the binding was displaced with unlabeled AII and specific AII antagonists. This is a rapid and sensitive technique for detection of cellular ligand bindings as well as antagonists screening in drug discovery.

  4. The conformation and activity relationship of benzofuran type of angiotensin II receptor antagonists.

    PubMed

    Yoo, S E; Kim, S K; Lee, S H; Kim, N J; Lee, D W

    2000-09-01

    As a continuing effort to establish the structure and activity relationship in a benzofuran type of angiotensin II antagonist, we synthesized various regioisomers and performed a series of QSAR analyses. The conformational analyses of target isomers were carried out using molecular mechanics and fine-tuned using the information from the NMR NOE experiment. The conformations of compounds with a good binding activity are quite similar to that of DuP753, a prototype of AII antagonist, suggesting that these compounds also bind to the same site of AII receptor. We then studied the compounds with a varied length of the hydroxyl group bearing side chain to find out the optimum distance between the hydroxyl group and the imidazole ring. The CoMFA with these compounds gave acceptable statistical measures (cross-validated r2 and conventional r2 to be 0.881 and 0.974, respectively) and the map was well consistent with the previously proposed pharmacophore. PMID:11026543

  5. A comparative molecular field analysis and molecular modelling studies on pyridylimidazole type of angiotensin II antagonists.

    PubMed

    Yoo, S E; Kim, S K; Lee, S H; Yi, K Y; Lee, D W

    1999-12-01

    A large number of compounds known as "AII (Angiotensin II) antagonists" have been developed for the treatment of various heart diseases such as hypertension, congestive heart failure, and chronic renal failure. Most of the currently known AII receptor antagonists share a similar chemical structure, consisting of nitrogen atoms, a lipophilic alkyl side chain and an acidic group. As a new series, we have designed and synthesized various pyridylimidazole derivatives. In this report we would like to discuss the structure-activity relationship of these series of compounds using the comparative molecular field analysis (CoMFA) methods. We could come up with a good CoMFA model (cross-validated and conventional r2 values equal to 0.702 and 0.991, respectively) and the validity of the model was confirmed by synthesizing and measuring their biological activity of additional 6 compounds suggested by the model. This result provides additional information on the structural requirement for structurally diverse group of AII receptor antagonists. PMID:10658603

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

    SciTech Connect

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

    1990-03-01

    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 {sup 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 {sup 125}I-AII alone, with {sup 125}I-AII and phenylarsine oxide to prevent internalization, or when the competitive inhibitor {sup 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.

  7. Renal sympathetic baroreflex effects of angiotensin II infusions into the rostral ventrolateral medulla of the rabbit.

    PubMed

    Saigusa, T; Head, G A

    1993-05-01

    1. The effects of local infusion of angiotensin II (AII) into the rostral ventrolateral medulla (RVLM) pressor area on the renal sympathetic baroreflex were compared with the excitatory amino acid glutamate in urethane anaesthetized rabbits with chronically implanted renal nerve electrodes. Baroreflex blood pressure-renal nerve activity curves were obtained by intravenous infusion of phenylephrine and nitroprusside before and after treatments. 2. Infusion of 4 pmol/min of AII into the RVLM increased blood pressure by 12 +/- 2 mmHg and transiently increased resting sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right. The upper plateau of the sympathetic reflex increased by 29 +/- 8% (n = 6, P < 0.025). 3. Infusions of glutamate into the RVLM, at a dose which was equipressor to that of AII, also increased resting renal sympathetic nerve activity. In contrast to AII, this increase was maintained throughout the infusion. Glutamate shifted the reflex curve to the right and increased the upper plateau of the sympathetic reflex by 44 +/- 5% without affecting the lower plateau. 4. These results support the suggestion that AII can act at the level of the RVLM pressor area to facilitate baroreflex control of renal sympathetic activity in a similar fashion to that produced by fourth ventricular administration. 5. Thus the RVLM is a likely candidate site for modulation of the renal sympathetic baroreflex. The similarity of the actions of AII to those of glutamate suggest that it may directly excite sympathetic vasomotor cells in this region. PMID:8100748

  8. Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: A HuGE review

    PubMed Central

    Mottl, Amy K.; Shoham, David A.; North, Kari E.

    2016-01-01

    The angiotensin II type 1