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Sample records for renin-angiotensin system activity

  1. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Suyeon [University of Tennessee, Knoxville (UTK); Soltani-Bejnood, Morvarid [University of Tennessee, Knoxville (UTK); Quignard-Boulange, Annie [Centre Biomedical des Cordeliers, Paris, France; Massiera, Florence [Centre de Biochimie, Nice, France; Teboul, Michele [Centre de Biochimie, Nice, France; Ailhaud, Gerard [Centre de Biochimie, Nice, France; Kim, Jung [University of Tennessee, Knoxville (UTK); Moustaid-Moussa, Naima [University of Tennessee, Knoxville (UTK); Voy, Brynn H [ORNL

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO), and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  2. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension

    NARCIS (Netherlands)

    van den Born, Bert-Jan H.; Koopmans, Richard P.; van Montfrans, Gert A.

    2007-01-01

    BACKGROUND: Malignant hypertension is a renin-dependent form of hypertension. However, the variations in renin-angiotensin system (RAS) activation in malignant hypertension are not completely understood. A proposed mechanism for ongoing RAS activation is the presence of microangiopathic hemolysis

  3. Severe hypoglycaemia during pregnancy in women with type 1 diabetes: possible role of renin-angiotensin system activity?

    DEFF Research Database (Denmark)

    Nielsen, L Ringholm; Pedersen-Bjergaard, U; Thorsteinsson, B

    2009-01-01

    AIMS: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin-angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). METHODS: Severe hypoglycaemic events the year preceding pregnancy were recorded...... retrospectively in 107 consecutive pregnant women with T1DM. Events during pregnancy were recorded prospectively. Measurements of ACE, renin and angiotensinogen were determined at 8, 14, 21, 27 and 33 weeks and postpartum. RESULTS: The rate of severe hypoglycaemia was 1.1 and 5.3 events/patient-year the year...... preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7-11.9), p=0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. CONCLUSIONS: In early...

  4. Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U.; Dhamrait, S.S.; Sethi, A.A.

    2008-01-01

    BACKGROUND: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system...... are similarly associated. METHODS: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma...... associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation Udgivelsesdato: 2008/3...

  5. The Renal Renin-Angiotensin System

    Science.gov (United States)

    Harrison-Bernard, Lisa M.

    2009-01-01

    The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and…

  6. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs.

    Science.gov (United States)

    Lantis, A C; Ames, M K; Atkins, C E; DeFrancesco, T C; Keene, B W; Werre, S R

    2015-02-01

    Pilot studies in our laboratory revealed that furosemide-induced renin-angiotensin-aldosterone system (RAAS) activation was not attenuated by the subsequent co-administration of benazepril. This study was designed to evaluate the effect of benazepril on angiotensin-converting enzyme (ACE) activity and furosemide-induced circulating RAAS activation. Our hypothesis was that benazepril suppression of ACE activity would not suppress furosemide-induced circulating RAAS activation, indicated by urinary aldosterone concentration. Ten healthy hound dogs were used in this study. The effect of furosemide (2 mg/kg p.o., q12h; Group F; n = 5) and furosemide plus benazepril (1 mg/kg p.o., q24h; Group FB; n = 5) on circulating RAAS was determined by plasma ACE activity, 4-6 h posttreatment, and urinary aldosterone to creatinine ratio (UAldo:C) on days -1, -2, 1, 3, and 7. There was a significant increase in the average UAldo:C (μg/g) after the administration of furosemide (Group F baseline [average of days -1 and -2] UAldo:C = 0.41, SD 0.15; day 1 UAldo:C = 1.1, SD 0.56; day 3 UAldo:C = 0.85, SD 0.50; day 7 UAldo:C = 1.1, SD 0.80, P Benazepril suppressed ACE activity (U/L) in Group FB (Group FB baseline ACE = 16.4, SD 4.2; day 1 ACE = 3.5, SD 1.4; day 3 ACE = 1.6, SD 1.3; day 7 ACE = 1.4, SD 1.4, P Benazepril decreased plasma ACE activity but did not prevent furosemide-induced RAAS activation, indicating aldosterone breakthrough (escape). This is particularly noteworthy in that breakthrough is observed at the time of initiation of RAAS suppression, as opposed to developing after months of therapy. © 2014 John Wiley & Sons Ltd.

  7. Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

    Science.gov (United States)

    van Twist, Daan J L; Houben, Alphons J H M; de Haan, Michiel W; de Leeuw, Peter W; Kroon, Abraham A

    2016-06-01

    Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

  8. Intramuscular renin-angiotensin system is activated in human muscular dystrophy.

    Science.gov (United States)

    Sun, Guilian; Haginoya, Kazuhiro; Dai, Hongmei; Chiba, Yoko; Uematsu, Mitsugu; Hino-Fukuyo, Naomi; Onuma, Akira; Iinuma, Kazuie; Tsuchiya, Shigeru

    2009-05-15

    To investigate the role of the muscular renin-angiotensin system (RAS) in human muscular dystrophy, we used immunohistochemistry and Western blotting to examine the cellular localization of angiotensin-converting enzyme (ACE), the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor (AT2) in muscle biopsies from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD). In normal muscle, ACE was expressed in vascular endothelial cells and neuromuscular junctions (NMJs), whereas AT1 was immunolocalized to the smooth muscle cells of blood vessels and intramuscular nerve twigs. AT2 was immunolocalized in the smooth muscle cells of blood vessels. These findings suggest that the RAS has a functional role in peripheral nerves and NMJs. ACE and AT1, but AT2 immunoreactivity were increased markedly in dystrophic muscle as compared to controls. ACE and the AT1 were strongly expressed in the cytoplasm and nuclei of regenerating muscle fibers, fibroblasts, and in macrophages infiltrating necrotic fibers. Double immunolabeling revealed that activated fibroblasts in the endomysium and perimysium of DMD and CMD muscle were positive for ACE and AT1. Triple immunolabeling demonstrated that transforming growth factor-beta1 (TGF-beta1) and ACE were colocalized on the cytoplasm of activated fibroblasts in dystrophic muscle. Furthermore, Western blotting showed increases in the expression of AT1 and TGF-beta1 protein in dystrophic muscle, which coincided with our immunohistochemical results. The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1. The activation of AT1 may induce fibrous tissue formation through overexpression of TGF-beta1, which potently activates fibrogenesis and suppresses regeneration. In conclusion, our results imply that the intramuscular RAS-TGF-beta1 pathway

  9. Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation

    Science.gov (United States)

    Koide, M.; Carabello, B. A.; Conrad, C. C.; Buckley, J. M.; DeFreyte, G.; Barnes, M.; Tomanek, R. J.; Wei, C. C.; Dell'Italia, L. J.; Cooper, G. 4th; hide

    1999-01-01

    Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the

  10. Differences in cortical and pituitary activity in response to hypoglycaemia and cognitive testing in healthy men with different basal activity of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Bie-Olsen, Lise G; Pedersen-Bjergaard, Ulrik; Kjaer, Troels W

    2010-01-01

    INTRODUCTION: High renin-angiotensin system (RAS) activity has been associated with a high risk of severe hypoglycaemia in patients with type 1 diabetes and with cognitive deterioration during experimental hypoglycaemia in healthy subjects. The aim of this study was to describe possible differenc...

  11. Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Høi-Hansen, Thomas; Pedersen-Bjergaard, Ulrik; Andersen, Rikke Due

    2009-01-01

    INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patient...

  12. The Protective Arm of the Renin Angiotensin System (RAS)

    DEFF Research Database (Denmark)

    understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor......The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...

  13. Interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

    Science.gov (United States)

    Yang, Ke-Ke; Sui, Yi; Zhou, Hui-Rong; Zhao, Hai-Lu

    2017-05-01

    Renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin-angiotensin system and adenosine monophosphate-activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate-activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate-activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate-activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate-activated protein kinase signaling pathway resulted in hyperlipidemia and

  14. The renin-angiotensin system and aging in the kidney

    OpenAIRE

    Yoon, Hye Eun; Choi, Bum Soon

    2014-01-01

    Aging is associated with progressive functional deterioration and structural changes in the kidney. Changes in the activity or responsiveness of the renin-angiotensin system (RAS) occur with aging. RAS changes predispose the elderly to various fluid and electrolyte imbalances as well as acute kidney injury and chronic kidney disease. Among the multiple pathways involved in renal aging, the RAS plays a central role. This review summarizes the association of the RAS with structural and function...

  15. Renin-Angiotensin System in Diabetes.

    Science.gov (United States)

    Rein, Johannes; Bader, Michael

    2017-11-17

    The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Boomsma, Frans

    2009-01-01

    hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF...... in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover...... study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased...

  17. Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

    2017-09-01

    A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

  18. A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats.

    Science.gov (United States)

    Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro; Wilcox, Christopher S

    2016-01-01

    The mechanism of activation of local renal renin-angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 μg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen.

  19. Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves

    Directory of Open Access Journals (Sweden)

    Divya Bhadoo

    2015-01-01

    Full Text Available Aims: Study on prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. Materials and Methods: Antenatally diagnosed hydronephrosis patients were included. Postnatally, they were divided into two groups, posterior urethral valve (PUV and non-PUV. The studied parameters were: Gestational age at detection, surgical intervention, ultrasound findings, cord blood and follow up plasma renin activity (PRA values, vesico-ureteric reflux (VUR, renal scars, and glomerular filtration rate (GFR. Results: A total of 25 patients were included, 10 PUV and 15 non-PUV. All infants with PUV underwent primary valve incision. GFR was less than 60 ml/min/1.73 m 2 body surface area in 4 patients at last follow-up. Keyhole sign, oligoamnios, absent bladder cycling, and cortical cysts were not consistent findings on antenatal ultrasound in PUV. Cord blood PRA was significantly higher (P < 0.0001 in PUV compared to non-PUV patients. Gestational age at detection of hydronephrosis, cortical cysts, bladder wall thickness, and amniotic fluid index were not significantly correlated with GFR while PRA could differentiate between poor and better prognosis cases with PUV. Conclusions: Ultrasound was neither uniformly useful in diagnosing PUV antenatally, nor differentiating it from cases with non-PUV hydronephrosis. In congenital hydronephrosis, cord blood PRA was significantly higher in cases with PUV compared to non-PUV cases and fell significantly after valve ablation. Cord blood PRA could distinguish between poor and better prognosis cases with PUV.

  20. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system.

    Science.gov (United States)

    Timmermans, Silke; Bogie, Jeroen F J; Vanmierlo, Tim; Lütjohann, Dieter; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J A

    2014-03-01

    Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.

  1. The renin-angiotensin system in kidney development

    DEFF Research Database (Denmark)

    Jensen, B L; Stubbe, J; Madsen, K

    2004-01-01

    Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the develo......Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data...... on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay...... glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture...

  2. [Renin-angiotensin-aldosterone system activity during head-up tilt testing in patients with vasovagal syncope].

    Science.gov (United States)

    Gajek, Jacek; Zyśko, Dorota; Mazurek, Walentyna

    2005-08-01

    The stimulation of renin-angiotensin-aldosterone (RAA) system during tilt table test is caused by sympathetic nervous system activation by orthostatic stress and a serotonin release as well. In healthy individuals increase of plasma renin activity during test with maximal values on the peak of the test was described. The aim of the study was to assess the activation of RAAS in patients with neurally mediated syncope during the tilt table test by means of plasma renin activity and serum aldosterone levels. The study was carried out in 31 patients aged 39.4 +/- 15.0 years (18 women and 13 men) with neurally mediated syncope during tilt test. Plasma renin activity was assessed in the baseline conditions, immediately after the test and 10 minutes after the test using radioenzymatic assay. Aldosterone concentrations were measured radioimmunologically, twice: after 30 minutes supine rest and after the syncope. Plasma renin activity during supine rest was 2.2 +/- 2.4 ng/ml/h, rose after the syncope 2.5-fold to 5.2 +/- 4.5 ng/ml/h (p < 0.001 comparing to baseline) stayed on similar level approximately for the next 10 minutes--4.9 +/- 5.5 ng/ml/h (p = n.s.). In 11 patients (35%) 10 minutes after the test even further increase of PRA was observed. Serum aldosterone level increased significantly immediately after tilt test (90.0 +/- 72.9 vs 178.8 +/- 150.1 pg/ml, p < 0.01). Authors showed, that in patients with NMS plasma renin activity increases and this increase lasts for 10 minutes after the syncope and the concentration of aldosterone increases immediately after tilt test.

  3. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

    Directory of Open Access Journals (Sweden)

    Dimitar Divchev

    2008-06-01

    Full Text Available Dimitar Divchev, Bernhard SchiefferDepartment of Cardiology and Angiology, Medizinische Hochschule Hannover, GermanyAbstract: Inflammation, lipid peroxidation and chronic activation of the renin–angiotensin system (RAS are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A2 (sPLA2-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by proinflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA2-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL. Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA2-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA2 decrease angiotensin (Ang II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA2-IIA in these processes and offering a possible target for treatment. The role of sPLA2-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipidperoxidation.Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis

  4. Living alone and activation of the renin-angiotensin-aldosterone-system: Differential effects depending on alexithymic personality features.

    Science.gov (United States)

    Terock, Jan; Hannemann, Anke; Janowitz, Deborah; Völzke, Henry; Nauck, Matthias; Freyberger, Harald-Jürgen; Wallaschofski, Henri; Grabe, Hans Jörgen

    2017-05-01

    Living alone is considered as a chronic stress factor predicting different health conditions and particularly cardiovascular disease (CVD). Alexithymia is associated with increased psychological distress, less social skills and fewer close relationships, making alexithymic subjects particularly susceptible to chronic stress imposed by "living alone". Only few studies investigated the renin-angiotensin-aldosterone-system (RAAS) activity in response to chronic stress. We aimed at evaluating the effects of "living alone" as a paradigm for chronic stress on RAAS activity and putatively differential effects depending on alexithymic personality features. Alexithymia and serum concentrations of renin and aldosterone were measured in 944 subjects from the population-based SHIP-1 study. Subgroups were formed using the median of the Toronto Alexithymia Scale-20 (TAS-20) and a cohabitation status of "living alone" or "living together". Analyses were adjusted for various psychosocial, behavioral and metabolic risk factors. "Living alone" was associated with elevated plasma renin (p<0.01, β=0.138) but not aldosterone concentrations in the total sample. On subgroup level, we found associations of "living alone" and elevated renin concentrations only in subjects low in TAS-20 scores (p<0.01, β=0.219). Interactional effects of alexithymia×cohabitation status were found for the aldosterone-to-renin ratio (p=0.02, β=-0.234). The association of chronic stress imposed by "living alone" with increased RAAS activity contributes to explain the relationship of this psychosocial stress condition and increased risk for CVD. In contrast, alexithymic subjects may be less affected by the deleterious effects of "living alone". Copyright © 2017 Elsevier Inc. All rights reserved.

  5. The influence of a tilt training programme on the renin-angiotensin-aldosterone system activity in patients with vasovagal syncope.

    Science.gov (United States)

    Gajek, Jacek; Zyśko, Dorota; Krzemińska, Sylwia; Mazurek, Walentyna

    2009-08-01

    We assessed the influence of short-term and long-term tilt training on the activity of the renin-angiotensin-aldosterone system (RAAS) in vasovagal patients. Thirty-nine patients (28 F, 11 M) aged 39.7 +/- 11.2 years with a history of vasovagal syncope and a positive head-up tilt test (HUT) were studied. Blood samples for plasma renin activity (PRA) and aldosterone (ALDO) concentration were drawn at the baseline, immediately after HUT and 10 min after HUT, during the diagnostic, the negative short-term (2-5 days) follow-up HUT and long-term (1-3 months) follow-up HUT. Tilt training was started after diagnostic HUT. In diagnostic HUT, PRA increased significantly immediately after HUT comparing to the baseline, during recovery the values did not change. ALDO concentration increased after HUT comparing to baseline and further increased during recovery. After short-term tilt training, PRA and ALDO concentrations did not significantly change compared to their corresponding values in diagnostic HUT. After long-term tilt training, PRA did not significantly change compared to the values in the diagnostic and short-term follow-up HUT. ALDO concentration also did not change significantly at the baseline and immediately after HUT, and 10 min after HUT ALDO concentration was significantly lower than after diagnostic HUT. Tilt training changes the response of RAAS to the prolonged orthostasis in vasovagal patients. The coupling between PRA and ALDO after diagnostic HUT has been found to be altered and the physiological relationship was restored after long-term tilt training. The beneficial effect of tilt training depends partially on changed RAAS activation.

  6. Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

    Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

  7. The renin-angiotensin system and its blockers

    Directory of Open Access Journals (Sweden)

    Igić Rajko

    2014-01-01

    Full Text Available Research on the renin-angiotensin system (RAS has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

  8. Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

    Science.gov (United States)

    McMullan, Ciaran J; Borgi, Lea; Fisher, Naomi; Curhan, Gary; Forman, John

    2017-05-08

    Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m 2 ) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group ( P =0.83), -4 (-16 to 9) in the allopurinol group ( P =0.32), and 1 (-21 to 17) in the placebo group ( P =0.96), with no significant treatment effect ( P =0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid ( P =0.43), -0.4±6.1 with allopurinol ( P =0.76), and 0.5±6.0 with placebo ( P =0.65); there was no significant treatment effect ( P =0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney

  9. The renin-angiotensin system and aging in the kidney.

    Science.gov (United States)

    Yoon, Hye Eun; Choi, Bum Soon

    2014-05-01

    Aging is associated with progressive functional deterioration and structural changes in the kidney. Changes in the activity or responsiveness of the renin-angiotensin system (RAS) occur with aging. RAS changes predispose the elderly to various fluid and electrolyte imbalances as well as acute kidney injury and chronic kidney disease. Among the multiple pathways involved in renal aging, the RAS plays a central role. This review summarizes the association of the RAS with structural and functional changes in the aging kidney and age-related renal injury, and describes the underlying mechanisms of RAS-related renal aging. An improved understanding of the renal aging process may lead to better individualized care of the elderly and improved renal survival in age-related diseases.

  10. Free Fatty Acids Activate Renin-Angiotensin System in 3T3-L1 Adipocytes through Nuclear Factor-kappa B Pathway

    Directory of Open Access Journals (Sweden)

    Jia Sun

    2016-01-01

    Full Text Available The activity of a local renin-angiotensin system (RAS in the adipose tissue is closely associated with obesity-related diseases. However, the mechanism of RAS activation in adipose tissue is still unknown. In the current study, we found that palmitic acid (PA, one kind of free fatty acid, induced the activity of RAS in 3T3-L1 adipocytes. In the presence of fetuin A (Fet A, PA upregulated the expression of angiotensinogen (AGT and angiotensin type 1 receptor (AT1R and stimulated the secretion of angiotensin II (ANG II in 3T3-L1 adipocytes. Moreover, the activation of RAS in 3T3-L1 adipocytes was blocked when we blocked Toll-like receptor 4 (TLR4 signaling pathway using TAK242 or NF-κB signaling pathway using BAY117082. Together, our results have identified critical molecular mechanisms linking PA/TLR4/NF-κB signaling pathway to the activity of the local renin-angiotensin system in adipose tissue.

  11. Differences in cortical and pituitary activity in response to hypoglycaemia and cognitive testing in healthy men with different basal activity of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Bie-Olsen, Lise G; Pedersen-Bjergaard, Ulrik; Kjaer, Troels W

    2010-01-01

    in cerebral activity during hypoglycaemia and cognitive testing in two groups of healthy men with different basal RAS activity. METHODS: Ten healthy men with high RAS activity and 10 with low activity underwent six oxygen-15-labelled water positron emission tomography scans: twice during normoglycaemia, twice......INTRODUCTION: High renin-angiotensin system (RAS) activity has been associated with a high risk of severe hypoglycaemia in patients with type 1 diabetes and with cognitive deterioration during experimental hypoglycaemia in healthy subjects. The aim of this study was to describe possible differences...... during insulin-induced hypoglycaemia and twice during post-hypoglycaemia. During the scans, the subjects performed a computer-based reaction time test. RESULTS: Occipital areas were consistently more activated in the low RAS group than in the high RAS group throughout all three conditions. During...

  12. Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, Rikke; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2008-01-01

    . Hypoglycaemia and hypoxaemia induced QTc prolongation (P VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0...

  13. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism.

    Science.gov (United States)

    Kobori, H; Ichihara, A; Suzuki, H; Takenaka, T; Miyashita, Y; Hayashi, M; Saruta, T

    1997-08-01

    This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism.

  14. The role of renin angiotensin system in retinal inflammation

    OpenAIRE

    Zhu, Tong

    2017-01-01

    Purpose: Retinopathy of prematurity (ROP) is the main cause of vision loss and blindness in children, and is replicated and intensively studied in rodent models of oxygen-induced retinopathy (OIR). One signature feature of ROP is retinal neovascularization, which is also present in patients with proliferative diabetic retinopathy (PDR). Inflammation is another feature in ROP and PDR. In both diseases, the renin angiotensin system (RAS) is dysregulated, and blockade of RAS via angiotensin II (...

  15. Renal Kallikrein Activation and Renoprotection after Dual Blockade of Renin-Angiotensin System in Diet-Induced Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Xia Zou

    2015-01-01

    Full Text Available Purpose. The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN. Methods. Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF- β and α-smooth muscle action (SMA. Results. DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all P<0.05. Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-β, and α-SMA. Conclusion. The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response.

  16. Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy.

    Science.gov (United States)

    Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

    1999-01-01

    We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.

  17. Emerging drugs which target the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Steckelings, Ulrike Muscha; Paulis, Ludovit; Unger, Thomas; Bader, Michael

    2011-12-01

    The renin-angiotensin-aldosterone system (RAAS) is already the most important target for drugs in the cardiovascular system. However, still new developments are underway to interfere with the system on different levels. The novel strategies to interfere with RAAS aim to reduce the synthesis of the two major RAAS effector hormones, angiotensin (Ang) II and aldosterone, or interfere with their receptors, AT1 and mineralocorticoid receptor, respectively. Moreover, novel targets have been identified in RAAS, such as the (pro)renin receptor, and molecules, which counteract the classical actions of Ang II and are therefore beneficial in cardiovascular diseases. These include the AT2 receptor and the ACE2/Ang-(1-7)/Mas axis. The search for drugs activating these tissue-protective arms of RAAS is therefore the most innovative field in RAAS pharmacology. Most of the novel pharmacological strategies to inhibit the classical RAAS need to prove their superiority above the existing treatment in clinical trials and then have to compete against these now quite cheap drugs in a competitive market. The newly discovered targets have functions beyond the cardiovascular system opening up novel therapeutic areas for drugs interfering with RAAS components.

  18. Brain renin angiotensin system in cardiac hypertrophy and failure

    Directory of Open Access Journals (Sweden)

    Luciana eCampos

    2012-01-01

    Full Text Available Brain renin-angiotensin system (RAS is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. The brain RAS is involved in the modulation of circadian rhythms of arterial pressure, contributing to nondipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as angiotensin converting inhibitors or receptor blockers having increased brain penetrability could be of advantage. These RAS-targeting drugs are first-line therapy for all heart failure patients. Since the RAS has both endocrine and local tissue components, RAS drugs are being developed to attain increased tissue penetrability and volume of distribution and consequently an efficient inhibition of both RAS components.

  19. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system

    DEFF Research Database (Denmark)

    Aachmann-Andersen, Niels J.; Christensen, Soren J.; Lisbjerg, Kristian

    2018-01-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect...... of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system....

  20. Hemodynamic, morphometric and autonomic patterns in hypertensive rats - renin-angiotensin system modulation

    Directory of Open Access Journals (Sweden)

    Fernanda S. Zamo

    2010-01-01

    Full Text Available BACKGROUND: Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system. AIMS: To investigate the effects of the time-course of hypertension over 1 hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate; 2 left ventricular hypertrophy; and 3 local and systemic Renin-angiotensin system of the spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were randomized into two groups: young (n=13 and adult (n=12. Hemodynamic signals (blood pressure, heart rate, blood pressure variability (BPV and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g, by myocyte diameter (μm and by relative fibrosis area (RFA, %. ACE and ACE2 activities were measured by fluorometry (UF/min, and plasma renin activity (PRA was assessed by a radioimmunoassay (ng/mL/h. Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU. RESULTS: The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components. CONCLUSIONS: The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent

  1. The role of renin angiotensin system intervention in stage B heart failure.

    LENUS (Irish Health Repository)

    Collier, Patrick

    2012-04-01

    This article outlines the link between the renin angiotensin aldosterone system (RAAS) and various forms of cardiomyopathy, and also reviews the understanding of the effectiveness of RAAS intervention in this phase of ventricular dysfunction. The authors focus their discussion predominantly on patients who have had previous myocardial infarction or those who have left ventricular hypertrophy and also briefly discuss the role of RAAS activation and intervention in patients with alcoholic cardiomyopathy.

  2. Renin angiotensin system and gender differences in dopaminergic degeneration

    Directory of Open Access Journals (Sweden)

    Rodriguez-Perez Ana I

    2011-08-01

    Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

  3. Regulation of the renin-angiotensin-aldosterone system in fibromyalgia.

    Science.gov (United States)

    Maliszewski, Anne M; Goldenberg, Don L; Hurwitz, Shelley; Adler, Gail K

    2002-07-01

    To assess the function of the renin-angiotensin-aldosterone (RAA) system in women with fibromyalgia (FM) compared to healthy women. Women with FM [n = 14, age 41.0+/-7.2 yrs, body mass index (BMI) 26.4+/-5.4 kg/m2] and healthy women (n = 13, age 40.0+/-7.7 yrs, BMI 25.0+/-5.0 kg/m2) were placed on a low sodium diet (10 mEq sodium/day) for 5 days. After being supine and fasting overnight, subjects received an intravenous infusion of angiotensin II at successive doses of 1, 3, and 10 ng/kg/min for 45 min per dose. Blood pressure (BP), plasma renin activity (PRA), aldosterone, and cortisol were measured at baseline and after each dose of angiotensin II. Prior to sodium restriction, women with FM completed the Hopkins Symptom Checklist-90, which included a question grading the extent of dizziness/faintness on a scale of 0 (none) to 4 (extremely). After dietary sodium restriction, baseline PRA, aldosterone, and supine BP were similar in healthy women and women with FM. Aldosterone and BP rose in response to infused angiotensin II; these responses did not differ significantly between healthy women and women with FM. In women with FM, symptoms of dizziness correlated inversely with BMI (r = -0.81, p < 0.001) and the systolic BP response to 10 ng/kg/min angiotensin II (r = -0.81, p < 0.001). The functioning of the RAA system, including the vascular response to angiotensin II, was intact in women with FM compared to healthy women. However, women with FM who complained of dizziness had a blunted vascular response to angiotensin II. This blunted vascular response may indicate intravascular volume depletion in women with symptoms of dizziness.

  4. Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome

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    V Raghunathan

    2017-01-01

    Full Text Available Hypertension is common in hemolytic uremic syndrome (HUS and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency.

  5. Radioimmunologic analysis of the state of the renin-angiotensin-aldosterone-system in arterial hypertension

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Gandzha, T.I.; Yugrinov, O.G.

    1985-01-01

    In 110 patients suffering from various forms of arterial hypertension (hypertension, aldosteronoma, phaeochromocytoma, corticosteroma) the parameters of the system renin-angiotensin-aldosterone were measured. Basal values of aldosterone, renin activity in blood as well as their concentration in blood taken from the vena cava inferior, renal and adrenal veins during selective renography were determined. The 24-hours rhythm of the hormones in the blood, the reaction of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under acute Lasix (furosemide) stress was evaluated. It was found, that the system renin-angiotensin-aldosterone is disturbed in all patients with arterial hypertension. This is indicated by changes of aldosterone concentration, renin activity in peripheral blood and in the blood from the vena cava inferior, renal and adrenal veins, the 24-hours rhythm of their concentrations in serum and the reaction to acute Lasix stress. The radioimmunoassays of quantitative parameters of the renin-angiotensin-aldosterone system are decisive for the differential diagnosis of hypertension and adrenal gland tumors connected with a hypertension syndrome. They facilitate a rational choice of the hypertension therapy and the daily distribution of the medicaments for patients with hypertension. The radioimmunoassays can be used for checking the efficiency of medicaments and surgery. (author)

  6. Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Dobešová, Zdenka; Behuliak, Michal; Pintérová, Mária; Kuneš, Jaroslav; Vaněčková, Ivana

    2014-01-01

    Roč. 63, č. 1 (2014), s. 13-26 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510; GA ČR(CZ) GA305/09/0336; GA ČR(CZ) GAP304/12/0259 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : voltage-gated caclium channels * sympathetic nervous system * renin-angiotensin system * nitric oxide Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.293, year: 2014

  7. Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

    this thesis was conducted to assess the significance of severe hypoglycaemia as a clinical problem in the type 1 diabetic population, to evaluate the impact of known risk factors on occurrence of severe hypoglycaemia, and to identify new markers that could contribute to improved prediction of, and inspire...... targets and thereby open for prevention of severe hypoglycaemia. Furthermore, subjects with elevated renin-angiotensin system activity and a high rate of severe hypoglycaemia might benefit from pharmacological blockade of the renin-angiotensin system by ACE inhibitors or angiotensin II receptor blockers...

  8. Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood.

    Science.gov (United States)

    Senko, Tomáš; Svitok, Pavel; Kršková, Lucia

    2017-10-01

    The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 μg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.

  9. Local Bone Marrow Renin-Angiotensin System and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Yavuz Beyazit

    2011-01-01

    Full Text Available Local hematopoietic bone marrow (BM renin-angiotensin system (RAS affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II, the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R, has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis.

  10. Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure.

    Science.gov (United States)

    Wei, Shun-Guang; Yu, Yang; Weiss, Robert M; Felder, Robert B

    2016-10-01

    We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

  11. Effects of dual renin-angiotensin system blockade on proteinuria in a ...

    African Journals Online (AJOL)

    Kidney diseases manifesting as proteinuria or elevated creatinine are increasingly prevalent complications of HIV infection. We report the effects of dual renin-angiotensin system blockade on proteinuria in a hypertensive black African HIV-infected patient.

  12. The importance of the renin-angiotensin system in normal cardiovascular homeostasis

    Science.gov (United States)

    Haber, E.

    1975-01-01

    Studies were carried out on adult mongrel dogs (20 to 30 kilograms) to investigate the importance of the renin-angiotensin system. Results indicate that the renin-angiotensin system plays a major role in the maintenance of circulatory homeostasis when extracellular fluid volume is depleted. It was also found that angiotensin II concentration, in addition to renal perfusion pressure, is a factor in the regulation of renin release.

  13. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis

    DEFF Research Database (Denmark)

    Schneider, Markus; Hua, Tsushung A; Böhm, Michael

    2010-01-01

    The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective.......The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective....

  14. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

    Science.gov (United States)

    Ishigaki, Sayaka; Ohashi, Naro; Isobe, Shinsuke; Tsuji, Naoko; Iwakura, Takamasa; Ono, Masafumi; Sakao, Yukitoshi; Tsuji, Takayuki; Kato, Akihiko; Miyajima, Hiroaki; Yasuda, Hideo

    2016-12-01

    Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = -0.31, p = 0.044) and U-Alb (β = -0.25, p = 0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

  15. Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs.

    Science.gov (United States)

    Ames, Marisa K; Atkins, Clarke E; Lee, Seunggon; Lantis, Andrea C; zumBrunnen, James R

    2015-12-01

    To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). 6 healthy Beagles. 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7. High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.

  16. Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin-angiotensin system in acute myocardial infracted dogs.

    Science.gov (United States)

    Feng, Qiaoli; Lu, Chengzhi; Wang, Li; Song, Lijun; Li, Chao; Uppada, Ravi Chandra

    2017-02-17

    This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded. Additionally, haemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured. Cardiac oxidative stress levels were evaluated based on the expression of p47 phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD). To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang(1-7)] and Mas receptor (MasR) in myocardial tissues were recorded. The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively. We found that MI deteriorated heart function and activated cardiac oxidative stress and the local neurohumoral system, while RDN partially reversed these changes. Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47 phox ,ACE2, Ang(1-7), MasR, AngII and TH-positive nerves were increased (all P < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all P < 0.05). However, after RDN therapy, these changes were significantly improved (P < 0.05), except that there were no significant differences observed in FS or LVSP between the two groups (P = 0

  17. RENIN ANGIOTENSIN SYSTEM GENE POLYMORPHISMS IN CHILDREN WITH NEPHROTIC SYNDROM

    Directory of Open Access Journals (Sweden)

    Zh.P. Sharnova

    2006-01-01

    Full Text Available To investigate the role of the reninangiotensin system genes polymorphisms in develop and progression of nephrotic syndrom (NS in children we determined the genotypes of angiotensin converting enzyme (ACE, angiotensinogen (AGT and angiotensin ii receptor (ATII-R of 1 type in 80 russian children with ns including and 15 children with chronic renal failure (CRF. Genotype frequencies did not differ between patients with ns and controls (n = 165. The distribution of ace, AGT and ATII-R 1 type genotypes was similar among ns sub groups, such as focal segmental glomerulosclerosis (FSGS (n = 18, steroid-sensitive nephrotic syndrome (n = 32, nephrotic syndrome with hypertension and hemoturia (n = 22 and with control group. When ns subjects with CRF (n = 15 were compared with control, the prevalence of ace DD genotype was significantly higher (47% VS 21%; χ2 = 4,44; p < 0,05. Our results indicate that the DD genotype ace may be a factor of risk for the dеvеlopment of progressive renal impairment in the children with nephrotic syndrome. The analysis of treatment's effect with inhibitor of ace in groups patients with steroid resistant NS (SRNS demonstrated decreasing of renoprotective effect of this drugs in patients with id and dd genotypes com? Pared with ii genotype: the degree of blood pressure, proteinuria and the rate of glomerular filtration decrease was significantly lower (55,46 ± 9,25 VS 92,74 ± 25; р < 0,05 in these patients.Key words: nephrotic syndrom, chronic renal failure, polymorphism of genes, renin-angiotensin system.

  18. Some Aspects of the Renin-Angiotensin-System in Hemodialysis Patients

    Directory of Open Access Journals (Sweden)

    Umar Malik

    2015-11-01

    Full Text Available Understanding of the renin-angiotensin system (RAS has changed remarkably over the past decade. Renin, angiotensin converting enzyme (ACE, angiotensin II (Ang II, and Ang II receptors are the main components of the RAS. Recent studies identified the ACE2/Ang 1-7/Mas receptor axis, which counter-regulates the classical RAS. Many studies have examined the effects of the RAS on the progression of cardiovascular disease and chronic kidney disease (CKD. In addition, many studies have documented increased levels of ACE in hemodialysis (HD patients, raising concerns about the negative effects of RAS activation on the progression of renal disease. Elevated ACE increases the level of Ang II, leading to vasoconstriction and cell proliferation. Ang II stimulation of the sympathetic system leads to renal and cardiovascular complications that are secondary to uncontrolled hypertension. This review provides an overview of the RAS, evaluates new research on the role of ACE2 in dialysis, and reviews the evidence for potentially better treatments for patients undergoing HD. Further understanding of the role of ACE and ACE2 in HD patients may aid the development of targeted therapies that slow the progression of CKD and cardiovascular disease.

  19. A Study on Renin-Angiotensin System and Total Exchangeable Sodium in Hypertension

    International Nuclear Information System (INIS)

    Choe, Kang Won; Park, Jung Sik; Lee, Jung Sang; Koh, Chang Soon

    1976-01-01

    The etiologic role of renin-angiotensin system and sodium-volume status in the pathophysiology of various forms of hypertension was investigated. Plasma renin activity (PRA) was measured by radioimmunoassay, while sodium-volume status was evaluated by the determination of total exchangeable sodium(NaE) using isotope dilution method. The subjects consisted of 25 controls, 24 patients with essential hypertension, 22 patients with chronic renal failure (13 with hypertension, 9 without hypertension) and 14 patients with malignant hypertension. The results were as follows: 1) An inverse correlation between NaE and PRA was noted in control subjects (r=-0.598, p 0.1) 3) Absolute value of PRA was not deviated significantly from control group (2.53±1.416 ng/ml/hr) except in malignant hypertension (6.09±2.042, p 0.1). It is suggested that renin-angiotensin system plays a predominant role in the pathogenesis of malignant hypertension and in hypertension of chronic renal failure, though sodium retention is also contributing factor. PRA variation in essential hypertension does not appear to be associated with any consistent change in Na-volume status, suggesting the existence of another mechanism in the genesis of hypertension and PRA variation.

  20. The Relevance of the Renin-Angiotensin System in the Development of Drugs to Combat Preeclampsia

    Directory of Open Access Journals (Sweden)

    Norikazu Ueki

    2015-01-01

    Full Text Available Preeclampsia is a hypertensive disorder that occurs during pregnancy. It has an unknown etiology and affects approximately 5–8% of pregnancies worldwide. The pathophysiology of preeclampsia is not yet known, and preeclampsia has been called “a disease of theories.” The central symptom of preeclampsia is hypertension. However, the etiology of the hypertension is unknown. In this review, we analyze the molecular mechanisms of preeclampsia with a particular focus on the pathogenesis of the hypertension in preeclampsia and its association with the renin-angiotensin system. In addition, we propose potential alternative strategies to target the renin-angiotensin system, which is enhanced during pregnancy.

  1. NT-pro-BNP during hypoglycemia and hypoxemia in normal subjects: impact of renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, R; Pedersen-Bjergaard, U; Høi-Hansen, T

    2008-01-01

    subjects with high-RAS activity and 10 subjects with low-RAS activity (age 26 +/- 1 yr; mean +/- SE) were studied in a single-blinded, randomized, counterbalanced, crossover study on three occasions separated by at least 3 wk: 1) hypoglycemia (mean nadir plasma glucose 2.7 +/- 0.5 mmol/l), 2) hypoxemia...

  2. Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2009-01-01

    diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion. RESULTS: Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response...... was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia...

  3. Structural adaptation to ischemia in skeletal muscle: effects of blockers of the renin-angiotensin system

    NARCIS (Netherlands)

    Scheidegger, K. J.; Nelissen-Vrancken, M. H.; Leenders, P. J.; Daemen, M. J.; Smits, J. F.; Wood, J. M.

    1997-01-01

    To investigate the effects of long-term treatment with blockers of the renin-angiotensin system on capillarization and growth of fibers in ischemic hind-limb muscles and in muscles under normal growth conditions. Ischemia was induced by partial ligation of the left common iliac artery. Ischemia

  4. Renoprotection by blockade of the renin-angiotensin-aldosterone system in diabetic and non-diabetic chronic kidney disease. Specific involvement of intra-renal angiotensin-converting enzyme activity in therapy resistance?

    NARCIS (Netherlands)

    Vogt, L.; Kocks, M. J. A.; Laverman, G. D.; Navis, G.

    2004-01-01

    Data of numerous clinical trials show that lowering of blood pressure is prerequisite for reducing the rate of renal function loss in chronic renal disease. There is evidence supporting that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an

  5. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    Science.gov (United States)

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  6. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Aachmann-Andersen, Niels J; Christensen, Soren J; Lisbjerg, Kristian; Oturai, Peter; Johansson, Pär I; Holstein-Rathlou, Niels-Henrik; Olsen, Niels V

    2018-03-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  7. Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels

    NARCIS (Netherlands)

    Asselbergs, Folkert W.; Williams, Scott M.; Hebert, Patricia R.; Coffey, Christopher S.; Hillege, Hans L.; Navis, Gerjan; Vaughan, Douglas E.; van Gilst, Wiek H.; Moore, Jason H.

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II

  8. Anthology of the renin-angiotensin system: a one hundred reference approach to angiotensin II antagonists.

    Science.gov (United States)

    Ménard, J

    1993-04-01

    To provide a historical overview of the renin-angiotensin system as a guide to the introduction of a new therapeutic pathway, non-peptide inhibition of a angiotensin II. One hundred references were selected as a personal preference, for their originality or for their potential impact on medicine. This review raises the following questions for future research. (1) Will the long-term cardiovascular effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II antagonism and renin inhibition be similar or not, and dependent or independent of blood pressure levels? (2) What are the local-regional interactions between vasoconstrictor and vasodilator systems, and does the renin-angiotensin system synchronize these regional hemodynamic regulatory mechanisms? (3) If hypertension is the result of an interaction between genetic and environmental factors, do proteins secreted through constitutive pathways contribute to the genetic abnormality (prorenin, angiotensinogen, ACE) while regulated secretion (renin) and other regulatory mechanisms (angiotensin II receptors) provide biological support for the environmental effects?

  9. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism

    OpenAIRE

    KOBORI, HIROYUKI; ICHIHARA, ATSUHIRO; SUZUKI, HIROMICHI; TAKENAKA, TSUNEO; MIYASHITA, YUTAKA; HAYASHI, MATSUHIKO; SARUTA, TAKAO

    1997-01-01

    This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was onl...

  10. The renin-angiotensin system; development and differentiation of the renal medulla

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Robdrup Tinning, Anne; Marcussen, Niels

    2013-01-01

    on mechanisms of postnatal development the renal medulla and putting medullary developmental lesions into perspective with regard to the programming effect. Moreover, the renin-angiotensin system is critically involved in mammalian kidney development and signaling disorders give rise to developmental renal...... disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given. Acta Physiologica © 2013 Scandinavian Physiological Society....... lesions that has been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional...

  11. Determinants of the renin-angiotensin-aldosterone system in cirrhosis with special emphasis on the central blood volume

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens H

    2006-01-01

    OBJECTIVE: Several studies have shown activation of the renin-angiotensin-aldosterone system (RAAS) in cirrhosis. Although the activated RAAS may have several determinants, the system is often considered a surrogate marker of effective hypovolaemia. In this study we investigated the activity...... of the RAAS and its potential determinants with special focus on the central and arterial blood volume (CBV). MATERIAL AND METHODS: Eighty-nine patients (Child class A/B/C: 19/41/29) and 32 controls were included in the study. All were given a haemodynamic examination with measurement of determinants...

  12. Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

    Science.gov (United States)

    Frantz, Eliete Dalla Corte; Medeiros, Renata Frauches; Giori, Isabele Gomes; Lima, Juliana Bittencourt Silveira; Bento-Bernardes, Thais; Gaique, Thaiane Gadioli; Fernandes-Santos, Caroline; Fernandes, Tiago; Oliveira, Edilamar Menezes; Vieira, Carla Paulo; Conte-Junior, Carlos Adam; Oliveira, Karen Jesus; Nobrega, Antonio Claudio Lucas

    2017-09-01

    What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l -1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day -1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and

  13. Radioimmunologic analysis of the state of the renin-angiotensin-aldosterone system in arterial hypertension

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Gandzha, T.I.; Yugrinov, O.G.

    1986-01-01

    For 110 patients having various forms of arterial hypertension (hypertension, aldersteronoma, phaeochromocytoma, corticosteroma) the parameters of the system renin-angiotensin-aldosterone (RAA) were measured. Basal values of aldosterone and renin activity in blood were determined as well as their concentration in blood taken from the vena cava inferior, renal and adrenal veins during selective renography. The 24-hours rhythm of the hormones in the blood, the reaction of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under acute lasix stress was evaluated. It was found, that the system RAA is disturbed in all patients with arterial hypertension. This is indicated by changes of aldosterone concentration, renin activity in peripheral blood and in the blood from the vena cava inferior, renal and adrenal veins, the 24-hour rhythm of their concentrations in serum and the reaction to acute lasix stress. The radioimmunoassays of quantitative parameters of the RAA system are decisive for the differential diagnostics of hypertension and suprarenomas connected with a hypertension syndrome. They facilitate a rational choice of the hypertension therapy and the daily distribution of the medicaments for patients with hypertension. The radioimmunoassays can be used for checking the efficiency of medicaments and surgery. (author)

  14. Sex differences in the aging pattern of renin-angiotensin system serum peptidases.

    Science.gov (United States)

    Fernández-Atucha, A; Izagirre, A; Fraile-Bermúdez, A B; Kortajarena, M; Larrinaga, G; Martinez-Lage, P; Echevarría, E; Gil, J

    2017-01-01

    Serum peptidases, such as angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (ACE2), neutral endopeptidase (NEP), aminopeptidase N (APN), and aminopeptidase A (APA), are important elements of the renin-angiotensin system (RAS). Dysregulation of these enzymes has been associated with hypertension and cardiovascular risk. In the present study, serum activities of RAS peptidases were analyzed to evaluate the existence of sexual differences, with a possible different pattern in pre- and post-andropausal/post-menopausal participants. One hundred and eighteen healthy men and women between 41 and 70 years of age (58 women and 60 men) were recruited to participate in the study. Serum RAS-regulating enzymes were measured by spectrofluorimetry. Enzymatic activity was recorded as units of enzyme per milliliter of serum (U/mL). Significantly lower serum APA activity was observed in men with respect to women; no sex differences were detected for ACE, ACE2, NEP, or APN. Significantly lower APA and ACE serum activity were observed in older men compared to older women. In contrast, younger (menopausia, on the critical serum enzymatic activities of the RAS, which could correlate with sexual differences in cardiovascular risk.

  15. Tissue Renin-Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Jeppe eSkov

    2014-02-01

    Full Text Available The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g. diabetes and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans.Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unify the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

  16. Role of the intrarenal renin-angiotensin system in the progression of renal disease.

    Science.gov (United States)

    Urushihara, Maki; Kagami, Shoji

    2017-09-01

    The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.

  17. The renin-angiotensin-aldosterone system and calcium-regulatory hormones.

    Science.gov (United States)

    Vaidya, A; Brown, J M; Williams, J S

    2015-09-01

    There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium-regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis, while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies and provide insight into the results of prior and ongoing intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

  18. Gene expression profiling following maternal deprivation: Involvement of the brain renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    Claudia Liebl

    2009-05-01

    Full Text Available The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP, where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differentially regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently up-regulated genes, angiotensinogen, was validated using in-situ hybridization. Angiotensinogen is the precursor of angiotensin II, the main effector of the brain renin-angiotensin system (RAS, which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1 antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain a nd ACTH release following maternal separation. AT(1 receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and contribute to identifying signaling cascades that control stress system activity in the neonate.

  19. The role of the renin-angiotensin-aldosterone system in heart failure

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    Thomas Unger

    2004-03-01

    Full Text Available Activity of the renin-angiotensin-aldosterone system (RAAS is increased in patients with heart failure, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodelling and sympathetic activation. Elevated renin activity has been demonstrated in patients with dilated cardiomyopathy. (Third-generation synthetic non-peptide renin inhibitors, with more favourable properties than earlier renin inhibitors, lower ambulatory blood pressure and may have a role to play in other cardiovascular disease. Chymase, a protease inhibitor stored in mast cells that generates angiotensin II (Ang II (in addition to angiotensin-converting enzyme [ACE], has been linked to extracellular matrix remodelling in heart failure. Again, chymase inhibitors have been developed to investigate its functions in vitro and in vivo. Bradykinin is thought to contribute to the cardioprotective effect of ACE inhibition through modification of nitric oxide release, calcium handling and collagen accumulation. Ang II is believed to influence a number of molecular and structural changes in the heart, mostly mediated through the AT1-receptor. The importance of the RAAS in heart failure is shown by the survival benefit conferred by treatment with ACE inhibitors.

  20. The role of local renin-angiotensin system in arterial chemoreceptors in sleep-breathing disorders

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    Man Lung eFung

    2014-09-01

    Full Text Available The renin-angiotensin system (RAS plays pivotal roles in the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Experimental studies have demonstrated a locally expressed RAS in the carotid body, which is functional significant in the effect of angiotensin peptides on the regulation of the activity of peripheral chemoreceptors and the chemoreflex. The physiological and pathophysiological implications of the RAS in the carotid body have been proposed upon recent studies showing a significant upregulation of the RAS expression under hypoxic conditions relevant to altitude acclimation and sleep apnea and also in animal model of heart failure. Specifically, the increased expression of angiotensinogen, angiotensin-converting enzyme and angiotensin AT1 receptors plays significant roles in the augmented carotid chemoreceptor activity and inflammation of the carotid body. This review aims to summarize these results with highlights on the pathophysiological function of the RAS under hypoxic conditions. It is concluded that the maladaptive changes of the RAS in the carotid body plays a pathogenic role in sleep apnea and heart failure, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.

  1. Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System.

    Science.gov (United States)

    Weidemann, Benjamin J; Voong, Susan; Morales-Santiago, Fabiola I; Kahn, Michael Z; Ni, Jonathan; Littlejohn, Nicole K; Claflin, Kristin E; Burnett, Colin M L; Pearson, Nicole A; Lutter, Michael L; Grobe, Justin L

    2015-06-11

    Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.

  2. Oxidative Stress/Angiotensinogen/Renin-Angiotensin System Axis in Patients with Diabetic Nephropathy

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    Masumi Kamiyama

    2013-11-01

    Full Text Available Although recent studies have proven that renin-angiotensin system (RAS blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS are important for intrarenal angiotensinogen (AGT augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II, 4-hydroxy-2-nonenal (4-HNE, and heme oxygenase-1 (HO-1 were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy.

  3. Methylation of Promoter Regions of Genes of the Human Intrauterine Renin Angiotensin System and Their Expression

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    Shane D. Sykes

    2015-01-01

    Full Text Available The intrauterine renin angiotensin system (RAS is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2, angiotensin converting enzyme (ACE, angiotensin II type 1 receptor (AGTR1, and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues.

  4. High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

    Science.gov (United States)

    Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

    2013-07-01

    Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

  5. Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

    Hypoglycaemia is an unavoidable side effect to insulin therapy of diabetes. In daily life some hypoglycaemic episodes are recognised by the patients and corrected by ingestion of glucose, but occasionally unrecognised episodes progress into severe hypoglycaemia with cognitive impairment and the n......Hypoglycaemia is an unavoidable side effect to insulin therapy of diabetes. In daily life some hypoglycaemic episodes are recognised by the patients and corrected by ingestion of glucose, but occasionally unrecognised episodes progress into severe hypoglycaemia with cognitive impairment...... both subjects at low and at high risk within a one-year period were identified. Preliminary data suggest that this is explained by impaired capability of subjects with high renin-angiotensin system activity to maintain cognitive function during hypoglycaemia. The clinical implications of this finding...... which, however, must await additional independent confirmation, include prediction and possibly some prevention of severe hypoglycaemia. An evaluation of renin-angiotensin system activity may - together with assessment of other risk factors - contribute to rational individualized setting of glycaemic...

  6. Role of Renin-Angiotensin System and Oxidative Stress on Vascular Inflammation in Insulin Resistence Model

    OpenAIRE

    Renna, N. F.; Lembo, C.; Diez, E.; Miatello, R. M.

    2013-01-01

    (1) is study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10−3 mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systo...

  7. Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

    DEFF Research Database (Denmark)

    Gribouval, Olivier; Morinière, Vincent; Pawtowski, Audrey

    2012-01-01

    , pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review...... the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS...

  8. Renin-angiotensin system antagonists, glomerular filtration rate and blood pressure

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    D.D. Ivanov

    2018-02-01

    Full Text Available The article deals with the mModern data on the influence of renin-angiotensin system blockers on the glomerular filtration rate, the level of arterial pressure and the outcome of chronic kidney disease. The strategy of  rennin-angiotensine blockade is offered to be changed depending on the criteria va­lues of glomerular filtration rate: a combination of inhibitors of angiotensin-converting enzyme + angiotensin receptors blo­ckers, monotherapy and drug withdrawal in glomerular filtration rate under 15–30 ml/min/m2. The formula BRIMONEL for treatment of chronic kidney disease is given.

  9. Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction

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    Smita I. Negi

    2015-01-01

    Full Text Available Animal models have suggested a role of renin-angiotensin system (RAS activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF. Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs, F2-isoprostanes (IsoPs, and ratios of oxidized to reduced glutathione (Eh GSH and cysteine (Eh CyS were measured. Angiotensin converting enzyme (ACE levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p=0.04, higher body mass index (BMI (p=0.003, less oxidized Eh CyS (p=0.001, lower DROMs (p=0.02, and lower IsoP (p=0.03. Higher BMI (OR: 1.3; 95% CI: 1.1–1.6 and less oxidized Eh CyS (OR: 1.2; 95% CI: 1.1–1.4 maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05, ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.

  10. Modulation of the cardiac sodium/bicarbonate cotransporter by the renin angiotensin aldosterone system: pathophysiological consequences.

    Science.gov (United States)

    De Giusti, Verónica C; Ciancio, María C; Orlowski, Alejandro; Aiello, Ernesto A

    2013-01-01

    The sodium/bicarbonate cotransporter (NBC) is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na(+) per 1 molecule of HCO(-) 3 (electroneutral isoform; NBCn1) and the other one that generates the co-influx of 1 molecule of Na(+) per 2 molecules of HCO(-) 3 (electrogenic isoform; NBCe1). Both isoforms are important to maintain intracellular pH (pH i ) and sodium concentration ([Na(+)] i ). In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD). The renin-angiotensin-aldosterone system (RAAS) is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II) exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pH i and [Na(+)] i , which indirectly, due to the stimulation of reverse mode of the Na(+)/Ca(2+) exchanger (NCX), conduces to an increase in the intracellular Ca(2+) concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pH i and [Na(+)] i , which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.

  11. Circadian rhythm of blood pressure and the renin-angiotensin system in the kidney.

    Science.gov (United States)

    Ohashi, Naro; Isobe, Shinsuke; Ishigaki, Sayaka; Yasuda, Hideo

    2017-05-01

    Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

  12. MODULATION OF THE CARDIAC SODIUM/BICARBONATE COTRANSPORTER BY THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM: PATHOPHYSIOLOGICAL CONSEQUENCES.

    Directory of Open Access Journals (Sweden)

    Verónica Celeste De Giusti

    2014-01-01

    Full Text Available The sodium/bicarbonate cotransporter (NBC is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na+ per 1 molecule of HCO3- (electroneutral isoform; NBCn1 and the other one that generates the co-influx of 1 molecule of Na+ per 2 molecules of HCO3- (electrogenic isoform; NBCe1. Both isoforms are important to maintain intracellular pH (pHi and sodium concentration ([Na+]i. In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD. The renin-angiotensin-aldosterone system (RAAS is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pHi and [Na+]i, which indirectly, due to the stimulation of reverse mode of the Na+/Ca2+ exchanger (NCX, conduces to an increase in the intracellular Ca2+ concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pHi and [Na+]i, which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.

  13. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

    Science.gov (United States)

    Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

    2017-12-27

    The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. [The changes in renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome].

    Science.gov (United States)

    Cui, Jia; Dou, Jingtao; Yang, Guoqing; Zang, Li; Jin, Nan; Chen, Kang; Du, Jin; Gu, Weijun; Wang, Xianling; Yang, Lijuan; Lyu, Zhaohui; Ba, Jianming; Mu, Yiming; Lu, Juming; Li, Jiangyuan; Pan, Changyu

    2015-07-01

    Cushing's syndrome is a clinical condition resulting from chronic exposure to excess glucocorticoid. As a consequence, long-term hypercortisolism contributes significantly to the development of systemic disorders by direct and/or indirect effects. The present study was to analyze the changes of renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome on the standard posture test. We retrospectively reviewed 150 patients with histologically confirmed Cushing's syndrome treated at the PLA General Hospital between 2002 and 2014. Among them, 128 patients were diagnosed as adreno-cortico-tropic-hormone (ACTH)-independent Cushing's syndrome, and 22 were ACTH-dependent Cushing's syndrome. All patients were undertaken the posture test. Plasma renin activity (PRA), angiotensin II, plasma aldosterone concertration (PAC) levels were measured before and after the test. Basal plasma PRA [0.5 (0.2,1.3)µg·L(-1)·h(-1), angiotensin II [(48.9±20.1) ng/L] and PAC [(285.0±128.1) pmol/L] levels were within the normal range in supine position. Compared with the subjects with ACTH-independent Cushing's syndrome, the basal PAC levels were higher in subjects with ACTH-dependent Cushing's syndrome [(348.0±130.4) pmol/L vs (274.2±125.0) pmol/L, PCushing's syndrome [(49.7±26.4)%] was significantly lower than that in those with ACTH-independent Cushing's syndrome [(81.2±69.3)%] upon upright posture stimulation (PCushing's syndrome was similar to that in normal control. The basal PAC level and its response to upright posture are differently associated with ACTH level in Cushing's syndrome.

  15. Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats

    NARCIS (Netherlands)

    Deelman, LE; Navis, G; Wietses, M; de Zeeuw, D; Henning, RH

    Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney. Unilateral adriamycin-induced proteinuria was obtained by clamping the

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  17. [Changes in the renin-angiotensin-aldosterone system and water-salt exchange in mining workers in coal mines].

    Science.gov (United States)

    Rebrov, B A

    1996-01-01

    Blood and urine content of electrolytes and creatinine was determined in 76 essentially healthy miners before and after work shift, as was activity of plasma renin, blood plasma level of aldosterone and its urinary excretion, with the aid of radioimmunoassay. The greatest activity of the renin-angiotensine-aldosterone system (RAAS) occurred in those individuals engaged in hard physical labour under most harsh conditions of underground workings, this being recordable not only is response to the load but also from the very start. Controls and miners doing jobs of medium-level strenuousness demonstrated changes in the correlations between RAAS and water-salt balance after the work shift as compared with those before the work shift, while in those miners engaged in hard work correlations RAAS-water-salt exchange remained practically the same throughout the study.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    . The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7...... be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very......The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure...

  19. A potential pathophysiological role for galectins and the renin-angiotensin system in preeclampsia.

    Science.gov (United States)

    Blois, Sandra M; Dechend, Ralf; Barrientos, Gabriela; Staff, Anne Cathrine

    2015-01-01

    This review discusses a potential role of galectins and the renin-angiotensin system (RAS) in the pathophysiology of preeclampsia (PE). Preeclampsia affects between 3 and 5 % of all pregnancies and is a heterogeneous disease, which may be caused by multiple factors. The only cure is the delivery of the placenta, which may result in a premature delivery and baby. Probably due to its heterogeneity, PE studies in human have hitherto only led to the identification of a limited number of factors involved in the pathogenesis of the disease. Animal models, particularly in mice and rats, have been used to gain further insight into the molecular pathology behind PE. In this review, we discuss the picture emerging from human and animal studies pointing to galectins and the RAS being associated with the PE syndrome and affecting a broad range of cellular signaling components. Moreover, we review the epidemiological evidence for PE increasing the risk of future cardiovascular disease later in life.

  20. Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics

    Directory of Open Access Journals (Sweden)

    Ronaldo Altenburg Gismondi

    2015-01-01

    Full Text Available AbstractBackground:Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness.Objective:To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness.Methods:Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring, endothelial function (brachial artery flow-mediated dilation, and vascular stiffness (pulse wave velocity were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively.Results:The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007, and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003 when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820. There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586.Conclusion:Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

  1. Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

    Directory of Open Access Journals (Sweden)

    Indu Dhar

    Full Text Available The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs. Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs. HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH, proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

  2. Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

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    Dhar, Indu; Dhar, Arti; Wu, Lingyun; Desai, Kaushik M

    2013-01-01

    The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

  3. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

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    Yan-Huan Feng

    2016-01-01

    Full Text Available Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an

  4. Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

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    Jose L. Labandeira-Garcia

    2017-05-01

    Full Text Available Microglia can transform into proinflammatory/classically activated (M1 or anti-inflammatory/alternatively activated (M2 phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory to M2 (immunoregulatory phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II, via its type 1 receptor (AT1, is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization

  5. 2C.07: INVOLVEMENT OF THE RENIN-ANGIOTENSIN SYSTEM IN A PREMATURE AGING MOUSE MODEL.

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    Van Thiel, B S; Ridwan, Y; Garrelds, I M; Vermeij, M; Groningen, M C Clahsen-Van; Danser, A H J; Essers, J; Van Der Pluijm, I

    2015-06-01

    Changes in the renin-angiotensin system (RAS), known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. Here we characterized the RAS and kidney pathology in mice with genomic instability due to a defective nucleotide excision repair gene (Ercc1d/- mice). These mice display premature features of aging, including vascular dysfunction. Studies were performed in male and female Ercc1d/- mice and their wild type controls (Ercc1+/+) at the age of 12 or 18 weeks before and after treatment with losartan. The renin-activatable near-infrared fluorescent probe ReninSense 680™ was applied in vivo to allow non-invasive imaging of renin activity. Plasma renin concentrations (PRC) were additionally measured ex vivo by quantifying Ang I generation in the presence of excess angiotensinogen. Kidneys were harvested and examined for markers of aging, and albumin was determined in urine. Kidneys of 12-week old Ercc1d/- mice showed signs of aging, including tubular anisokaryosis, cell-senescence and increased apoptosis. This was even more pronounced at the age of 18 weeks. Yet, urinary albumin was normal at 12 weeks. The ReninSense 680™ probe showed increased intrarenal renin activity in Ercc1d/- mice versus Ercc1+/+ mice, both at 12 and 18 weeks of age, while PRC in these mice tended to be lower compared to Ercc1+/+ mice. Renin was higher in male than female mice, both in the kidney and in plasma, and losartan increased kidney and plasma renin in both Ercc1d/- and Ercc1+/+ mice. Rapidly aging Ercc1d/- mice display an activated intrarenal RAS, as evidenced by the increased fluorescence detected with the ReninSense 680™ probe. This increased RAS activity may contribute to the disturbed kidney pathology in these mice. The increased intrarenal activity detected with the ReninSense 680™ probe in male vs. female mice, as well as after losartan treatment, are in full agreement with the literature, and

  6. Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence.

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    Anil Kumar, K V; Nagwar, Shrasti; Thyloor, Rama; Satyanarayana, Sreemantula

    2015-12-01

    Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. © The Author(s) 2014.

  7. Association between polymorphisms in renin-angiotensin system genes and primary ovarian insufficiency in Korean women.

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    Jung, Yong Wook; Jeon, Young Joo; Park, Hye Mi; Lee, Bo Eun; Rah, Hyungchul; Lee, Woo Sik; Yoon, Tae Ki; Kim, Nam Keun

    2013-05-01

    The purpose of this study was to evaluate the relationship between angiotensin-converting enzyme (ACE; insertion/deletion), angiotensinogen (AGT M235T), and angiotensin II type 1 receptor (AT1R 1166A>C) and the prevalence of primary ovarian insufficiency (POI) in Korean women. A total of 133 women with POI and 238 controls were genotyped for polymorphic sites in each gene using polymerase chain reaction-restriction fragment length polymorphism analysis. ACE ID and ID + II variants occurred more frequently in women with POI than in controls (odds ratio [OR], 1.830; 95% CI, 1.040-3.221; P = 0.040; and OR, 1.797; 95% CI, 1.055-3.060; P = 0.031, respectively). The AT1R 1166AC genotype occurred more frequently in participants with POI than in controls (OR, 3.171; 95% CI, 1.562-6.436; P = 0.002). Comparing the combined genotype frequencies of ACE/AT1R revealed that the frequencies of ID/AA, ID/AC, and II/AC were higher in participants than in controls (OR, 1.916; 95% CI, 1.053-3.485; P = 0.043; OR, 3.544; 95% CI, 1.207-10.407; P = 0.036; and OR, 7.875; 95% CI, 2.224-27.881; P = 0.001, respectively). The TT/AC genotype for combined genotyping of AGT/AT1R was more frequently observed in the POI group than in the control group (OR, 3.472; 95% CI, 1.450-8.313; P = 0.006). In multifactor dimensionality reduction-based haplotype analysis, the I-T-C genotype of ACE/AGT/AT1R was a possible predisposing factor for POI (OR, 4.678; 95% CI, 1.721-12.717; P = 0.002). This study demonstrates that polymorphisms in the renin-angiotensin system are related to the prevalence of POI. Thus, these renin-angiotensin system genes may serve as a novel marker for predicting the development of POI.

  8. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.

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    Verdonk, Koen; Saleh, Langeza; Lankhorst, Stephanie; Smilde, J E Ilse; van Ingen, Manon M; Garrelds, Ingrid M; Friesema, Edith C H; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy; Danser, A H Jan

    2015-06-01

    Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness

  9. Investigating the association of vitamin D with blood pressure and the renin-angiotensin-aldosterone system in hypertensive subjects: a cross-sectional prospective study.

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    Cremer, Antoine; Tambosco, Chloé; Corcuff, Jean-Benoît; Boulestreau, Romain; Gaillard, Prune; Lainé, Marion; Papaioannou, Georgios; Gosse, Philippe

    2018-02-01

    The hypothesis that vitamin D (25(OH)D) insufficiency plays a role in occurring of various disease has led to a rise in requests of dosages and to an increase of health-care costs. 25(OH)D insufficiency is associated with increased risk of cardiovascular disease and hypertension in many studies. Animal studies demonstrated that 25(OH)D insufficiency activates renin angiotensin system but corresponding humans data are limited. The aim of the study was to document relationship between 25(OH)D, blood pressure, and renin angiotensin system in hypertensive subjects. In all, 248 hypertensive individuals, 46.8 years (±14), were hospitalized for an etiological assessment of hypertension in this cross-sectional study over two calendar years. 25(OH)D, plasma renin activity, and aldosterone were determined in stringent conditions and blood pressure was measure. Statistical analyses were carried out to analyze the association between 25(OH)D, blood pressure, and renin angiotensin system using linear and logistic regressions with adjustments on relevant variables. In all, 80% of the studied population had a 25(OH)D insufficiency. There were no significant association between 25(OH)D and levels of systolic or diastolic blood pressure, plasma renin activity, and aldosterone whatever the statiscal method used after adjustment. 25(OH)D is not associated with blood pressure and renin angiontensin component in hypertensive subjects. These results corroborate the interventional studies which are for a large majority negatives. A new definition of the 25(OH)D insufficiency in general population is necessary.

  10. The physiology of a local renin-angiotensin system in the pancreas.

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    Leung, Po Sing

    2007-04-01

    The systemic renin-angiotensin system (RAS) plays an important role in regulating blood pressure, electrolyte and fluid homeostasis. However, local RASs also exist in diverse tissues and organs, where they play a multitude of autocrine, paracrine and intracrine physiological roles. The existence of a local RAS is now recognized in pancreatic acinar, islet, duct, endothelial and stellate cells, the expression of which is modulated in response to physiological and pathophysiological stimuli such as hypoxia, pancreatitis, islet transplantation, hyperglycaemia, and diabetes mellitus. This pancreatic RAS has been proposed to have important endocrine and exocrine roles in the pancreas, regulating local blood flow, duct cell sodium bicarbonate secretion, acinar cell digestive enzyme secretion, islet beta-cell (pro)insulin biosynthesis, and thus, glucose-stimulated insulin release, delta-cell somatostatin secretion, and pancreatic cell proliferation and differentiation. It may further mediate oxidative stress-induced cell inflammation, apoptosis and fibrosis. Further exploration of this system would probably offer new insights into the pathogenesis of pancreatitis, diabetes, cystic fibrosis and pancreatic cancer formation. New therapeutic targets and strategies might thus be suggested.

  11. Renin-angiotensin system: an old player with novel functions in skeletal muscle.

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    Cabello-Verrugio, Claudio; Morales, María Gabriela; Rivera, Juan Carlos; Cabrera, Daniel; Simon, Felipe

    2015-05-01

    Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.

  12. Role of Renin-Angiotensin system and oxidative stress on vascular inflammation in insulin resistence model.

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    Renna, N F; Lembo, C; Diez, E; Miatello, R M

    2013-01-01

    (1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10(-3) mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

  13. Role of Renin-Angiotensin System and Oxidative Stress on Vascular Inflammation in Insulin Resistence Model

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    N. F. Renna

    2013-01-01

    Full Text Available (1 This study aims to demonstrate the causal involvement of renin angiotensin system (RAS and oxidative stress (OS on vascular inflammation in an experimental model of metabolic syndrome (MS achieved by fructose administration to spontaneously hypertensive rats (FFHR during 12 weeks. (2 Chronic treatment with candesartan (C (10 mg/kg per day for the last 6 weeks or 4OH-Tempol (T (10−3 mmol/L in drinking water for the last 6 weeks reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3 Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4 The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

  14. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension.

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    Shim, Kwang Yong; Eom, Young Woo; Kim, Moon Young; Kang, Seong Hee; Baik, Soon Koo

    2018-05-01

    The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

  15. Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention.

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    Madhu Nath

    Full Text Available Examining the Retinal Renin Angiotensin System (RRAS in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR model.Vitreous of ROP patients (n = 44, median age 5.5 months was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI and Angiotensin Receptor Blocker (ARB was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS.Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan, ACEI (lisinopril and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels.This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model.

  16. Expression of the Components of the Renin-Angiotensin System in Venous Malformation

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    Sam eSiljee

    2016-05-01

    Full Text Available Background Venous malformation (VM is the most common form of vascular malformation, consisting of a network of thin-walled ectatic venous channels with deficient or absent media. This study investigated the expression of the components of the renin-angiotensin system (RAS, namely (prorenin receptor (PRR, angiotensin converting enzyme (ACE, angiotensin II receptor 1 (ATIIR1 and angiotensin II receptor 2 (AIITR2 in subcutaneous (SC and intramuscular (IM VM. Materials and Methods SC (n=7 and IM (n=7 VM were analyzed for the expression of PRR, ACE, ATIIR1, and ATIIR2 using 3,3-diaminobenzidine (DAB and immunofluorescent (IF immunohistochemical (IHC staining and NanoString gene expression analysis. Results IHC staining showed expression of PRR, ACE, ATIIR1 and faint expression of ATIIR2 in the endothelium of SC and IM VM. Furthermore, ATIIR2 was expressed by cells away from the endothelium in both SC and IM VM lesions examined. NanoString analysis demonstrated the presence of PRR, ACE and ATIIR1 but not ATIIR2.Conclusions The presence of PRR, ACE, ATIIR1 and potentially ATIIR2, in both SC and IM VM suggests a role for the RAS in the biology of VM. This novel finding may lead to a mechanism-based therapy for VM.

  17. Renin-Angiotensin System Genes Polymorphisms and Essential Hypertension in Burkina Faso, West Africa

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    Daméhan Tchelougou

    2015-01-01

    Full Text Available Objective. This study aimed to investigate the association between three polymorphisms of renin-angiotensin system and the essential hypertension in the population of Burkina Faso. Methodology. This was a case-control study including 202 cases and 204 matched controls subjects. The polymorphisms were identified by a classical and a real-time PCR. Results. The AGT 235M/T and AT1R 1166A/C polymorphisms were not associated with the hypertension while the genotype frequencies of the ACE I/D polymorphism between patients and controls (DD: 66.83% and 35.78%, ID: 28.22% and 50.98%, II: 4.95% and 13.24%, resp. were significantly different (p < 10−4. The genotype DD of ACE gene (OR = 3.40, p < 0.0001, the increasing age (OR = 3.83, p < 0.0001, obesity (OR = 4.84, p < 0.0001, dyslipidemia (OR = 3.43, p = 0.021, and alcohol intake (OR = 2.76, p < 0.0001 were identified as the independent risk factors for hypertension by multinomial logistic regression. Conclusion. The DD genotype of the ACE gene is involved in susceptibility to hypertension. Further investigations are needed to better monitor and provide individualized care for hypertensive patients.

  18. Skeletal muscle wasting: new role of nonclassical renin-angiotensin system.

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    Cabello-Verrugio, Claudio; Rivera, Juan C; Garcia, Dominga

    2017-05-01

    Skeletal muscle can be affected by many physiological and pathological conditions that contribute to the development of muscle weakness, including skeletal muscle loss, inflammatory processes, or fibrosis. Therefore, research into therapeutic treatment alternatives or alleviation of these effects on skeletal muscle is of great importance. Recent studies have shown that angiotensin (1-7) [Ang-(1-7)] - a vasoactive peptide of the nonclassical axis in the renin-angiotensin system (RAS) - and its Mas receptor are expressed in skeletal muscle. Ang-(1-7), through its Mas receptor, prevents or diminishes deleterious effects induced by skeletal muscle disease or injury. Specifically, the Ang-(1-7)-Mas receptor axis modulates molecular mechanisms involved in muscle mass regulation, such as the ubiquitin proteasome pathway, the insulin-like growth factor type 1/Akt (protein kinase B) pathway, or myonuclear apoptosis, and also inflammation and fibrosis pathways. Although further research into this topic and the possible side effects of Ang-(1-7) is necessary, these findings are promising, and suggest that the Ang-(1-7)-Mas axis can be considered a possible therapeutic target for treating patients with muscular disorders.

  19. Outcome of Venom Bradykinin Potentiating Factor on Renin Angiotensin System in Irradiated Rats

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    Ashry, O.; Farouk, H.; Moustafa, M.; Abu Sinn, G.; Abd ElBaset, A.

    2011-01-01

    Scorpion Venom contains a strong bradykinin potentiating factor (BPF) exhibiting angiotensin converting enzyme inhibition (ACEI). Irradiation and stimulation of renin-angiotensin system (RAS) induce oxidative stress. Interruption of the RAS by an ACEI or angiotensin II receptor blocker (ARB) losartan (LOS) and/or gamma-rays (4 Gy) were evaluated. Rats received 6 doses of BPF (1μg/g body wt) or of LOS (5 μg/g body wt). Treatment with BPF induced significant elevation in the level of potassium (K) and significant drop in the level of sodium (Na) and uric acid. Treatment with LOS significantly depressed the level of Na and uric acid compared to control. Irradiation discerned a significant elevation in malondialdehyde (MDA), advanced oxidative protein product (AOPP), aldosterone, Na, urea and creatinine, and a significant drop in the haematological values, glutathione (GSH), calcium (Ca) and uric acid. A significant decrease in MDA, aldosterone, urea, creatinine and uric acid compared to irradiated group was observed in irradiated treated groups. Irradiated animals treated with LOS showed a significant decrease in Na and chloride (Cl) compared to the irradiated group. Considerable amelioration of radiation-induced depression in haematopoiesis, improvement of oxidative stress and kidney function by BPF as ACEI or LOS as ARB are detected. Results add further identification to the properties of BPF

  20. Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

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    Aline Cristina Piratello

    2010-01-01

    Full Text Available OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated showed an increase on mean blood pressure compared with normotensive ones (controls and denervated. Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

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

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

    2011-08-01

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

  2. Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system.

    Directory of Open Access Journals (Sweden)

    Giuseppina Mattace Raso

    Full Text Available Palmitoylethanolamide (PEA, a peroxisome proliferator-activated receptor-α agonist, has been demonstrated to reduce blood pressure and kidney damage secondary to hypertension in spontaneously hypertensive rat (SHR. Currently, no information is available concerning the putative effect of PEA on modulating vascular tone. Here, we investigate the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids, CYP-dependent arachidonic acid metabolites, as endothelium-derived hyperpolarizing factors (EDHF, and renin angiotensin system (RAS modulation. To achieve this aim SHR and Wistar-Kyoto rats were treated with PEA (30 mg/kg/day for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF-mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure CYP2C23 and CYP2J2, the key isoenzymes in the formation of epoxyeicosatrienoic acids, and the soluble epoxide hydrolase, which is responsible for their degradation in the corresponding diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme and angiotensin receptor 1 expression. Here, we showed that EDHF-mediated dilation in response to acetylcholine was increased in mesenteric beds of PEA-treated SHR. Western blot analysis revealed that the increase in CYP2C23 and CYP2J2 observed in SHR was significantly attenuated in mesenteric beds of PEA-treated SHR, but unchanged in the carotids. Interestingly, in both vascular tissues, PEA significantly decreased the soluble epoxide hydrolase protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid, implying a reduction in epoxyeicosatrienoic acid hydrolisis. Moreover, PEA treatment down-regulated angiotensin receptor 1 and angiotensin converting enzyme expression, indicating a reduction in angiotensin II-mediated effects. Consistently, a damping of the

  3. High maternal sodium intake alters sex-specific renal renin-angiotensin system components in newborn Wistar offspring.

    Science.gov (United States)

    Maia, D R R; Lopes, K L; Heimann, J C; Furukawa, L N S

    2016-01-28

    This study aimed to evaluate the systemic and renal renin-angiotensin-aldosterone system (RAAS) at birth in male and female offspring and in mothers fed a high sodium diet (HSD) before and during gestation. Female Wistar rats were fed a HSD (8.0% NaCl) or a normal sodium diet (1.3% NaCl) from 8 weeks of age until delivery of their first litter. Maternal body weight, tail blood pressure, and food and water intake were evaluated. The litter sizes were assessed, and the body and kidney weights of the offspring were measured. Both mothers and offspring were euthanized immediately following the birth of the pups to evaluate plasma renin activity (PRA), renal renin content (RRC), renal angiotensin-converting enzyme (ACE) activity, renal angiotensin (Ang) II content, serum aldosterone (ALDO) levels, and renal cortical and medullary renin messenger RNA expression. In mothers in the HSD group, water intake and kidney mass were higher, whereas renal ACE activity, Ang II, PRA, ALDO and RRC were decreased. In the offspring of HSD-fed dams, the body and kidney mass were lower in both genders, renal ACE activity was lower in females and renal Ang II was lower in males. PRA, RRC, renin gene expression and ALDO levels did not differ between the groups of offspring. The data presented herein showed that a maternal HSD during pregnancy induces low birth weight and a sex-specific response in the RAAS in offspring.

  4. New Frontiers in the Intrarenal Renin-Angiotensin System: A Critical Review of Classical and New Paradigms

    Science.gov (United States)

    Zhuo, Jia L.; Ferrao, Fernanda M.; Zheng, Yun; Li, Xiao C.

    2013-01-01

    The renin-angiotensin system (RAS) is well-recognized as one of the oldest and most important regulators of arterial blood pressure, cardiovascular, and renal function. New frontiers have recently emerged in the RAS research well beyond its classic paradigm as a potent vasoconstrictor, an aldosterone release stimulator, or a sodium-retaining hormone. First, two new members of the RAS have been uncovered, which include the renin/(Pro)renin receptor (PRR) and angiotensin-converting enzyme 2 (ACE2). Recent studies suggest that prorenin may act on the PRR independent of the classical ACE/ANG II/AT1 receptor axis, whereas ACE2 may degrade ANG II to generate ANG (1–7), which activates the Mas receptor. Second, there is increasing evidence that ANG II may function as an intracellular peptide to activate intracellular and/or nuclear receptors. Third, currently there is a debate on the relative contribution of systemic versus intrarenal RAS to the physiological regulation of blood pressure and the development of hypertension. The objectives of this article are to review and discuss the new insights and perspectives derived from recent studies using novel transgenic mice that either overexpress or are deficient of one key enzyme, ANG peptide, or receptor of the RAS. This information may help us better understand how ANG II acts, both independently or through interactions with other members of the system, to regulate the kidney function and blood pressure in health and disease. PMID:24273531

  5. Maternal hyperthyroidism alters the pattern of expression of cardiac renin-angiotensin system components in rat offspring.

    Science.gov (United States)

    Lino, Caroline A; Shibata, Caroline E R; Barreto-Chaves, Maria Luiza M

    2014-03-01

    Changes in perinatal environment can lead to physiological, morphological, or metabolic alterations in adult life. It is well known that thyroid hormones (TH) are critical for the development, growth, and maturation of organs and systems. In addition, TH interact with the renin-angiotensin system (RAS), and both play a critical role in adult cardiovascular function. The objective of this study was to evaluate the effect of maternal hyperthyroidism on cardiac RAS components in pups during development. From gestational day nine (GD9), pregnant Wistar rats received thyroxine (T4, 12 mg/l in tap water; Hyper group) or vehicle (control group). Dams and pups were killed on GD18 and GD20. Serum concentrations of triiodothyronine (T3) and T4 were higher in the Hyper group than in the control group dams. Cardiac hypertrophy was observed in Hyper pups on GD20. Cardiac angiotensin-converting enzyme (ACE) activity was significantly lower in Hyper pups on both GD18 and GD20, but there was no difference in Ang I/Ang II levels. Ang II receptors expression was higher in the Hyper pup heart on GD18. Maternal hyperthyroidism is associated with alterations in fetal development and altered pattern of expression in RAS components, which in addition to cardiac hypertrophy observed on GD20 may represent an important predisposing factor to cardiovascular diseases in adult life.

  6. Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies.

    Science.gov (United States)

    Burks, Tyesha N; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J; Foster, D Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D; Abadir, Peter M

    2015-05-20

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT(1)R:AT(2)R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT(1)R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.

  7. Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism.

    Science.gov (United States)

    Li, Jianchang; Qiu, Mingning; Chen, Lieqian; Liu, Lei; Tan, Guobin; Liu, Jianjun

    2017-02-01

    The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

  8. The Brain Renin-Angiotensin System and Mitochondrial Function: Influence on Blood Pressure and Baroreflex in Transgenic Rat Strains

    Directory of Open Access Journals (Sweden)

    Manisha Nautiyal

    2013-01-01

    Full Text Available Mitochondrial dysfunction is implicated in many cardiovascular diseases, including hypertension, and may be associated with an overactive renin-angiotensin system (RAS. Angiotensin (Ang II, a potent vasoconstrictor hormone of the RAS, also impairs baroreflex and mitochondrial function. Most deleterious cardiovascular actions of Ang II are thought to be mediated by NADPH-oxidase- (NOX- derived reactive oxygen species (ROS that may also stimulate mitochondrial oxidant release and alter redox-sensitive signaling pathways in the brain. Within the RAS, the actions of Ang II are counterbalanced by Ang-(1–7, a vasodilatory peptide known to mitigate against increased oxidant stress. A balance between Ang II and Ang-(1–7 within the brain dorsal medulla contributes to maintenance of normal blood pressure and proper functioning of the arterial baroreceptor reflex for control of heart rate. We propose that Ang-(1–7 may negatively regulate the redox signaling pathways activated by Ang II to maintain normal blood pressure, baroreflex, and mitochondrial function through attenuating ROS (NOX-generated and/or mitochondrial.

  9. Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy.

    Science.gov (United States)

    Goyal, Ravi; Goyal, Dipali; Leitzke, Arthur; Gheorghe, Ciprian P; Longo, Lawrence D

    2010-03-01

    Maternal protein malnutrition during pregnancy can lead to significant alterations in the systemic renin-angiotensin system (RAS) in the fetus. All components of the RAS are present in brain and may be altered in many disease states. Importantly, these disorders are reported to be of higher incidence in prenatally malnourished individuals. In the current study, we tested the hypothesis that antenatal maternal low protein diet (MLPD) leads to epigenetic changes and alterations in gene expression of brain RAS of the mouse fetus. Mice dams were given control and 50% MLPD during second half of the gestation. We analyzed messenger RNA (mRNA), microRNA (miRNA), promoter DNA methylation, and protein expression of various RAS genes in the fetal offspring. As a consequence of 50% MLPD, fetal brains showed increased mRNA expression of angiotensinogen and angiotensin converting enzyme-1 (ACE-1), with a decrease in mRNA levels of angiotensin II type-2 (AT2) receptors. In contrast, while angiotensinogen protein expression was unaltered, the protein levels of ACE-1 and AT2 receptor genes were significantly reduced in the fetal brain from the MLPD dams. Our results also demonstrated hypomethylation of the CpG islands in the promoter regions of ACE-1 gene, and upregulation of the miRNAs, mmu-mir-27a and 27b, which regulate ACE-1 mRNA translation. Furthermore, our study showed reduced expression of the miRNA mmu-mir-330, which putatively regulates AT2 translation. For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.

  10. Renin-angiotensin system blockade therapy after transcatheter aortic valve implantation.

    Science.gov (United States)

    Ochiai, Tomoki; Saito, Shigeru; Yamanaka, Futoshi; Shishido, Koki; Tanaka, Yutaka; Yamabe, Tsuyoshi; Shirai, Shinichi; Tada, Norio; Araki, Motoharu; Naganuma, Toru; Watanabe, Yusuke; Yamamoto, Masanori; Hayashida, Kentaro

    2018-04-01

    The persistence of left ventricular (LV) hypertrophy is associated with poor clinical outcomes after transcatheter aortic valve implantation (TAVI) for aortic stenosis. However, the optimal medical therapy after TAVI remains unknown. We investigated the effect of renin-angiotensin system (RAS) blockade therapy on LV hypertrophy and mortality in patients undergoing TAVI. Between October 2013 and April 2016, 1215 patients undergoing TAVI were prospectively enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry. This cohort was stratified according to the postoperative usage of RAS blockade therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Patients with at least two prescriptions dispensed 180 days apart after TAVI and at least a 6-month follow-up constituted the RAS blockade group (n=371), while those not prescribed any ACE inhibitors or ARBs after TAVI were included in the no RAS blockade group (n=189). At 6 months postoperatively, the RAS blockade group had significantly greater LV mass index regression than the no RAS blockade group (-9±24% vs -2±25%, p=0.024). Kaplan-Meier analysis revealed a significantly lower cumulative 2-year mortality in the RAS blockade than that in the no RAS blockade group (7.5% vs 12.5%; log-rank test, p=0.031). After adjusting for confounding factors, RAS blockade therapy was associated with significantly lower all-cause mortality (HR, 0.45; 95% CI 0.22 to 0.91; p=0.025). Postoperative RAS blockade therapy is associated with greater LV mass index regression and reduced all-cause mortality. These data need to be confirmed by a prospective randomised controlled outcome trial. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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

    Science.gov (United States)

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

    2016-06-01

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

  12. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

    International Nuclear Information System (INIS)

    Neo, Jaclyn H; Ager, Eleanor I; Angus, Peter W; Zhu, Jin; Herath, Chandana B; Christophi, Christopher

    2010-01-01

    Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade

  13. Renin-angiotensin system at the crossroad of hypertension and hypercholesterolemia.

    Science.gov (United States)

    Borghi, C; Urso, R; Cicero, A F

    2017-02-01

    The aim of this study is to discuss the reliable scientific evidence of an interactive link between hypertension and hypercholesterolemia considering the metabolic pathways and the pathogenetic mechanisms connecting the two risk factors. Hypertension and hypercholesterolemia are highly prevalent in the general population and their coexistence in the same subjects additively increases the risk of cardiovascular disease. Probably, hypercholesterolemia is also a risk factor for the development of hypertension. On the other side, it is also possible that lipid-lowering treatment could improve blood pressure control. Although the mechanisms of interaction between these two risk factors have not been completely elucidated thus far, there is rapidly growing evidence that the involvement of the renin-angiotensin system (RAS) can be considered as the common link between hypertension and hypercholesterolemia. In particular, hypercholesterolemia seems to promote the upregulation of type 1 angiotensin II (AT1) receptor genes because of an increase in the stability of mRNA followed by structural overexpression of vascular AT1 receptors for angiotensin II. The treatment of both risk factors greatly improves individual risk profile, especially when statins and RAS blockers are used together. Hypertension and hypercholesterolemia are highly coprevalent and strongly related from a pathophysiological point of view. The RAS could be the main mediator of this link. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  14. Preoperative renin-angiotensin system inhibitors protect renal function in aging patients undergoing cardiac surgery.

    Science.gov (United States)

    Barodka, Viachaslau; Silvestry, Scott; Zhao, Ning; Jiao, Xiangyin; Whellan, David J; Diehl, James; Sun, Jian-Zhong

    2011-05-15

    Renal failure (RF) represents a major postoperative complication for elderly patients undergoing cardiac surgery. This observational cohort study examines effects of preoperative use of renin-angiotensin system (RAS) inhibitors on postoperative renal failure in aging patients undergoing cardiac surgery. We retrospectively analyzed a cohort of 1287 patients who underwent cardiac surgery at this institution (2003-2007). The patients included were ≥65 years old, scheduled for elective cardiac surgery, and without preexisting RF (defined by the criteria of the Society of Thoracic Surgeons as described in Method). Of all patients evaluated, 346 patients met the inclusion criteria and were divided into two groups: using (n = 122) or not using (n = 224) preoperative RAS inhibitors. A comparison of the two groups showed no significant differences in baseline parameters, including creatinine clearance, body mass index, history of diabetes and smoking, preoperative medicines (except that more patients with RAS inhibitors had a history of hypertension or congestive heart failure, fewer RAS inhibitor patients had chronic lung disease), in intraoperative perfusion and aortic cross-clamp time, and in postoperative complications and 30-d mortality. Multivariate logistic regression analysis demonstrated, however, that preoperative RAS inhibitors significantly and independently reduced the incidence of postoperative RF in the patients undergoing cardiac surgery compared with those not taking RAS inhibitors: 1.6% versus 7.6%, yielding an odds ratio of 0.19 (95 % CI 0.04-0.84, P = 0.029). Preoperative RAS inhibitors may have significant renoprotective effects for aging patients undergoing elective cardiac surgery. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Analysis of renin-angiotensin aldosterone system gene polymorphisms in malaysian essential hypertensive and type 2 diabetic subjects

    OpenAIRE

    Ramachandran, Vasudevan; Ismail, Patimah; Stanslas, Johnson; Shamsudin, Norashikin

    2009-01-01

    Abstract Background The renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS...

  16. Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

    DEFF Research Database (Denmark)

    Heijnen, Bart Fj; Pelkmans, Leonie Pj; Danser, Ah Jan

    2013-01-01

    This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral...... administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically...

  17. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury.

    Science.gov (United States)

    Dreischulte, Tobias; Morales, Daniel R; Bell, Samira; Guthrie, Bruce

    2015-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.

  18. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle.

    Science.gov (United States)

    Henriksen, Erik J; Prasannarong, Mujalin

    2013-09-25

    The canonical renin-angiotensin system (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated glucose transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive ß-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent glucose transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent glucose transport system in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. The role of tissue renin angiotensin aldosterone system in the development of endothelial dysfunction and arterial stiffness

    Directory of Open Access Journals (Sweden)

    Annayya R Aroor

    2013-10-01

    Full Text Available Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin angiotensin aldosterone system (RAAS in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.

  20. Embryonic Stem Cell-Like Population in Dupuytren’s Disease Expresses Components of the Renin-Angiotensin System

    Directory of Open Access Journals (Sweden)

    Nicholas On

    2017-07-01

    Full Text Available Background:. The renin-angiotensin system (RAS mediates cardiac and renal fibrosis. Dupuytren’s disease (DD is a proliferative fibromatosis affecting the hands. This study investigated the expression of the RAS in DD. Methods:. 3,3-Diaminobenzidine (DAB and immunofluorescent immunohistochemical (IHC staining for (prorenin receptor (PRR, angiotensin-converting enzyme (ACE, angiotensin II receptor 1 (ATIIR1, and angiotensin II receptor 2 (ATIIR2 was performed on 4-μm thick formalin-fixed paraffin-embedded sections of DD cords and nodules from 6 patients. Western blotting (WB and NanoString mRNA analysis were performed to confirm RAS protein expression and transcriptional activation, respectively. Results:. IHC staining demonstrated the expression of PRR, ACE, ATIIR1, and ATIIR2 on the ERG+ and CD34+ endothelium of the micro vessels surrounding the DD cords and nodules. PRR was also expressed on the pericyte layer of these microvessels. WB confirmed protein expression of PRR, ACE, and ATIIR2 but not ATIIR1. NanoString analysis confirmed transcriptional activation of PRR, ACE, ATIIR1, but ATIIR2 was below detectable levels. Conclusions:. We demonstrated expression of PRR, ATIIR1, ATIIR2, and ACE on the embryonic stem cell–like cell population on the microvessels surrounding DD nodules and cords by IHC staining, although the expression of ATIIR1 was not confirmed by WB and that of ATIIR2 was below detectable levels on NanoString analysis. These findings suggest the embryonic stem cell–like cell population as a potential therapeutic target for DD, by using RAS modulators.

  1. Cancer Stem Cells in Moderately Differentiated Buccal Mucosal Squamous Cell Carcinoma Express Components of the Renin-Angiotensin System

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    Therese Featherston

    2016-09-01

    Full Text Available Aim We have recently identified and characterized cancer stem cell (CSC subpopulations within moderately differentiated buccal mucosal squamous cell carcinoma (MDBMSCC. We hypothesized that these CSCs express components of the renin-angiotensin system (RAS.Methods 3,3-Diaminobenzidine (DAB immunohistochemical (IHC staining was performed on formalin-fixed paraffin-embedded MDBMSCC samples to investigate the expression of the components of the RAS: pro(renin receptor (PRR, angiotensin converting enzyme (ACE, angiotensin II receptor 1 (ATIIR1 and angiotensin II receptor 2 (ATIIR2. NanoString mRNA gene expression analysis and Western Blotting (WB were performed on snap-frozen MDBMSCC samples to confirm gene expression and translation of these transcripts, respectively. Double immunofluorescent (IF IHC staining of these components of the RAS with the embryonic stem cell markers OCT4 or SALL4 was performed to demonstrate their localization in relation to the CSC subpopulations within MDBMSCC.Results DAB IHC staining demonstrated expression of PRR, ACE, ATIIR1 and ATIIR2 in MDBMSCC. IF IHC staining showed that PRR was expressed by the CSC subpopulations within the tumor nests, the peri-tumoral stroma and the endothelium of the microvessels within the peri-tumoral stroma. ATIIR1 and ATIIR2 were localized to the CSC subpopulations within the tumor nests and the peri-tumoral stroma, while ACE was localized to the endothelium of the microvessels within the peri-tumoral stroma. WB and NanoString analyses confirmed protein expression and transcription activation of PRR, ACE and ATIIR1 but not of ATIIR2, respectively.

  2. Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Schievink, B; Kröpelin, T; Mulder, S

    2016-01-01

    AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from...

  3. Varying patterns of the antihypertensive and antialbuminuric response to higher doses of renin-angiotensin-aldosterone system blockade in albuminuric hypertensive type 2 diabetes mellitus patients

    DEFF Research Database (Denmark)

    Weir, Matthew R; Hollenberg, Norman K; Remuzzi, Giuseppe

    2011-01-01

    In patients with type 2 diabetes mellitus (T2DM), blocking of the renin-angiotensin-aldosterone system (RAAS) has demonstrated efficacy in lowering blood pressure (BP) and urinary albumin excretion rate (UAER). Nonetheless, not all patients successfully respond to RAAS blockade with a reduction...

  4. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade: A Randomized Clinical Trial

    NARCIS (Netherlands)

    de Vries, Laura V.; Dobrowolski, Linn C.; van den Bosch, Jacqueline J. O. N.; Riphagen, Ineke J.; Krediet, C. T. Paul; Bemelman, Frederike J.; Bakker, Stephan J. L.; Navis, Gerjan

    2016-01-01

    In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown. We therefore

  5. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade : A Randomized Clinical Trial

    NARCIS (Netherlands)

    de Vries, Laura V; Dobrowolski, Linn C; van den Bosch, Jacqueline J O N; Riphagen, Ineke J; Krediet, C T Paul; Bemelman, Frederike J; Bakker, Stephan J L; Navis, Gerjan

    BACKGROUND: In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown.

  6. Multilocus analyses of renin-angiotensin-aldosterone system gene variants on blood pressure at rest and during behavioral stress in young normotensive subjects

    NARCIS (Netherlands)

    Ge, Dongliang; Zhu, Haidong; Huang, Ying; Treiber, Frank A.; Harshfield, Gregory A.; Snieder, Harold; Dong, Yanbin

    The renin-angiotensin-aldosterone system (RAAS) is a proteolytic cascade that regulates and maintains blood pressure (BP). This study aimed to explore the interactive and integrative effects of multiple RAAS polymorphisms on BP at rest and during behavioral stress in a normotensive population. A

  7. The PGE(2)-EP4 receptor is necessary for stimulation of the renin-angiotensin-aldosterone system in response to low dietary salt intake in vivo

    DEFF Research Database (Denmark)

    Pöschke, Antje; Kern, Niklas; Maruyama, Takayuki

    2012-01-01

    , creatinine clearance, and plasma antidiuretic hormone (ADH) concentration. Following salt restriction, plasma renin and aldosterone concentrations and kidney renin mRNA level rose significantly in EP4(+/+) but not in EP4(-/-) and in wild-type mice treated with EP4 antagonist ONO-AE3-208. In the latter two...... groups, the low-salt diet caused a significantly greater rise in PGE(2) excretion. Furthermore, mRNA expression for COX-2 and PGE(2) synthetic activity was significantly greater in EP4(-/-) than in EP4(+/+) mice. We conclude that low dietary salt intake induces expression of COX-2 followed by enhanced...... renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss....

  8. THE RENIN-ANGIOTENSIN SYSTEM AND THE BIOLOGY OF SKELETAL MUSCLE: MECHANISMS OF MUSCLE WASTING IN CHRONIC DISEASE STATES.

    Science.gov (United States)

    Delafontaine, Patrice; Yoshida, Tadashi

    2016-01-01

    Sarcopenia and cachexia are muscle-wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure, diabetes, cancer, chronic obstructive pulmonary disease, and renal failure. While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). We found that Ang II infusion in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor-1 signaling, increased apoptosis, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides orexin and neuropeptide Y. Furthermore, Ang II inhibits skeletal muscle stem cell proliferation, leading to lowered muscle regenerative capacity. Distinct stem cell Ang II receptor subtypes are critical for regulation of muscle regeneration. In ischemic mouse congestive heart failure model skeletal muscle wasting and attenuated muscle regeneration are Ang II dependent. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states.

  9. Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, Frederik; Lindhardt, Morten; Rossing, Peter

    2016-01-01

    Hypothesis/objectives: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can...... prevent development of microalbuminuria. Materials and methods: We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis......-cause mortality(p=0.07). Conclusions: We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria....

  10. A high sodium intake reduces antiproteinuric response to renin-angiotensin-aldosterone system blockade in kidney transplant recipients.

    Science.gov (United States)

    Monfá, Elena; Rodrigo, Emilio; Belmar, Lara; Sango, Cristina; Moussa, Fozi; Ruiz San Millán, Juan Carlos; Piñera, Celestino; Fernández-Fresnedo, Gema; Arias, Manuel

    Post-transplant proteinuria is associated with lower graft and patient survival. Renin-angiotensin-aldosterone system blockers are used to reduce proteinuria and improve renal outcome. Although it is known that a high salt intake blunts the antiproteinuric effect of ACEI and ARB drugs in non-transplant patients, this effect has not been studied in kidney transplant recipients. To analyse the relationship between sodium intake and the antiproteinuric effect of ACEI/ARB drugs in kidney transplant recipients. We selected 103 kidney transplant recipients receiving ACEI/ARB drugs for more than 6 months due to proteinuria>1 g/day. Proteinuria was analysed at baseline and at 6 months after starting ACEI/ARB treatment. Salt intake was estimated by urinary sodium to creatinine ratio (uNa/Cr). Proteinuria fell to less than 1g/day in 46 patients (44.7%). High uNa/Cr was associated with a smaller proteinuria decrease (r=-0.251, P=.011). The percentage proteinuria reduction was significantly lower in patients in the highest uNa/Cr tertile [63.9% (IQR 47.1%), 60.1% (IQR 55.4%), 38.9% (IQR 85.5%), P=.047]. High uNa/Cr independently relates (OR 2.406 per 100 mEq/g, 95% CI: 1.008-5.745, P=.048) to an antiproteinuric response <50% after renin-angiotensin-aldosterone system blockade. A high salt intake results in a smaller proteinuria decrease in kidney transplant recipients with proteinuria treated with ACEI/ARB drugs. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  11. Effects of aerobic exercise training on cardiac renin-angiotensin system in an obese Zucker rat strain.

    Directory of Open Access Journals (Sweden)

    Diego Lopes Mendes Barretti

    Full Text Available OBJECTIVE: Obesity and renin angiotensin system (RAS hyperactivity are profoundly involved in cardiovascular diseases, however aerobic exercise training (EXT can prevent obesity and cardiac RAS activation. The study hypothesis was to investigate whether obesity and its association with EXT alter the systemic and cardiac RAS components in an obese Zucker rat strain. METHODS: THE RATS WERE DIVIDED INTO THE FOLLOWING GROUPS: Lean Zucker rats (LZR; lean Zucker rats plus EXT (LZR+EXT; obese Zucker rats (OZR and obese Zucker rats plus EXT (OZR+EXT. EXT consisted of 10 weeks of 60-min swimming sessions, 5 days/week. At the end of the training protocol heart rate (HR, systolic blood pressure (SBP, cardiac hypertrophy (CH and function, local and systemic components of RAS were evaluated. Also, systemic glucose, triglycerides, total cholesterol and its LDL and HDL fractions were measured. RESULTS: The resting HR decreased (∼12% for both LZR+EXT and OZR+EXT. However, only the LZR+EXT reached significance (p<0.05, while a tendency was found for OZR versus OZR+EXT (p = 0.07. In addition, exercise reduced (57% triglycerides and (61% LDL in the OZR+EXT. The systemic angiotensin I-converting enzyme (ACE activity did not differ regardless of obesity and EXT, however, the OZR and OZR+EXT showed (66% and (42%, respectively, less angiotensin II (Ang II plasma concentration when compared with LZR. Furthermore, the results showed that EXT in the OZR prevented increase in CH, cardiac ACE activity, Ang II and AT2 receptor caused by obesity. In addition, exercise augmented cardiac ACE2 in both training groups. CONCLUSION: Despite the unchanged ACE and lower systemic Ang II levels in obesity, the cardiac RAS was increased in OZR and EXT in obese Zucker rats reduced some of the cardiac RAS components and prevented obesity-related CH. These results show that EXT prevented the heart RAS hyperactivity and cardiac maladaptive morphological alterations in obese Zucker rats.

  12. Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats.

    Science.gov (United States)

    Gomes-Santos, Igor Lucas; Fernandes, Tiago; Couto, Gisele Kruger; Ferreira-Filho, Julio César Ayres; Salemi, Vera Maria Cury; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Brum, Patricia Chakur; Rossoni, Luciana Venturini; de Oliveira, Edilamar Menezes; Negrao, Carlos Eduardo

    2014-01-01

    Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1-7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1-7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF. Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1-7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1-7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle. Exercise training causes a shift in RAS towards the Ang-(1-7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal

  13. Radioimmunoassay of renin-angiotensin-aldosterone in patients with adrenal tumors

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Yugrinov, O.G.; Gandzha, T.I.

    1983-01-01

    The results are presented of a study of the renin-angiotensin-aldosterone system in 89 patients with aldosteronoma, corticosteroma, pheochromocytoma and hypertension. Radioimmunoassay was used to measure aldosterone concentration and renin activity in the peripheral blood and blood from vena cava inferior, the renal and adrenal veins, the circadian cycle of their content and the responsiveness of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under the influence of lasix intake and the change over from a horizontal into vertical position. Patients with adrenal tumors have shown disorders of renin-angiotensin-aldosterone function. Radioimmunoassay of the renin-angiotensin-aldosterone system promotes early detection of adrenal tumors in the general population of patients with hypertension and can be used for control over therapeutic efficacy

  14. Acute and chronic role of nitric oxide, renin-angiotensin system and sympathetic nervous system in the modulation of calcium sensitization in Wistar Rats

    Czech Academy of Sciences Publication Activity Database

    Brunová, Aneta; Bencze, Michal; Behuliak, Michal; Zicha, Josef

    2015-01-01

    Roč. 64, č. 4 (2015), s. 447-457 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GAP304/12/0259; GA MZd(CZ) NV15-25396A Institutional support: RVO:67985823 Keywords : blood pressure * kalcium sensitization * Rho kinase * nitric oxide * renin-angiotensin system * sympathetic nervous system * fasudil Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.643, year: 2015

  15. Changes in the renin-angiotensin-aldosterone system in response to dietary salt intake in normal and hypertensive pregnancy. A randomized trial

    DEFF Research Database (Denmark)

    Nielsen, Lise Hald; Ovesen, Per; Hansen, Mie R

    2016-01-01

    It was hypothesized that primary renal sodium retention blunted the reactivity of the renin-angiotensin-aldosterone system to changes in salt intake in preeclampsia (PE). A randomized, cross-over, double-blinded, dietary intervention design was used to measure the effects of salt tablets or place...... of plasma renin and angiotensin II in response to changes in dietary salt intake compatible with a primary increase in renal sodium reabsorption in hypertensive pregnancies.......It was hypothesized that primary renal sodium retention blunted the reactivity of the renin-angiotensin-aldosterone system to changes in salt intake in preeclampsia (PE). A randomized, cross-over, double-blinded, dietary intervention design was used to measure the effects of salt tablets or placebo...

  16. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY)

    DEFF Research Database (Denmark)

    Lindhardt, Morten; Persson, Frederik; Currie, Gemma

    2016-01-01

    INTRODUCTION: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment...... AND DISSEMINATION: The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy...

  17. The protective arm of the renin-angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves.

    Science.gov (United States)

    Rocha, Natalia P; Bastos, Fernando M; Vieira, Érica L M; Prestes, Thiago R R; Silveira, Katia D da; Teixeira, Mauro M; Simões E Silva, Ana Cristina

    2018-03-11

    Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end-stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme-linked immunosorbent assay. Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang-(1-7) and angiotensin-converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-(1-7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  18. What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

    Institute of Scientific and Technical Information of China (English)

    Maria; da; Graa; Naffah-Mazzacoratti; Telma; Luciana; Furtado; Gouveia; Priscila; Santos; Rodrigues; Simōes; Sandra; Regina; Perosa

    2014-01-01

    The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

  19. Capturing the dynamics of systemic Renin-Angiotensin-Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs.

    Science.gov (United States)

    Mochel, J P; Peyrou, M; Fink, M; Strehlau, G; Mohamed, R; Giraudel, J M; Ploeger, B; Danhof, M

    2013-04-01

    In dogs, activation of the Renin-Angiotensin-Aldosterone System (RAAS) is an important feature of congestive heart failure (CHF). Long-term increases in angiotensin II (AII) and aldosterone (ALD) lead to the progression of heart failure to its end stage. Angiotensin-converting enzyme inhibitors (ACEIs) are the foremost therapeutic option in the management of CHF. Recent literature has challenged the efficacy of ACEIs, based on modest reduction in urinary aldosterone (UALD) excretion despite marked inhibition of ACE activity. This study was designed to heighten the understanding of the effect of benazepril, a potent ACEI, on the RAAS, using a low-sodium diet as an experimental model of RAAS activation. Time course profiles of RAAS peptides and related areas under the curve (AUC) were used for comparison between benazepril and placebo groups. Results indicated substantial changes in the dynamics of these biomarkers. At presumed benazeprilat steady state, significant differences in AUC of plasma renin activity (+90%), angiotensin I (+43%), and AII (-53%) were found between benazepril and placebo-treated dogs. ALD decreased by 73% in plasma but only by 5% in urine. In conclusion, despite modest reduction in UALD excretion, benazepril markedly influences RAAS dynamics in dogs. © 2012 Blackwell Publishing Ltd.

  20. Acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis in the dog.

    Science.gov (United States)

    Anderson, W P; Johnston, C I; Korner, P I

    1979-01-01

    1. The acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. 2. Stenosis was induced over 30 sec by inflation of a cuff around the renal artery to lower distal pressure to 60, 40 or 20 mmHg, with stenosis maintained for 1 hr. This resulted in an immediate fall in renal vascular resistance, but over the next 5--30 min both resistance and renal artery pressure were restored back towards prestenosis values. Only transient increases in systemic arterial blood pressure and plasma renin and angiotensin levels were seen with the two milder stenoses. Despite restoration of renal artery pressure, renal blood flow remained reduced at all grades of stenosis. 3. Pre-treatment with angiotensin I converting enzyme inhibitor or sarosine1, isoleucone8 angiotensin II greatly attenuated or abolished the restoration of renal artery pressure and renal vascular resistance after stenosis, and plasma renin and angiotensin II levels remained high. Renal dilatation was indefinitely maintained, but the normal restoration of resistance and pressure could be simulated by infusing angiotensin II into the renal artery. 4. The effective resistance to blood flow by the stenosis did not remain constant but varied with changes in the renal vascular resistance. PMID:219182

  1. Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system.

    Science.gov (United States)

    Maranon, Rodrigo O; Reckelhoff, Jane F

    2016-02-01

    Hypertension in postmenopausal women is less well controlled than in age-matched men. The aging female SHR is a model of postmenopausal hypertension that is mediated in part by activation of the renin-angiotensin system (RAS) and by the renal sympathetic nervous system. In this study, the hypothesis was tested that renal denervation would lower the blood pressure in old female SHR and would attenuate the antihypertensive effects of AT1 receptor antagonism. Retired breeder female SHR were subjected to right uninephrectomy (UNX) and left renal denervation (RD) or UNX and sham, and 2 weeks later, baseline mean arterial pressure (MAP; radiotelemetry) was measured for 4 days, and then rats were treated with angiotensin (AT1) receptor antagonist, losartan (40 mg/kg/day po) for 6 days. Renal denervation reduced MAP in old females compared to sham (172 ± 6 vs. 193 ± 6 mm Hg; P renal sympathetic nervous system and the RAS have independent effects to control the blood pressure in old female SHR. Since the denervated rats treated with losartan remained hypertensive, the data also suggest that other mechanisms than the RAS and renal sympathetic nervous system contribute to the hypertension in old female SHR. The data also suggest that multiple mechanisms may mediate the elevated blood pressure in postmenopausal women. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  2. The effect of renin-angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia.

    Science.gov (United States)

    Lee, Ju-Hyun; Kwon, Young Eun; Park, Jung Tak; Lee, Mi Jung; Oh, Hyung Jung; Han, Seung Hyeok; Kang, Shin-Wook; Choi, Kyu Hun; Yoo, Tae-Hyun

    2014-12-01

    The aim of this study was to determine the effects of renin-angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08-1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade. © The Author(s) 2014.

  3. Farmácia Popular Program: pharmaceutical market analysis of antihypertensive acting on the renin-angiotensin system medicines

    Directory of Open Access Journals (Sweden)

    Rondineli Mendes da Silva

    Full Text Available Abstract This paper aims to analyse changes in the retail pharmaceutical market following policy changes in the Farmácia Popular Program (FP, a medicines subsidy program in Brazil. The retrospective longitudinal analyses focus on therapeutic class of agents acting on the renin-angiotensin system. Data obtained from QuintilesIMS (formerly IMS Health included private retail pharmacy sales volume (pharmaceutical units and sales values from 2002 to 2013. Analyses evaluated changes in market share following key FP policy changes. The therapeutic class was selected due to its relevance to hypertension treatment. Market share was analysed by therapeutic sub-classes and by individual company. Losartan as a single product accounted for the highest market share among angiotensin II antagonists. National companies had higher sales volume during the study period, while multinational companies had higher sales value. Changes in pharmaceutical market share coincided with the inclusion of specific products in the list of medicines covered by FP and with increases in or exemption from patient copayment.

  4. Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling

    Directory of Open Access Journals (Sweden)

    Maricica Pacurari

    2015-01-01

    Full Text Available MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS- mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling.

  5. Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin-angiotensin system on myocyte remodeling.

    Science.gov (United States)

    Hu, L W; Benvenuti, L A; Liberti, E A; Carneiro-Ramos, M S; Barreto-Chaves, M L M

    2003-12-01

    The present study assessed the possible involvement of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) in thyroxine (T4)-induced cardiac hypertrophy. Hemodynamic parameters, heart weight (HW), ratio of HW to body weight (HW/BW), and myocyte width were evaluated in absence of thyroid hormone (hypothyroidism) and after T4 administration. Male Wistar rats were used. Some were subjected to thyroidectomies, whereas hyperthyroidism was induced in others via daily intraperitoneal injection of T4 (25 or 100 microg x 100 g BW(-1) x day(-1)) for 7 days. In some cases, T4 administration was combined with the angiotensin I-converting enzyme inhibitor enalapril (Ena), with the angiotensin type 1 (AT1) receptor blocker losartan (Los) or with the beta-adrenergic blocker propanolol (Prop). Hemodynamics and morphology were then evaluated. Systolic blood pressure (SBP) was not altered by administration of either T4 alone or T4 in combination with the specific inhibitors. However, SBP decreased significantly in hypothyroid rats. An increased heart rate was seen after administration of either T4 alone or T4 in combination with either Los or Ena. Although the higher dose of T4 significantly increased HW, HW/BW increased in both T4-treated groups. Ena and Prop inhibited the increase in HW or HW/BW in hyperthyroid rats. Morphologically, both T4 dose levels significantly increased myocyte width, an occurrence prevented by RAS or SNS blockers. There was a good correlation between changes in HW/BW and myocyte width. These results indicate that T4-induced cardiac hypertrophy is associated with both the SNS and the RAS.

  6. Prolonged fasting increases the response of the renin-angiotensin-aldosterone system, but not vasopressin levels, in postweaned northern elephant seal pups

    Science.gov (United States)

    Ortiz, R. M.; Wade, C. E.; Ortiz, C. L.

    2000-01-01

    The 8- to 12-week postweaning fast exhibited by northern elephant seal pups (Mirounga angustirostris) occurs without any apparent deleterious effects on fluid and electrolyte homeostasis. However, during the fast the role of vasopressin (AVP) has been shown to be inconclusive and the involvement of the renin-angiotensin-aldosterone system (RAAS) has yet to be examined. To examine the effects of prolonged fasting on these osmoregulatory hormones, 15 postweaned pups were serially blood-sampled during the first 49 days of their fast. Fasting did not induce significant changes in ionic or osmotic concentrations, suggesting electrolyte homeostasis. Total proteins were reduced by day 21 of fasting and remained depressed, suggesting a lack of dehydration. Aldosterone and plasma renin activity exhibited a correlated, linear increase over the first 49 days of the fast, suggesting an active RAAS. Aldosterone exhibited a parabolic trend over the fast with a peak at day 35, suggesting a shift in the sensitivity of the kidney to aldosterone later in the fast. AVP was elevated at day 49 only, but concentrations were relatively low. RAAS was modified during the postweaning fast in pups and appears to play a significant role in the regulation of electrolyte and, most likely, water homeostasis during this period. Copyright 2000 Academic Press.

  7. Effect of ipsilateral ureteric obstruction on contralateral kidney and role of renin angiotensin system blockade on renal recovery in experimentally induced unilateral ureteric obstruction

    Directory of Open Access Journals (Sweden)

    Shasanka S Panda

    2013-01-01

    Full Text Available Aims: To study, the effects of ipsilateral ureteric obstruction on contralateral kidney and the role of renin angiotensin system (RAS blockade on renal recovery in experimentally induced unilateral ureteric obstruction. Materials and Methods: Unilateral upper ureteric obstruction was created in 96 adult Wistar rats that were reversed after pre-determined intervals. Losartan and Enalapril were given to different subgroups of rats following relief of obstruction. Results: The severity of dilatation on the contralateral kidney varied with duration of ipsilateral obstruction longer the duration more severe the dilatation. There is direct correlation between renal parenchymal damage, pelvi-ureteric junction (PUJ fibrosis, inflammation and severity of pelvi-calyceal system dilatation of contralateral kidney with duration of ipsilateral PUJ obstruction. Conclusions: Considerable injury is also inflicted to the contralateral normal kidney while ipsilateral kidney remains obstructed. Use of RAS blocking drugs has been found to significantly improve renal recovery on the contralateral kidney. It can, thus, be postulated that contralateral renal parenchymal injury was mediated through activation of RAS.

  8. Effects of aqueous extract of Hibiscus sabdariffa on the renin-angiotensin-aldosterone system of Nigerians with mild to moderate essential hypertension: A comparative study with lisinopril.

    Science.gov (United States)

    Nwachukwu, Daniel Chukwu; Aneke, Eddy Ikemefuna; Obika, Leonard Fidelis; Nwachukwu, Nkiru Zuada

    2015-01-01

    The present study investigated the effects of aqueous extract of Hibiscus sabdariffa (HS) on the three basic components of renin-angiotensin-aldosterone system: Plasma renin, serum angiotensin-converting enzyme (ACE), and plasma aldosterone (PA) in mild to moderate essential hypertensive Nigerians and compared with that of lisinopril, an ACE inhibitor. A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreated mild to moderate hypertensive subjects attending Medical Outpatients Clinic of Enugu State University Teaching Hospital, Enugu were recruited for the study. Those in Group A received placebo (150 mg/kg/day), Group B were given lisinopril (10 mg once daily) while those in Group C received aqueous extract of HS (150 mg/kg/day). After 4 weeks of treatment, the levels of plasma renin, serum ACE, and PA were determined. HS and lisinopril significantly (P < 0.001) reduced PA compared to placebo by 32.06% and 30.01%, respectively. Their effects on serum ACE and plasma renin activity (PRA) were not significant compared to placebo; they reduced ACE by 6.63% and 5.67% but increased plasma PRA by 2.77% and 5.36%, respectively. HS reduced serum ACE and PA in mild to moderate hypertensive Nigerians with equal efficacy as lisinopril. These actions are possibly due to the presence of anthocyanins in the extract.

  9. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    Science.gov (United States)

    Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

    2015-01-01

    Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1–7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1–7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID:26569234

  10. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

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    Guoxing Wang

    2015-11-01

    Full Text Available Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg group. Thirty min after drug infusion, ventricular fibrillation (8 min and cardiopulmonary resuscitation (up to 30 min was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II and Ang (1–7 levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE, ACE2, Ang II type 1 receptor (AT1R, and the Ang (1–7 receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS, cyclic guanosine monophosphate (cGMP and inducible nitric oxide synthase(iNOS. Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation.

  11. Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B.

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    Saber, Sameh; Mahmoud, Amr A A; Helal, Noha S; El-Ahwany, Eman; Abdelghany, Rasha H

    2018-06-01

    Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl 4 -induced liver fibrosis. Mice were treated with silymarin (30 mg·kg -1 ), perindopril (1 mg·kg -1 ), fosinopril (2 mg·kg -1 ), or losartan (10 mg·kg -1 ). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

  12. Effector peptides of the renin-angiotensin system in the central mechanisms of acquired and innate behavior in thirst in rats.

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    Vlasenko, R Ya; Kotov, A V

    2007-03-01

    We report here a comparative analysis of the involvement of a number of components of the renin-angiotensin system in the performance of simple and complex forms of drinking behavior and thirst-associated non-drinking types of behavior. On central (intracerebroventricular) microinjection, [des-Asp1]-angiotensin I at doses equieffective to those of angiotensins II and III was found to be involved only in the performance of simple (taking water from the bowl) and linked forms of activity (comfort behavior, stress grooming, orientational-investigative, and feeding behavior). Angiotensin II was involved in the central mechanisms of complex acquired drinking behavior, selectively modulating its key stages (initial, final), while angiotensin III was involved only in the mechanisms of reproduction of the complex skill. All three substances induced "innate patterns of behavior" specific for each compound, these occurring at fixed periods of time after intracerebral microinjection. The effects of these substances were selectively suppressed by the AT1 receptor blocker losartan potassium.

  13. Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model

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    Yuki Narita

    2016-02-01

    Full Text Available We previously reported that camostat mesilate (CM had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE, a renin-angiotensin-aldosterone system (RAS inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day and/or TE (10 mg/kg/day on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA and plasma aldosterone concentration (PAC was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

  14. Protection against death and renal failure by renin-angiotensin system blockers in patients with diabetes and kidney disease.

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    Shen, Jian; Huang, Yan-Mei; Song, Xin-Nan; Hong, Xue-Zhi; Wang, Min; Ling, Wei; Zhang, Xiao-Xi; Zhao, Hai-Lu

    2016-07-01

    Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used to block the renin-angiotensin system (RAS). Yet it remains uncertain whether these drugs are equally effective and safe. Systematic reviews and meta-analyses of ACEis/ARBs in diabetes and kidney disease published in PubMed, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for clinical outcomes including all-cause mortality, end-stage renal disease (ESRD), hyperkalemia and cough. Eight meta-analyses included 2177-61,264 patients with follow-up of 6-108 months. RAS blockers reduced mortality (relative risk ratio (RR), 0.90, 95% confidence interval (CI), 0.86-0.95) without heterogeneity. The death protection was significant specifically with ACEis (RR, 0.85, 95% CI, 0.79-0.91), but not with ARBs. Protection against ESRD was homogenously evident by ARBs (RR, 0.79, 95% CI, 0.73-0.87), ACEis (RR, 0.79, 95% , 0.64-0.94), and both (RR, 0.79, 95% CI, 0.73-0.87). Significant side effects were hyperkalemia by ARBs (RR, 2.44, 95% CI, 1.13-5.26), and cough by ACEis (RR, 2.38, 95% CI, 1.75-3.22) CONCLUSIONS: In patients with diabetes and kidney disease, ACEis and ARBs are consistently protective for the development of ESRD. Use of ACEis alone additionally reduces deaths and increases the risk for cough. Use of ARBs alone increases the risk for hyperkalemia without additional benefit of death protection. © The Author(s) 2016.

  15. Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

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    Abraham, Alison G; Betoko, Aisha; Fadrowski, Jeffrey J; Pierce, Christopher; Furth, Susan L; Warady, Bradley A; Muñoz, Alvaro

    2017-04-01

    Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m 2 , median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

  16. Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

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    Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

    2015-09-01

    Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Analysis of renin-angiotensin aldosterone system gene polymorphisms in malaysian essential hypertensive and type 2 diabetic subjects

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    Stanslas Johnson

    2009-02-01

    Full Text Available Abstract Background The renin-angiotensin aldosterone system (RAAS plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT, MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects. Methods RAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM, 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects. Results There was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, MboI of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05. However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p Conclusion Among the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.

  18. Renin angiotensin system blockage associates with insertion/deletion polymorphism of angiotensin-converting enzyme in patients with hypertensive emergency.

    Science.gov (United States)

    Vilela-Martin, José F; Vaz-de-Melo, Renan O; Cosenso-Martin, Luciana N; Kuniyoshi, Cristina H; Yugar-Toledo, Juan C; Pinhel, Marcela A S; de Souza, Gisele F; Souza, Dorotéia R S; Pimenta, Eduardo; Moreno, Heitor; Cipullo, José P

    2013-09-01

    Hypertensive crisis (HC) stands out as a form of acute elevation of blood pressure (BP). It can manifest itself as hypertensive emergency (HE) or hypertensive urgency (HU), which is usually accompanied with levels of diastolic BP ≥120 mmHg. Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism may influence manifestations of HC. Thus, this study evaluated the influence of ACE I/D polymorphism in individuals with HC. A total of 187 patients admitted with HC (HU [n=69] and HE [n=118]) and 75 normotensive individuals were included in the study. Peripheral blood was drawn for a biochemical and genetic analysis of the ACE I/D polymorphism by Polymerase Chain Reaction. HC group showed higher systolic BP, body mass index (BMI), glycemia, creatinine, and lower high-density lipoprotein (HDL) cholesterol compared with normotensive individuals. The use of renin-angiotensin system (RAS) blockers was more frequent in the HU group than in the HE group (p=0.020). The II genotype was more predominant in normotensive and HU individuals than among HE individuals (18.7%, 11.6%, and 2.5%, respectively; p=0.004). Higher BMI and glycemia were associated with HC in the logistic regression model. ACE II genotype (odds ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.51) and HDL cholesterol were protective for the development of HE. ACE II genotype was present in the HU group, compared with the HE group (OR 0.18; 95% CI 0.04-0.88). This study shows an association between the low prevalence of ACE I/D polymorphism II genotype and a greater occurrence of HE in Brazilian individuals. The lower blockage of RAS, which was detected in the HE group, may interact with the low frequency of II genotype, conferring an increased risk for HE.

  19. Association of renin-angiotensin system genes polymorphism with progression of diabetic nephropathy in patients with type 1 diabetes mellitus

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    Ilić Vesna

    2014-01-01

    Full Text Available Background/Aim. Diabetic nephropathy (DN as a major microvascular complication of diabetes mellitus (DM include a progressive increase in urinary albumin excretion in association with an increase in blood pressure and to end stage renal failure. Hypertension connected with renin-angiotensin system (RAS hyperactivity and corresponding genotypes, angiotensinogen (AGT, angiotensine-converting enzyme (ACE and angiotensin II type 1 receptor (AT1R, predispose the increasing risk of DN. The aim of this study was to assess the distribution of AGT, ACE and AT1R gene polymorphisms in patients with type 1 DM according to the level of DN and patients clinical characteristics. Methods. The study included 79 type 1 diabetic patients. Inclusion criteria were: age between 20-40, duration of diabetes > 5 years, and no other severe diseases. Clinical characteristics were gained from interviewing the patients. Polymorphism was detected by polymerase chain reaction (PCR and restriction fragment length polymorphism using restriction enzymes Psy I (Tth 111 I and Hae III. Results. The patients with proteinuria compared with normo- and microalbuminuric patients, highly differed in age, diabetes duration, blood pressure level, hypertension, rethynopathy and urinary albumin excretion values (p < 0.001. No statistically significant difference between the groups was found for the ACE and AT1R gene polymorphisms distribution. The presence of TT genotype of the M235T polymorphism was significantly higher in the group with proteinuria (p < 0.05. The patients with hypertension raised nephropathy 5.2 times higher (OR = 5.20, p < 0.05 while carriers of TT allel developed nephropathy 28.38 times higher (OR = 28.389, p < 0.01 than those with MM genotype. Conclusion. Increased association of hypertension and TT angiotensinogen gene polymorphism in patients with diabetes mellitus with proteinuria could be a significant marker of diabetic nephropathy.

  20. Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

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    Chadwick, Jessica A; Bhattacharya, Sayak; Lowe, Jeovanna; Weisleder, Noah; Rafael-Fortney, Jill A

    2017-02-01

    Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD. Copyright © 2017 the American Physiological Society.

  1. Renin-angiotensin system blockers protect pancreatic islets against diet-induced obesity and insulin resistance in mice.

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    Eliete Dalla Corte Frantz

    Full Text Available BACKGROUND: The associations between obesity, hypertension and diabetes are well established, and the renin-angiotensin system (RAS may provide a link among them. The effect of RAS inhibition on type 2 diabetes is still unclear; however, RAS seems to play an important role in the regulation of the pancreas and glucose intolerance of mice fed high-fat (HF diet. METHODS: C57BL/6 mice fed a HF diet (8 weeks were treated with aliskiren (50 mg/kg/day, enalapril (30 mg/kg/day or losartan (10 mg/kg/day for 6 weeks, and the protective effects were extensively compared among groups by morphometry, stereological tools, immunostaining, Western blotting and hormonal analysis. RESULTS: All RAS inhibitors significantly attenuated the increased blood pressure in mice fed a HF diet. Treatment with enalapril, but not aliskiren or losartan, significantly attenuated body mass (BM gain, glucose intolerance and insulin resistance, improved the alpha and beta cell mass and prevented the reduction of plasma adiponectin. Furthermore, enalapril treatment improved the protein expression of the pancreatic islet Pdx1, GLUT2, ACE2 and Mas receptors. Losartan treatment showed the greatest AT2R expression. CONCLUSION: Our findings indicate that ACE inhibition with enalapril attenuated several of the deleterious effects of the HF diet. In summary, enalapril appears to be responsible for the normalization of islet morphology and function, of alpha and beta cell mass and of Pdx1 and GLUT2 expression. These protective effects of enalapril were attributed, primarily, to the reduction in body mass gain and food intake and the enhancement of the ACE2/Ang (1-7 /Mas receptor axis and adiponectin levels.

  2. Renin-angiotensin-aldosterone system inhibitors lower hemoglobin and hematocrit only in renal transplant recipients with initially higher levels.

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    Mikolasevic, I; Zaputovic, L; Zibar, L; Begic, I; Zutelija, M; Klanac, A; Majurec, I; Simundic, T; Minazek, M; Orlic, L

    2016-04-01

    We have analyzed the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on evolution of hemoglobin (Hb) and hematocrit (Htc) levels as well as on the evaluation of kidney graft function in stable renal transplant recipients (RTRs) in respect with initially higher or lower Hb and Htc values. The study group comprised of 270 RTRs with stable graft function. Besides other prescribed antihypertensive therapy, 169 of them have been taking RAAS inhibitors. We wanted to analyze the effect of the use of RAAS inhibitors on Hb and Htc in patients with initially higher or lower Hb/Htc values. For this analysis, only RTRs that were taking RAAS inhibitors were stratified into two groups: one with higher Hb and Htc (initial Hb≥150g/L and Htc≥45%) and another one with lower Hb and Htc (initial Hb<150g/L and Htc<45%) values. Thirty-four RTRs with initially higher Hb and 41 RTRs with initially higher Htc had a statistically significant decrease in Hb (p=0.006) and Htc (p<0.0001) levels after 12-months of follow-up. In the group of patients with initially lower Hb (135 RTRs) and Htc (128 RTRs) there was a significant increase in Hb (p=0.0001) and Htc (p=0.004) levels through the observed period. The use of RAAS inhibitors has been associated with a trend of slowing renal insufficiency in RTRs (p=0.03). RAAS inhibitors lower Hb and Htc only in RTRs with initially higher levels. In patients with initially lower Hb and Htc levels, the use of these drugs is followed by beneficial impact on erythropoiesis and kidney graft function. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  3. Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.

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    Zhou, Tian-Biao; Ou, Chao; Rong, Liang; Drummen, Gregor P C

    2014-09-01

    All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p system under hypoxia/reoxygenation conditions. © The Author(s) 2014.

  4. Interaction between sympathetic nervous system and renin angiotensin system on MMPs expression in juvenile rat aorta.

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

    2011-09-01

    The aim of our present study is to investigate the interaction between angiotensin II (ANG II) and sympathetic nervous system (SNS) on matrix metalloproteinase MMP-2 and MMP-9 expression and activity in juvenile rat aorta under normal conditions. Sympathectomy with guanethidine and blockade of the ANG II receptors (AT1R) by losartan were performed alone or in combination on new-born rats. mRNA, protein expression and activity of MMP-2 and MMP-9 were examined by Q-RT-PCR, immunoblotting and zymography, respectively. MMP-2 mRNA and protein amount were decreased after sympathectomy or AT1R blockade and an additive effect was observed after combined treatment. However, MMP-9 expression was reduced to the same level in the three treated groups. There were some detectable gelatinolytic activity of the MMPs in both control and treated rats. We concluded that ANG II stimulates directly and indirectly (via sympathostimulator pathway) the MMP-2 expression but seems unable to affect MMP-9 expression through direct pathway. Combined inhibition of SNS and ANG II were more efficient than a single inhibition in reducing MMP amounts in rat vessels.

  5. Role of the renin-angiotensin system, renal sympathetic nerve system, and oxidative stress in chronic foot shock-induced hypertension in rats.

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    Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

    2015-01-01

    The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.

  6. Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

    Science.gov (United States)

    Clase, Catherine M; Barzilay, Joshua; Gao, Peggy; Smyth, Andrew; Schmieder, Roland E; Tobe, Sheldon; Teo, Koon K; Yusuf, Salim; Mann, Johannes F E

    2017-03-01

    Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  7. The renin-angiotensin-aldosterone system (RAAS – physiology and molecular mechanisms of functioning

    Directory of Open Access Journals (Sweden)

    Monika Chaszczewska-Markowska

    2016-09-01

    Full Text Available Secretion of renin juxtaglomerular cells into bloodstream initiates activation of an enzymatic-hormonal cascade known as the RAAS (renin – angiotensin – aldosterone system. As a result, blood pressure is increased by the means several interrelated mechanisms. Mechanism of Zjednoczoaction of this system has been known for decades, but a few previously unknown components were recently added, such as ACE-2 and Ang(1-7, and their role often seems to be opposite to that of the conventional components. Local tissue systems also have important biological functions. They operate largely independently of the systemic activity, and their activity is observed primarily in the kidney, heart, in blood vessels, adrenal gland and nervous system. Angiotensin-2 (Ang-2, the main RAAS effector, has a wide scope of action, and thus abnormalities in its functioning have many consequences. Excessive activation is accompanied by chronic inflammation, as Ang-2 stimulates inflammatory mediators. As a result, degenerative processes and atherosclerosis are initiated. RAAS imbalance is associated with the most common diseases of civilization, such as cardio-vascular diseases, diabetes, kidney diseases, preeclampsia, osteoporosis and even neurodegenerative diseases. Many of these pathological processes are attributed to the excessive activation of tissue RA system. Therapeutic strategies based on inhibition of the RAAS are commonly used mainly in the treatment of hypertension and other cardiovascular disorders. The benefits of this class of drugs is primarily a decrease in blood pressure, but also the suppression of inflammatory processes and other pathological phenomena resulting from excessive activation of the RAAS. For that reason, some consider to use RAAS inhibitors in other diseases, e.g. Parkinson’s disease. Further studies give hope for the improvement of RAAS inhibitor therapy and the development of new therapeutic strategies

  8. Involvement of skeletal renin-angiotensin system and kallikrein-kinin system in bone deteriorations of type 1 diabetic mice with estrogen deficiency.

    Science.gov (United States)

    Zhang, Yan; Wang, Liang; Liu, Jin-Xin; Wang, Xin-Luan; Shi, Qi; Wang, Yong-Jun

    This study was aimed to investigate the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in bone deteriorations of mice in response to the combination treatment of estrogen deficiency and hyperglycemia. The female C57BL/6J mice were sham-operated or ovariectomized with vehicle or streptozotocin (STZ) treatment. Two weeks later, the biochemistries in serum and urine were determined by standard colorimetric methods or ELISA. The H&E and TRAP staining were performed at the tibial proximal metaphysis. The polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. The mice after treating with ovariectomy and STZ showed the decreased level of serum Ca and the increased level of serum PTH and urine Ca. The H&E staining showed trabecular bone abnormalities as demonstrated by the loss, disconnection and separation of trabecular bone network as well as the loss of chondrocytes and appearance of chondrocyte cluster at growth plate of tibia. The significant increase of matured osteoclast number was shown in group with double treatments. The combination treatment significantly up-regulated mRNA expression of AGT, ACE, renin receptor, MMP-9 and CAII, and protein expression of renin, and decreased the ratio of OPG/RANKL and the expression of bradykinin receptors in bone tissue. Ovariectomy combined with STZ induction produced more detrimental actions on bone through the activation of local bone RAS and the down-regulation of bradykinin receptors, as compared to the respective single treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Dietary calcium intake and Renin Angiotensin System polymorphisms alter the blood pressure response to aerobic exercise: a randomized control design

    Directory of Open Access Journals (Sweden)

    Tsongalis Gregory J

    2007-01-01

    Full Text Available Abstract Background Dietary calcium intake and the renin angiotensin system (RAS regulate blood pressure (BP by modulating calcium homeostasis. Despite similar BP regulatory effects, the influence of dietary calcium intake alone and combined with RAS polymorphisms on the BP response following acute aerobic exercise (i.e., postexercise hypotension has not been studied. Thus, we examined the effect of dietary calcium intake and selected RAS polymorphisms on postexercise hypotension. Methods Subjects were men (n = 50, 43.8 ± 1.3 yr with high BP (145.3 ± 1.5/85.9 ± 1.1 mm Hg. They completed three experiments: non-exercise control and two cycle bouts at 40% and 60% of maximal oxygen consumption (VO2max. Subjects provided 3 d food records on five protocol-specific occasions. Dietary calcium intake was averaged and categorized as low (1R A/C were analyzed with molecular methods. Genotypes were reduced from three to two: ACE II/ID and ACE DD; or AT1R AA and AT1R CC/AC. Repeated measure ANCOVA tested if BP differed among experiments, dietary calcium intake level and RAS polymorphisms. Results Systolic BP (SBP decreased 6 mm Hg after 40% and 60% VO2max compared to non-exercise control for 10 h with LowCa (p 2max versus non-exercise control for 10 h among ACE II/ID (6 mm Hg and AT1R AA (8 mm Hg; and by 8 mm Hg after 40% VO2max among ACE DD and AT1R CC/CA (p 2max compared to non-exercise control for 10 h (p 2max (p ≥ 0.05. Conclusion SBP decreased after exercise compared to non-exercise control among men with low but not high dietary calcium intake. Dietary calcium intake interacted with the ACE I/D and AT1R A/C polymorphisms to further modulate postexercise hypotension. Interactions among dietary calcium intake, exercise intensity and RAS polymorphisms account for some of the variability in the BP response to exercise.

  10. Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: "The Triple Whammy".

    Science.gov (United States)

    Camin, Rosa Maria Garcia; Cols, Montse; Chevarria, Julio Leonel; Osuna, Rosa García; Carreras, Marc; Lisbona, Josep Maria; Coderch, Jordi

    2015-01-01

    Renin-angiotensin system inhibitors (ACEI/ARB-II), diuretics and NSAIDs, a combination known as "Triple Whammy", can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI). Objectives: To describe the incidence of AKI for each drug type and their combinations. To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs (AKITW), with an assessment of costs and mortality. A retrospective observational 15-month study developed in three stages: - First: a cross-sectional stage to identify and describe hospitalizations due to AKITW. - Second: a follow-up stage of an outpatient cohort consuming these drugs (15,307 subjects). - Third: a cohort stage to assess costs and mortality, which compared 62 hospitalized patients with AKITW and 62 without AKI, paired by medical specialty, sex, age and comorbidity according to their Clinical Risk Groups. There were 85 hospitalization episodes due to AKITW, and 78% of patients were over the age of 70. The incidence of AKITW in the population was 3.40 cases/1000 users/year (95% CI: 2.59-4.45). By categories, these were: NSAIDs + diuretics 8.99 (95% CI: 3.16-25.3); Triple Whammy 8.82 (95% CI: 4.4-17.3); ACEI/ARB-II + diuretics 6.87 (95% CI: 4.81-9.82); and monotherapy with diuretics 3.31 (95% CI: 1.39-7.85). Mean hospital stay was 7.6 days (SD 6.4), and mean avoidable costs were estimated at €214,604/100,000 inhabitants/year. Mortality during hospitalization and at 12 months was 11.3% and 38.7% respectively, and there were no significant differences when compared with the control group. Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence. AKITW involves high health care costs and avoidable mortality. Copyright © 2015. Published by Elsevier España, S.L.U.

  11. Impact of The Protective Renin-Angiotensin System (RAS) on The Vasoreparative Function of CD34+ CACs in Diabetic Retinopathy

    Science.gov (United States)

    Duan, Yaqian; Moldovan, Leni; Miller, Rehae C.; Beli, Eleni; Salazar, Tatiana; Hazra, Sugata; Al-Sabah, Jude; Chalam, KV; Raghunandan, Sneha; Vyas, Ruchi; hide

    2016-01-01

    Purpose: In diabetes, the impaired vasoreparative function of Circulating Angiogenic Cells (CACs) is believed to contribute to the progression of diabetic retinopathy (DR). Accumulating evidence suggests that the protective arm of renin-angiotensin system (RAS) ACE2 Angiotensin-(1-7) Mas plays an important role in restoring the function of diabetic CACs. We examined the protective RAS in CACs in diabetic individuals with different stages of retinopathy. Methods: Study subjects (n43) were recruited as controls or diabetics with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fundus photography and fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ CACs were isolated from peripheral blood of diabetics and control subjects. RAS gene expressions in CACs were measured by qPCR. The vasoreparative function of CACs was assessed by migration ability toward CXCL12 using the QCM 5M 96-well chemotaxis cell migration assay. Results: ACE2 gene is a key enzyme converting the deleterious Angiotensin II to the beneficial Angiotensin-(1-7). ACE2 expression in CACs from diabetic subjects without DR was increased compared to controls, suggestive of compensation (p0.0437). The expression of Mas (Angiotensin-(1-7) receptor) in CACs was also increased in diabetics without DR, while was reduced in NPDR compared to controls (p0.0002), indicating a possible loss of compensation of the protective RAS at this stage of DR. The presence of even mild NPDR was associated with CD34+ CAC migratory dysfunction. When pretreating CACs of DR subjects with Angiotensin-(1-7), migratory ability to a chemoattractant CXCL12 was restored (p0.0008). By VESGEN analysis, an increase in small vessel density was observed in NPDR subjects when compared with the controls. Conclusions: These data suggest the protective RAS axis within diabetic CACs may help maintain their vasoreparative potential

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

    Science.gov (United States)

    Thomas, Julia D J; Dattani, Abhishek; Zemrak, Filip; Burchell, Thomas; Akker, Scott A; Kaplan, Felicity J L; Khoo, Bernard; Aylwin, Simon; Grossman, Ashley B; Davies, L Ceri; Korbonits, Márta

    2017-06-01

    Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m 2 , ANOVA p=0.034, B vs. C pAcromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension. © Georg Thieme Verlag KG Stuttgart · New York.

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

    Science.gov (United States)

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

    2016-01-01

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

  15. High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion.

    Science.gov (United States)

    Li, Caixia; Culver, Silas A; Quadri, Syed; Ledford, Kelly L; Al-Share, Qusai Y; Ghadieh, Hilda E; Najjar, Sonia M; Siragy, Helmy M

    2015-11-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis. Copyright © 2015 the American Physiological Society.

  16. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

    Science.gov (United States)

    Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

    2016-01-01

    Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

  17. Shifts in renin-angiotensin system components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa region of streptozotocin-induced diabetic mice.

    Science.gov (United States)

    Qian, Xiaobing; Lin, Leilei; Zong, Yao; Yuan, Yongguang; Dong, Yanmin; Fu, Yue; Shao, Wanwen; Li, Yujie; Gao, Qianying

    2018-03-01

    This study aimed to analyse shifts in renin-angiotensin system (RAS) components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa (LC) region in streptozotocin (STZ)-induced diabetic mice. Six months after diabetes induction, the retinal vessels of male C57BL/6 J mice were observed by colour photography, fundus fluorescein angiography (FFA), and immunofluorescent staining following incubation with CD31. Immunofluorescence for glial fibrillary acidic protein (GFAP), alpha-smooth muscle actin (α-SMA),and NG2 was also performed. Angiotensin-converting enzyme 1 (ACE1), angiotensin II type I receptor (AT1R), renin, hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and haeme oxygenase 1 (HO-1) expression levels were confirmed by immunohistochemical and western blotting analyses. Compared with control mice, diabetic mice had significantly higher blood glucose concentrations (p diabetic mice; however, immunostaining of whole-mount retinas revealed an increased number of retinal vessels. Furthermore, histopathological staining showed significant reduction in the whole retinal thickness. GFAP expression was slightly higher, whereas fewer NG2 + pericytes were observed in diabetic mice than in control mice. ACE1, AT1R, renin, HIF-1α, VEGF, VEGFR2, and HO-1 expression were up-regulated in the LC of the STZ-induced diabetic mice. Collectively, ACE 1, AT1R, HIF-1α, VEGF, VEGFR2, and HO-1 activation in the LC region in diabetic mice may be involved in diabetes via the RAS and induction of angiogenesis and oxidative stress.

  18. Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.

    Science.gov (United States)

    Boshra, Vivian; Abbas, Amr M

    2017-07-26

    Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 μg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 μg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.

  19. Study on the dynamic changes of the renin angiotensin system (RAS) in patients with acute pancreatitis

    International Nuclear Information System (INIS)

    An Yuliang; Zhou Li

    2002-01-01

    Objective: To assess the severity of acute pancreatitis (AP) by observing the changes of the plasma renin activity (PRA) and plasma angiotensin-II levels in those patients. Methods: Plasma concentrations of the PRA and AGT-II were determined with RIA in patients with severe acute pancreatitis (SAP), mild acute pancreatitis (MAP), acute cholecystitis (AC), acute appendicitis (AA), acute phase of peptic ulcer (PU, only AGT-II was measured) and in healthy controls (HC). In SAP and MAP patients, a second determination was done. Results: The plasma levels of the PRA and AGT-II within 24 hours after admission were 3.84 ±1.92 ng/ml·h, 386.68 ±178.53 pg/ml in SAP. A group; 1.88 ± 0.93 ng/ml·h, 142.68 ± 83.57 pg/ml in MAP. A group; 0.68 ±0.45 ng/ml·h, 43.51 ± 31.04 pg/ml in HC group. These variables are significantly higher in SAP. A and MAP. A groups than those in other groups. During the recovery period, they were 1.34 ± 0.76 ng/ml·h, 44.71 ± 27.93 pg/ml in SAP. R group, and 1.18 ± 0.69 ng/ml·h, 41.82 ± 17.88 pg/ml in MAP. R group. There were significant differences (p < 0.05) when comparing the SAP. A group with MAP. A group, and comparing HC group with SAP. A group and with MAP. A group respectively. The paired compartment of the AP (SAP. R/SAP. A and MAP. R/MAP. A) are also significantly differences (p < 0.05). For the same group of AP patients at different stage (SAP. R/SAP. A and MAP. R/MAP. A) those were also significant difference (p < 0.05 ). There are also significant (p < 0.05) difference comparing those values in SAP. A and MAP. A group with the AC, AA and PU group respectively. Conclusion: 1. RAAS are activated in patients with AP on account of the circulatory hypovolemia with various causes. The degree of activation is positively correlated to the seriousness of the disease process. Increase of the plasma level of AGT-II in patients with AP is a compensatory mechanism but it exacerbates the microcirculation impediment of the pancreas

  20. Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice.

    Science.gov (United States)

    Zhang, Y; Wang, L; Song, Y; Zhao, X; Wong, M S; Zhang, W

    2016-03-01

    The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and

  1. Assessment of the degree of oxidative stress injury, renin-angiotensin system activity and podocyte loss after combined treatment of keto acid with low protein diet for patients with diabetic nephropathy

    OpenAIRE

    Yuan-Hua Xu; Mei Wang

    2016-01-01

    Objective: To analyze the degree of oxidative stress injury, RAS activity and podocyte loss after patients with diabetic nephropathy received keto acid combined with low protein diet. Methods: A total of 106 cases of patients with diabetic nephropathy who received hospital treatment in our hospital from September 2012 to July 2015 were selected as research subjects and randomly divided into observation group and control group according to different treatment, each group with 53...

  2. Assessment of the degree of oxidative stress injury, renin-angiotensin system activity and podocyte loss after combined treatment of keto acid with low protein diet for patients with diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yuan-Hua Xu

    2016-03-01

    Full Text Available Objective: To analyze the degree of oxidative stress injury, RAS activity and podocyte loss after patients with diabetic nephropathy received keto acid combined with low protein diet. Methods: A total of 106 cases of patients with diabetic nephropathy who received hospital treatment in our hospital from September 2012 to July 2015 were selected as research subjects and randomly divided into observation group and control group according to different treatment, each group with 53 cases. Control group received low protein diet treatment alone, observation group received keto acid combined with low protein diet treatment, and then the degree of oxidative stress injury, RAS activity and podocyte loss of two groups were compared. Results: Serum MDA and AOPP levels of observation group after treatment were lower than those of control group, and levels of SOD and T-AOC were higher than those of control group; PRA, Ang栻 and Aldosterone levels of observation group after treatment were lower than those of control group; mRNA expression levels of podocin and synaptopodin in urine sediment of observation group after treatment were lower than those of control group. Conclusion: Keto acid combined with low protein diet treatment for patients with diabetic nephropathy can reduce the degree of oxidative stress injury and RAS activity, decrease podocyte loss and optimize patients’ condition.

  3. Potential impact of renin-angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients

    International Nuclear Information System (INIS)

    Nakagawa, Naoki; Yao, Naoyuki; Hirayama, Tomoya

    2011-01-01

    Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P<0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin-angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin-angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients. (author)

  4. Expression of renin-angiotensin system signalling compounds in maternal protein-restricted rats: effect on renal sodium excretion and blood pressure.

    Science.gov (United States)

    Mesquita, Flávia Fernandes; Gontijo, José Antonio Rocha; Boer, Patrícia Aline

    2010-02-01

    Intrauterine growth restriction due to low maternal dietary protein during pregnancy is associated with retardation of foetal growth, renal alterations and adult hypertension. The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. In the kidney, all the components of the renin-angiotensin system including angiotensin II type 1 (AT1) and type 2 (AT2) receptors are expressed locally during nephrogenesis. Hence, we investigated whether low protein diet intake during pregnancy altered kidney and adrenal expression of AT1(R) and AT2(R) receptors, their pathways and if the modified expression of the RAS compounds occurs associated with changes in urinary sodium and in arterial blood pressure in sixteen-week-old males' offspring of the underfed group. The pregnancy dams were divided in two groups: with normal protein diet (pups named NP) (17% protein) or low protein diet (pups LP) (6% protein) during all pregnancy. The present data confirm a significant enhancement in arterial pressure in the LP group. Furthermore, the study showed a significantly decreased expression of RAS pathway protein and Ang II receptors in the kidney and an increased expression in the adrenal of LP rats. The detailed immunohistochemical analysis of RAS signalling proteins in the kidney confirm the immunoblotting results for both groups. The present investigation also showed a pronounced decrease in fractional urinary sodium excretion in maternal protein-restricted offspring, compared with the NP age-matched group. This occurred despite unchanged creatinine clearance. The current data led us to hypothesize that foetal undernutrition could be associated with decreased kidney expression of AT(R) resulting in the inability of renal tubules to handle the hydro-electrolyte balance, consequently causing arterial hypertension.

  5. Living high training low induces physiological cardiac hypertrophy accompanied by down-regulation and redistribution of the renin-angiotensin system

    Science.gov (United States)

    Shi, Wei; Meszaros, J Gary; Zeng, Shao-ju; Sun, Ying-yu; Zuo, Ming-xue

    2013-01-01

    Aim: Living high training low” (LHTL) is an exercise-training protocol that refers living in hypoxia stress and training at normal level of O2. In this study, we investigated whether LHTL caused physiological heart hypertrophy accompanied by changes of biomarkers in renin-angiotensin system in rats. Methods: Adult male SD rats were randomly assigned into 4 groups, and trained on living low-sedentary (LLS, control), living low-training low (LLTL), living high-sedentary (LHS) and living high-training low (LHTL) protocols, respectively, for 4 weeks. Hematological parameters, hemodynamic measurement, heart hypertrophy and plasma angiotensin II (Ang II) level of the rats were measured. The gene and protein expression of angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor I (AT1) in heart tissue was assessed using RT-PCR and immunohistochemistry, respectively. Results: LLTL, LHS and LHTL significantly improved cardiac function, increased hemoglobin concentration and RBC. At the molecular level, LLTL, LHS and LHTL significantly decreased the expression of ACE, AGT and AT1 genes, but increased the expression of ACE and AT1 proteins in heart tissue. Moreover, ACE and AT1 protein expression was significantly increased in the endocardium, but unchanged in the epicardium. Conclusion: LHTL training protocol suppresses ACE, AGT and AT1 gene expression in heart tissue, but increases ACE and AT1 protein expression specifically in the endocardium, suggesting that the physiological heart hypertrophy induced by LHTL is regulated by region-specific expression of renin-angiotensin system components. PMID:23377552

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

    Directory of Open Access Journals (Sweden)

    Graziela S Ceravolo

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

  7. 8C.03: A KEY ROLE FOR ENDOTHELIN-1 IN THE PATHOGENESIS OF PREECLAMPSIA AND THE ASSOCIATED SUPPRESSION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM.

    Science.gov (United States)

    Verdonk, K; Saleh, L; Smilde, J E; van Ingen, M M; Garrelds, I M; Friesema, E C; Russcher, H; Steegers, E A P; van den Meiracker, A H; Visser, W; Danser, A H J

    2015-06-01

    Women with preeclampsia (PE) display low renin-angiotensin-aldosterone system (RAAS) activity and a high anti-angiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase-1(sFlt-1) and reduced levels of placental growth factor (PlGF). In the present study, we hypothesized that the RAAS suppression in PE is the consequence of the disturbed angiogenic balance. In a group of pregnant women with hypertensive disease of pregnancy and a group of healthy pregnant women, matched for gestational age (GA) we measured mean arterial blood pressure (MAP), urinary protein-to-creatinine ratio (PCR), and the plasma levels of sFlt-1, PlGF, albumin, creatinine, endothelin-1 (ET-1), renin (concentration and activity, PRC and PRA), angiotensinogen, and aldosterone. Since initial analysis revealed that these parameters strongly correlated with each other, multiple regression analysis was applied to establish independent determinants of ET-1, PRC, aldosterone and PCR. A sFlt-1/PlGF ratio >85 was considered to be representative for a high anti-angiogenic state. Of the 103 pregnant women included, 65 had a sFlt-1/PlGF ratio 85. Plasma ET-1 and creatinine levels were increased in women with a high ratio, whereas PRA and the plasma levels of renin, angiotensinogen, aldosterone and albumin were decreased in these women. The PRA-aldosterone relationship was identical in both groups. Multiple regression analysis revealed that PRC correlated independently with MAP and plasma ET-1 (R2 0.30). In turn, plasma ET-1 correlated positively with sFlt-1 and negatively with PRC (R2 0.52). Independent determinants of plasma aldosterone were GA and PRA (R2 0.56). Finally we found that plasma PlGF, plasma ET-1 and MAP determined PCR (R2 0.69). The high anti-angiogenic state in PE induces ET-1 activation. Together with the increased MAP in PE this factor suppresses renin release, and in parallel (via PRA reduction) aldosterone synthesis. The identical reduction in PRA and

  8. The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease.

    Science.gov (United States)

    Oh, Yun Jung; Kim, Sun Moon; Shin, Byung Chul; Kim, Hyun Lee; Chung, Jong Hoon; Kim, Ae Jin; Ro, Han; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Lee, Chungsik; Jung, Ji Yong

    2017-01-01

    Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071-1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123-1.500; P renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

  9. Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure - Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers.

    Science.gov (United States)

    Miura, Masanobu; Sugimura, Koichiro; Sakata, Yasuhiko; Miyata, Satoshi; Tadaki, Soichiro; Yamauchi, Takeshi; Onose, Takeo; Tsuji, Kanako; Abe, Ruri; Oikawa, Takuya; Kasahara, Shintaro; Nochioka, Kotaro; Takahashi, Jun; Shimokawa, Hiroaki

    2016-05-25

    It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients. From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (Pdiuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both Pdiuretics. Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

  10. Nephroprotective action of renin-angiotensin-aldosterone system blockade in chronic kidney disease patients: the landscape after ALTITUDE and VA NEPHRON-D trails.

    Science.gov (United States)

    Rutkowski, Boleslaw; Tylicki, Leszek

    2015-03-01

    The intervention in the renin-angiotensin-aldosterone system (RAAS) is currently the most effective strategy that combines blood pressure lowering and renoprotection. Several large, randomized, controlled trials evidenced the renoprotective potential of the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in nephropathies of almost any etiology. Mineralocorticoid receptor antagonists and direct renin inhibitor, aliskiren, as add-on treatments to standard therapy including the optimal dose of ACEIs or ARBs reduce albuminuria or proteinuria and slow development of renal dysfunction more than placebo. No clinical evidence is available however about whether these strategies may influence on long-term kidney outcome. Three recent trials suggested that aggressive RAAS blockade, that is, combination of 2 RAAS-blocking agents, does not decrease cardiovascular and renal morbidity and may carry an increased risk of serious complications. This article reviews an evidence-based approach on the use of RAAS-inhibiting agents in chronic kidney disease and considers the implementation of dual RAAS blockade with reference to the results of ALTITUDE and VA NEPHRON-D trails aiming to aid clinicians in their treatment decisions for patients with chronic kidney disease. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  11. Addition of ETA receptor blockade increases renoprotection provided by renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats

    Czech Academy of Sciences Publication Activity Database

    Čertíková; Chábová, V.; Vernerová, Z.; Kujal, P.; Husková, Z.; Škaroupková, P.; Tesař, V.; Kramer, H. J.; Kompanowska; Jezierska, E.; Walkowska, A.; Sadowski, J.; Červenka, L.; Vaněčková, Ivana

    2014-01-01

    Roč. 118, č. 2 (2014), s. 297-305 ISSN 0024-3205 R&D Projects: GA ČR(CZ) GAP304/12/0259 Institutional support: RVO:67985823 Keywords : renal failure * 5/6 nephrectomy * renin-angiotensin * endothelin * survival Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.702, year: 2014

  12. Expression of genes of the cardiac and renal renin-angiotensin systems in preterm piglets: is this system a suitable target for therapeutic intervention?

    Science.gov (United States)

    Kim, Eleanor; Eiby, Yvonne; Lumbers, Eugenie; Boyce, Amanda; Gibson, Karen; Lingwood, Barbara

    2015-10-01

    The newborn circulating, cardiac and renal renin-angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. © The Author(s), 2015.

  13. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system.

    Science.gov (United States)

    Wang, Lei; Zhu, Qing; Lu, Aihua; Liu, Xiaofen; Zhang, Linlin; Xu, Chuanming; Liu, Xiyang; Li, Haobo; Yang, Tianxin

    2017-09-01

    Butyrate, a short-chain fatty acid, is the end product of the fermentation of complex carbohydrates by the gut microbiota. Recently, sodium butyrate (NaBu) has been found to play a protective role in a number of chronic diseases. However, it is still unclear whether NaBu has a therapeutic potential in hypertension. The present study was aimed to investigate the role of NaBu in angiotensin II (Ang II)-induced hypertension and to further explore the underlying mechanism. Ang II was infused into uninephrectomized Sprague-Dawley rats with or without intramedullary infusion of NaBu for 14 days. Mean arterial blood pressure was recorded by the telemetry system. Renal tissues, serum samples, and 24-h urine samples were collected to examine renal injury and the regulation of the (pro)renin receptor (PRR) and renin. Intramedullary infusion of NaBu in Sprague-Dawley rats lowered the Ang II-induced mean arterial pressure from 129 ± 6 mmHg to 108 ± 4 mmHg (P renal injury, including urinary albumin, glomerulosclerosis, and renal fibrosis, as well as the expression of inflammatory mediators tumor necrosis factor α, interleukin 6. The renal expression of PRR, angiotensinogen, angiotensin I-converting enzyme and the urinary excretion of soluble PRR, renin, and angiotensinogen were all increased by Ang II infusion but decreased by NaBu treatment. In cultured innermedullary collecting duct cells, NaBu treatment attenuated Ang II-induced expression of PRR and renin. These results demonstrate that NaBu exerts an antihypertensive action, likely by suppressing the PRR-mediated intrarenal renin-angiotensin system.

  14. The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

    Science.gov (United States)

    Kelly, Tanika N; Raj, Dominic; Rahman, Mahboob; Kretzler, Matthias; Kallem, Radhakrishna R; Ricardo, Ana C; Rosas, Sylvia E; Tao, Kaixiang; Xie, Dawei; Hamm, Lotuce Lee; He, Jiang

    2015-10-01

    We conducted single-marker, gene- and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P renal events in both groups (both P < 1.00 × 10(-6)). No single-marker associations with CKD progression were observed. The current study provides strong evidence for a role of the RAAS in CKD progression. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  15. Maternal corticosterone exposure in the mouse programs sex-specific renal adaptations in the renin-angiotensin-aldosterone system in 6-month offspring.

    Science.gov (United States)

    Cuffe, James S M; Burgess, Danielle J; O'Sullivan, Lee; Singh, Reetu R; Moritz, Karen M

    2016-04-01

    Short-term maternal corticosterone (Cort) administration at mid-gestation in the mouse reduces nephron number in both sexes while programming renal and cardiovascular dysfunction in 12-month male but not female offspring. The renal renin-angiotensin-aldosterone system (RAAS), functions in a sexually dimorphic manner to regulate both renal and cardiovascular physiology. This study aimed to identify if there are sex-specific differences in basal levels of the intrarenal RAAS and to determine the impact of maternal Cort exposure on the RAAS in male and female offspring at 6 months of age. While intrarenal renin concentrations were higher in untreated females compared to untreated males, renal angiotensin II concentrations were higher in males than females. Furthermore, basal plasma aldosterone concentrations were greater in females than males. Cort exposed male but not female offspring had reduced water intake and urine excretion. Cort exposure increased renal renin concentrations and elevated mRNA expression of Ren1, Ace2, and Mas1 in male but not female offspring. In addition, male Cort exposed offspring had increased expression of the aldosterone receptor, Nr3c2 and renal sodium transporters. In contrast, Cort exposure increased Agtr1a mRNA levels in female offspring only. This study demonstrates that maternal Cort exposure alters key regulators of renal function in a sex-specific manner at 6 months of life. These finding likely contribute to the disease outcomes in male but not female offspring in later life and highlights the importance of renal factors other than nephron number in the programming of renal and cardiovascular disease. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  16. High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats.

    Science.gov (United States)

    Frantz, Eliete Dalla Corte; Giori, Isabele Gomes; Machado, Marcus Vinícius; Magliano, D'Angelo Carlo; Freitas, Fernanda Marques; Andrade, Mariana Sodré Boêta; Vieira, Aline Bomfim; Nóbrega, Antonio Claudio Lucas; Tibiriçá, Eduardo

    2017-10-01

    Metabolic syndrome is a cluster of metabolic risk factors that is linked to central obesity, elevated blood pressure, insulin resistance (IR), and dyslipidemia, where the renin-angiotensin system (RAS) may provide a link among them. This study aimed to evaluate volume exercise effects comparing low vs. high volume of chronic aerobic exercise on RAS axes in skeletal muscle in a diet-induced obesity (DIO) rat model. For this, male Wistar-Kyoto rats were fed a standard chow (SC) diet or a high-fat (HF) diet for 32 wk. Animals receiving the HF diet were randomly divided into low exercise volume (LEV, 150 min/wk) and high exercise volume (HEV, 300 min/wk) at the 20th week. After 12 wk of aerobic treadmill training, the body mass and composition, blood pressure, glucose and lipid metabolism, RAS axes, insulin signaling, and inflammatory pathway were performed. HEV slowed the body mass gain, reduced intra-abdominal fat pad and leptin levels, improved total and peripheral body composition and inflammatory cytokine, reduced angiotensin II type 1 receptor expression, and increased Mas receptor protein expression compared with the HF animals. Sedentary groups (SC and HF) presented lower time to exhaustion and maximal velocity compared with the LEV and HEV groups. Both exercise training groups showed reduced resting systolic blood pressure and heart rate, improved glucose tolerance, IR, insulin signaling, and lipid profile. We conclude that the HEV, but not LEV, shifted the balance of RAS toward the ACE2/Mas receptor axis in skeletal muscle, presenting protective effects against the DIO model. Copyright © 2017 the American Physiological Society.

  17. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade: A Randomized Clinical Trial.

    Science.gov (United States)

    de Vries, Laura V; Dobrowolski, Linn C; van den Bosch, Jacqueline J O N; Riphagen, Ineke J; Krediet, C T Paul; Bemelman, Frederike J; Bakker, Stephan J L; Navis, Gerjan

    2016-06-01

    In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown. We therefore studied the effects of dietary sodium restriction on BP and urinary albumin excretion (UAE) in kidney transplant recipients receiving RAAS blockade. Two-center randomized crossover trial. Stable outpatient kidney transplant recipients with creatinine clearance > 30mL/min, BP ≥120/80mmHg, receiving stable RAAS blockade therapy. 6-week regular-sodium diet (target, 150mmol/24 h) and a 6-week low-sodium diet (target, 50mmol/24 h). Main outcome parameters were systolic and diastolic BP, UAE, and estimated glomerular filtration rate (eGFR) at the end of each diet period. Dietary adherence was assessed by 24-hour urinary sodium excretion. We randomly assigned 23 kidney transplant recipients, of whom 22 (mean age, 58±8 [SD] years; 50% men; mean eGFR, 51±21mL/min/1.73m(2)) completed the study. One patient withdrew from the study because of concerns regarding orthostatic hypotension on the low-sodium diet. Sodium excretion decreased from 164±50mmol/24 h during the regular-sodium diet to 87±55mmol/24 h during the low-sodium diet (mean difference, -77 [95% CI, -110 to -44] mmol/24 h; Padherence to sodium diet was achieved in 86% of patients. In stable kidney transplant recipients receiving RAAS blockade, dietary sodium restriction effectively reduces BP without affecting eGFR. Dietary sodium restriction is relevant to BP management in kidney transplant recipients receiving RAAS blockade. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  18. Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Serena Pelusi

    Full Text Available The clinical determinants of fibrosis progression in nonalcoholic fatty liver disease (NAFLD are still under definition.To assess the clinical determinants of fibrosis progression rate (FPR in NAFLD patients with baseline and follow-up histological evaluation, with a special focus on the impact of pharmacological therapy.In an observational cohort of 118 Italian patients from tertiary referral centers, liver histology was evaluated according to Kleiner. Independent predictors of FPR were selected by a stepwise regression approach.Median follow-up was 36 months (IQR 24-77. Twenty-five patients (18% showed some amelioration, 63 (53% had stability, 30 (25% had progression of fibrosis. Patients with nonalcoholic steatohepatitis (NASH had similar demographic and anthropometric features, but a higher prevalence of type 2 diabetes (T2D; p = 0.010, and use of renin-angiotensin axis system (RAS inhibitors (p = 0.005. Fibrosis progression was dependent of the length of follow-up, and was associated with, but did not require, the presence of NASH (p<0.05. Both fibrosis progression and faster FPR were independently associated with higher APRI score at follow-up, absence of treatment with RAS inhibitors, and T2D diagnosis at baseline (p<0.05. There was a significant interaction between use of RAS inhibitors and T2D on FPR (p = 0.002. RAS inhibitors were associated with slower FPR in patients with (p = 0.011, but not in those without (p = NS T2D.NASH is not required for fibrosis progression in NAFLD, whereas T2D seems to drive fibrogenesis independently of hepatic inflammation. Use of RAS inhibitors may contrast fibrosis progression especially in high-risk patients affected by T2D.

  19. Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

    Science.gov (United States)

    Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

    2018-01-01

    In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

  20. Low birth weight in response to salt restriction during pregnancy is not due to alterations in uterine-placental blood flow or the placental and peripheral renin-angiotensin system.

    Science.gov (United States)

    Leandro, Sandra Márcia; Furukawa, Luzia Naôko Shinohara; Shimizu, Maria Heloisa Massola; Casarini, Dulce Elena; Seguro, Antonio Carlos; Patriarca, Giuliana; Coelho, Michella Soares; Dolnikoff, Miriam Sterman; Heimann, Joel Claudio

    2008-09-03

    A number of studies conducted in humans and in animals have observed that events occurring early in life are associated with the development of diseases in adulthood. Salt overload and restriction during pregnancy and lactation are responsible for functional (hemodynamic and hormonal) and structural alterations in adult offspring. Our group observed that lower birth weight and insulin resistance in adulthood is associated with salt restriction during pregnancy. On the other hand, perinatal salt overload is associated with higher blood pressure and higher renal angiotensin II content in adult offspring. Therefore, we hypothesised that renin-angiotensin system (RAS) function is altered by changes in sodium intake during pregnancy. Such changes may influence fetoplacental blood flow and thereby fetal nutrient supply, with effects on growth in utero and, consequently, on birth weight. Female Wistar rats were fed low-salt (LS), normal-salt (NS), or high-salt (HS) diet, starting before conception and continuing until day 19 of pregnancy. Blood pressure, heart rate, fetuses and dams' body weight, placentae weight and litter size were measured on day 19 of pregnancy. Cardiac output, uterine and placental blood flow were also determined on day 19. Expressions of renin-angiotensin system components and of the TNF-alpha gene were evaluated in the placentae. Plasma renin activity (PRA) and plasma and tissue angiotensin-converting enzyme (ACE) activity, as well as plasma and placental levels of angiotensins I, II, and 1-7 were measured. Body weight and kidney mass were greater in HS than in NS and LS dams. Food intake did not differ among the maternal groups. Placental weight was lower in LS dams than in NS and HS dams. Fetal weight was lower in the LS group than in the NS and HS groups. The PRA was greater in LS dams than in NS and HS dams, although ACE activity (serum, cardiac, renal, and placental) was unaffected by the level of sodium intake. Placental levels of

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

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2004-01-01

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

  2. Angiotensin-converting enzyme 2, Angiotensin-(1-7) and Mas: new players of the Renin Angiotensin System

    DEFF Research Database (Denmark)

    Santos, Robson AS; Ferreira, Anderson J; Verano-Braga, Thiago

    2013-01-01

    /proliferative arm of the RAS consisting of ACE, Ang II and AT1 receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions...

  3. Benefits of early intervention in the progression of cardiovascular disease - role of renin-angiotensin system blockade

    International Nuclear Information System (INIS)

    Jaffary, M.H.

    2002-01-01

    Atherosclerosis is a slowly progressive process. It begins early, progresses insidiously for many years, remains asymptotic and by the time it manifests as coronary artery disease or stroke, the atherosclerotic burden is immense. The question in that why does it remain asymptotic for so long? The answer lies in the fact that blood vessels are able to accommodate huge amount of plaque before the lumen becomes compromised. It is only when the plaque burden becomes severe that the lumen of the vessels becomes clogged and the symptoms start appearing. In fact the atherosclerotic process begins after the first decade of life. More so in the recent years when the fast food culture has prevailed along with significant changes in life style with decreased physical activity and increasing trend towards obesity. The process progresses steadily over the third and fourth decade of life and beyond. The fatty streaks grow to form fibrous plaques which may narrow or occlude the arterial lumen. Complex lesions may become unstable and rupture, leading to acute coronary events such as unstable angina, myocardial infarction and stroke. (author)

  4. Differential control of collagen synthesis by the sympathetic and renin-angiotensin systems in the rat left ventricle.

    Science.gov (United States)

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

    2009-12-03

    In the present study, we tested the hypothesis of the indirect (via the sympathetic nervous system (SNS)) and direct (via AT1 receptors) contributions of Angiotensin II (Ang II) on the synthesis of collagen types I and III in the left ventricle (LV) in vivo. Sympathectomy and blockade of the Ang II receptor AT1 were performed alone or in combination in normotensive rats. The mRNA and protein synthesis of collagen types I and III were examined by Q-RT-PCR and immunoblotting in the LV. Collagen types I and III mRNA were decreased respectively by 53% and 22% after sympathectomy and only collagen type I mRNA was increased by 52% after AT1 receptor blockade. mRNA was not changed for collagen type I but was decreased by 25% for collagen type III after double treatment. Only collagen protein type III was decreased after sympathectomy by 12%, but collagen proteins were increased respectively for types I and III by 145% and 52% after AT1 receptor blockade and by 45% and 60% after double treatment. Deducted interpretations from our experimental approach suggest that Ang II stimulates indirectly (via SNS) and inhibits directly (via AT1 receptors) the collagen type I at transcriptional and protein levels. For collagen type III, it stimulates indirectly the transcription and inhibited directly the protein level. Therefore, the Ang II regulates collagen synthesis differently through indirect and direct pathways.

  5. Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses.

    Science.gov (United States)

    Catalá-López, Ferrán; Macías Saint-Gerons, Diego; González-Bermejo, Diana; Rosano, Giuseppe M; Davis, Barry R; Ridao, Manuel; Zaragoza, Abel; Montero-Corominas, Dolores; Tobías, Aurelio; de la Fuente-Honrubia, César; Tabarés-Seisdedos, Rafael; Hutton, Brian

    2016-03-01

    Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with

  6. Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses.

    Directory of Open Access Journals (Sweden)

    Ferrán Catalá-López

    2016-03-01

    Full Text Available Medications aimed at inhibiting the renin-angiotensin system (RAS have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes.Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014. Interventions of interest were angiotensin-converting enzyme (ACE inhibitors, angiotensin receptor blockers (ARBs, and direct renin (DR inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants, with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18, ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19, DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81, and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38. For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40, ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29, DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57, and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84. No significant differences were showed between ACE inhibitors and ARBs with

  7. Expressions of renin, angiotensin II and aldosterone in patients with viral hepatitis or hepatic cirrhosis

    International Nuclear Information System (INIS)

    Huo Ying; Zhu Yalin; Liu Yun

    2008-01-01

    Objective: To explore the changes of renin, angiotensin and aldosterone system in patients with hepatic disorders. Methods: Plasma renin activity (PRA), AT-II and Ald levels were measured with RIA in 31 patients with viral hepatitis, 35 patients with hepatic cirrhosis and 38 controls. Results: The levels of PRA, AT-II and Ald in patients with viral hepatitis were slightly but non-significantly higher than those in controls (P>0.05). The levels of PRA, AT-II and Ald in patients with cirrhosis were significantly higher than those in controls (P<0.01). Conclusion: RAAS was activated during progression of hepatic disorders and participated in the development of hepatic fibrosis. (authors)

  8. Association between renin-angiotensin system antagonist use and mortality in heart failure with severe renal insufficiency: a prospective propensity score-matched cohort study.

    Science.gov (United States)

    Edner, Magnus; Benson, Lina; Dahlström, Ulf; Lund, Lars H

    2015-09-07

    In heart failure (HF) with reduced ejection fraction (EF), renin-angiotensin receptor (RAS) antagonists reduce mortality. However, severe renal insufficiency was an exclusion criterion in trials. We tested the hypothesis that RAS antagonists are associated with reduced mortality also in HF with severe renal insufficiency. We studied patients with EF ≤39% registered in the prospective Swedish Heart Failure Registry. In patients with creatinine >221 µmol/L or creatinine clearance renal insufficiency. Between 2000 and 2013, there were 24 283 patients of which 2410 [age, mean (SD), 82 (9), 45% women] had creatinine >221 µmol/L or creatinine clearance renal insufficiency [n = 21 873; age 71 (12), 27% women], the matched HR was 0.79 (95% CI 0.72-0.86, P renal insufficiency, the use of RAS antagonists was associated with lower all-cause mortality. Prospective randomized trials are needed before these findings can be applied to clinical practice. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  9. High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets.

    Science.gov (United States)

    de Oliveira Sá, Guilherme; Dos Santos Neves, Vívian; de Oliveira Fraga, Shyrlei R; Souza-Mello, Vanessa; Barbosa-da-Silva, Sandra

    2017-11-15

    HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed. Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group). HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT. This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot.

    Science.gov (United States)

    Bokma, Jouke P; Winter, Michiel M; van Dijk, Arie P; Vliegen, Hubert W; van Melle, Joost P; Meijboom, Folkert J; Post, Martijn C; Berbee, Jacqueline K; Boekholdt, S Matthijs; Groenink, Maarten; Zwinderman, Aeilko H; Mulder, Barbara J M; Bouma, Berto J

    2018-04-03

    The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] 0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EFtetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905. © 2017 American Heart Association, Inc.

  11. Polymorphisms of three genes (ACE, AGT and CYP11B2) in the renin-angiotensin-aldosterone system are not associated with blood pressure salt sensitivity: A systematic meta-analysis.

    Science.gov (United States)

    Sun, Jiahong; Zhao, Min; Miao, Song; Xi, Bo

    2016-01-01

    Many studies have suggested that polymorphisms of three key genes (ACE, AGT and CYP11B2) in the renin-angiotensin-aldosterone system (RAAS) play important roles in the development of blood pressure (BP) salt sensitivity, but they have revealed inconsistent results. Thus, we performed a meta-analysis to clarify the association. PubMed and Embase databases were searched for eligible published articles. Fixed- or random-effect models were used to pool odds ratios and 95% confidence intervals based on whether there was significant heterogeneity between studies. In total, seven studies [237 salt-sensitive (SS) cases and 251 salt-resistant (SR) controls] for ACE gene I/D polymorphism, three studies (130 SS cases and 221 SR controls) for AGT gene M235T polymorphism and three studies (113 SS cases and 218 SR controls) for CYP11B2 gene C344T polymorphism were included in this meta-analysis. The results showed that there was no significant association between polymorphisms of these three polymorphisms in the RAAS and BP salt sensitivity under three genetic models (all p > 0.05). The meta-analysis suggested that three polymorphisms (ACE gene I/D, AGT gene M235T, CYP11B2 gene C344T) in the RAAS have no significant effect on BP salt sensitivity.

  12. The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point.

    Science.gov (United States)

    Sica, Domenic A

    2010-04-01

    The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.

  13. Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis.

    Science.gov (United States)

    Zhao, Hong-Jin; Li, Yan; Liu, Shan-Mei; Sun, Xiang-Guo; Li, Min; Hao, Yan; Cui, Lian-Qun; Wang, Ai-Hong

    2016-07-01

    The renoprotective effect of inhibitors of renin-angiotensin system (RAS) has been identified through placebo-controlled trials. However, the effect of calcium-channel blockers (CCBs) on renal system is still controversial. Our current meta-analysis includes available evidences to compare the effect of dihydropyridine CCBs and ACEIs or ARBs on renal outcomes and mortality. We also further investigate whether CCBs can be used in combination with inhibitors of RAS to improve the prognosis of patients with chronic kidney disease (CKD). Electronic databases were searched up to July 2012, for clinical randomized controlled trials, assessing the effect of dihydropyridine CCBs on the incidence of end-stage renal disease (ESRD) and all-cause mortality in contrast to ACEIs or ARBs. Eight clinical trials were included containing 25,647 participants. ESRD showed significantly higher frequency with CCBs therapy compared with ACEIs or ARBs therapy, though blood pressure was decreased similarly in both groups in every trial (OR, 1.25; 95% CI, 1.05-1.48; p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEIs or ARBs exhibited better renoprotective effect compared to CCBs (OR, 0.96; 95% CI, 0.89-1.03; p = 0.24). CCBs did not increase all-cause mortality incidence in patients with CKD though they displayed weaker renoprotective, compared to ACEIs or ARBs therapy. Our results suggest the combination of a CCB and an ACEI or ARB should be a preferable antihypertensive therapy in patients with CKD, considering their higher effect in decreasing blood pressure and fewer adverse metabolic problems caused.

  14. Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20).

    Science.gov (United States)

    Erdmann, Erland; Spanheimer, Robert; Charbonnel, Bernard

    2010-09-01

    Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  15. Radioimmunoassay - renin - angiotensin. Principles of radioimmunoassay and their application in measuring renin and angiotensin

    Energy Technology Data Exchange (ETDEWEB)

    Krause, D K; Hummerich, W; Poulsen, K [eds.

    1978-01-01

    Typical pitfalls such as impurity of 'standard', tracer damage, crossreactivity of antiserum, unspecific binding of protecting proteins, blank effects with negative results, charcoal stripping, invisible coprecipitate or uncertainty in the analysis of the calibration curve (graph, logit-log, polynormal or spline function) can occur in any type of radioimmunoassay; they are detailed in the general part of this book. The special position occupied by radioimmunological quantification of parameters of the renin-angiotensin system creates additional, even more serious problems. While the radioimmunological determination of the decapeptide angiotensin I no longer causes major obstacles, measurement of the biologically active octapeptide angiotensin II is still only possible in a few centers. The (indirect) determination of plasma renin is characterized by a situation where the enzyme renin may be clearly defined in theory as a specific 10-11-leucine-leucine-endopeptidase cleaving only a decapeptide, but the actual renin assay, however, measures various forms of renin and other angiotensin-forming (or angiotensin-destroying) enzymes at the same time.

  16. The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-I levels

    NARCIS (Netherlands)

    Asselbergs, Folkert W.; Williams, Scott M.; Hebert, Patricia R.; Coffey, Christopher S.; Hillege, Hans L.; Navis, Gerjan; Vaughan, Douglas E.; van Gilst, Wiek H.; Moore, Jason H.

    2006-01-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor I (PAI-I) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-I levels in a large population-based sample from the

  17. The renin-angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis

    OpenAIRE

    Arganaraz, Gustavo Adolfo [UNIFESP; Konno, Ana Carla [UNIFESP; Perosa, Sandra Regina [UNIFESP; Santiago, Joselita Ferreira Carvalho [UNIFESP; Boim, Mirian A. [UNIFESP; Vidotti, Daniela Berguio [UNIFESP; Varella, Pedro Paulo Vasconcellos [UNIFESP; Costa, Luciana Gilbert [UNIFESP; Canzian, Mauro; Porcionatto, Marimelia Aparecida [UNIFESP; Yacubian, Elza Marcia [UNIFESP; Sakamoto, Americo Ceiki [UNIFESP; Carrete, Henrique [UNIFESP; Centeno, Ricardo Silva [UNIFESP; Amado, Debora [UNIFESP

    2008-01-01

    Purpose: As reported by several authors, angiotensin II (AngII) is a proinflammatory molecule that stimulates the release of inflammatory cytokines and activates nuclear factor kappa B (NF kappa B), being also associated with the increase of cellular oxidative stress. Its production depends on the activity of the angiotensin converting enzyme (ACE) that hydrolyzes the inactive precursor angiotensin I (AngI) into AngII. It has been suggested that AngII underlies the physiopathological mechanis...

  18. Differential control of MMP and t-PA/PAI-1 expressions by sympathetic and renin-angiotensin systems in rat left ventricle.

    Science.gov (United States)

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

    2009-10-05

    In the present study, we tested the hypothesis that angiotensin II (Ang II) has both direct (via AT1 receptors) and indirect (via sympathostimulator pathway) actions on the synthesis and activity of the enzymes involved in the extracellular matrix degradation in vivo. For this purpose, sympathectomy and blockade of the Ang II receptor AT1 were performed alone or in combination in normotensive rats. The mRNA of the plasminogen activator (t-PA) and its inhibitor (PAI-1), the mRNA, protein and activity of the matrix metalloproteinases MMP-2 and MMP-9 were examined by Q-RT-PCR, immunoblotting and zymographic methods in the left ventricle. t-PA and PAI-1 mRNA were decreased after sympathectomy and remained unchanged after AT1 receptors blockade. mRNA was increased for t-PA and decreased by similar degree for PAI-1 after double treatment. MMPs mRNA and protein levels were decreased either after sympathectomy or AT1 receptors blockade and an additive effect was acquired after double treatment. MMPs activity was decreased by similar degree in the three treated groups. Deducted interpretations from our experimental approach suggest that Ang II inhibits directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) t-PA mRNA synthesis. It seems unable to influence directly PAI-1 mRNA, but stimulates indirectly PAI-1 mRNA synthesis. Ang II stimulates directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) MMPs synthesis at both transcriptional and protein levels. The enzymatic activity of MMPs does not seem to be influenced directly by Ang II but it could be stimulated indirectly (via sympathostimulator pathway).

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

    NARCIS (Netherlands)

    Mirkovic, K.; Frenay, A.S.; Born, J. van den; Goor, H van; Navis, G.; Borst, M.H. de; Bindels, R.J.M.; Hoenderop, J.G.J.; Hillebrands, J.L.

    2017-01-01

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

  20. The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats.

    Science.gov (United States)

    Maleki, Maryam; Hasanshahi, Jalal; Moslemi, Fatemeh

    2018-01-01

    Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin-Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. In female rats, the serum and kidney nitrite levels increased significantly by Ang II ( P < 0.05) and decreased significantly ( P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups ( P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats ( P < 0.05). Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.

  1. QGQS Granule in SHR Serum Metabonomics Study Based on Tools of UPLC-Q-TOF and Renin-Angiotensin-Aldosterone System Form Protein Profilin-1

    Directory of Open Access Journals (Sweden)

    Ke Li

    2017-01-01

    Full Text Available QGQS granule is effective for the therapeutic of hypertension in clinic. The aim of this research is to observe the antihypertension effect of QGQS granule on SHR and explain the mechanism of its lowering blood pressure. 30 SHR were selected as model group, captopril group, and QGQS group, 10 WKYr were used as control group, and RBP were measured on tail artery consciously. And all the serum sample analysis was carried out on UPLC-TOF-MS system to determine endogenous metabolites and to find the metabonomics pathways. Meanwhile, ELISA kits for the determination pharmacological indexes of PRA, AngI, AngII, and ALD were used for pathway confirmatory; WB for determination of profilin-1 protein expression was conducted for Ang II pathway analysis as well. It is demonstrated that QGQS granule has an excellent therapeutic effect on antihypertension, which exerts effect mainly on metabonomics pathway by regulating glycerophospholipid, sphingolipid, and arachidonic acid metabolism, and it could inhibit the overexpression of the profilin-1 protein. We can come to a conclusion that RAAS should be responsible mainly for the metabonomics pathway of QGQS granule on antihypertension, and it plays a very important role in protein of profilin-1 inhibition.

  2. Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload.

    Directory of Open Access Journals (Sweden)

    Elena Montes-Cobos

    Full Text Available Mineralocorticoid receptor (MR inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox. Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes.

  3. [The effects of renin-angiotensin system blockade on the liver steatosis in rats on long-term high-fat diet].

    Science.gov (United States)

    Chen, Ying-Hua; Yuan, Li; Chen, Yuan-Yuan; Qi, Cui-Juan

    2008-03-01

    To observe the relationship between liver steatosis in rats with long-term high-caloric and high-fat diet and the expression of angiotensinogen (AGT), uncoupling protein 2 (UCP-2) and transforming growth factor beta1 (TGFbeta1). Then angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) drugs were given to investigate whether rennin-angiotensin system (RAS) blockade can mitigate the liver steatosis and to probe its mechanisms. Forty male Wistar rats were divided into normal control group (NC group, n = 10), high-calorie and high-fat fed group (HF group, n = 10), ARB treated group (AR group, n = 10) and ACEI treated group (AE group, n = 10). Rats were fed with high-calorie and high-fat diet and given RAS inhibitor drugs (valsartan 40 mg/kg to the AR group and perindopril 4 mg/kg to the AE group) for eight weeks. Serum TG, free fatty acids (FFAs) lever and the fat content in liver were then measured with biochemical tests; insulin resistance was evaluated with euglycemic hyperinsulinemia clamp technique, the expression of UCP-2 and TGFbeta1 in liver tissue were examined with immunohistochemical staining and AGT mRNA, UCP-2 mRNA and TGFbeta1 mRNA were tested with RT-PCR. With the administration of RAS inhibitor drugs, following changes were observed. The levels of TG and FFAs and the fat content in liver decreased (P liver steatosis, inflammation and fibrosis were mitigated. The levels of UCP-2 decreased by 36.5% (P liver injury of long term high-fat fed rats and have a protective effect on liver. The mechanism may be associated with the effects of improved insulin resistance, the interaction within RAS and the down-regulation of UCP-2 and TGFbeta1 in liver tissue.

  4. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs.

    Science.gov (United States)

    Mochel, Jonathan P; Fink, Martin; Peyrou, Mathieu; Soubret, Antoine; Giraudel, Jérôme M; Danhof, Meindert

    2015-06-01

    The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs. Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed. The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span. The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.

  5. Renin-angiotensin system blockade alone or combined with ETA receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic hypertensive rats

    Czech Academy of Sciences Publication Activity Database

    Sedláková, L.; Čertíková; Chábová, V.; Doleželová, Š.; Škaroupková, P.; Kopkan, L.; Husková, Z.; Červenková, L.; Kikerlová, S.; Vaněčková, Ivana; Sadowski, J.; Kompanowska; Jezierska, E.; Kujal, P.; Kramer, H. J.; Červenka, L.

    2017-01-01

    Roč. 39, č. 2 (2017), s. 183-195 ISSN 1064-1963 Institutional support: RVO:67985823 Keywords : chronic kidney disease * endothelin system * hypertension * renin–angiotensin system * 5/6 nephrectomy Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery OBOR OECD: Cardiac and Cardiovascular systems Impact factor: 1.162, year: 2016

  6. Dual renin-angiotensin system blockade plus oral methylprednisone for the treatment of proteinuria in IgA nephropathy Doble bloqueo del sistema renina-angiotensina más metilprednisona oral para el tratamiento de la proteinuria en la nefropatía por IgA

    Directory of Open Access Journals (Sweden)

    Hernán Trimarchi

    2007-10-01

    Full Text Available Renin-angiotensin system inhibition is a widely accepted approach to initially deal with proteinuria in IgA nephropathy, while the role of immunosuppressants remains controversial in many instances. A prospective, uncontrolled, open-label trial was undertaken in patients with biopsy-proven IgA nephropathy with proteinuria > 0.5 g/day and normal renal function to assess the efficacy of a combination treatment of angiotensin converting enzyme inhibitors plus angiotensin receptor blockers enalapril valsartan coupled with methylprednisone to decrease proteinuria to levels below 0.5 g/day. Twenty patients were included: Age 37.45 ± 13.26 years (50% male; 7 patients (35% were hypertensive; proteinuria 2.2 ± 1.86 g/day; serum creatinine 1.07 ± 0.29 mg/dl; mean follow-up 60.10 ± 31.47 months. IgA nephropathy was subclassified according to Haas criteria. Twelve patients (60% were class II; seven (35% were class III and one (5% class V. All patients received dual reninangiotensin system blockade as tolerated. Oral methylprednisone was started at 0.5 mg/kg/day for the initial 8 weeks and subsequently tapered bi-weekly until the maintenance dose of 4 mg was reached. Oral steroids were discontinued after 24 weeks (6 months of therapy but renin-angiotensin inhibition remained unchanged. At 10 weeks of therapy proteinuria decreased to 0.15 ± 0.07 g/day (P El doble bloqueo del sistema renina-angiotensina con inhibidores de la enzima convertidora de angiotensina junto a bloqueadores del receptor tipo I de angiotensina II es aceptado como tratamiento en la proteinuria de la nefropatía por IgA, ya que el rol de los inmunosupresores continúa siendo controvertido. Estudio prospectivo, no controlado, abierto para pacientes con nefropatía por IgA con proteinurias >0.5 g/día y creatininas séricas <1.4 mg/dl, para evaluar la eficacia de tratamiento de enalapril más valsartán asociado a metilprednisona vía oral para disminuir las proteinurias a <0.5 g

  7. Effects of single and repeated doses of the calcium antagonist felodipine on blood pressure, renal function, electrolytes and water balance, and renin-angiotensin-aldosterone system in hypertensive patients.

    Science.gov (United States)

    Leonetti, G; Gradnik, R; Terzoli, L; Fruscio, M; Rupoli, L; Cuspidi, C; Sampieri, L; Zanchetti, A

    1986-01-01

    Doses of 10 mg b.i.d. of the new dihydropyridine calcium antagonist, felodipine, were tested for seven consecutive days in 11 hospitalized hypertensive patients. A significant reduction of both systolic and diastolic blood pressures, with patients in both the supine and upright positions, occurred immediately after the first dose and was maintained (daily average 15%) throughout the following days. An increase in heart rate was observed after the first dose (15 and 23 beats/min, in supine and upright postures), and subsequently declined to average values of 8 and 14 beats/min on the seventh day. There was a marked natriuretic response during the first and second day, during which an average negative sodium balance of 95 mmol developed; on the following days sodium output was not significantly different from control, but a negative balance averaging 135 mmol was still present on the seventh day of felodipine administration. A moderate negative potassium balance also progressively developed and reached -48 mmol on the seventh day. Glomerular filtration rate was unchanged, but renal plasma flow increased significantly during administration of felodipine. Plasma renin activity and plasma aldosterone were also increased very moderately by felodipine. Compared with previous observations by our group with higher doses of felodipine (12.5, 25, and 50 mg t.i.d.), 10 mg b.i.d. of this new calcium antagonist appear to exert a marked and prolonged blood pressure reduction, accompanied by a definite natriuretic instead of an antinatriuretic effect.

  8. Modulation of the renin-angiotensin system by food protein ...

    African Journals Online (AJOL)

    Chibuike

    high fat, high sugar, low fibre diet – is another modifiable risk factor for .... identifying appropriate proteolytic enzymes and food protein raw materials, based on .... consumption of milk protein hydrolysates enriched with the LTPs,. IPP/VPP ...

  9. Lipids, inflammation, and the Renin-Angiotensin System

    NARCIS (Netherlands)

    Harst, Pim van der

    2006-01-01

    Summary and Future Perspectives Impaired endothelial function is recognized as one of the earliest events of atherogenesis.1, 2 In Part I, chapter 1, we discussed the clinical value of the different techniques to evaluate endothelium-dependent vasomotor function. We also reviewed the efficacy of

  10. Effect of Dual Blockade of Renin-Angiotensin Aldosterone System ...

    African Journals Online (AJOL)

    Purpose: To investigate the dual effect of angiotensin blockade by irbesartan and enalapril on proteinuria in diabetic patients with azotemia. Methods: Patients with diabetes of > 5 years duration, proteinuria at a nephrotic level and serum creatinine > 1.5 mg/dL were enrolled in the study. Forty-five enrolled patients were ...

  11. Effect of Dual Blockade of Renin-Angiotensin Aldosterone System ...

    African Journals Online (AJOL)

    Methods: Patients with diabetes of > 5 years duration, proteinuria at a ... nephropathy, Azotemia, Proteinuria, Aldosterone, Renin, Blood pressure ... Hypertension is a risk factor that exacerbates all ... Arterial tension values of the patients were measured with an. ERKA sleeve .... receiving treatment remained within normal.

  12. Therapeutic targets of renin-angiotensin system in ocular disorders

    Directory of Open Access Journals (Sweden)

    Rajesh Choudhary

    2017-03-01

    Conclusions: The RAS components are present in the extrarenal tissues including ocular tissue and have an imperative role in the ocular pathophysiology. The clinical studies are needed to show the role of therapeutic modalities targeting RAS in the treatment of different ocular disorders.

  13. Renin-angiotensin system in human coronavirus pathogenesis

    NARCIS (Netherlands)

    Wevers, Brigitte A.; van der Hoek, Lia

    2010-01-01

    Although initially considered relatively harmless pathogens, human coronaviruses (HCoVs) are nowadays known to be associated with more severe clinical complications. Still, their precise pathogenic potential is largely unknown, particularly regarding the most recently identified species HCoV-NL63

  14. Recent Advances in the Gastric Mucosal Protection Against Stress-induced Gastric Lesions. Importance of Renin-angiotensin Vasoactive Metabolites, Gaseous Mediators and Appetite Peptides.

    Science.gov (United States)

    Brzozowski, Tomasz; Magierowska, Katarzyna; Magierowski, Marcin; Ptak-Belowska, Agata; Pajdo, Robert; Kwiecien, Slawomir; Olszanecki, Rafal; Korbut, Ryszard

    2017-01-01

    Stress is known to cause severe adverse effects in the human gastrointestinal tract including mucosal microbleedings and erosions or even gastric ulceration but the mechanism of these complications has not been fully elucidated. The pathogenesis of stress-induced gastric damage involves the fall in Gastric Blood Flow (GBF), an increase in gastric acid secretion and gastric motility, enhanced adrenergic and cholinergic nerve activity and the rise in gastric mucosal generation of reactive oxygen species. The gastric mucosal defense mechanisms against the deleterious effect of stress include the activation of the hypothalamic-pituitary-adrenal axis which has been linked with glucocorticoids release capable of counteracting of stress-induced gastric lesions. Here we summarize the novel gastroprotective mechanisms against stress damage exhibited by angiotensin-(1-7), the newly discovered metabolite of Renin-Angiotensin System (RAS), the gaseous mediators such as nitric oxide (NO), hydrogen sulfide (H2S) or Carbon Monoxide (CO), and the food intake controlling peptides ghrelin, nesfatin- 1 and apelin possibly acting via brain-gut axis. These bioactive molecules such as RAS vasoactive metabolite angiotensin-(1-7) and appetite peptides have been shown to afford gastroprotective effect against stressinduced gastric lesions mainly mediated by an increase in gastric microcirculation. Gaseous mediators protect the gastric mucosa against stress lesions by mechanism involving the activation of PG/COX and CO/HO-1 biosynthetic pathways, and their anti-inflammatory and anti-oxidizing properties. Thus, these new components add new mechanistic aspects to the common cooperation of NO/NO-synthase, PG/COX systems and vasoactive sensory neuropeptides including CGRP but their gastroprotective efficacy against experimental stress ulcerogenesis requires the confirmation in human clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

    Science.gov (United States)

    Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

    2015-11-01

    Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in

  16. Effect of Renin-Angiotensin Blockers on Left Ventricular Remodeling in Severe Aortic Stenosis.

    Science.gov (United States)

    Goh, Serene Si-Ning; Sia, Ching-Hui; Ngiam, Nicholas Jinghao; Tan, Benjamin Yong-Qiang; Lee, Poay Sian; Tay, Edgar Lik-Wui; Kong, William Kok-Fai; Yeo, Tiong Cheng; Poh, Kian-Keong

    2017-06-01

    Studies have shown that medical therapy with renin-angiotensin blockers (RABs) may benefit patients with aortic stenosis (AS). However, its use and efficacy remains controversial, including in patients with low flow (LF) with preserved left ventricular ejection fraction (LVEF). We examined the effects of RAB use on LV remodeling in patients with severe AS with preserved LVEF, analyzing the differential effects in patients with LF compared with normal flow (NF). This is a retrospective study of 428 consecutive subjects from 2005 to 2014 with echocardiographic diagnosis of severe AS and preserved LVEF. Clinical and echocardiographic parameters were systematically collected and analyzed. Two hundred forty-two (57%) patients had LF. Sixty-four LF patients (26%) were treated with RAB. Patients on RAB treatment had a higher incidence of hyperlipidemia (69% vs 44%) and diabetes mellitus (53% vs 34%). Severity of AS in terms of valve area, transvalvular mean pressure gradient, and aortic valve resistance were similar between both groups as was the degree of LV diastolic function. The RAB group demonstrated significantly lower LV mass index with a correspondingly lower incidence of concentric LV hypertrophy. Regardless of the duration of RAB therapy, patients had increased odds of having a preserved LV mass index compared with those without RAB therapy. In conclusion, RAB therapy may be associated with less LV pathological remodeling and have a role in delaying patients from developing cardiovascular complications of AS. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow

    DEFF Research Database (Denmark)

    Sørensen, Charlotte Mehlin; Leyssac, Paul Peter; Skøtt, Ole

    2000-01-01

    The role for ANG II in renal blood flow (RBF) autoregulation is unsettled. The present study was designed to test the effect of clamping plasma ANG II concentrations ([ANG II]) by simultaneous infusion of the angiotensin-converting enzyme inhibitor captopril and ANG II on RBF autoregulation...... in halothane-anesthetized Sprague-Dawley rats. Autoregulation was defined as the RBF response to acute changes in renal perfusion pressure (RPP). Regulation was defined as changes in RBF during long-lasting changes in RPP. The results showed that a prolonged reduction of RPP reset the lower limit...

  18. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study.

    Science.gov (United States)

    Schmidt, Morten; Mansfield, Kathryn E; Bhaskaran, Krishnan; Nitsch, Dorothea; Sørensen, Henrik Toft; Smeeth, Liam; Tomlinson, Laurie A

    2017-03-09

    Objective  To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. Design  Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics. Setting  UK primary care, 1997-2014. Participants  Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363). Main outcome measures  Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs. Results  Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. The Relevance of the Renin-Angiotensin System in the Development of Drugs to Combat Preeclampsia

    OpenAIRE

    Ueki, Norikazu; Takeda, Satoru; Koya, Daisuke; Kanasaki, Keizo

    2015-01-01

    Preeclampsia is a hypertensive disorder that occurs during pregnancy. It has an unknown etiology and affects approximately 5?8% of pregnancies worldwide. The pathophysiology of preeclampsia is not yet known, and preeclampsia has been called ?a disease of theories.? The central symptom of preeclampsia is hypertension. However, the etiology of the hypertension is unknown. In this review, we analyze the molecular mechanisms of preeclampsia with a particular focus on the pathogenesis of the hyper...

  20. Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review

    DEFF Research Database (Denmark)

    Sjølie, A K; Dodson, P; Hobbs, F R R

    2011-01-01

    Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates...... the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril...

  1. Renin-angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure.

    Science.gov (United States)

    Sorbets, Emmanuel; Labreuche, Julien; Simon, Tabassome; Delorme, Laurent; Danchin, Nicolas; Amarenco, Pierre; Goto, Shinya; Meune, Christophe; Eagle, Kim A; Bhatt, Deepak L; Steg, Philippe Gabriel

    2014-07-01

    The aim of this study was to determine whether angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-II receptor blocker (ARB) use is associated with lower rates of cardiovascular events in patients with stable coronary artery disease (CAD) but without heart failure (HF) receiving contemporary medical management. Using data from the Reduction of Atherothrombosis for Continued Health (REACH) registry, we examined, using propensity score approaches, relationships between cardiovascular outcomes and ACEI/ARB use (64.1% users) in 20 909 outpatients with stable CAD and free of HF at baseline. As internal control, we assessed the relation between statin use and outcomes. At 4-year follow-up, the risk of cardiovascular death, MI, or stroke (primary outcome) was similar in ACEI/ARB users compared with non-users (hazard ratio, 1.03; 95% confidence interval [CI], 0.91-1.16; P = 0.66). Similarly, the risk of the primary outcome and cardiovascular hospitalization for atherothrombotic events (secondary outcome) was not reduced in ACEI/ARB users (hazard ratio, 1.08; 95% CI, 1.01-1.16; P = 0.04), nor were the rates of any of its components. Analyses using propensity score matching yielded similar results, as did sensitivity analyses accounting for missing covariates, changes in medications over time, or analysing separately ACEI and ARB use. In contrast, in the same cohort, statin use was associated with lower rates for all outcomes. Use of ACEI/ARB was not associated with better outcomes in stable CAD outpatients without HF. The benefit of ACEI/ARB seen in randomized clinical trials was not replicated in this large contemporary cohort, which questions their value in this specific subset. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  2. Discovery and Characterization of Alamandine, a Novel Component of the Renin-Angiotensin System

    DEFF Research Database (Denmark)

    Lautner, Roberto Q.; Villela, Daniel C; Fraga-Silva, Rodrigo A

    2013-01-01

    by angiotensin-(1-7), including vasodilation, anti-fibrosis, anti-hypertensive and central effects. Interestingly, our data reveals that its actions are independent of the known vasodilator receptors of the RAS, Mas and AT2. Rather, we demonstrate that alamandine acts through the Mas-related G-Protein coupled...

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

    International Nuclear Information System (INIS)

    Eliahou, H.E.; Iaina, A.

    1980-01-01

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

  4. Inhibition of the Renin-Angiotensin-Aldosterone System for Cerebrorenal Protection

    NARCIS (Netherlands)

    Lambers Heerspink, Hiddo; Toyoda, K

    2013-01-01

    Blood pressure is a strong risk factor for ischemic and atherosclerotic events such as stroke. Blood pressure is often elevated in patients with chronic kidney disease. Consequently, chronic kidney disease patients are at high risk of developing cardiovascular and cerebrovascular damage. Blood

  5. Interactions of renin-angiotensin system gene polymorphisms and antihypertensive effect of benazepril in Chinese population.

    Science.gov (United States)

    Chen, Qing; Yu, Can-Qing; Tang, Xun; Chen, Da-Fang; Tian, Jun; Cao, Yang; Fan, Wen-Yi; Cao, Wei-Hua; Zhan, Si-Yan; Lv, Jun; Guo, Xiao-Xia; Hu, Yong-Hua; Lee, Li-Ming

    2011-05-01

    Angiotensin-converting enzyme inhibitors are widely used antihypertensive drugs with individual response variation. We studied whether interactions of AGT, AGTR1 and ACE2 gene polymorphisms affect this response. Our study is based on a 3-year field trial with 1831 hypertensive patients prescribed benazepril. Generalized multifactor dimensionality reduction was used to explore interaction models and logistic regressions were used to confirm them. A two-locus model involving the AGT and ACE2 genes was found in males, the sensitive genotypes showed an odds ratio (OR) of 1.9 (95% CI: 1.3-2.8) when compared with nonsensitive genotypes. Two AGT-AGTR1 models were found in females, with an OR of 3.5 (95% CI: 2.0-5.9) and 3.1 (95% CI: 1.8-5.3). Gender-specific gene-gene interactions of the AGT, AGTR1 and ACE2 genes were associated with individual variation of response to benazepril. Further studies are needed to confirm this finding.

  6. The renin-angiotensin-aldosterone system in cerebral small vessel disease

    NARCIS (Netherlands)

    Brenner, D.; Labreuche, J.; Pico, F.; Scheltens, P.; Poirier, O.; Cambien, F.; Amarenco, P.

    2008-01-01

    Introduction: Cerebral small vessel disease (SVD) appears on magnetic resonance imaging (MRI) as leukoaraiosis (LA), état criblé (EC), and multiple lacunar infarctions (MLI). Although the pathophysiology of SVD is poorly understood, there is evidence of a genetic contribution. We sought to analyze

  7. Role of Renin-Angiotensin-converting Enzyme Level and ACE Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Tekatas, Demet D; Bahcecioglu, Ibrahim H; Ispiroglu, Murat; Sahin, Abdurrahman; Ilhan, Necip; Yalniz, Mehmet; Demirel, Ulvi

    2016-01-01

    In this study, we aimed to investigate the histological and clinical effect of angiotensin-converting enzyme (ACE) and ACE gene polymorphism in nonalcoholic fatty liver disease (NAFLD) and their roles in the progression of the disease. Liver function tests, body mass index, waist circumference, lipid parameters, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), homeostasis model assessment-IR (HOMA-IR), ACE, and ACE gene polymorphism were evaluated in the NAFLD group and control group. The study group was evaluated by dividing the group into four subgroups by ACE gene polymorphism (D/D homozygous, I/I homozygous, D/I heterozygous, I/D heterozygous). Liver biopsies were evaluated according to Brunt Classification. A total of 31 patients who were diagnosed with NAFLD and 40 healthy individuals were included in the study. The ACE level was found to be 11.69 ± 1.99 in the NAFLD group and 11.52 ± 1.72 in the control group (p = 0.70). There was a negative correlation between ACE levels and HOMA-IR levels (p = 0.008, r= -0.512). Biochemical parameters were not different among ACE gene polimorphism subgroups, except FBG (between D/D, I/D and D/I, I/D; p = 0.02). When the ACE levels were compared in terms of grade and stage, no significant difference was found (for stage and grade p = 0.68). The ACE gene polymorphism subgroups did not differ by histopathologic findings; grade and stage (for grade p = 0.42, for stage p = 0.92). In this study, we could not find a correlation of ACE and ACE gene polymorphism with metabolic risk factors and the disease severity in NAFLD. Tekatas DD, Bahcecioglu IH, Ispiroglu M, Sahin A, Ilhan N, Yalniz M, Demirel U. Role of Renin-Angiotensin-converting Enzyme Level and ACE Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(2):137-142.

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

    Science.gov (United States)

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

    2015-01-01

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

  9. Does the renin-angiotensin system determine the renal and systemic hemodynamic response to sodium in patients with essential hypertension?

    NARCIS (Netherlands)

    vanPaassen, P; deZeeuw, D; Navis, G; deJong, PE

    Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the

  10. Progression of Renal Insufficiency in Patients with Essential Hypertension Treated with Renin Angiotensin Aldosterone System Blockers: An Electrocardiographic Correlation.

    Science.gov (United States)

    Rodriguez-Padial, Luis; Akerström, Finn; Barderas, María G; Vivanco, Fernando; Arias, Miguel A; Segura, Julian; Ruilope, Luis M

    2017-12-08

    There is a frequent association between renal insufficiency and cardiovascular disease in patients with essential hypertension (HTN). The aim of this study was to analyze the relationship between ECG parameters and the progress of renal damage in patients with treated HTN. 109 patients with HTN had their microalbuminuria monitored over a 3-year time frame. During the last 3 months of follow-up, an ECG was recorded. Patients were divided into 3 groups according to the deterioration of their renal function: normoalbuminuria during the study period (normo-normo; n = 51); normoalbuminuria developing microalbuminuria (normo-micro; n = 29); and microalbuminuria at baseline (micro-micro; n = 29). There were no differences in presence of left ventricular hypertrophy between the 3 groups. RV6/RV5 >1 was observed more frequently as renal function declined ( p = 0.025). The 12-lead QRS-complex voltage-duration product was significantly increased in patients without microalbuminuria at baseline who went on to develop microalbuminuria ( p = 0.006). Patients who developed microalbuminuria during follow-up, with positive Cornell voltage criteria, showed a lesser degree of progression of microalbuminuria when compared with the rest of the subgroups ( p = 0.044). Furthermore, patients with microalbuminuria at baseline treated with angiotensin receptor blockers and diuretics, and positive Cornell voltage criteria, showed a higher degree of microalbuminuria compared to those with negative Cornell voltage criteria ( p = 0.016). In patients with HTN, we identified some ECG parameters, which predict renal disease progression in patients with HTN, which may permit the identification of patients who are at risk of renal disease progression, despite optimal antihypertensive pharmacotherapy.

  11. Exposure to fine particulate matter in the air alters placental structure and the renin-angiotensin system.

    Directory of Open Access Journals (Sweden)

    Sônia de Fátima Soto

    Full Text Available Female Wistar rats were exposed to filtered air (F or to concentrated fine particulate matter (P for 15 days. After mating, the rats were divided into four groups and again exposed to F or P (FF, FP, PF, PP beginning on day 6 of pregnancy. At embryonic day 19, the placenta was collected. The placental structure, the protein and gene expression of TGFβ1, VEGF-A, and its receptor Flk-1 and RAS were evaluated by indirect ELISA and quantitative real-time PCR.Exposure to P decreased the placental mass, size, and surface area as well as the TGFβ1, VEGF-A and Flk-1 content. In the maternal portion of the placenta, angiotensin II (AngII and its receptors AT1 (AT1R and AT2 (AT2R were decreased in the PF and PP groups. In the fetal portion of the placenta, AngII in the FP, PF and PP groups and AT2R in the PF and PP groups were decreased, but AT1R was increased in the FP group. VEGF-A gene expression was lower in the PP group than in the FF group.Exposure to pollutants before and/or during pregnancy alters some characteristics of the placenta, indicating a possible impairment of trophoblast invasion and placental angiogenesis with possible consequences for the maternal-fetal interaction, such as a limitation of fetal nutrition and growth.

  12. Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: The Rotterdam study

    NARCIS (Netherlands)

    R. van der Knaap (Ronald); C. Siemes (Claire); J.W.W. Coebergh (Jan Willem); P. Tikka-Kleemola (Päivi); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2008-01-01

    textabstractBACKGROUND. Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current

  13. From preeclampsia to renal disease : a role of angiogenic factors and the renin-angiotensin aldosterone system?

    NARCIS (Netherlands)

    van der Graaf, Anne Marijn; Toering, Tsjitske J.; Faas, Marijke M.; Lely, A. Titia

    2012-01-01

    Complicating up to 8% of pregnancies, preeclampsia is the most common glomerular disease worldwide and remains a leading cause of infant and maternal morbidity and mortality. Although the exact pathogenesis of this syndrome of hypertension and proteinuria is still incomplete, a consistent line of

  14. Pooled Analysis of Multiple Crossover Trials To Optimize Individual Therapy Response to Renin-Angiotensin-Aldosterone System Intervention

    DEFF Research Database (Denmark)

    Petrykiv, Sergei I; Laverman, Gozewijn Dirk; Persson, Frederik

    2017-01-01

    to angiotensin receptor blockers; n=5) or NSAIDs (n=1), changing from RAASi to NSAIDs (n=2), and changing from high to low sodium intake (n=5). A two-stage meta-analysis was conducted: Deming regression was conducted in each study to assess correlations in response, and individual study results were then meta...

  15. Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.

    Science.gov (United States)

    Giles, Thomas D; Bakris, George; Oparil, Suzanne; Weber, Michael A; Li, Huiling; Mallick, Madhuja; Bharucha, David B; Chen, ChunLin; Ferguson, William G

    2015-11-01

    After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Study of the components of renin-angiotensinaldosterone system and KalliKrein -Kinin system in normal pregnancy

    International Nuclear Information System (INIS)

    Abreu Fagundes, V.G. de.

    1984-01-01

    The alterations in the renin-angiotensin-aldosterone system and Kallikrein-Kinin system were studied. The possible interferences of these systems on the arterial pressure and on the evolution of normal pregnancy were presented in the following situations: when the pregnant change from dorsal decumbency to left lateral decumbency and to orthostatic position. (M.A.C.) [pt

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

  18. Calcium channel blocker prevents stress-induced activation of renin and aldosterone in conscious pig

    International Nuclear Information System (INIS)

    Ceremuzynski, L.K.; Klos, J.; Barcikowski, B.; Herbaczynska-Cedro, K.

    1991-01-01

    A considerable amount of data suggest the involvement of calcium-mediated processes in the activation of the renin-angiotensin-aldosterone (RAA) cascade. To investigate the effect of calcium-channel inhibition on the RAA system, the authors studied 21 conscious pigs. Blood renin and aldosterone levels increased by subjecting animals to 24 hours of immobilization stress. Renin and aldosterone levels were repeatedly measured by radioimmunoassay in blood samples taken periodically over 24 hours from a chronically implanted arterial cannula. Pretreatment of the animals (N = 11) with nisoldipine, 2 x 20 mg p.o. daily for 2 days before and on the day of immobilization, transiently attenuated the stress-induced increase of plasma renin activity and completely prevented the rise of aldosterone, as compared to nontreated controls (N = 10). The finding that nisoldipine suppresses RAA activation induced by a nonpharmacologic stimulus in the conscious intact animal may have clinical implications

  19. Angiotensin II dependent cardiac remodeling in the eel Anguilla anguilla involves the NOS/NO system

    DEFF Research Database (Denmark)

    Filice, Mariacristina; Amelio, Daniela; Garofalo, Filippo

    2017-01-01

    Angiotensin II (AngII), the principal effector of the Renin-Angiotensin System (RAS), plays an important role in controlling mammalian cardiac morpho-functional remodelling. In the eel Anguilla anguilla, one month administration of AngII improves cardiac performance and influences the expression ...

  20. The influence of the ACE (I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive, normoalbuminuric Type 1 diabetes mellitus

    NARCIS (Netherlands)

    Luik, PT; Hoogenberg, K; Kerstens, MN; Beusekamp, BJ; de Jong, PE; Dullaart, RPF; Navis, GJ

    Aim/hypothesis. The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To

  1. Role of renal sympathetic nerve activity in prenatal programming of hypertension.

    Science.gov (United States)

    Baum, Michel

    2018-03-01

    Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

  2. Adherence to guidelines for creatinine and potassium monitoring and discontinuation following renin-angiotensin system blockade: a UK general practice-based cohort study.

    Science.gov (United States)

    Schmidt, Morten; Mansfield, Kathryn E; Bhaskaran, Krishnan; Nitsch, Dorothea; Sørensen, Henrik Toft; Smeeth, Liam; Tomlinson, Laurie A

    2017-01-09

    To examine adherence to serum creatinine and potassium monitoring and discontinuation guidelines following initiation of treatment with ACE inhibitors (ACEI) or angiotensin receptor blockers (ARBs); and whether high-risk patients are monitored. A general practice-based cohort study using electronic health records from the UK Clinical Practice Research Datalink and Hospital Episode Statistics. UK primary care, 2004-2014. 223 814 new ACEI/ARB users. Proportion of patients with renal function monitoring before and after ACEI/ARB initiation; creatinine increase ≥30% or potassium levels >6 mmol/L at first follow-up monitoring; and treatment discontinuation after such changes. Using logistic regression models, we also examined patient characteristics associated with these biochemical changes, and with follow-up monitoring within the guideline recommendation of 2 weeks after treatment initiation. 10% of patients had neither baseline nor follow-up monitoring of creatinine within 12 months before and 2 months after initiation of an ACEI/ARB, 28% had monitoring only at baseline, 15% only at follow-up, and 47% both at baseline and follow-up. The median period between the most recent baseline monitoring and drug initiation was 40 days (IQR 12-125 days). 34% of patients had baseline creatinine monitoring within 1 month before initiating therapy, but creatinine increase ≥30% (n=567, 1.2%) or potassium level >6 mmol/L (n=191, 0.4%), 80% continued treatment. Although patients with prior myocardial infarction, hypertension or baseline potassium >5 mmol/L were at high risk of ≥30% increase in creatinine after ACEI/ARB initiation, there was no evidence that they were more frequently monitored. Only one-tenth of patients initiating ACEI/ARB therapy receive the guideline-recommended creatinine monitoring. Moreover, the vast majority of the patients fulfilling postinitiation discontinuation criteria for creatinine and potassium increases continue on treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Effects of cilostazol and renin-angiotensin system (RAS) blockers on the renal disease progression of Korean patients: a retrospective cohort study.

    Science.gov (United States)

    Noh, Yoojin; Lee, Jimin; Shin, Sooyoung; Park, Inwhee; Bae, Soo Kyung; Oh, Euichul; Lee, Sukhyang

    2018-02-01

    Background Decline in estimated glomerular filtration rate (eGFR) is an important surrogate marker for the assessment of renal function. Addition of a second agent to angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) treatment may improve current therapeutic strategies aimed at suppressing renal disease progression. Objective To determine the effect of cilostazol in combination with ACEI or ARB treatment on the decline in eGFR. Setting A tertiary hospital in Korea. Method In an observational cohort study, we analyzed 5505 patients who were prescribed ACEI or ARB and cilostazol or other antiplatelet agents. Main outcome measure The primary outcome assessed was worsening of renal function defined as a 30% decline in eGFR per year. The secondary outcomes included commencement of dialysis, renal transplantation, death, myocardial infarction, and ischemic stroke. Results Following propensity score matching, eGFR decreased over time in the majority of patients, but the decline was less in patients in the cilostazol treated (CT) group of stage 1-2 category compared to the cilostazol untreated (CU) group (OR 0.80; 95% CI 0.66-0.98). In the subgroup analysis, the strongest effect in slowing eGFR decline was observed in CT patients at a high risk of diabetes (OR 0.782; 95% CI 0.615-0.993) and the elderly (OR 0.693; 95% CI 0.504-0.953) in the stage 1-2 category. No significant increase in cardiovascular risk was observed between the CT and CU groups. Conclusion Treatment with cilostazol plus ACEI or ARB was observed to prevent worsening of renal progression in patients in the stages 1-2.

  4. Effects of exercise on central aortic pressure before and after treatment with renin-angiotensin system blockade in patients with hypertension.

    Science.gov (United States)

    Lacy, Peter S; Brunel, Patrick; Baschiera, Fabio; Botha, Jaco; Williams, Bryan

    2015-12-01

    Brachial blood pressure increases with exercise and an excessive rise predicts increased cardiovascular risk. Measurement of brachial blood pressure alone may exaggerate the true blood pressure elevation due to exercise-induced change to pressure amplification. Whether blood pressure-lowering treatment modulates pressure amplification during exercise is unknown. Thirty-two participants with stage 1-2 hypertension (mean age 59.2 years) received eight weeks' blood pressure lowering with either aliskiren (300mg, n=16) or valsartan (320mg, n=16). Brachial and central aortic pressure (CASP) were measured non-invasively during treadmill exercise (Bruce protocol) at baseline, after eight weeks' treatment and 48 hours following treatment withdrawal. The rise in brachial blood pressure with exercise exceeded the rise in CASP, indicative of enhanced pressure amplification. Eight weeks' treatment elicited similar reductions in brachial blood pressure and CASP which did not differ between rest and peak exercise (p>0.05). The exercise-induced increase in systolic pressure amplification did not differ between baseline and following eight weeks' treatment (p>0.05). These effects remained unchanged following treatment withdrawal. Blood pressure lowering does not directly influence the relationship between aortic and brachial pressure either at rest or during exercise in patients with hypertension, other than through proportionate lowering of both pressures. These effects remained unchanged 48 hours after a simulated missed medication dose. © The Author(s) 2014.

  5. Biochemical monitoring after initiation of aldosterone antagonist therapy in users of renin-angiotensin system blockers: a UK primary care cohort study.

    Science.gov (United States)

    Sinnott, Sarah-Jo; Mansfield, Kathryn E; Schmidt, Morten; Bhaskaran, Krishnan; Smeeth, Liam; Nitsch, Dorothea; Tomlinson, Laurie A

    2017-11-16

    To determine the frequency of biochemical monitoring after initiation of aldosterone antagonists(AA) in patients also using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB). UK primary care. ACEI/ARB users who initiated AA between 2004 and 2014. We calculated the proportions with: (1) biochemical monitoring ≤2 weeks post initiation of AA, (2) adverse biochemical values ≤2 months (potassium ≥6 mmol/L, creatinine ≥220 µmol/L and ≥30% increase in creatinine from baseline) and (3) discontinuers of AA in those with an adverse biochemical value. We used logistic regression to study patient characteristics associated with monitoring and adverse biochemical values. In 10 546 initiators of AA, 3291 (31.2%) had a record of biochemical monitoring ≤2 weeks post initiation. A total of 2.0% and 2.7% of those with follow-up monitoring within 2 months of initiation experienced potassium ≥6 mmol/L and creatinine ≥220 µmol/L, respectively, whereas 13.5% had a ≥30% increase in creatinine. Baseline potassium (OR 3.59, 95% CI 2.43 to 5.32 for 5.0-5.5 mmol/L compared with monitoring within 2 weeks of initiating AAs. Higher levels of monitoring may reduce adverse biochemical events. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Polymorphisms of renin-angiotensin system and natriuretic peptide receptor A genes in patients of Greek origin with a history of myocardial infarction.

    Science.gov (United States)

    Karayannis, George; Tsezou, Aspasia; Giannatou, Eirini; Papanikolaou, Vassilios; Giamouzis, Gregory; Triposkiadis, Filippos

    2010-11-01

    We assessed the association between (CA)n repeat polymorphism of angiotensinogen (AGT), 250 base pair (bp) insertion/deletion (I/D) of angiotensin-converting enzyme (ACE), tetranucleotide repeat polymorphism (TCTG)n of renin (REN), (CT)n repeat polymorphism of the natriuretic peptide receptor A (NPRA) genes, and the presence and extent of coronary artery disease (CAD) in Greek patients with a history of myocardial infarction (MI). A total of 158 post-MI patients referred for coronary angiography were compared with 144 controls. The SS genotype of the AGT gene was related with an increased risk for 3-vessel CAD (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.05-3.61; P = .041), whereas the SL genotype was related with a decreased risk (OR, 0.44; 95% CI, 0.22-0.87; P = .019). Moreover, there was a trend for the SL genotype of the REN gene toward increased risk for CAD. There was a significant association between (CA)n polymorphism of the AGT gene and the extent of CAD in Greek patients with a history of MI.

  7. The efficacy and safety of dual blockage of the renin-angiotensin-aldosterone system in patients with type 2 diabetes, hypertension and obesity without renal dysfunction

    Directory of Open Access Journals (Sweden)

    2012-09-01

    Full Text Available The purpose of the study was to evaluate the clinical efficacy and safety of dual RAAS blockage during treatment with angiotensin-converting enzyme (ACE inhibitors in combination with a direct renin inhibitor (PIR aliskiren versus combination therapy with ACE inhibitors and angiotensin receptor blocker II (ARB valsartan in patients with type 2 diabetes mellitus (T2DM, arterial hypertension (AH and obesity, without renal dysfunction. Materials and methods. The study included 26 patients with T2DM (10 men and 16 women, mean age 59,0±6,2 years with inadequate control of blood pressure (over 130 and/or 80 mm Hg on prior antihypertensive therapy and without renal dysfunctions (glomerular filtration rate (GFR> 60 ml/min/1, 73 m2 and the of albumin/creatinine (A/C ratio in the morning urine sample <10 mg/mol. After screening with the continuation of the initial therapy, including ACE inhibitors, 14 patients were added aliskiren 150–300 mg/day, 12 patients – valsartan 80–160 mg/day. Evaluation of the treatment effectiveness in terms of blood pressure (mean of three consecutive measurements in the sitting position and the parameters of renal function (serum creatinine and potassium, GFR, A/C ratio in the urine was performed at 4, 12 and 24 weeks of therapy. Results. In the group of patients treated with aliskiren, after 4 weeks of treatment a significant decrease in systolic and diastolic blood pressure (SBP and DBP, respectively was noted as compared to baseline: 146,1 and 138,9 mm Hg, p<0,05, 87,1 and 81,1 mm Hg, p <0,05, respectively; with systolic BP after 24 weeks of treatment decreased to 127,8 (-18,2 mm Hg, p<0,05, diastolic BP to 75,0 (-12, 1 mm Hg, p<0,05, the target blood pressure (≤130/80 mm Hg was achieved in 83% of patients. The group of patients treated with valsartan, after 4 weeks of therapy showed a significant reduction in systolic BP 148 and 141,6 mm Hg, p <0,05, diastolic BP - to 85,8 and 81,7 mm Hg, p=0,059; after 24 weeks systolic BP decreased to 128,7 (-19,3 mm Hg, p=0,05, diastolic BP – to 77,5 (-8,3 mm Hg, p=0,07, the target blood pressure was achieved in 78% of patients. When monitoring the safety of therapy in terms of potassium, serum creatinine, GFR, and A/C urine ratio statistically significant differences between the groups at 4, 12, 24 weeks of treatment were observed. Conclusion. Results of the study demonstrate the efficacy and safety of dual RAAS blockage in patients with T2DM and obesity with no prior renal impairment.

  8. Cardiovascular and Renal Outcomes of Renin?Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses

    OpenAIRE

    Catal?-L?pez, Ferr?n; Mac?as Saint-Gerons, Diego; Gonz?lez-Bermejo, Diana; Rosano, Giuseppe M.; Davis, Barry R.; Ridao, Manuel; Zaragoza, Abel; Montero-Corominas, Dolores; Tob?as, Aurelio; de la Fuente-Honrubia, C?sar; Tabar?s-Seisdedos, Rafael; Hutton, Brian

    2016-01-01

    Editors' Summary Background Chronic high blood pressure can damage blood vessels, heart, and kidneys, and cause cardiovascular and kidney (or renal) disease. Diabetes increases the risk for high blood pressure. An estimated two-thirds of adults with diabetes have high blood pressure or take blood-pressure-reducing drugs (also called antihypertensives). Because diabetes itself increases the risk for heart and kidney diseases, controlling blood pressure is important. Several of the drugs common...

  9. Venous responses during exercise in rainbow trout, Oncorhynchus mykiss : [alpha]-adrenergic control and the antihypotensive function of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Sandblom, E.; Axelsson, M.; McKenzie, David

    2006-01-01

    ) was investigated during exercise after [alpha]-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s-1 (BL s-1) while Pven, dorsal aortic blood pressure (Pda) and relative cardiac output (Q) was recorded continuously. Heart rate (fH), cardiac stroke volume (SV) and total...

  10. Effect of renin-angiotensin -aldosterone system blockers on myocardial remodeling processes and risk for atrial fibrillation in patients with arterial hypertension

    Directory of Open Access Journals (Sweden)

    O. M. Drapkina

    2014-07-01

    Full Text Available The given review considers the mechanisms underlying the development and maintenance of atrial fibrillations (AF. It is noted that the processes of atrial fibrosis, ion channel remodeling, inflammation, apoptosis, impaired intercellular interactions, and myocardiocyte hypertrophy may give rise to atrial structural and functional changes in AF. The efficacy of angiotensinonverting enzyme inhibitors and angiotensin receptor antagonists is justified in patients with left ventricular systolic dysfunction.

  11. Potential Beneficial Effects of Tulbaghia violacea William Henry ...

    African Journals Online (AJOL)

    violacea may modulate the renin-angiotensin system, the autonomic nervous system, oxidative stress .... increases sympathetic nervous system activity, stimulates thirst and ..... 464 p. 28. Nock LP, Mazelis M. The C-S Lyases of Higher Plants:.

  12. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease

    DEFF Research Database (Denmark)

    de Zeeuw, Dick; Akizawa, Tadao; Audhya, Paul

    2013-01-01

    Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown....

  13. Organisation and functional role of the brain angiotensin system

    OpenAIRE

    Catherine Llorens-Cortes; Frederic AO Mendelsohn

    2002-01-01

    The discovery that all components of the renin-angiotensin system (RAS) are present in the brain led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurones have been visualised in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular and supraoptic nuclei, and a second pathway connecting the hypothalamus to the medulla oblongata. Bloo...

  14. [Characteristics of central nervous system activity in patients with complications of arterial hypertension and dependence on psychomotor status and treatment].

    Science.gov (United States)

    Usenko, A G; Velichko, N P; Usenko, G A; Nishcheta, O V; Kozyreva, T Iu; Demin, A A

    2013-01-01

    Changes in certain CNS characteristics were used as indicators of the efficacy of antihypertensive therapy (AHT) both targeted (T-AHT) and empirical (E-AHT) designed to suppress activity of the sympathetic component of vegetative nervous system (VNS) and renin-angiotensin-aldosterone system (RAAS) in patients of different psychic status and AH. A group of 835 men (mean age 54.2+-1.8yr) was divided into cholerics, sanguinics, melancholics and phlegmatics with a high and low anxiety level (HA and LA). 416 healthy men served as controls. The following parameters were estimated: mobility of cortical processes, balance between sympathetic and parasympathetic activities, blood corrisol and aldosterone levels, oxygen utilization coefficient, resistance to breath holding, severity of dyscirculatory encephalopathy and the fraction of patients with AH complications during 12 month T-AHT for the suppression of sympathetic activity in cholerics and sanguinics by beta-adrenoblockers and PAA C- ACE inhibitors in phlegmatics and melancholics and during E-AHT (ACE inhibitors in cholerics and sanguinics, BAB in phlegmatics and melancholics). The functional activity of CNS in phlegmatics and melancholics before and during AHT was lower and severity of encephalopathy and the number ofAH complications higher than in cholerics and sanguinics. . The changes wiere more pronounced in patients with HA than in those with LA. Unlike E-AHT T-AHT (anxiolytics for cholerics and sanguinics with HA, antidepressants for phlegmatics and melancholics with HA) normalized the study parameters and decreased the frequency of complications by 2-3 times.

  15. Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats

    Czech Academy of Sciences Publication Activity Database

    Alánová, Petra; Husková, Z.; Kopkan, L.; Sporková, A.; Jíchová, Š.; Neckář, Jan; Imig, J. D.; Klevstig, Martina; Kolář, František; Reddy, N. R.; Falck, J. R.; Sadowski, J.; Nishiyama, A.; Kramer, H. J.; Melenovský, V.; Červenková, L.; Kujal, P.; Vernerová, Z.; Červenka, L.

    2015-01-01

    Roč. 73, Oct 2015 (2015), s. 45-56 ISSN 1537-1891 R&D Projects: GA ČR(CZ) GA15-08066S; GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : renovascular hypertension * myocardial ischemia/reperfusion injury * 14,15-epoxyeicosatrienoic acid analog * renin-angiotensin system Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.500, year: 2015

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

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2008-01-01

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

  17. Differential effects of isoproterenol on the activity of angiotensin-converting enzyme in the rat heart and aorta

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    Busatto V.C.W.

    1999-01-01

    Full Text Available The excessive stimulation of beta-adrenergic receptors in the heart induces myocardial hypertrophy. There are several experimental data suggesting that this hypertrophy may also depend, at least partially, on the increase of local production of angiotensin II secondary to the activation of the cardiac renin-angiotensin system. In this study we investigated the effects of isoproterenol on the activity of angiotensin-converting enzyme (ACE in the heart and also in the aorta and plasma. Male Wistar rats weighing 250 to 305 g were treated with a dose of (±-isoproterenol (0.3 mg kg-1 day-1, N = 8 sufficient to produce cardiac hypertrophy without deleterious effects on the pumping capacity of the heart. Control rats (N = 7 were treated with vehicle (corn oil. The animals were killed one week later. ACE activity was determined in vitro in the four cardiac chambers, aorta and plasma by a fluorimetric assay. A significant hypertrophy was observed in both ventricular chambers. ACE activity in the atria remained constant after isoproterenol treatment. There was a significant increase (P<0.05 of ACE activity in the right ventricle (6.9 ± 0.9 to 8.2 ± 0.6 nmol His-Leu g-1 min-1 and in the left ventricle (6.4 ± 1.1 to 8.9 ± 0.8 nmol His-Leu g-1 min-1. In the aorta, however, ACE activity decreased (P<0.01 after isoproterenol (41 ± 3 to 27 ± 2 nmol His-Leu g-1 min-1 while it remained unchanged in the plasma. These data suggest that ACE expression in the heart can be increased by stimulation of beta-adrenoceptors. However, this effect is not observed on other local renin-angiotensin systems, such as the aorta. Our data also suggest that the increased sympathetic discharge and the elevated plasma concentration of catecholamines may contribute to the upregulation of ACE expression in the heart after myocardial infarction and heart failure.

  18. Baroreflex control of sympathetic activity in experimental hypertension

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    M.C.C. Irigoyen

    1998-09-01

    Full Text Available The arterial baroreceptor reflex system is one of the most powerful and rapidly acting mechanisms for controlling arterial pressure. The purpose of the present review is to discuss data relating sympathetic activity to the baroreflex control of arterial pressure in two different experimental models: neurogenic hypertension by sinoaortic denervation (SAD and high-renin hypertension by total aortic ligation between the renal arteries in the rat. SAD depresses baroreflex regulation of renal sympathetic activity in both the acute and chronic phases. However, increased sympathetic activity (100% was found only in the acute phase of sinoaortic denervation. In the chronic phase of SAD average discharge normalized but the pattern of discharges was different from that found in controls. High-renin hypertensive rats showed overactivity of the renin angiotensin system and a great depression of the baroreflexes, comparable to the depression observed in chronic sinoaortic denervated rats. However, there were no differences in the average tonic sympathetic activity or changes in the pattern of discharges in high-renin rats. We suggest that the difference in the pattern of discharges may contribute to the increase in arterial pressure lability observed in chronic sinoaortic denervated rats.

  19. Plasma Renin Activity in Diabetes Mellitus

    International Nuclear Information System (INIS)

    Pyo, Heui Jung; Park Jung Sik; Kim, Sung Kwon; Choi, Kang Won; Lee, Jung Sang; Lee, Mun Ho

    1979-01-01

    To evaluate the renin-angiotensin-aldosterone system in diabetes mellitus, basal plasma renin activity (PRA) and its response to intravenous furosemide were determined in 40 diabetic subjects. The diabetics were divided into 4 groups according to the presence of nephropathy and/or hypertension. Uncomplicated diabetics (Group I) were taken as control group and the results of the other groups were compared to this group. In diabetics with nephropathy alone (Group II), and with nephropathy and hypertension (Group III), basal PRA values were 0.63±0.59 ng/ml/hr., and 0.79±0.62 ng/ml/hr., respectively, both significantly lower than control group. (1.53±1.09 ng/ml/hr.). (p<0.05) In both of the above groups, the responses to intravenous furosemide tended to be blunted. On the other hand, in diabetics, with hypertension only (Group IV), the basal and stimulated PRA were not significantly different from control. Above results suggests that nephropathy may be one of the factors which suppress renin activity in diabetes mellitus

  20. Plasma Renin Activity in Diabetes Mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Pyo, Heui Jung; Sik, Park Jung; Kim, Sung Kwon; Choi, Kang Won; Lee, Jung Sang; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1979-03-15

    To evaluate the renin-angiotensin-aldosterone system in diabetes mellitus, basal plasma renin activity (PRA) and its response to intravenous furosemide were determined in 40 diabetic subjects. The diabetics were divided into 4 groups according to the presence of nephropathy and/or hypertension. Uncomplicated diabetics (Group I) were taken as control group and the results of the other groups were compared to this group. In diabetics with nephropathy alone (Group II), and with nephropathy and hypertension (Group III), basal PRA values were 0.63+-0.59 ng/ml/hr., and 0.79+-0.62 ng/ml/hr., respectively, both significantly lower than control group. (1.53+-1.09 ng/ml/hr.). (p<0.05) In both of the above groups, the responses to intravenous furosemide tended to be blunted. On the other hand, in diabetics, with hypertension only (Group IV), the basal and stimulated PRA were not significantly different from control. Above results suggests that nephropathy may be one of the factors which suppress renin activity in diabetes mellitus

  1. The role of urocortins in the cardiovascular system.

    Science.gov (United States)

    Walczewska, J; Dzieza-Grudnik, A; Siga, O; Grodzicki, T

    2014-12-01

    Urocortins (Ucn) 1, 2 and 3 are a group of endogenous peptide hormones belonging to the corticotropin-releasing hormone (CRH) family of peptides. The presence of urocortins has been detected in the central nervous system as well as in peripheral tissues. They play an important role in a stress response (with respect to its duration, intensity and restoration of homeostasis). They also act as regulatory factors of the cardiovascular, gastrointestinal, reproductive and immune systems. Urocortins act by binding to G-protein-coupled receptors (GPCR). The "central" effects of urocortins are mediated mainly by activation of CRH receptor 1 (CRH-R1), and the "peripheral" effects by activation of CRH-R2. Ucn2 and Ucn3 are selective CRH-R2 agonists and have much higher binding affinity to this receptor than CRH and Ucn1. Recent studies have shown that urocortins exert various biological effects in the cardiovascular system, such as vasodilation, positive inotropic and lusitropic effects, as well as cardioprotection against ischemia-reperfusion injury. They also suppress the renin-angiotensin system and may have an impact on the sympathetic nervous system. Urocortins and CRH-R2 may be a potential therapeutic target in coronary heart disease, congestive heart failure and hypertension. This review summarizes the data published to date on the role of urocortins in the cardiovascular system.

  2. Targeting Renin–Angiotensin System Against Alzheimer’s Disease

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    Abadi Kahsu Gebre

    2018-04-01

    Full Text Available Renin Angiotensin System (RAS is a hormonal system that regulates blood pressure and fluid balance through a coordinated action of renal, cardiovascular, and central nervous systems. In addition to its hemodynamic regulatory role, RAS involves in many brain activities, including memory acquisition and consolidation. This review has summarized the involvement of RAS in the pathology of Alzheimer’s disease (AD, and the outcomes of treatment with RAS inhibitors. We have discussed the effect of brain RAS in the amyloid plaque (Aβ deposition, oxidative stress, neuroinflammation, and vascular pathology which are directly and indirectly associated with AD. Angiotensin II (AngII via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP mRNA, β-secretase activity, and presenilin expression. Similarly, it was associated with tau phosphorylation, and reactive oxygen species generation. However, these effects are counterbalanced by Ang II mediated AT2 signaling. The protective effect observed with angiotensin receptor blockers (ARBs and angiotensin converting enzyme inhibitors (ACEIs could be as the result of inhibition of Ang II signaling. ARBs also offer additional benefit by shifting the effect of Ang II toward AT2 receptor. To conclude, targeting RAS in the brain may benefit patients with AD though it still requires further in depth understanding.

  3. Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities.

    Science.gov (United States)

    Jafri, Salema; Ormiston, Mark L

    2017-12-01

    Systemic hypertension, preeclampsia, and pulmonary arterial hypertension (PAH) are diseases of high blood pressure in the systemic or pulmonary circulation. Beyond the well-defined contribution of more traditional pathophysiological mechanisms, such as changes in the renin-angiotensin-aldosterone system, to the development of these hypertensive disorders, there is substantial clinical evidence supporting an important role for inflammation and immunity in the pathogenesis of each of these three conditions. Over the last decade, work in small animal models, bearing targeted deficiencies in specific cytokines or immune cell subsets, has begun to clarify the immune-mediated mechanisms that drive changes in vascular structure and tone in hypertensive disease. By summarizing the clinical and experimental evidence supporting a contribution of the immune system to systemic hypertension, preeclampsia, and PAH, the current review highlights the cellular and molecular pathways that are common to all three hypertensive disorders. These mechanisms are centered on an imbalance in CD4 + helper T cell populations, defined by excessive Th17 responses and impaired T reg activity, as well as the excessive activation or impairment of additional immune cell types, including macrophages, dendritic cells, CD8 + T cells, B cells, and natural killer cells. The identification of common immune mechanisms in systemic hypertension, preeclampsia, and PAH raises the possibility of new therapeutic strategies that target the immune component of hypertension across multiple disorders. Copyright © 2017 the American Physiological Society.

  4. Influence of thyroid disorders on the kidney expression and plasma activity of aminopeptidase A.

    Science.gov (United States)

    Wangensteen, R; Segarra, A B; Ramirez-Sanchez, M; Gasparo, M De; Dominguez, G; Banegas, I; Vargas, F; Vives, F; Prieto, I

    2015-04-01

    Thyroid disorders may affect blood pressure and renal function modifying factors of the plasmatic and kidney renin-angiotensin system such as aminopeptidase A (AP A) that metabolizes angiotensin II to angiotensin III. We investigated the expression of AP A in the kidney, as well as its enzymatic activity in the plasma of euthyroid, hyperthyroid, and hypothyroid adult male rats. Hyperthyroidism was induced by daily subcutaneous injections of tetraiodothyronine. Hypothyroid rats were obtained by administration of methimazole in drinking water. Expression of AP A was determined by Western blot analysis. Plasma AP A activity was measured fluorometrically using glutamyl-β-naphthylamide as substrate. While hyperthyroid rats exhibited lower levels of plasma AP A activity than controls, the kidney of hyperthyroid animals expressed significantly higher AP A than controls and hypothyroid animals. A discrepancy between the high expression of AP A in kidney of hyperthyroid rats and the low activity of AP A measured in plasma and kidney of hyperthyroid animals was found. The posttranslational influence of environmental biochemical factors may be in part responsible for that divergence.

  5. Inactivation of adipose angiotensinogen reduces adipose tissue macrophages and increases metabolic activity.

    Science.gov (United States)

    LeMieux, Monique J; Ramalingam, Latha; Mynatt, Randall L; Kalupahana, Nishan S; Kim, Jung Han; Moustaïd-Moussa, Naïma

    2016-02-01

    The adipose renin-angiotensin system (RAS) has been linked to obesity-induced inflammation, though mechanisms are not completely understood. In this study, adipose-specific angiotensinogen knockout mice (Agt-KO) were generated to determine whether Agt inactivation reduces inflammation and alters the metabolic profile of the Agt-KO mice compared to wild-type (WT) littermates. Adipose tissue-specific Agt-KO mice were created using the Cre-LoxP system with both Agt-KO and WT littermates fed either a low-fat or high-fat diet to assess metabolic changes. White adipose tissue was used for gene/protein expression analyses and WAT stromal vascular cells for metabolic extracellular flux assays. No significant differences were observed in body weight or fat mass between both genotypes on either diet. However, improved glucose clearance was observed in Agt-KO compared to WT littermates, consistent with higher expression of genes involved in insulin signaling, glucose transport, and fatty acid metabolism. Furthermore, Agt inactivation reduced total macrophage infiltration in Agt-KO mice fed both diets. Lastly, stroma vascular cells from Agt-KO mice revealed higher metabolic activity compared to WT mice. These findings indicate that adipose-specific Agt inactivation leads to reduced adipose inflammation and increased glucose tolerance mediated in part via increased metabolic activity of adipose cells. © 2015 The Obesity Society.

  6. Plasma volume, osmolality, vasopressin, and renin activity during graded exercise in man

    Science.gov (United States)

    Convertino, V. A.; Keil, L. C.; Bernauer, E. M.; Greenleaf, J. E.

    1981-01-01

    The influence of work intensity on plasma volume, osmolality, vasopressin and renin activity and the interrelationships between these responses are investigated. Plasma volume, renin activity and osmotic, sodium and arginine vasopressin concentrations were measured in venous blood samples taken from 15 healthy male subjects before and after six minutes of bicycle ergometer exercise at 100, 175 and 225 W. Plasma volume is found to decrease significantly with increasing work intensity, while increases in Na(+) concentration, osmolality and vasopressin are only observed to be significant when the work intensity exceeds 40% maximal aerobic capacity and plasma resin activity increased linearly at all work levels. In addition, significant correlations are observed between plasma volume and osmolality and sodium changes, and between vasopressin and osmolality and sodium content changes. Data thus support the hypotheses that (1) vasopressin may be the primary controlling endocrine for fluid and electrolyte levels following exercise; (2) an exercise intensity greater than 40% maximal aerobic capacity is required to stimulate vasopressin release through changes in plasma osmolality; and (3) the stimulation of the renin-angiotensin system is a more general stress response.

  7. Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood

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    Kely ede Picoli Souza

    2015-04-01

    Full Text Available We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system is expressed and functional in the white adipose tissue (WAT and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass or saline, starting at the first day of life until the age of 16 days. Between days 90th and 180th, a group of these animals received high fat diet (HFD. Molecular, biochemical, histological and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY and cocaine- and amphetamine-regulated transcript (CART gene expression in hypothalamus, fatty acid synthase (FAS and hormone-sensitive lipase (HSL gene expression in retroperitoneal WAT and decreases peroxixome proliferators-activated receptor (PPAR γ, PPARα, uncoupling protein (UCP 2 and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood.

  8. Progressive nature of heart failure and systems biology

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    George E. Louridas

    2015-01-01

    Full Text Available The progressive nature of heart failure (HF is the predominant cause for the clinical course that the HF syndrome is taking. Systems biology methodology is of the utmost importance to explain and comprehend the built-in mechanisms of adverse clinical progression. Various heart diseases produce myocardial damage with subsequent left ventricular remodeling which is the principal underlying pathophysiological mechanism for the clinical progression of HF. The self-organized positive feedback stabilization mechanisms of left ventricular remodeling, adrenergic stimulation and activation of the renin-angiotensin-aldosterone system and natriuretic peptide systems, are hierarchical adaptive processes. These adaptive processes are responsible for further left ventricular remodeling with subsequent clinical deterioration and for the emergence of clinical phenotypes. These mechanisms are counteracted with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and β-blockers in an attempt to improve the adverse clinical phenomena of HF progression in a new but clinically worse stabilization level. In this review our intention is to underline the progressive nature of the HF syndrome and to demonstrate the significance of ventricular remodeling and the role of self-organized positive feedback adaptive processes.

  9. Relationship of angiotensin ase and vasopressin ase enzymatic activities between hypothalamus and plasma in an obese rat model by high-fat diet

    International Nuclear Information System (INIS)

    Domínguez-Vías, G.; Segarra Robles, A.B.; Ramirez-Sánchez, M.; Jiménez Serrano, S.

    2016-01-01

    High-fat diets are associated with the development of hypertension. However, a high intake of monounsaturated fat has been proposed to be a dietary factor that can decrease the incidence of hypertension. The renin-angiotensin system (RAS) and vasopressin interact to regulate blood pressure at central and peripheral level. In this study, we investigated the effect of different degrees of dietary fatty acid saturation in the control of RAS and vasopressin on brain-blood. To improve our understanding of their interaction and their relationship, we analyzed angiotensin- and vasopressin-metabolizing activities in hypothalamus and plasma, collected from Wistar rats fed during 24 weeks with diets enriched with extra virgin olive oil (monounsaturated fat) or butter plus cholesterol (saturated fat) compared with a standard diet. As results no angiotensinase and vasopressinase activities were found in hypothalamus and plasma, however significant correlations between enzymatic activities in both regions were noticed. They indicated that our results do not support the beneficial influence of extra virgin olive oil on central and systemic level to regulate blood pressure. Therefore, the substrates hydrolyzed by these activities as well as their functions may be similarly affected and suggest that these studies should be continued because of beneficial of Mediterranean diet, found previously in different works, which may also be an effective tool in the treatment of hypertension.

  10. Relationship of angiotensinase and vasopressinase enzymatic activities between hypothalamus and plasma in an obese rat model by high-fat diet

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    Germán Domínguez-Vías

    2016-07-01

    Full Text Available High-fat diets are associated with the development of hypertension. However, a high intake of monounsaturated fat has been proposed to be a dietary factor that can decrease the incidence of hypertension. The renin-angiotensin system (RAS and vasopressin interact to regulate blood pressure at central and peripheral level. In this study, we investigated the effect of different degrees of dietary fatty acid saturation in the control of RAS and vasopressin on brain-blood. To improve our understanding of their interaction and their relationship, we analyzed angiotensin- and vasopressin-metabolizing activities in hypothalamus and plasma, collected from Wistar rats fed during 24 weeks with diets enriched with extra virgin olive oil (monounsaturated fat or butter plus cholesterol (saturated fat compared with a standard diet. As results no angiotensinase and vasopressinase activities were found in hypothalamus and plasma, however significant correlations between enzymatic activities in both regions were noticed. They indicated that our results do not support the beneficial influence of extra virgin olive oil on central and systemic level to regulate blood pressure. Therefore, the substrates hydrolyzed by these activities as well as their functions may be similarly affected and suggest that these studies should be continued because of beneficial of Mediterranean diet, found previously in different works, which may also be an effective tool in the treatment of hypertension.

  11. Relationship of angiotensin ase and vasopressin ase enzymatic activities between hypothalamus and plasma in an obese rat model by high-fat diet

    Energy Technology Data Exchange (ETDEWEB)

    Domínguez-Vías, G.; Segarra Robles, A.B.; Ramirez-Sánchez, M.; Jiménez Serrano, S.

    2016-07-01

    High-fat diets are associated with the development of hypertension. However, a high intake of monounsaturated fat has been proposed to be a dietary factor that can decrease the incidence of hypertension. The renin-angiotensin system (RAS) and vasopressin interact to regulate blood pressure at central and peripheral level. In this study, we investigated the effect of different degrees of dietary fatty acid saturation in the control of RAS and vasopressin on brain-blood. To improve our understanding of their interaction and their relationship, we analyzed angiotensin- and vasopressin-metabolizing activities in hypothalamus and plasma, collected from Wistar rats fed during 24 weeks with diets enriched with extra virgin olive oil (monounsaturated fat) or butter plus cholesterol (saturated fat) compared with a standard diet. As results no angiotensinase and vasopressinase activities were found in hypothalamus and plasma, however significant correlations between enzymatic activities in both regions were noticed. They indicated that our results do not support the beneficial influence of extra virgin olive oil on central and systemic level to regulate blood pressure. Therefore, the substrates hydrolyzed by these activities as well as their functions may be similarly affected and suggest that these studies should be continued because of beneficial of Mediterranean diet, found previously in different works, which may also be an effective tool in the treatment of hypertension.

  12. The crosstalk between the kidney and the central nervous system: the role of renal nerves in blood pressure regulation.

    Science.gov (United States)

    Nishi, Erika E; Bergamaschi, Cássia T; Campos, Ruy R

    2015-04-20

    What is the topic of this review? This review describes the role of renal nerves as the key carrier of signals from the kidneys to the CNS and vice versa; the brain and kidneys communicate through this carrier to maintain homeostasis in the body. What advances does it highlight? Whether renal or autonomic dysfunction is the predominant contributor to systemic hypertension is still debated. In this review, we focus on the role of the renal nerves in a model of renovascular hypertension. The sympathetic nervous system influences the renal regulation of arterial pressure and body fluid composition. Anatomical and physiological evidence has shown that sympathetic nerves mediate changes in urinary sodium and water excretion by regulating the renal tubular water and sodium reabsorption throughout the nephron, changes in the renal blood flow and the glomerular filtration rate by regulating the constriction of renal vasculature, and changes in the activity of the renin-angiotensin system by regulating the renin release from juxtaglomerular cells. Additionally, renal sensory afferent fibres project to the autonomic central nuclei that regulate blood pressure. Hence, renal nerves play a key role in the crosstalk between the kidneys and the CNS to maintain homeostasis in the body. Therefore, the increased sympathetic nerve activity to the kidney and the renal afferent nerve activity to the CNS may contribute to the outcome of diseases, such as hypertension. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  13. Organisation and functional role of the brain angiotensin system

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    Catherine Llorens-Cortes

    2002-03-01

    Full Text Available The discovery that all components of the renin-angiotensin system (RAS are present in the brain led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurones have been visualised in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular and supraoptic nuclei, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood-brain-barrier deficient circumventricular organs are rich in angiotensin II (Ang II receptors. By activating these receptors, circulating Ang II may act on central cardiovascular centres via angiotensinergic neurones, providing a link between peripheral and central Ang II systems. Among the effector peptides of the brain RAS, Ang II and angiotensin III (Ang III have the same affinity for type 1 and type 2 Ang II receptors. When injected into the brain, both peptides increase blood pressure (BP, water intake and pituitary hormone release and may modify learning and memory. Since Ang II is converted in vivo to Ang III, the nature of the true effector is unknown. This review summarises new insights into the predominant role of brain Ang III in the control of BP and underlines the fact that brain aminopeptidase A, the enzyme forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension.

  14. The role of sympathetic nervous system in the progression of chronic kidney disease in the era of catheter based sympathetic renal denervation.

    Science.gov (United States)

    Petras, Dimitrios; Koutroutsos, Konstantinos; Kordalis, Athanasios; Tsioufis, Costas; Stefanadis, Christodoulos

    2013-08-01

    The kidney has been shown to be critically involved as both trigger and target of sympathetic nervous system overactivity in both experimental and clinical studies. Renal injury and ischemia, activation of renin angiotensin system and dysfunction of nitric oxide system have been implicated in adrenergic activation from kidney. Conversely, several lines of evidence suggest that sympathetic overactivity, through functional and morphological alterations in renal physiology and structure, may contribute to kidney injury and chronic kidney disease progression. Pharmacologic modulation of sympathetic nervous system activity has been found to have a blood pressure independent renoprotective effect. The inadequate normalization of sympathoexcitation by pharmacologic treatment asks for novel treatment options. Catheter based renal denervation targets selectively both efferent and afferent renal nerves and functionally denervates the kidney providing blood pressure reduction in clinical trials and renoprotection in experimental models by ameliorating the effects of excessive renal sympathetic drive. This review will focus on the role of sympathetic overactivity in the pathogenesis of kidney injury and CKD progression and will speculate on the effect of renal denervation to these conditions.

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

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    Yuki Hamano

    2011-09-01

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

  16. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: association with BNP and aldosterone levels.

    Science.gov (United States)

    Tanaka, Masami; Sekioka, Risa; Nishimura, Takeshi; Ichihara, Atsuhiro; Itoh, Hiroshi

    2014-12-01

    Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus. In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated. Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Regulation of the renin–angiotensin system in coronary atherosclerosis: A review of the literature

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    Ramadan A Hammoud

    2008-01-01

    Full Text Available Ramadan A Hammoud, Christopher S Vaccari, Sameer H Nagamia, Bobby V KhanEmory University School of Medicine, Division of Cardiology, Grady Memorial Hospital Vascular Research Laboratory, Atlanta, Georgia, USAAbstract: Activation of the renin–angiotensin system (RAS is significant in the pathogenesis of cardiovascular disease and specifically coronary atherosclerosis. There is strong evidence that the RAS has effects on the mechanisms of action of atherosclerosis, including fibrinolytic balance, endothelial function, and plaque stability. Pharmacological inhibition of the renin angiotensin system includes angiotensin converting enzyme (ACE inhibitors, angiotensin receptor blockers (ARBs, and renin inhibitors. These agents have clinical benefits in reducing morbidity and mortality in the management of hypertension. In addition, ACE inhibitors and ARBs have shown to be effective in the management of congestive heart failure and acute myocardial infarction. This review article discusses the biochemical and molecular mechanisms involving the RAS in coronary atherosclerosis as well as the effects of RAS inhibition in clinical studies involving coronary atherosclerosis.Keywords: angiotensin II, atherosclerosis, endothelium, inflammation, vasculature

  18. Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

    Science.gov (United States)

    Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

    2017-08-01

    It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

  19. Once and for all, LXRα and LXRβ are gatekeepers of the endocrine system.

    Science.gov (United States)

    Maqdasy, Salwan; Trousson, Amalia; Tauveron, Igor; Volle, David H; Baron, Silvère; Lobaccaro, Jean-Marc A

    2016-06-01

    Liver X receptors (LXRs) α and β are nuclear receptors whose transcriptional activity is regulated by oxysterols, the oxidized forms of cholesterol. Described in the late 1990s as lipid sensors, both LXRs regulate cholesterol and fatty acid homeostasis. Over the years, deep phenotypic analyses of mouse models deficient for LXRα and/or LXRβ have pointed out various other physiological functions including glucose homeostasis, immunology, and neuroprotection. This review enlightens the "endocrine" functions of LXRs; they deeply impact plasma glucose directly and by modulating insulin signaling, renin-angiotensin-aldosterone axis, thyroid and pituitary hormone levels, and bone homeostasis. Besides, LXR signaling is also involved in adrenal physiology, steroid synthesis, and male and female reproduction. Hence, LXRs are definitely involved in the endocrine system and could thus be considered as endocrine receptors, even though oxysterols do not fully correspond to the definition of hormones. Finally, because they are ligand-regulated transcription factors, LXRs are potential pharmacological targets with promising beneficial metabolic effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation

    Science.gov (United States)

    Mateos, Laura; Maioli, Silvia; Ali, Zeina; Gulyás, Balázs; Winblad, Bengt; Savitcheva, Irina

    2017-01-01

    Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)–mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders. PMID:28213512

  1. Effect of Renin-Angiotensin-Aidosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease : A Post Hoc Analysis of a Randomized Controlled Trial

    NARCIS (Netherlands)

    Waanders, Femke; Vaidya, Vishal S.; van Goor, Harry; Leuvenink, Henri; Damman, Kevin; Hamming, Inge; Bonventre, Joseph V.; Vogt, Liffert; Navis, Gerjan

    Background: Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using

  2. Antihypertensive and cardiovascular effects of combined blockade of renin-angiotensin system with ACE inhibitor and angiotensin II type 1 receptor blocker in hypertensive patients: A 24-week randomized controlled double-dummy trial

    Directory of Open Access Journals (Sweden)

    Giuseppe Licata

    2010-05-01

    Full Text Available Background. In this study the effects of 24 weeks losartan and ramipril treatment, both alone and in combination, on blood pressure and left ventricular mass (LVM and function, have been evaluated in hypertensives. Methods. 57 hypertensives with stage 1 and 2 essential hypertension were included. After 4 weeks run in, a randomized double-blind, 3 arm, double dummy, independent trial was used. All patients were randomly allocated to 3 treatment arms consisting of losartan (50 mg/daily, ramipril (5 mg/daily, and combined (losartan 50 mg/ramipril 5 mg/daily for 24 weeks. LVM, LVM/h2.7 and other echocardiographic measurements, BUN, creatinine and clearance and potassium were determined after run in and 24 weeks. Results. All groups were comparable for gender, age, BMI, BP and LVM. The prevalence of baseline left ventricular hypertrophy (LVH was not significantly different among 3 groups. At the end of treatment, a significant (p<0.05 reduction in SBP, DBP, MBP, LVM and LVM/h2.7 were observed in all groups. The absolute and percent reduction in LVM/h2.7 were significantly higher in combined than losartan or ramipril groups and also in hypertensives with LVH. No significant change in absolute and percent reduction of SBP, DBP and MBP were found. Conclusions. These data indicate an additional cardioprotective effect of dual blockade of RAS in hypertensive patients with and without left ventricular hypertrophy.

  3. Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in type I diabetic patients

    DEFF Research Database (Denmark)

    Tarnow, L; Kjeld, T; Knudsen, E

    2000-01-01

    AIMS/HYPOTHESIS: Reports on a putative synergism between poor glycaemic control and carriage of the angiotensin II type 1 receptor (AGTR1) C1166-allele and risk of diabetic nephropathy have been conflicting. Therefore, we investigated the interaction between long-term glycaemic control and three...... studied Caucasian patients with Type I (insulin-dependent) diabetes mellitus and nephropathy (120 men 74 women, age 41.1 +/- 9.6 years, diabetes duration 28 +/- 8 years) and long-standing Type I diabetic patients with persistent normoalbuminuria (112 men 69 women, age 42.5 +/- 10.0 years, diabetes...... duration 27 +/- 9 years). Genotyping was PCR-based and metabolic control estimated from all measurements of HbA1c done in each patient [average (range) n = 31 (6-74)]. The median observation time (range) was 13.5 (2-14) years. RESULTS: Type I diabetic patients with a history of poor glycaemic control (HbA1...

  4. Pre- and/or Intra-Operative Prescription of Diuretics, but Not Renin-Angiotensin-System Inhibitors, Is Significantly Associated with Acute Kidney Injury after Non-Cardiac Surgery: A Retrospective Cohort Study.

    Science.gov (United States)

    Tagawa, Miho; Ogata, Ai; Hamano, Takayuki

    2015-01-01

    Pre- and/or intra-operative use of diuretics, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) constitutes a potentially modifiable risk factor for postoperative acute kidney injury (AKI). It has been studied whether use of these drugs predicts AKI after cardiac surgery. The objective of this study was to examine whether administration of these agents was independently associated with AKI after non-cardiac surgery. This was a retrospective observational study. Inclusion criteria were adult patients (age ≥ 18) who underwent non-cardiac surgery under general anesthesia from 2007 to 2009 at Kyoto Katsura Hospital. Exclusion criteria were urological surgery, missing creatinine values, and preoperative dialysis. The exposures of interest were pre- and/or intra-operative use of diuretics or ACE-I/ARB. Outcome variables were postoperative AKI as defined by the AKI Network (increase in creatinine ≥ 0.3 mg/dL or 150% within 48 hours, or urine output 6 hours). Multivariable logistic regression analyses were conducted and adjusted for potential confounders. Propensity scores (PS) for receiving diuretics or ACE-I/ARB therapy were estimated and PS adjustment, PS matching, and inverse probability weighting were performed. There were 137 AKI cases (5.0%) among 2,725 subjects. After statistical adjustment for patient and surgical characteristics, odds (95% CI) of postoperative AKI were 2.07 (1.10-3.89) (p = 0.02) and 0.89 (0.56-1.42) (p = 0.63) in users of diuretics and ACE-I/ARB, respectively, compared with non-users. PS adjustment, PS matching, and inverse probability weighting yielded similar results. The effect size of diuretics was significantly greater in the patients with lower propensity for diuretic use (p for interaction diuretics, but not ACE-I/ARB, was independently associated with postoperative AKI after non-cardiac surgery, especially in patients with low propensity for diuretic use. It might be reasonable to withhold preoperative diuretics in these patients.

  5. Effects of Combined Endothelin A Receptor and Renin-Angiotensin System Blockade on the Course of End-Organ Damage in 5/6 Nephrectomized Ren-2 Hypertensive Rats

    Czech Academy of Sciences Publication Activity Database

    Vaněčková, Ivana; Kujal, P.; Husková, Z.; Vaňourková, Z.; Vernerová, Z.; Čertíková; Chábová, V.; Škaroupková, P.; Kramer, H. J.; Tesař, V.; Červenka, L.

    2012-01-01

    Roč. 35, č. 5 (2012), s. 382-392 ISSN 1420-4096 Institutional research plan: CEZ:AV0Z50110509 Keywords : 5/6 nephrectomy * Endothelin receptor type A * AT1 receptor blocker * end-organ damage * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.596, year: 2012

  6. Urinary renin and angiotensinogen in type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, Frederik; Lu, Xifeng; Rossing, Peter

    2013-01-01

    Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade.......Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade....

  7. Active immunization against renin in normotensive marmoset

    International Nuclear Information System (INIS)

    Michel, J.B.; Guettier, C.; Philippe, M.; Galen, F.X.; Corvol, P.; Menard, J.

    1987-01-01

    Primate renins (human and monkey) are very similar. We used pure human renin to immunize marmosets (Callithrix jacchus) and thereby produce a chronic blockade of the renin-angiotensinogen reaction. After a control period of 2 months, five male marmosets, on their usual sodium-poor diet, were immunized against pure human renin by three subcutneous injections of 30 μg each, with complete and then incomplete Freund's adjuvant. Three marmosets were injected with adjuvant only and served as controls. Blood sampling and blood pressure measurements were performed weekly. After the third injection, the five marmosets immunized against renin developed a high titer of renin antibodies (50% binding of 125 I-labeled human renin at a dilution of ≥ 1:10,000). The antibodies inhibited the enzymatic activity of both marmoset and human renins. At the same time, systolic blood pressure decreased significantly. Plasma renin enzyme activity was undetectable in the animals. Plasma aldosterone decreased significantly. After 1-4 months with low blood pressure, a normal urinary output, and a normal plasma creatinine, the five marmosets became sick and died within one month. At autopsy an immunological renal disease, characterize by the presence of immunoglobulin and macrophage infiltration colocalized with renin, was found. No immunoglobulin was detectable in extrarenal vessels or in other organs. These experiments demonstrate that, in this primate, a chronic blockade of the renin-angiotensin system can be achieved by active immunization against homologous renin, but this blockade is associated with the development of an autoimmune disease localized in the kidney

  8. Prolonged fasting activates Nrf2 in post-weaned elephant seals.

    Science.gov (United States)

    Vázquez-Medina, José Pablo; Soñanez-Organis, José G; Rodriguez, Ruben; Viscarra, Jose A; Nishiyama, Akira; Crocker, Daniel E; Ortiz, Rudy M

    2013-08-01

    Elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting). In humans, rats and mice, prolonged food deprivation activates the renin-angiotensin system (RAS) and increases oxidative damage. In elephant seals, prolonged fasting activates RAS without increasing oxidative damage likely due to an increase in antioxidant defenses. The mechanism leading to the upregulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated whether prolonged fasting activates the redox-sensitive transcription factor Nrf2, which controls the expression of antioxidant genes, and if such activation is potentially mediated by systemic increases in RAS. Blood and skeletal muscle samples were collected from seals fasting for 1, 3, 5 and 7 weeks. Nrf2 activity and nuclear content increased by 76% and 167% at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 5000% and 250% higher at week 7 than at week 1. Phosphorylation of Smad2, an effector of Ang II and TGF signaling, increased by 120% at week 7 and by 84% in response to intravenously infused Ang II. NADPH oxidase 4 (Nox4) mRNA expression, which is controlled by smad proteins, increased 430% at week 7, while Nox4 protein expression, which can activate Nrf2, was 170% higher at week 7 than at week 1. These results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. The results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals.

  9. Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

    Directory of Open Access Journals (Sweden)

    Wei Luo

    Full Text Available OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS, has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL. Spironolactone was administered orally (20 mg/kg/d after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR. Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6. Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS, phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and

  10. Circulating nitric oxide products do not solely reflect nitric oxide release in cirrhosis and portal hypertension

    DEFF Research Database (Denmark)

    Afzelius, Pia; Bazeghi, Nassim; Bie, Peter

    2011-01-01

    Patients with cirrhosis often develop a systemic vasodilatation and a hyperdynamic circulation with activation of vasoconstrictor systems such as the renin-angiotensin-aldosterone system (RAAS), and vasopressin. Increased nitric oxide (NO) synthesis has been implicated in the development of this ...

  11. Short-term treatment with diminazene aceturate ameliorates the reduction in kidney ACE2 activity in rats with subtotal nephrectomy.

    Directory of Open Access Journals (Sweden)

    Elena Velkoska

    Full Text Available Angiotensin converting enzyme (ACE 2 is an important modulator of the renin angiotensin system (RAS through its role to degrade angiotensin (Ang II. Depletion of kidney ACE2 occurs following kidney injury due to renal mass reduction and may contribute to progressive kidney disease. This study assessed the effect of diminazine aceturate (DIZE, which has been described as an ACE2 activator, on kidney ACE2 mRNA and activity in rats with kidney injury due to subtotal nephrectomy (STNx. Sprague Dawley rats were divided into Control groups or underwent STNx; rats then received vehicle or the DIZE (s.c. 15 mg/kg/day for 2 weeks. STNx led to hypertension (P<0.01, kidney hypertrophy (P<0.001 and impaired kidney function (P<0.001 compared to Control rats. STNx was associated with increased kidney cortical ACE activity, and reduced ACE2 mRNA in the cortex (P<0.01, with reduced cortical and medullary ACE2 activity (P<0.05, and increased urinary ACE2 excretion (P<0.05 compared to Control rats. Urinary ACE2 activity correlated positively with urinary protein excretion (P<0.001, and negatively with creatinine clearance (P=0.04. In STNx rats, DIZE had no effect on blood pressure or kidney function, but was associated with reduced cortical ACE activity (P<0.01, increased cortical ACE2 mRNA (P<0.05 and increased cortical and medullary ACE2 activity (P<0.05. The precise in vivo mechanism of action of DIZE is not clear, and its effects to increase ACE2 activity may be secondary to an increase in ACE2 mRNA abundance. In ex vivo studies, DIZE did not increase ACE2 activity in either Control or STNx kidney cortical membranes. It is not yet known if chronic administration of DIZE has long-term benefits to slow the progression of kidney disease.

  12. R1 autonomic nervous system in acute kidney injury.

    Science.gov (United States)

    Hering, Dagmara; Winklewski, Pawel J

    2017-02-01

    Acute kidney injury (AKI) is a rapid loss of kidney function resulting in accumulation of end metabolic products and associated abnormalities in fluid, electrolyte and acid-base homeostasis. The pathophysiology of AKI is complex and multifactorial involving numerous vascular, tubular and inflammatory pathways. Neurohumoral activation with heightened activity of the sympathetic nervous system and renin-angiotensin-aldosterone system play a critical role in this scenario. Inflammation and/or local renal ischaemia are underlying mechanisms triggering renal tissue hypoxia and resultant renal microcirculation dysfunction; a common feature of AKI occurring in numerous clinical conditions leading to a high morbidity and mortality rate. The contribution of renal nerves to the pathogenesis of AKI has been extensively demonstrated in a series of experimental models over the past decades. While this has led to better knowledge of the pathogenesis of human AKI, therapeutic approaches to improve patient outcomes are scarce. Restoration of autonomic regulatory function with vagal nerve stimulation resulting in anti-inflammatory effects and modulation of centrally-mediated mechanisms could be of clinical relevance. Evidence from experimental studies suggests that a therapeutic splenic ultrasound approach may prevent AKI via activation of the cholinergic anti-inflammatory pathway. This review briefly summarizes renal nerve anatomy, basic insights into neural control of renal function in the physiological state and the involvement of the autonomic nervous system in the pathophysiology of AKI chiefly due to sepsis, cardiopulmonary bypass and ischaemia/reperfusion experimental model. Finally, potentially preventive experimental pre-clinical approaches for the treatment of AKI aimed at sympathetic inhibition and/or parasympathetic stimulation are presented. © 2016 John Wiley & Sons Australia, Ltd.

  13. Oral contraceptives, angiotensin-dependent renal vasoconstriction, and risk of diabetic nephropathy

    DEFF Research Database (Denmark)

    Ahmed, Sofia B; Hovind, Peter; Parving, Hans-Henrik

    2005-01-01

    OBJECTIVE: Diabetes, the leading cause of end-stage renal disease in the U.S., is believed to involve activation of the renin angiotensin system (RAS) as a risk factor for nephropathy. RAS activation occurs in healthy women using oral contraceptives (OCs), but the effects of OC use on the diabeti...

  14. Hydronephrosis is associated with elevated plasmin in urine in pediatric patients and rats and changes in NCC and γ-ENaC abundance in rat kidney

    DEFF Research Database (Denmark)

    Zachar, Rikke; Al-Mashhadi, Ammar; Dimke, Henrik

    2018-01-01

    , and with a stimulated renin-angiotensin-aldosterone system (RAAS) in rodent models. This study aimed at investigating the hypothesis that i) in pediatric patients with UPJO the RAAS is activated prior to surgical relief of the obstruction; ii) in rats with UPJO the RAAS activation is reflected by increased abundance...

  15. Effect of long-term treatment with urocortin on the activity of somatic angiotensin-converting enzyme in spontaneously hypertensive rats.

    Science.gov (United States)

    Yang, Cui; Liu, Xiuxia; Li, Shengnan

    2010-02-01

    Our previous acute study on urocortin (Ucn) demonstrated that Ucn altered serum and tissue angiotensin-converting enzyme (ACE) activity in rats. Therefore, the present investigation was designed to explore the effect of long-term treatment with Ucn on somatic ACE (sACE) and other components of the renin-angiotensin system (RAS). After 8 weeks of intravenous administration of Ucn in spontaneously hypertensive rats (SHR), serum and tissue sACE, angiotensin II (Ang II), nitric oxide (NO), Ang-(1-7), and tissue chymase activities were evaluated. RT-PCR analysis was performed to determine the quantity of tissue sACE mRNA. Serum sACE activity was reduced by Ucn, although tissue sACE activity and tissue sACE mRNA were elevated. Chymase activity was observed to be enhanced by Ucn, whereas the ACE inhibitor enalapril failed to influence chymase. Serum and tissue Ang II activity was reduced, but NO and Ang-(1-7) production was increased in a concentration-dependent manner after Ucn treatment. Meanwhile, a significant decrease of the systolic blood pressure (SBP) was observed after the long-term Ucn administration, and there was a significant positive correlation (r2 = 0.6993) between serum ACE activity and SBP. Pretreatment with the corticotropin-releasing factor (CRF) blocker astressin and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway blocker PD98059 abolished these effects of Ucn. Our findings further support the hypothesis that the changes of sACE activity and the production of other RAS components may play roles in the vasodilatory property of Ucn via the activation of the ERK1/2 pathway.

  16. Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system.

    Science.gov (United States)

    Rukavina Mikusic, N L; Kravetz, M C; Kouyoumdzian, N M; Della Penna, S L; Rosón, M I; Fernández, B E; Choi, M R

    2014-01-01

    The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation.

  17. Antiglaucomatous effects of the activation of intrinsic Angiotensin-converting enzyme 2.

    Science.gov (United States)

    Foureaux, Giselle; Nogueira, José C; Nogueira, Bárbara S; Fulgêncio, Gustavo O; Menezes, Gustavo B; Fernandes, Simone O A; Cardoso, Valbert N; Fernandes, Renata S; Oliveira, Gabriel P; Franca, Juçara R; Faraco, André A G; Raizada, Mohan K; Ferreira, Anderson J

    2013-06-21

    To evaluate the effects of the activation of endogenous angiotensin-converting enzyme 2 (ACE2) using the compound diminazene aceturate (DIZE) in an experimental model of glaucoma in Wistar rats. DIZE (1 mg/kg) was administered daily, either systemically or topically, and the IOP was measured weekly. To examine the role of the Mas receptor in the effects of DIZE, the Ang-(1-7) antagonist A-779 was co-administered. Drainage of the aqueous humor was evaluated by using scintigraphy. The analysis of ACE2 expression by immunohistochemistry and the counting of retinal ganglion cells (RGCs) were performed in histologic sections. Additionally, the nerve fiber structure was evaluated by transmission electron microscopy. The systemic administration and topical administration (in the form of eye drops) of DIZE increased the ACE2 expression in the eyes and significantly decreased the IOP of glaucomatous rats without changing the blood pressure. Importantly, this IOP-lowering action of DIZE was similar to the effects of dorzolamide. The antiglaucomatous effects of DIZE were blocked by A-779. Histologic analysis revealed that the reduction in the number of RGCs and the increase in the expression of caspase-3 in the RGC layer in glaucomatous animals were prevented by DIZE. This compound also prevented alterations in the cytoplasm of axons in glaucomatous rats. In addition to these neuroprotective effects, DIZE facilitated the drainage of the aqueous humor. Our results evidence the pathophysiologic relevance of the ocular ACE2/Ang-(1-7)/Mas axis of the renin-angiotensin system and, importantly, indicate that the activation of intrinsic ACE2 is a potential therapeutic strategy to treat glaucoma.

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

    Directory of Open Access Journals (Sweden)

    Max Thorwald

    2018-04-01

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

  19. Cardiovascular, endocrine, and renal effects of urodilatin in normal humans

    DEFF Research Database (Denmark)

    Bestle, M H; Olsen, Niels Vidiendal; Christensen, P

    1999-01-01

    highest doses. The renin-angiotensin-aldosterone system was inhibited by the three lowest doses but activated by the hypotensive dose of 40 ng. kg-1. min-1. Plasma vasopressin increased by factors of up to 5 during infusion of the three highest doses. Atrial natriuretic peptide immunoreactivity (including...

  20. Renal renin secretion as regulator of body fluid homeostasis

    DEFF Research Database (Denmark)

    Damkjær, Mads; Isaksson, Gustaf L; Stubbe, Jane

    2013-01-01

    The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium...

  1. Regulation of renin secretion by renal juxtaglomerular cells

    DEFF Research Database (Denmark)

    Friis, Ulla G; Madsen, Kirsten; Stubbe, Jane

    2013-01-01

    A major rate-limiting step in the renin-angiotensin-aldosterone system is the release of active renin from endocrine cells (juxtaglomerular (JG) cells) in the media layer of the afferent glomerular arterioles. The number and distribution of JG cells vary with age and the physiological level...

  2. Blood pressure is the major driving force for plaque formation in aortic-constricted ApoE-/- mice

    DEFF Research Database (Denmark)

    Johansson, Maria E.; Wickman, Anna; Skøtt, Ole

    2006-01-01

    OBJECTIVE: Using an aortic constriction model in mice, we studied whether the increase in pressure or the activation of the renin-angiotensin system (RAS) and its main receptors is the main driving force for plaque progression. METHODS: Male ApoE mice underwent sham surgery or placement of a supr...

  3. Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden.CETP transgenic mice with or without treatment with atorvastatin

    NARCIS (Netherlands)

    Kühnast, S.; Hoorn, J.W.A. van der; Hoek, A.M. van den; Havekes, L.M.; Liau, G.; Jukema, J.W.; Princen, H.M.G.

    2012-01-01

    Objective: Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to

  4. Therapeutic embolization of renal artery to control severe hypertension due to renal trauma

    Energy Technology Data Exchange (ETDEWEB)

    Cotroneo, A R; Patane, D; De Cinque, M; Falappa, P; Doglietto, G

    1987-05-01

    In a young patient with a post-traumatic renal hematoma, severe systemic hypertension, secondary to the activation of the renin-angiotensin axis, developed. Because of persistent hypertension, after 3 months of drug therapy, selective percutaneous embolization of the damaged vessels was performed. One year after procedure, the patient is normotensive without drugs.

  5. Therapeutic embolization of renal artery to control severe hypertension due to renal trauma

    International Nuclear Information System (INIS)

    Cotroneo, A.R.; Patane, D.; De Cinque, M.; Falappa, P.; Doglietto, G.

    1987-01-01

    In a young patient with a post-traumatic renal hematoma, severe systemic hypertension, secondary to the activation of the renin-angiotensin axis, developed. Because of persistent hypertension, after 3 months of drug therapy, selective percutaneous embolization of the damaged vessels was performed. One year after procedure, the patient is normotensive without drugs. (orig.)

  6. ACACβ gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Shah, Viral N; Cheema, Balneek Singh; Sharma, Rajni

    2013-01-01

    Patients with type 2 diabetes (T2DM) are usually obese and concurrent obesity results into activation of the renin-angiotensin-system (RAS) which is a risk factor for diabetic nephropathy (DN). Gene-gene interaction between acetyl-coenzymeA carboxylase beta (ACACβ) gene, which is involved in fatt...

  7. Atrial distension, haemodilution, and acute control of renin release during water immersion in humans

    DEFF Research Database (Denmark)

    Gabrielsen, A; Pump, B; Bie, P

    2002-01-01

    immersion. During WI, central venous pressure (CVP) and left atrial diameter (LAD) increased (P ... is not the single pivotal stimulus for the acute suppression of renin release in response to intravascular volume expansion by water immersion in humans. Haemodilution constitutes a significant and conceivably the principal stimulus for the acute immersion-induced suppression of renin-angiotensin system activity....

  8. Expression and effect of inhibition of aminopeptidase-A during nephrogenesis.

    NARCIS (Netherlands)

    Dijkman, H.B.P.M.; Assmann, K.J.M.; Steenbergen, E.; Wetzels, J.F.M.

    2006-01-01

    Aminopeptidase-A (APA) is a metalloprotease that cleaves N-terminal aspartyl and glutamyl residues from peptides. Its best-known substrate is angiotensin II (Ang II), the most active compound of the renin-angiotensin system (RAS). The RAS is involved in renal development. Most components of the RAS

  9. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise

    2015-01-01

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

  10. Controlled treatment of primary hypertension with propranolol and spironolactone. A crossover study with special reference to initial plasma renin activity.

    Science.gov (United States)

    Karlberg, B E; Kågedal, B; Tegler, L; Tolagen, K; Bergman, B

    1976-03-31

    Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 +/- 16/7(mean +/- standard deviation) mm Hg supine and 188/118 +/- 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions. Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 +/- 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension.

  11. Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

    Science.gov (United States)

    Singh, Jagmohan; Kumar, Sumit; Phillips, Benjamin

    2015-01-01

    The extracellular signal that triggers activation of rho-associated kinase (RhoA/ROCK), the major molecular determinant of basal internal anal sphincter (IAS) smooth muscle tone, is not known. Using human IAS tissues, we identified the presence of the biosynthetic machineries for angiotensin II (ANG II), thromboxane A2 (TXA2), and prostaglandin F2α (PGF2α). These end products of the renin-angiotensin system (RAS) (ANG II) and arachidonic acid (TXA2 and PGF2α) pathways and their effects in human IAS vs. rectal smooth muscle (RSM) were studied. A multipronged approach utilizing immunocytochemistry, Western blot analyses, and force measurements was implemented. Additionally, in a systematic analysis of the effects of respective inhibitors along different steps of biosynthesis and those of antagonists, their end products were evaluated either individually or in combination. To further describe the molecular mechanism for the IAS tone via these pathways, we monitored RhoA/ROCK activation and its signal transduction cascade. Data showed characteristically higher expression of biosynthetic machineries of RAS and AA pathways in the IAS compared with the RSM. Additionally, specific inhibition of the arachidonic acid (AA) pathway caused ∼80% decrease in the IAS tone, whereas that of RAS lead to ∼20% decrease. Signal transduction studies revealed that the end products of both AA and RAS pathways cause increase in the IAS tone via activation of RhoA/ROCK. Both AA and RAS (via the release of their end products TXA2, PGF2α, and ANG II, respectively), provide extracellular signals which activate RhoA/ROCK for the maintenance of the basal tone in human IAS. PMID:25882611

  12. Interaction of the endocrine system with inflammation: a function of energy and volume regulation.

    Science.gov (United States)

    Straub, Rainer H

    2014-02-13

    During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic

  13. Skin Autofluorescence, as Marker of Accumulation of Advanced Glycation Endproducts and of Cumulative Metabolic Stress, Is Not Increased in Patients with Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    M. E. Hettema

    2011-01-01

    Full Text Available Objective. To investigate whether advanced glycation endproducts (AGEs in the skin are increased in patients with systemic sclerosis (SSc and are related to the presence of disease-related and traditional cardiovascular risk factors. Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded. Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68±0.58 a.u. versus 1.63±0.41 a.u., P=0.684. Skin AF-EEMS in SSc patients was associated with levels of CRP (r=0.44, P=0.004, Medsger's severity scale (r=0.45, P=0.006, and use of agents intervening in the renin-angiotensin system (r=0.33, P=0.027. When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS. Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients.

  14. Alamandine acts via MrgD to induce AMPK/NO activation against Ang II hypertrophy in cardiomyocytes.

    Science.gov (United States)

    de Jesus, Itamar Couto Guedes; Scalzo, Sergio; Alves, Fabiana; Marques, Kariny; Rocha-Resende, Cibele; Bader, Michael; Santos, Robson A Souza; Guatimosim, Silvia

    2018-02-14

    The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. New members of this system have been characterized and shown to have biologically relevant actions. Alamandine and its receptor MrgD are recently identified components of RAS. In the cardiovascular system alamandine actions included vasodilation, antihypertensive and anti-fibrosis effects. Currently, the actions of alamandine on cardiomyocytes are unknown. Here our goal was twofold: (1) to unravel the signaling molecules activated by the alamandine/MrgD axis in cardiomyocytes; (2) to evaluate the ability of this axis to prevent against Angiotensin II (Ang II)-induced hypertrophy. In cardiomyocytes from C57BL/6 mice, alamandine treatment induced an increase in nitric oxide (NO) production, which was blocked by D-Pro 7 -Ang-(1-7), a MrgD antagonist. This NO rise correlated with increased phosphorylation of AMPK. Alamandine induced NO production was preserved in Mas -/- myocytes, and lost in MrgD -/- cells. Binding of fluorescent-labeled alamandine was observed in wild-type cells, but it was dramatically reduced in MrgD -/- myocytes. We also assessed the consequences of prolonged alamandine exposure to cultured neonatal rat cardiomyocytes (NRCMs) treated with Ang II. Treatment of NRCMs with alamandine prevented Ang II-induced hypertrophy. Moreover, antihypertrophic actions of alamandine were mediated via MrgD and NO, since they could be prevented by D-Pro 7 -Ang-(1-7) or inhibitors of NO synthase or AMPK. β-alanine, a MrgD agonist, recapitulated alamandine's cardioprotective effects in cardiomyocytes. Our data show that alamandine via MrgD induces AMPK/NO signaling to counterregulate Ang II induced hypertrophy. These findings highlight the therapeutic potential of the alamandine/MrgD axis in the heart.

  15. Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2/Mas receptor axis.

    Science.gov (United States)

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

    2017-05-23

    The local and systemic renin angiotensin system (RAS) influences the skeletal system micro-structure and metabolism. Studies suggested angiotensin 1-7 (Ang(1-7)) as the beneficial RAS molecule via Mas receptor activation. This study examines the function of Ang(1-7) in bone micro-architecture and metabolism in an ovariectomized (OVX) rodent model of osteoporosis. OVX rats showed structural and bone metabolic degeneration in parallel with suppressed expressions of the angiotensin converting enzyme-2 (ACE-2)/Ang(1-7)/Mas components. The infusion of Ang(1-7) markedly alleviated the altered bone metabolism and significantly enhanced both trabecular (metaphyseal) and cortical (metaphyseal-diaphyseal) morphometry. Urinary and bones minerals were also improved in OVX rats by Ang(1-7). The infusion of the heptapeptide enhanced ACE-2/Mas receptor expressions, while down-regulated AngII, ACE, and AngII type-1 receptor (AT1R) in OVX animals. Moreover, Ang(1-7) markedly improved osteoprotegerin (OPG) and lowered receptor activator NF-κB ligand (RANKL) expressions. The defensive properties of Ang(1-7) on bone metabolism, structure and minerals were considerably eradicated after blockage of Mas receptor with A-779. Ang(1-7)-induced up-regulated ACE-2/Ang(1-7)/Mas cascade and OPG expressions were abolished and the expressions of ACE/AngII/AT1R and RANKL were provoked by A-779. These findings shows for the first time the novel valuable therapeutic role of Ang(1-7) on bone health and metabolism through the ACE-2/Mas cascade.

  16. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population.

    Science.gov (United States)

    Firouzabadi, Negar; Shafiei, Massoumeh; Bahramali, Ehsan; Ebrahimi, Soltan Ahmed; Bakhshandeh, Hooman; Tajik, Nader

    2012-12-30

    Genetic factors contribute substantially to the likelihood of developing major depressive disorder (MDD). The importance of renin-angiotensin system (RAS) elements in cognition and behaviour and their involvement in aetiology and treatment of depression imply that RAS gene polymorphism(s) associated with RAS overactivity might also be associated with depression. In the present study, genotype and allele frequencies of six common polymorphisms of genes encoding for RAS components were determined in DNAs extracted from venous blood of 191 depressed and 104 healthy individuals using polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and serum angiotensin-converting enzyme (ACE) activity was assayed using a high-performance liquid chromatography (HPLC) method. The results showed, for the first time, that GG genotype of ACE A2350G was significantly associated with MDD among Iranian participants (P=0.001; odds ratio (OR)=6.2; 95% confidence interval (CI)=2.1-18.3). Significant higher serum ACE activity (P=0.0001) as well as higher diastolic blood pressure (P=0.036) were observed in depressed patients compared to the healthy control group. Depressed patients carrying GG genotype of the A2350G polymorphism had a significantly higher serum ACE activity (P=0.02) than individuals with either AA or AG genotype. In conclusion, this study supports the hypothesis of RAS overactivity in depression in that the genotype associated with higher serum ACE activity in an Iranian population was also associated with MDD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

    Directory of Open Access Journals (Sweden)

    E.P. Velloso

    2007-04-01

    Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

  18. Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

    Directory of Open Access Journals (Sweden)

    E.P. Velloso

    Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

  19. The Impact of Age-Related Dysregulation of the Angiotensin System on Mitochondrial Redox Balance

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    Ramya eVajapey

    2014-11-01

    Full Text Available Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS. A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II by angiotensin-converting enzyme (ACE. Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R and type 2 (AT2R. The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS. This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell.AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b discuss the effect of age-related activation of RAS on generation of free radicals.

  20. Bartter/Gitelman syndromes as a model to study systemic oxidative stress in humans.

    Science.gov (United States)

    Maiolino, Giuseppe; Azzolini, Matteo; Rossi, Gian Paolo; Davis, Paul A; Calò, Lorenzo A

    2015-11-01

    Reactive oxygen species (ROS) are intermediates in reduction-oxidation reactions that begin with the addition of one electron to molecular oxygen, generating the primary ROS superoxide, which in turn interacts with other molecules to produce secondary ROS, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. ROS are continuously produced during metabolic processes and are deemed to play an important role in cardiovascular diseases, namely, myocardial hypertrophy and fibrosis and atherosclerosis, via oxidative damage of lipids, proteins, and deoxyribonucleic acid. Angiotensin II (Ang II) is a potent vasoactive agent that also exerts mitogenic, proinflammatory, and profibrotic effects through several signaling pathways, in part involving ROS, particularly superoxide and hydrogen peroxide. Moreover, Ang II stimulates NADPH oxidases, leading to higher ROS generation and oxidative stress. Bartter/Gitelman syndrome patients, despite elevated plasma renin activity, Ang II, and aldosterone levels, exhibit reduced peripheral resistance, normal/low blood pressure, and blunted pressor effect of vasoconstrictors. In addition, notwithstanding the activation of the renin-angiotensin system and the increased plasma levels of Ang II, these patients display decreased production of ROS, reduced oxidative stress, and increased antioxidant defenses. In fact, Bartter/Gitelman syndrome patients are characterized by reduced levels of p22(phox) gene expression and undetectable plasma peroxynitrite levels, while showing increased plasma antioxidant power and expression of antioxidant enzymes, such as heme oxygenase-1. In conclusion, multifarious data suggest that Bartter and Gitelman syndrome patients are a model of low oxidative stress and high antioxidant defenses. The contribution offered by the study of these syndromes in elucidating the molecular mechanisms underlying this favorable status could offer chances for new therapeutic targets in disease characterized by high

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

    Science.gov (United States)

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

    2009-12-15

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

  2. Angiotensin II up-regulates PAX2 oncogene expression and activity in prostate cancer via the angiotensin II type I receptor.

    Science.gov (United States)

    Bose, Sudeep K; Gibson, Willietta; Giri, Shailendra; Nath, Narender; Donald, Carlton D

    2009-09-01

    Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type 1 receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). Here we have demonstrated that A-II up-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by an AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the down-regulation of its expression by targeting the AT1R signaling pathways.

  3. Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

    Energy Technology Data Exchange (ETDEWEB)

    Mahmood, Javed [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Jelveh, Salomeh [Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Zaidi, Asif [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Doctrow, Susan R. [Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts (United States); Medhora, Meetha [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

    2014-07-15

    Purpose: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats. Methods and Materials: The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay. Results: The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207. Conclusion: Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.

  4. Captopril and Valsartan May Improve Cogniti ve Function Through Potentiation of the Brain Antioxidant Defense System and Attenuation of Oxidative/Nitrosative Damage in STZ - Induced Dementia in Rat

    Directory of Open Access Journals (Sweden)

    Yasaman Arjmand Abbassi

    2016-12-01

    Full Text Available Purpose: Previous findings have shown the crucial roles of brain renin-angiotensin system (RAS in pathogenesis of Alzheimer’s disease (AD. Since RAS inhibitors may have beneficial effects on dementia and cognitive function in elderly people, the aim of present study was to examine the neuroprotective actions of captopril and valsartan on memory function and neuronal damage in experimental model of AD. Methods: Adult forty male Wistar rats (220-280g were randomly divided into 5 groups; Control, Vehicle, Alzheimer and treatment groups. AD was induced by the injections of streptozotocin (3mg/kg, bilateral intracerebroventricular at days 1&3. Treated rats received orally captopril (50mg/kg/day and valsartan (30mg/kg/day. Memory function and histological assessments were done at termination of experiment. Finally, superoxide dismutase (SOD and catalase (CAT activities as well as malondialdehyde (MDA and NOx contents were determined. Results: There was a significant increase in the mean value of latency in Alzheimer group (66%. Captopril and valsartan considerably decreased this value in both treatment groups (45% and 72%, respectively. In Alzheimer group the activities of brain’s SOD and CAT reduced (40% and 47%, respectively in accompany with an increase in MDA and NOx contents (49% and 50%, respectively. Captopril and valsartan significantly increased the activities of brain’s SOD and CAT concomitant reduction in MDA and NOx contents. Also, histopathological damages noticeably decreased in both treatment groups. Conclusion: Our findings indicate that RAS inhibition by using captopril and valsartan potentiates the antioxidant defense system of brain and reduces oxidative/nitrosative stress in accompany with neuronal damage during AD.

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

    Science.gov (United States)

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

    2016-06-01

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

  6. How does obesity affect the endocrine system? A narrative review.

    Science.gov (United States)

    Poddar, M; Chetty, Y; Chetty, V T

    2017-06-01

    Obesity is a chronic, relapsing medical condition that results from an imbalance of energy expenditure and consumption. It is a leading cause of preventable illness, disability and premature death. The causes of obesity are multifactorial and include behavioural, socioeconomic, genetic, environmental and psychosocial factors. Rarely are endocrine diseases, e.g., hypothyroidism or Cushing's syndrome, the cause of obesity. What is less understood is how obesity affects the endocrine system. In this review, we will discuss the impact of obesity on multiple endocrine systems, including the hypothalamic-pituitary axis, changes in vitamin D homeostasis, gender steroids and thyroid hormones. We will also examine the renin angiotensin aldosterone system and insulin pathophysiology associated with obesity. We will provide a general overview of the biochemical changes that can be seen in patients with obesity, review possible aetiologies of these changes and briefly consider current guidelines on their management. This review will not discuss endocrine causes of obesity. © 2017 World Obesity Federation.

  7. Urinary serine proteases and activation of ENaC in kidney

    DEFF Research Database (Denmark)

    Svenningsen, Per; Andersen, Henrik; Nielsen, Lise Hald

    2015-01-01

    with albuminuria compatible with impaired renal Na(+) excretion: hypertension and volume retention is secondary to proteinuria in, e.g., preeclampsia and nephrotic syndrome; plasma concentrations of renin, angiotensin II, and aldosterone are frequently suppressed in proteinuric conditions, e.g., preeclampsia......Serine proteases, both soluble and cell-attached, can activate the epithelial sodium channel (ENaC) proteolytically through release of a putative 43-mer inhibitory tract from the ectodomain of the γ-subunit. ENaC controls renal Na(+) excretion and loss-of-function mutations lead to low blood...... pressure, while gain-of-function mutations lead to impaired Na(+) excretion, hypertension, and hypokalemia. We review an emerging pathophysiological concept that aberrant glomerular filtration of plasma proteases, e.g., plasmin, prostasin, and kallikrein, contributes to proteolytic activation of ENaC, both...

  8. Antihypertensive effects of double the maximum dose of valsartan in African-American patients with type 2 diabetes mellitus and albuminuria

    DEFF Research Database (Denmark)

    Weir, Matthew R; Hollenberg, Norman K; Zappe, Dion H

    2010-01-01

    The blood pressure (BP)-lowering response to renin-angiotensin-aldosterone system blockade in hypertensive African-Americans is typically less than in whites. To determine whether higher than conventional doses of renin-angiotensin-aldosterone system blockade can improve BP reduction in African-A...

  9. The DD genotype of the angiotensin converting enzyme gene is negatively associated with right ventricular hypertrophy in male patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    van Suylen, R. J.; Wouters, E. F.; Pennings, H. J.; Cheriex, E. C.; van Pol, P. E.; Ambergen, A. W.; Vermelis, A. M.; Daemen, M. J.

    1999-01-01

    The renin angiotensin system plays an important role in the development of pulmonary artery remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary hypertension as may occur in patients with COPD. Several polymorphisms of genes encoding for components of the renin angiotensin

  10. Magnesium deficiency and metabolic syndrome: stress and inflammation may reflect calcium activation.

    Science.gov (United States)

    Rayssiguier, Yves; Libako, Patrycja; Nowacki, Wojciech; Rock, Edmond

    2010-06-01

    Magnesium (Mg) intake is inadequate in the western diet and metabolic syndrome is highly prevalent in populations around the world. Epidemiological studies suggest that high Mg intake may reduce the risk but the possibility of confounding factors exists, given the strong association between Mg and other beneficial nutriments (vegetables, fibers, cereals). The concept that metabolic syndrome is an inflammatory condition may explain the role of Mg.Mg deficiency results in a stress effect and increased susceptibility to physiological damage produced by stress. Stress activates the hypothalamic-pituitary-adrenal axis (HPA) axis and the sympathetic nervous system. The activation of the renin-angiotensin-aldosterone system is a factor in the development of insulin resistance by increasing oxidative stress. In both humans and rats, aldosteronism results in an immunostimulatory state and leads to an inflammatory phenotype. Stress response induces the release of large quantities of excitatory amino acids and activates the nuclear factor NFkappaB, promoting translation of molecules involved in cell regulation, metabolism and apoptosis. The rise in neuropeptides is also well documented. Stress-induced HPA activation has been identified to play an important role in the preferential body fat accumulation but evidence that Mg is involved in body weight regulation is lacking. One of the earliest events in the acute response to stress is endothelial dysfunction. Endothelial cells actively contribute to inflammation by elaborating cytokines, synthesizing chemical mediators and expressing adhesion molecules. Experimental Mg deficiency in rats induces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, synthesis of inflammatory cytokines and acute phase proteins, extensive production of free radicals. An increase in extracellular Mg concentration decreases inflammatory effects, while reduction in extracellular Mg results in cell activation. The

  11. Non-Traditional Systemic Treatments for Diabetic Retinopathy: An
Evidence-Based Review

    Science.gov (United States)

    Simó, Rafael; Ballarini, Stefania; Cunha-Vaz, José; Ji, Linong; Haller, Hermann; Zimmet, Paul; Wong, Tien Y.

    2015-01-01

    The rapid escalation in the global prevalence diabetes, with more than 30% being afflicted with diabetic retinopathy (DR), means it is likely that associated vision-threatening conditions will also rise substantially. This means that new therapeutic approaches need to be found that go beyond the current standards of diabetic care, and which are effective in the early stages of the disease. In recent decades several new pharmacological agents have been investigated for their effectiveness in preventing the appearance and progression of DR or in reversing DR; some with limited success while others appear promising. This up-to-date critical review of non-traditional systemic treatments for DR is based on the published evidence in MEDLINE spanning 1980-December 2014. It discusses a number of therapeutic options, paying particular attention to the mechanisms of action and the clinical evidence for the use of renin-angiotensin system blockade, fenofibrate and calcium dobesilate monohydrate in DR. PMID:25989912

  12. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    Directory of Open Access Journals (Sweden)

    Nofar Torika

    Full Text Available The circulating renin-angiotensin system (RAS, including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker on tumor necrosis factor-α (TNF-α, interleukin 1-β (IL1-β and nitric oxide (NO release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor. Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the

  13. Role of the inhibitors of angiotensin renin system on the DNA integrity of irradiated spermatozoids

    International Nuclear Information System (INIS)

    Spadella, Maria A.; Mansano, Naira S.; Schwarz, Franciele C.; Viani, Gustavo A.; Chies, Agnaldo B.

    2016-01-01

    Radiation action in the testes can significantly affect the reproductive capacity due to oxidative stress generated; phenomenon in which there is evidence of involvement of the Renin Angiotensin System (RAS). This study evaluated the role of AT1 receptor inhibitors, in mitigating the radioinduced DNA damage sperm from semen samples left vas deferens. Male Wistar rats were divided into six experimental groups: Control, 5Gy, Telmisartan (12mg/kg/day) and Losartan (34mg/kg/2x/day), 5 Gy + Telmisartan and 5 Gy + Losartan. The results showed increase in the percentage of sperm with fragmented DNA in irradiated groups when compared to controls, which was not reversed in the irradiated and treated groups. The radiation of 5Gy (single dose) affected the DNA-protein complex of the sperm and the treatments did not influence in reversing this damage, considering the experimental protocol used. (author)

  14. Sacubitril/valsartan: an Important Piece in the Therapeutic Puzzle of Heart Failure

    OpenAIRE

    Marques da Silva, P; Aguiar, C

    2017-01-01

    Sacubitril/valsartan (LCZ696), a supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, was recently approved in the EU and the USA for the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF) (NYHA class II-IV). Inhibition of chronically activated neurohormonal pathways (the renin-angiotensin-aldosterone system [RAAS] and sympathetic nervous system [SNS]) is central to the treatment of ...

  15. Blockade of Rennin-Angiotensin system blunts the fibrotic response in experimental acute pyelonephritis

    Directory of Open Access Journals (Sweden)

    Singal A

    2005-01-01

    Full Text Available Aim: To study the impact of Renin-Angiotensin system blockade in experimental acute pyelonephritis, induced by a novel surgical approach via dorsal lumbotomy incision. Materials and Methods : 45 Adult female WISTAR rats aged 8-12 weeks, underwent direct inoculation of 0.1 ml of E.coli suspension into the parenchyma of the surgically exposed kidney. 3 groups of rats were studied: Group A - treated with antibiotics only; Group B- Captopril and antibiotics and Group C- Losartan and antibiotics. Changes of acute inflammation, parenchymal destruction and scarring were compared between the groups on histopathological sections. Kruskal-Wallis test was used for statistical analysis. Results : Changes consistent with acute pyelonephritis were seen in all the kidneys. Mean% scar area in Group A, Group B and Group C was 37.08±1.79, 24.40±1.88 and 24.68±1.32% respectively at end of six weeks. Mean tubular density in Group A, B and C was 17.26±1.92, 47.18±3.00 and 47.00±5.08-tubules/lac mm2 respectively. The differences between the control and the treated animals were significant, though the results did not differ between the losartan and captopril treated rats. Conclusions : Dorsal lumbotomy approach to the kidney provides a good exposure of the kidney. Induction of acute pyelonephritis by direct inoculation of bacteria into renal cortex produced a consistent scar at 6 weeks. Blockade of renin angiotensin system by either captopril or losartan decreased the renal scar area by almost 1/3 at 6 weeks.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-24

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

  17. A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice.

    Science.gov (United States)

    Jackson, Kristy L; Marques, Francine Z; Watson, Anna M D; Palma-Rigo, Kesia; Nguyen-Huu, Thu-Phuc; Morris, Brian J; Charchar, Fadi J; Davern, Pamela J; Head, Geoffrey A

    2013-10-01

    Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.

  18. Comprehensive Approach to Heart Failure: an Urgent Need

    Directory of Open Access Journals (Sweden)

    Yanier Coll Muñoz

    2015-11-01

    Full Text Available Heart failure leads to the activation of a neurohormonal response that interacts with the hemodynamic changes, which are joined by functional and structural myocardial abnormalities, that may exist. This paper addresses the role of the renin-angiotensin system in the pathophysiology of heart failure and the use of non-invasive complementary methods that provide additional information necessary for the assessment and comprehensive management of patients, without losing the essential connection between the doctor and the patient.

  19. Acute AT1-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone

    OpenAIRE

    Shaltout, Hossam A.; Rose, James C.; Figueroa, Jorge P.; Chappell, Mark C.; Diz, Debra I.; Averill, David B.

    2010-01-01

    To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressu...

  20. Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly

    Directory of Open Access Journals (Sweden)

    Bodh I Jugdutt

    2010-12-01

    Full Text Available Bodh I JugduttDivision of Cardiology, Department of Medicine, University of Alberta and Hospital, Edmonton, CanadaAbstract: Elderly patients (age≥65 years with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT1 receptor blocker (ARB, telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes.Keywords: elderly, hypertension, telmisartan, angiotensin II type 1 receptor blocker, peroxisome proliferator-activated receptor-γ, diabetes, vascular risk

  1. Role of the inhibitors of angiotensin renin system on the DNA integrity of irradiated spermatozoids; Papel dos inibidores dos sistema renina angiotensina sobre a integridade do DNA de espermatozoides irradiados

    Energy Technology Data Exchange (ETDEWEB)

    Spadella, Maria A.; Mansano, Naira S.; Schwarz, Franciele C.; Viani, Gustavo A.; Chies, Agnaldo B. [Faculdade de Medicina de Marilia (FAMEMA), Marilia, SP (Brazil)

    2016-07-01

    Radiation action in the testes can significantly affect the reproductive capacity due to oxidative stress generated; phenomenon in which there is evidence of involvement of the Renin Angiotensin System (RAS). This study evaluated the role of AT1 receptor inhibitors, in mitigating the radioinduced DNA damage sperm from semen samples left vas deferens. Male Wistar rats were divided into six experimental groups: Control, 5Gy, Telmisartan (12mg/kg/day) and Losartan (34mg/kg/2x/day), 5 Gy + Telmisartan and 5 Gy + Losartan. The results showed increase in the percentage of sperm with fragmented DNA in irradiated groups when compared to controls, which was not reversed in the irradiated and treated groups. The radiation of 5Gy (single dose) affected the DNA-protein complex of the sperm and the treatments did not influence in reversing this damage, considering the experimental protocol used. (author)

  2. Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry.

    Directory of Open Access Journals (Sweden)

    Yasuhiro Idewaki

    Full Text Available Aldehyde dehydrogenase 2 (ALDH2 detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671 was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity and drinking habits (lifetime abstainers vs. former or current drinkers was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2. The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI]: *1/*1 abstainers as the referent, 0.94 [0.76-1.16] in abstainers with *2, 1.00 [0.80-1.26] in *1/*1 drinkers, 0.71 [0.54-0.93] in drinkers with *2. Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with *2, 1.89 [0.89-4.51] in *1/*1 drinkers, 2.35 [1.06-5.79] in drinkers with *2. In summary, patients with type 2 diabetes and ALDH2 *2

  3. Renal hyperfiltration and systemic blood pressure in patients with uncomplicated type 1 diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Gary K Yang

    Full Text Available Patients with type 1 diabetes mellitus (DM and renal hyperfiltration also exhibit systemic microvascular abnormalities, including endothelial dysfunction. The effect of renal hyperfiltration on systemic blood pressure (BP is less clear. We therefore measured BP, renal hemodynamic function and circulating renin angiotensin aldosterone system (RAAS mediators in type 1 DM patients with hyperfiltration (n = 36, DM-H, GFR≥135 ml/min/1.73 m(2 or normofiltration (n = 40, DM-N, and 56 healthy controls (HC. Since renal hyperfiltration represents a state of intrarenal RAAS activation, we hypothesized that hyperfiltration would be associated with higher BP and elevated levels of circulating RAAS mediators.BP, glomerular filtration rate (GFR - inulin, effective renal plasma flow (paraaminohippurate and circulating RAAS components were measured in DM-H, DM-N and HC during clamped euglycemia (4-6 mmol/L. Studies were repeated in DM-H and DM-N during clamped hyperglycemia (9-11 mmol/L.Baseline GFR was elevated in DM-H vs. DM-N and HC (167±6 vs. 115±2 and 115±2 ml/min/1.73 m(2, p<0.0001. Baseline systolic BP (SBP, 117±2 vs. 111±2 vs. 109±1, p = 0.004 and heart rate (76±1 vs. 67±1 vs. 61±1, p<0.0001 were higher in DM-H vs. DM-N and HC. Despite higher SBP in DM-H, plasma aldosterone was lower in DM-H vs. DM-N and HC (42±5 vs. 86±14 vs. 276±41 ng/dl, p = 0.01. GFR (p<0.0001 and SBP (p<0.0001 increased during hyperglycemia in DM-N but not in DM-H.DM-H was associated with higher heart rate and SBP values and an exaggerated suppression of systemic aldosterone. Future work should focus on the mechanisms that explain this paradox in diabetes of renal hyperfiltration coupled with systemic RAAS suppression.

  4. Remodelação miocárdica após infarto agudo do miocárdio experimental em ratos: efeito do bloqueio do sistema renina angiotensina aldosterona Myocardial remodeling after experimental acute myocardial infarction in rats: effect of renin-angiotensin-aldosterone system blockade

    Directory of Open Access Journals (Sweden)

    Hindalis Ballesteros Epifanio

    2005-01-01

    Full Text Available OBJETIVO: Verificar a ação do lisinopril e do losartan sobre a remodelação miocárdica no infarto experimental em ratos. MÉTODOS: Ratos machos Wistar foram submetidos a infarto e tratados com lisinopril 20 mg/kg/dia (LIS, n=13 ou losartan 20 mg/kg/dia (LOS, n=11, ou mantidos sem tratamento (NT, n=11, por três meses e os resultados comparados com grupo controle (CONT, n=11 de ratos sem infarto. Após a eutanásia, o ventrículo esquerdo foi separado e pesado. Foram medidas a área seccional dos miócitos (AC, fração de colágeno intersticial (CVF e a hidroxiprolina (HOP miocárdica. As variáveis foram comparadas pela ANOVA de uma via, para nível de significância de pOBJECTIVE: To assess the effect of lisinopril and losartan on myocardial remodeling in experimental infarction in rats. METHODS: Male Wistar rats underwent myocardial infarction and were either treated with lisinopril [20 mg/kg/day (LIS, n=13] or losartan [20 mg/kg/day (LOS, n=11], or kept without any treatment (NT, n=11 for 3 months. Their results were compared with those of a control group (CONT, n=11 comprising noninfarcted rats. After euthanasia, the left ventricle was isolated and weighed. The following measurements were taken: the sectional area of myocytes (AC, interstitial collagen fraction (CVF, and myocardial hydroxyproline (HOP. The variables were compared by using 1-way ANOVA, with a significance level of P<0.05. RESULTS: Acute myocardial infarction caused left ventricular hypertrophy. The treatments with lisinopril or losartan could prevent hypertrophy, which was quantified by use of left ventricular weight (LOS=1.06±0.12g, LIS=0.97±0.18g, NT=1.26±0.17g, CONT=1.02±0.09g; P<0.05, of left ventricular weight-to-body weight ratio LV/BW (LOS=2.37± 0.21mg/g, LIS=2.41±0.38mg/g, NT=2.82±0.37mg/g, CONT=2.27± 0.15mg/g, and of left ventricular AC measure-ment (LOS=210±39µ², LIS=217±35µ², NT=256±35µ², CONT=158±06 µ²; P<0.05. The CVF was significantly greater in the left ventricle of the infarcted group, and its increase was prevented with treatment (LOS=1.16±0.4%, LIS=1.27±0.5%, NT=1.8± 0.4%, CONT=0.7±0.5%. Myocardial hydroxyproline was greater in the infarcted group (NT=6.91±2.98mg/g vs. CONT=2.81± 1.21mg/g and did not change with treatment. CONCLUSION: Myocardial remodeling after infarction is characterized by an increase in the remaining ventricular mass and in interstitial collagen. The angiotensin-converting-enzyme blockers and the selective angiotensin II AT1 antagonist prevent hypertrophy of the myocyte and interstitial fibrosis.

  5. EL SISTEMA RENINA−ANGIOTENSINA DESDE LA CIRCULACIÓN HASTA LA CÉLULA: IMPLICACIONES MÁS ALLÁ DE LA HIPERTENSIÓN / The renin−angiotensin system from circulation to the cell: implications beyond hypertension

    Directory of Open Access Journals (Sweden)

    Arik Ponce Gutiérrez

    2012-10-01

    Full Text Available ResumenEl sistema renina-angiotensina es más complejo de lo que se conocía hasta hace poco tiempo, ya que su acción no solo se circunscribe al plasma sanguíneo, sino que igualmente se ha demostrado su existencia en tejidos como: corazón, cerebro, riñón, páncreas, aparato reproductor, sistema linfático y el tejido adiposo; con acciones activas específicas en todos ellos, y al mismo tiempo está presente en el interior de diferentes tipos de células, como cardiomiocitos y fibroblastos. Constituye un sistema endocrino, paracrino y autocrino que es capaz de actuar a sus diferentes niveles de manera independiente o relacionada, y participa no solo en el control de la presión arterial y homeostasis del agua y sodio como se le atribuía inicialmente, sino que también interviene en el correcto funcionamiento de numerosos órganos, así como en el mecanismo fisiopatológico de alteraciones estructurales y funcionales, fundamentalmente cardiovasculares y renales que van mucho más allá de la hipertensión arterial. / AbstractThe renin-angiotensin system is more complex than was known until recently, since its action is not only limited to the plasma. Its presence has been shown in tissues such as the heart, brain, kidney, pancreas, reproductive system, lymphatic system and adipose tissue, with specific active actions in all of them, and at the same time it is present at the intracellular level of different cell types such as cardiomyocytes and fibroblasts. It is an endocrine, paracrine and autocrine system which is capable of acting at different levels in an independent or related form, taking part not only in the control of blood pressure and homeostasis of water and sodium as initially attributed, but it is also involved in the proper functioning of numerous organs and in the pathophysiological mechanism of structural and functional alterations, mainly cardiovascular and renal, which go far beyond hypertension.

  6. Preadmission use of renin-angiotensin blockers and rupture of abdominal aortic aneurysm

    DEFF Research Database (Denmark)

    Wemmelund, Holger; Høgh, Annette; Hundborg, Heidi H.

    2016-01-01

    PURPOSE: Rupture of abdominal aortic aneurysms (rAAA) is associated with high mortality. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) has been suggested to reduce the risk of rAAA. This nationwide, combined case-control and follow-up st...

  7. Reduction of regurgitation in aortic insufficiency by inhibition of the renin/angiotensin conversion enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Reske, S.N.; Heck, I.; Mattern, H.

    1984-10-01

    The effect of captopril-mediated afterload reduction on regurgitation was investigated in 10 patients with aortic insufficiency. Regurgitation was quantitated by the regurgitation fraction and the relation of regurgitant volume to end-diastolic volume, which were derived from gated radionuclide ventriculography. 19 patients with coronary artery disease and no evidence of valvular heart disease served as controls. In patients with coronary artery disease no significant reguration was found. In patients with aortic regurgitation the blood concentration of angiotensin I increased whereas that of angiotensin II decreased significantly after captopril-medication; thus, the conversion of angiotensin I to II was reduced to about 50% of the control value. Whereas blood pressure and heart rate did not change significantly, the regurgitation fraction and the normalized regurgitant volume were significantly reduced. The ejection fraction remained essentially unchanged. These findings suggest a favorable influence of captopril-induced afterload reduction on hemodynamics in aortic regurgitation.

  8. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers

    NARCIS (Netherlands)

    Heerspink, H. J. L.; Johnsson, E.; Gause-Nilsson, I.; Cain, V. A.; Sjostrom, C. D.

    Aims: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. Methods: We conducted a

  9. Angiotensin II Receptor Blockers

    Science.gov (United States)

    ... 2010. Mann JFE, et al. Renin-angiotensin system inhibition in the treatment of hypertension. http://www.uptodate. ... profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any ...

  10. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: A systematic review and meta-analysis

    NARCIS (Netherlands)

    Currie, G. (Gemma); Taylor, A.H.M. (Alison H. M.); Fujita, T. (Toshiro); Ohtsu, H. (Hiroshi); Lindhardt, M. (Morten); K. Rossing; Boesby, L. (Lene); Edwards, N.C. (Nicola C.); Ferro, C.J. (Charles J.); J. Townend (Jonathan); A.H. van den Meiracker (Anton); Saklayen, M.G. (Mohammad G.); Oveisi, S. (Sonia); Jardine, A.G. (Alan G.); C. Delles (Christian); Preiss, D.J. (David J.); Mark, P.B. (Patrick B.)

    2016-01-01

    textabstractBackground: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease.

  11. Drug: D05147 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available atriuretic peptide (BNP) [HSA:4879] Renin-angiotensin system antagonist Treatment of congestive heart fail...ure NPR1 [HSA:4881] [KO:K12323] ... CAS: 124584-08-3 PubChem: 47206871 ...

  12. The complex field of interplay between vasoactive agents

    DEFF Research Database (Denmark)

    Hansen, Pernille B

    2009-01-01

    Lai et al. provide important new information regarding the interaction between the sympathetic and renin-angiotensin systems in the regulation of glomerular afferent arteriolar contractility. Their study demonstrates a calcium-independent enhanced contractile response to angiotensin II following ...

  13. Lupus nephritis: An approach to diagnosis and treatment in South ...

    African Journals Online (AJOL)

    In all patients, treatment should include adjunctive therapies such as renin angiotensin aldosterone system .... Switching to an alternative agent is recommended for ... gastritis, cataracts, avascular necrosis of femur, cushingoid appearance.

  14. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials

    DEFF Research Database (Denmark)

    Chaturvedi, Nish; Porta, Massimo; Klein, Ronald

    2008-01-01

    BACKGROUND: Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of ...

  15. Effect of additive renin inhibition with aliskiren on renal blood flow in patients with Chronic Heart Failure and Renal Dysfunction (Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction).

    Science.gov (United States)

    Schroten, Nicolas F; Damman, Kevin; Hemmelder, Marc H; Voors, Adriaan A; Navis, Gerjan; Gaillard, Carlo A J M; van Veldhuisen, Dirk J; Van Gilst, Wiek H; Hillege, Hans L

    2015-05-01

    We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007). Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction. Copyright © 2015 Mosby, Inc. All rights reserved.

  16. ADASY (Active Daylighting System)

    Science.gov (United States)

    Vázquez-Moliní, Daniel; González-Montes, Mario; Fernández-Balbuena, Antonio Á.; Bernabéu, Eusebio; García-Botella, Ángel; García-Rodríguez, Lucas; Pohl, Wilfried

    2009-08-01

    The main objective of ADASY (Active Daylighting System) work is to design a façade static daylighting system oriented to office applications, mainly. The goal of the project is to save energy by guiding daylight into a building for lighting purpose. With this approach we can reduce the electrical load for artificial lighting, completing it with sustainable energy. The collector of the system is integrated on a vertical façade and its distribution guide is always horizontal inside of the false ceiling. ADASY is designed with a specific patent pending caption system, a modular light-guide and light extractor luminaire system. Special care has been put on the final cost of the system and its building integration purpose. The current ADASY configuration is able to illuminate 40 m2 area with a 300lx-400lx level in the mid time work hours; furthermore it has a good enough spatial uniformity distribution and a controlled glare. The data presented in this study are the result of simulation models and have been confirmed by a physical scaled prototype. ADASY's main advantages over regular illumination systems are: -Low maintenance; it has not mobile pieces and therefore it lasts for a long time and require little attention once installed. - No energy consumption; solar light continue working even if there has been a power outage. - High quality of light: the colour rendering of light is very high - Psychological benefits: People working with daylight get less stress and more comfort, increasing productivity. - Health benefits

  17. Vitamin D and male reproductive system.

    Science.gov (United States)

    Costanzo, Pablo R; Knoblovits, Pablo

    2016-12-01

    Vitamin D deficiency is a highly prevalent worldwide condition and affects people of all ages. The most important role of vitamin D is the regulation of intestinal calcium absorption and metabolism of calcium and phosphorus to maintain muscle and bone homeostasis. Furthermore, in recent years it has been discovered that the vitamin D receptor (VDR) is widely distributed in many organs and tissues where vitamin D can perform other actions that include the modulation of the immune response, insulin secretion, anti-proliferative effect on cells of vascular smooth muscle, modulation of the renin-angiotensin-aldosterone system and regulates cell growth in several organs. The VDR is widely distributed in the male reproductive system. Vitamin D induces changes in the spermatozoa's calcium and cholesterol content and in protein phosphorylation to tyrosine/threonine residues. These changes could be involved in sperm capacitation. Vitamin D seems to regulate aromatase expression in different tissues. Studies analyzing seasonal variations of sex steroids in male populations yield conflicting results. This is probably due to the wide heterogeneity of the populations included according to age, systemic diseases and obesity.

  18. Neurohumoral fluid regulation in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik Sahl

    1998-01-01

    oxide and vasodilating peptides seem to play an important role. The development of central hypovolaemia and activation of potent vasoconstricting systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system lead to a hyperdynamic circulation with increased heart rate...... and lungs. It is still an enigma why patients with chronic liver disease are at the same time overloaded and functional hypovolaemic with a hyperdynamic, hyporeactive circulation. Further research is needed to find the solution to this apparent haemodynamic conflict concerning the abnormal neurohumoral...

  19. Hypertension as a risk factor for heart failure.

    Science.gov (United States)

    Kannan, Arun; Janardhanan, Rajesh

    2014-07-01

    Hypertension remains a significant risk factor for development of congestive heart failure CHF), with various mechanisms contributing to both systolic and diastolic dysfunction. The pathogenesis of myocardial changes includes structural remodeling, left ventricular hypertrophy, and fibrosis. Activation of the sympathetic nervous system and renin-angiotensin system is a key contributing factor of hypertension, and thus interventions that antagonize these systems promote regression of hypertrophy and heart failure. Control of blood pressure is of paramount importance in improving the prognosis of patients with heart failure.

  20. Angiotensin-converting enzyme insertion/deletion polymorphism association with obesity and some related disorders in Egyptian females: a case-control observational study

    OpenAIRE

    Motawi, Tarek K.; Shaker, Olfat G.; Shahin, Nancy N.; Ahmed, Nancy M.

    2016-01-01

    Background According to the WHO report in 2015, obesity is the fifth leading cause of death worldwide, and the prevalence of Egyptian female obesity is 37.5?%. Since obesity is highly influenced by genetics, and adipose tissue renin-angiotensin system is over-activated in obesity, the effect of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism on obesity and related disorders was studied in several populations, because of its effect on ACE activity. Our objective was t...

  1. Mechanisms of renal NaCl retention in proteinuric disease

    DEFF Research Database (Denmark)

    Svenningsen, Per; Friis, Ulla G; Versland, Jostein B

    2013-01-01

    In diseases with proteinuria, for example nephrotic syndrome and pre-eclampsia, there often are suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed...... of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the gamma ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and pre-eclampsia...

  2. Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.

    Science.gov (United States)

    Wolke, Carmen; Teumer, Alexander; Endlich, Karlhans; Endlich, Nicole; Rettig, Rainer; Stracke, Sylvia; Fiene, Beate; Aymanns, Simone; Felix, Stephan B; Hannemann, Anke; Lendeckel, Uwe

    2017-03-01

    , resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.

  3. Cardiovascular, endocrine and renal effects of urodilatin in normal humans

    DEFF Research Database (Denmark)

    Bestle, M.H.; Olsen, N.V.; Christensen, P.

    1999-01-01

    remained below 0.1%. The results indicate that even moderately natriuretic doses of urodilatin exert protracted effects on systemic hemodynamic, endocrine, and renal functions, including decreases in cardiac output and renal blood flow, without changes in arterial pressure or glomerular filtration rate...... highest doses. The renin-angiotensin-aldosterone system was inhibited by the three lowest doses but activated by the hypotensive dose of 40 ng. kg-1. min-1. Plasma vasopressin increased by factors of up to 5 during infusion of the three highest doses. Atrial natriuretic peptide immunoreactivity (including...

  4. Hyponatremic hypertensive syndrome secondary to renal ischemia – Case report

    Directory of Open Access Journals (Sweden)

    Joana Cunha Oliveira

    2018-01-01

    Full Text Available Hyponatremic hypertensive syndrome (HHS is characterized by hypertensive crisis, and hyponatremia secondary to unilateral renal damage with glomerular and tubular dysfunction. Elevated plasma levels of renin in most cases suggest that the stimulation of renin release from the ischemic kidney plays an important pathophysiologic role. Activation of the renin-angiotensin system results in hypertension and causes secondary hyperfiltration, pressure diuresis and sodium loss from contralateral non-damaged kidney. An elevated renin level is a pathognomonic finding in HHS. Potassium deficiency from hyperaldosteronism may further stimulate renin secretion and intensify this vicious circle.We report a female term newborn, who presented with hypertensive crisis on the seventh day after traumatic birth. The first three days of life were uneventful. Initial treatment with captopril resulted in severe hypotension and hemodynamic instability. Lab work revealed hyponatremia, hypokalemia, and elevated peripheral renin activity and aldosterone levels. Complementary sonography and magnetic resonance confirmed right adrenal gland hematoma and several ischemic areas in the upper pole of the right kidney. The diagnosis of HHS secondary to renal ischemia was evoked.HHS is a rare condition in the neonatal period, though still under-recognized. In the neonatal and early infancy period, renovascular disease is the most common cause of secondary hypertension. In this case, there was no sign of vascular disease, the renin-angiotensin system was activated secondary to direct renal ischemia and infarction. The intense renin stimulation and pressure through the contralateral normal kidney results in high pressure natriuresis facilitating a severe volume-depleted state. Although the use of renin-angiotensin system inhibitors is the treatment of choice, it is imperative to re-establish hydration and renal perfusion before starting this antihypertensive medication. We aimed to

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

    Directory of Open Access Journals (Sweden)

    C. Becari

    2011-09-01

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

  6. Captopril in the hepatorenal syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Cobden, I.; Shore, A.; Wilkinson, R.; Record, C.O.

    1985-08-01

    Five patients with hepatorenal syndrome were treated with the orally active angiotensin-converting enzyme inhibitor captopril (25 or 50 mg 6 hourly) for up to 48 hours. Only one patient showed a significant increase in urinary sodium concentration (from less than 10 to 70 mmol/liter), but without associated diuresis; renal function continued to deteriorate in all patients with persistent oliguria and rising serum creatinine. The outcome was uniformly fatal. These results suggest that in the hepatorenal syndrome, captopril in standard dosage is without benefit, and provide further evidence that the changes in the renin-angiotensin system are probably secondary to reduced renal perfusion from some other cause.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  8. Rationale and trial design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes

    DEFF Research Database (Denmark)

    de Zeeuw, Dick; Akizawa, Tadao; Agarwal, Rajiv

    2013-01-01

    Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic...... triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved...

  9. Hypertension after bilateral kidney irradiation in young and adult rats

    International Nuclear Information System (INIS)

    Jongejan, H.T.; van der Kogel, A.J.; Provoost, A.P.; Molenaar, J.C.

    1987-01-01

    The mechanism of a rise in blood pressure after kidney irradiation is unclear but most likely of renal origin. We have investigated the role of the renin-angiotensin system and dietary salt restriction in the development of systolic hypertension after bilateral kidney irradiation in young and adult rats. Three to 12 months after a single X-ray dose of 7.5 or 12.5 Gy to both kidneys of young and adult rats, the systolic blood pressure (SBP) and plasma renin concentration (PRC) were measured regularly. A single X-ray dose of 12.5 Gy caused a moderate rise in SBP and a slight reduction in PRC in both young and adult rats. A dose of 7.5 Gy did not significantly alter the SBP or PRC during the follow-up period of 1 year. In a second experiment, the kidneys of young rats received an X-ray dose of 20 Gy. Subsequently, rats were kept on a standard diet (110 mmol sodium/kg) or a sodium-poor diet (10 mmol sodium/kg). On both diets, SBP started to rise rapidly 3 months after kidney irradiation. Sodium balance studies carried out at that time revealed an increased sodium retention in the irradiated rats compared to controls on the same diet. In rats on a low sodium intake, there was neither a delay nor an alleviation in the development of hypertension. Compared to controls, the PRC tended to be lower in irradiated rats up to 4 months after irradiation. Subsequently, malignant hypertension developed in all 20 Gy rats, resulting in pressure natriuresis, stimulating the renin-angiotensin system. Our findings indicated that hypertension after bilateral kidney irradiation was not primarily the result of an activation of the renin-angiotensin system. Although there were some indications that sodium retention played a role, dietary sodium restriction did not influence the development of hypertension

  10. ENDOCRINE PANCREATIC FUNCTION IN ACUTE PANCREATITIS

    Directory of Open Access Journals (Sweden)

    P. V. Novokhatny

    2014-02-01

    Full Text Available Introduction Among the organs of internal secretion pancreas has a special place thanks to active exocrine function and a wide range of physiological actions of produced hormones. Violations of endocrine pancreas arises in 6.5-38 % of patients with acute pancreatitis. However, there is still no clear understanding of the pathogenetic mechanisms of hormonal dysfunction of the pancreas in acute pancreatitis, there is no uniform algorithms for its correction. Aim of the research was to study the endocrine function of pancreas in acute pancreatitis. To define the role of endocrine pancreatic function in the etiology and pathogenesis of the acute pancreatitis. To assess the prospects of the use of pancreatic hormones in the treatment and predicting the outcomes of acute pancreatitis. Materials and methods of the research Survey of publications in specialized periodical medical journals, PubMed sources developed by the National Center for Biotechnology Information. Search in PubMed was carried out in the following databases: MEDLINE, Pre MEDLINE. Results of the research. In a significant proportion of patients who recovered from acute pancreatitis, exocrine and endocrine functional impairments were found. This finding was not detected only in patients after severe acute pancreatitis. Routine evaluation of pancreatic function after acute pancreatitis should be considered. The comparative analysis of the synthetic analogues (somatostatin, calcitonin, leu-enkefalin-dalargin influence on the glucose metabolism of rats in acute pancreatitis of was made. Physiological reaction of beta-cells is preserved in infusion of somatostatin. However, infusion of calcitonin results in the distortion of counterregulatory action of insulin and glucagon. It was detected that pancreatic renin-angiotensin system is markedly activated in the experimental rat models of chronic hypoxia and acute pancreatitis. The activation of the pancreatic renin-angiotensin system by

  11. Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

    Science.gov (United States)

    Padda, Ranjit Singh; Shi, Yixuan; Lo, Chao-Sheng; Zhang, Shao-Ling; Chan, John S D

    2015-10-14

    The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, anti-fibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage.

  12. Redox modification of caveolar proteins in the cardiovascular system- role in cellular signalling and disease.

    Science.gov (United States)

    Bubb, Kristen J; Birgisdottir, Asa Birna; Tang, Owen; Hansen, Thomas; Figtree, Gemma A

    2017-08-01

    Rapid and coordinated release of a variety of reactive oxygen species (ROS) such as superoxide (O 2 .- ), hydrogen peroxide (H 2 O 2 ) and peroxynitrite, in specific microdomains, play a crucial role in cell signalling in the cardiovascular system. These reactions are mediated by reversible and functional modifications of a wide variety of key proteins. Dysregulation of this oxidative signalling occurs in almost all forms of cardiovascular disease (CVD), including at the very early phases. Despite the heavily publicized failure of "antioxidants" to improve CVD progression, pharmacotherapies such as those targeting the renin-angiotensin system, or statins, exert at least part of their large clinical benefit via modulating cellular redox signalling. Over 250 proteins, including receptors, ion channels and pumps, and signalling proteins are found in the caveolae. An increasing proportion of these are being recognized as redox regulated-proteins, that reside in the immediate vicinity of the two major cellular sources of ROS, nicotinamide adenine dinucleotide phosphate oxidase (Nox) and uncoupled endothelial nitric oxide synthase (eNOS). This review focuses on what is known about redox signalling within the caveolae, as well as endogenous protective mechanisms utilized by the cell, and new approaches to targeting dysregulated redox signalling in the caveolae as a therapeutic strategy in CVD. Copyright © 2017. Published by Elsevier Inc.

  13. Skeletal muscle myoblasts possess a stretch-responsive local angiotensin signalling system.

    Science.gov (United States)

    Johnston, Adam P W; Baker, Jeff; De Lisio, Michael; Parise, Gianni

    2011-06-01

    A paucity of information exists regarding the presence of local renin-angiotensin systems (RASs) in skeletal muscle and associated muscle stem cells. Skeletal muscle and muscle stem cells were isolated from C57BL/6 mice and examined for the presence of a local RAS using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), Western blotting and liquid chromatography-mass spectrometry (LC-MS). Furthermore, the effect of mechanical stimulation on RAS member gene expression was analysed. Whole skeletal muscle, primary myoblasts and C2C12 derived myoblasts and myotubes differentially expressed members of the RAS including angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 (AT(1)) and type 2 (AT(2)). Renin transcripts were never detected, however, mRNA for the 'renin-like' enzyme cathepsin D was observed and Ang I and Ang II were identified in cell culture supernatants from proliferating myoblasts. AT(1) appeared to co-localise with polymerised actin filaments in proliferating myoblasts and was primarily found in the nucleus of terminally differentiated myotubes. Furthermore, mechanical stretch of proliferating and differentiating C2C12 cells differentially induced mRNA expression of angiotensinogen, AT(1) and AT(2). Proliferating and differentiated muscle stem cells possess a local stress-responsive RAS in vitro. The precise function of a local RAS in myoblasts remains unknown. However, evidence presented here suggests that Ang II may be a regulator of skeletal muscle myoblasts.

  14. Automated activation-analysis system

    International Nuclear Information System (INIS)

    Minor, M.M.; Hensley, W.K.; Denton, M.M.; Garcia, S.R.

    1981-01-01

    An automated delayed neutron counting and instrumental neutron activation analysis system has been developed at Los Alamos National Laboratory's Omega West Reactor (OWR) to analyze samples for uranium and 31 additional elements with a maximum throughput of 400 samples per day. The system and its mode of operation for a large reconnaissance survey are described

  15. Hypertensive effects of the iv administration of picomoles of ouabain

    Directory of Open Access Journals (Sweden)

    A.S. Padilha

    2011-09-01

    Full Text Available Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the α-subunit of the Na+ pump, inhibiting its activity. Inhibition of this pump increases intracellular Na+, which reduces the activity of the sarcolemmal Na+/Ca2+ exchanger and thereby reduces Ca2+ extrusion. Consequently, intracellular Ca2+ increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.

  16. Essential hypertension in adolescents and children: Recent advances in causative mechanisms

    Directory of Open Access Journals (Sweden)

    Manu Raj

    2011-01-01

    Full Text Available Essential hypertension is the most common form of hypertension in adults, and it is recognized more often in adolescents than in younger children. It is well known that the probability of a diagnosis of essential hypertension increases with age from birth onward. The initiation of high blood pressure burden starts in childhood and continues through adolescence to persist in the remaining phases of life. The genesis of essential hypertension is likely to be multifactorial. Obesity, insulin resistance, activation of sympathetic nervous system, sodium homeostasis, renin-angiotensin system, vascular smooth muscle structure and reactivity, serum uric acid levels, genetic factors and fetal programming have been implicated in this disorder. In addition, erythrocyte sodium transport, the free calcium concentration in platelets and leukocytes, urine kallikrein excretion, and sympathetic nervous system receptors have also been investigated as other possible mechanisms. Obesity in children appears to be the lead contributor of essential hypertension prevalence in children and adolescents. Suggested mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of renin-angiotensin-aldosterone, and altered vascular function. The etiopathogenesis of essential hypertension in children and adolescents appears to closely resemble that of adults. The minor variations seen could probably be due to the evolving nature of this condition. Many of the established mechanisms that are confirmed in adult population need to be replicated in the pediatric age group by means of definitive research for a better understanding of this condition in future.

  17. Narrative Inquiry With Activity Systems

    Directory of Open Access Journals (Sweden)

    Lisa C. Yamagata-Lynch

    2017-04-01

    Full Text Available The goal of this article is to introduce activity systems as a methodological tool in narrative inquiry to gain a holistic understanding of socially shared experiences from an examination of documents. The research question was how can qualitative researchers use activity systems as a tool for engaging in narrative inquiry of socially shared experiences to uncover new meanings by constructing a story? In this article, we share a sample analysis of our experience relying on documents and media as a form of narrative to begin to understand the socially shared human activity associated with net neutrality and its potential impact on U.S. residents. We end this article with reflections of lessons learned from our activity systems guided story construction process.

  18. Active Response Gravity Offload System

    Science.gov (United States)

    Valle, Paul; Dungan, Larry; Cunningham, Thomas; Lieberman, Asher; Poncia, Dina

    2011-01-01

    The Active Response Gravity Offload System (ARGOS) provides the ability to simulate with one system the gravity effect of planets, moons, comets, asteroids, and microgravity, where the gravity is less than Earth fs gravity. The system works by providing a constant force offload through an overhead hoist system and horizontal motion through a rail and trolley system. The facility covers a 20 by 40-ft (approximately equals 6.1 by 12.2m) horizontal area with 15 ft (approximately equals4.6 m) of lifting vertical range.

  19. Information system development activities and inquiring systems

    DEFF Research Database (Denmark)

    Carugati, Andrea

    2008-01-01

    This article presents a framework that maps information system development (ISD) activities on systems for the creation of knowledge. This work addresses the relevant and persisting problem of improving the chances of ISD success. The article builds upon previous research on knowledge aspects...... based on ISD literature and on Churchman's (1971) inquiring systems. The second part presents the use of the framework in an ISD project. The case is used to show the applicability of the framework and to highlight the advantages of this approach. The main theoretical implication is that the framework...

  20. Rol del sistema kallicreína kinina y su interrelación con sistemas vasoactivos durante la preñez Role of the kallikrein kinin system and its interrelationship with vasoactive systems in pregnancy

    Directory of Open Access Journals (Sweden)

    Elisabet Oddo

    2011-10-01

    systems. It was demonstrated in rats that activation of KKS precedes the installation of glomerular hyperfiltration as aprotinin prevents the increase in glomerular filtration. In addition, individual or associated inhibition of specific kallikrein kinin system effectors, prostaglandins (PGs and nitric oxide (NO, confirm the glomerular filtration rate dependence of KKS during pregnancy. It was also found that the renin-angiotensin system (RAS contributes to glomerular hyperfiltration as this is affected by the administration of RAS blockers. The peak of hyperfiltration maximum inhibition was obtained by the blockade of both systems (KKS and RAS. In addition, strategies used to alter the glomerular hyperfiltration and increased sodium reabsorption during pregnancy, showed abnormalities in the development of the fetus and placenta, fewer offspring, more fetus resorptions and intrauterine growth retardation. KKS inhibitors associated with RAS or nitric oxide blockers showed the greatest impact. As a consequence, it was demonstrated that KKS plays a central role in the adaptation phenomenom that accompanies normal pregnancy. The interplay of KKS with several vasoactive systems, seem to arrange a network involved in the hemodynamic adaptations to allow the proper development of pregnancy and the fetus and placenta.

  1. Expression and nutritional regulation of the (pro)renin receptor in rat visceral adipose tissue.

    Science.gov (United States)

    Achard, V; Tassistro, V; Boullu-Ciocca, S; Grino, M

    2011-12-01

    Early life nutritional environment plays an important role in the development of visceral adipose tissue and interacts with nutritional regulations in adulthood, leading to metabolic dysregulations. We hypothesized that the renin-angiotensin system may play a role in the programming-induced development of visceral adipose tissue. We studied, using a model of programming of overweight and glucose intolerance, obtained by post-natal overfeeding with consecutive highfat diet, the status of plasma renin activity and mesenteric adipose renin-angiotensin system, including the recently identified (pro)renin receptor, in adult rats. Post-natal overfeeding or high-fat feeding lead to overweight with increased visceral fat mass and adipocytes surface. When both paradigms were associated, adipocytes surface showed a disproportionate increase. A strong immunoreactivity for (pro)renin receptor was found in stromal cells. Plasma renin activity increased in programmed animals whereas (pro)renin receptor expressing cells density was stimulated by high-fat diet. There was a positive, linear relationship between plasma renin activity and (pro)renin receptor expressing cells density and adipocytes surface. Our experiments demonstrate that association of post-natal overfeeding and high-fat diet increased plasma renin activity and adipose (pro)renin receptor expression. Such phenomenon could explain, at least in part, the associated disproportionate adipocyte hypertrophy and its accompanying increased glucose intolerance.

  2. MNC Headquarters as Activity Systems

    DEFF Research Database (Denmark)

    Nell, Phillip C.; Larsen, Marcus M.

    2012-01-01

    Recent literature has questioned why multinational corporations (MNC) relocate their headquarters activities overseas. In this paper, we investigate the consequences of this phenomenon. To do this, we conceptualize the MNC headquarters activities as an interdependent system, and develop a set...... of propositions that links headquarters unbundling and relocation to complexity and rising coordination costs. Moreover, we argue that the coordination costs are often neglected in the headquarters reconfiguration process. In sum, we provide a novel perspective on modern MNC headquarters configurations, derive...

  3. Automated activation-analysis system

    International Nuclear Information System (INIS)

    Minor, M.M.; Garcia, S.R.; Denton, M.M.

    1982-01-01

    An automated delayed neutron counting and instrumental neutron activation analysis system has been developed at Los Alamos National Laboratory's Omega West Reactor (OWR) to analyze samples for uranium and 31 additional elements with a maximum throughput of 400 samples per day

  4. System for actively reducing sound

    NARCIS (Netherlands)

    Berkhoff, Arthur P.

    2005-01-01

    A system for actively reducing sound from a primary noise source, such as traffic noise, comprising: a loudspeaker connector for connecting to at least one loudspeaker for generating anti-sound for reducing said noisy sound; a microphone connector for connecting to at least a first microphone placed

  5. Active Space Debris Removal System

    Directory of Open Access Journals (Sweden)

    Gabriele GUERRA

    2017-06-01

    Full Text Available Since the start of the space era, more than 5000 launches have been carried out, each carrying satellites for many disparate uses, such as Earth observation or communication. Thus, the space environment has become congested and the problem of space debris is now generating some concerns in the space community due to our long-lived belief that “space is big”. In the last few years, solutions to this problem have been proposed, one of those is Active Space Debris Removal: this method will reduce the increasing debris growth and permit future sustainable space activities. The main idea of the method proposed below is a drag augmentation system: use a system capable of putting an expanded foam on a debris which will increase the area-to-mass ratio to increase the natural atmospheric drag and solar pressure. The drag augmentation system proposed here requires a docking system; the debris will be pushed to its release height and then, after un-docking, an uncontrolled re-entry takes place ending with a burn up of the object and the foam in the atmosphere within a given time frame. The method requires an efficient way to change the orbit between two debris. The present paper analyses such a system in combination with an Electric Propulsion system, and emphasizes the choice of using two satellites to remove five effective rockets bodies debris within a year.

  6. Is the fixed-dose combination of telmisartan and hydrochlorothiazide a good approach to treat hypertension?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2007-07-01

    Full Text Available Marc P Maillard, Michel BurnierService of Nephrology, Department of Internal Medicine, Lausanne University Hospital, SwitzerlandAbstract: Blockade of the renin-angiotensin system with selective AT1 receptor antagonists is recognized as an effective mean to lower blood pressure in hypertensive patients. Among the class of AT1 receptor antagonists, telmisartan offers the advantage of a very long half-life. This enables blood pressure control over 24 hours using once-daily administration. The combination of telmisartan with hydrochlorothiazide is a logical step because numerous previous studies have demonstrated that sodium depletion enhances the antihypertensive efficacy of drugs interfering with the activity of the renin-angiotensin system (RAS. In accordance with past experience using similar compounds blocking the RAS, several controlled studies have now demonstrated that the fixed-dose combination of telmisartan/hydrochlorothiazide is superior in lowering blood pressure than either telmisartan or hydrochlorothiazide alone. Of clinical interest also is the observation that the excellent clinical tolerance of the angiotensin II receptor antagonist is not affected by the association of the low-dose thiazide. Thus telmisartan/hydrochlorothiazide is an effective and well-tolerated antihypertensive combination. Finally, the development of fixed-dose combinations should improve drug adherence because of the one-pill-a-day regimen.Keywords: telmisartan, hydrochlorothiazide, fixed-dose combinations, antihypertensive agent, safety, compliance

  7. Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

    Directory of Open Access Journals (Sweden)

    Eduardo Pimenta

    2009-05-01

    Full Text Available Eduardo Pimenta1, Suzanne Oparil21Endocrine Hypertension Research Center and Clinical Center of Research Excellence in Cardiovascular Disease and Metabolic Disorders, University of Queensland School of Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia; 2Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, AL, USAbstract: The renin-angiotensin-aldosterone system (RAAS is an important mediator of blood pressure (BP and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II. Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs, is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.Keywords: hypertension, renin inhibitors, renin-angiotensin-aldosterone system

  8. PWR system reliability improvement activities

    International Nuclear Information System (INIS)

    Yoshikawa, Yuichiro

    1985-01-01

    In Japan lacking in energy resources, it is our basic energy policy to accelerate the development program of nuclear power, thereby reducing our dependence. As referred to in the foregoing, every effort has been exerted on our part to improve the PWR system reliability by dint of the so-called 'HOMEMADE' TQC activities, which is our brain-child as a result of applying to the energy industry the quality control philosophy developed in the field of manufacturing industry

  9. System for optimizing activation measurements

    International Nuclear Information System (INIS)

    Antonov, V.A.

    1993-01-01

    Optimization procedures make it possible to perform committed activation investigations, reduce the number of experiments, make them less laborious, and increase their productivity. Separate mathematical functions were investigated for given optimization conditions, and these enable numerical optimal parameter values to be established only in the particular cases of specific techniques and mathematical computer programs. In the known mathematical models insufficient account is taken of the variety and complexity of real nuclide mixtures, the influence of background radiation, and the wide diversity of activation measurement conditions, while numerical methods for solving the optimization problem fail to reveal the laws governing the variations of the activation parameters and their functional interdependences. An optimization method was proposed in which was mainly used to estimate the time intervals for activation measurements of a mononuclide, binary or ternary nuclide mixture. However, by forming a mathematical model of activation processes it becomes possible to extend the number of nuclides in the mixture and to take account of the influence of background radiation and the diversity of the measurement alternatives. The analytical expressions and nomograms obtained can be used to determine the number of measurements, their minimum errors, their sensitivities when estimating the quantity of the tracer nuclide, the permissible quantity of interfering nuclides, the permissible background radiation intensity, and the flux of activating radiation. In the worker described herein these investigations are generalized to include spectrally resolved detection of the activation effect in the presence of the tracer and the interfering nuclides. The analytical expressions are combined into a system from which the optimal activation parameters can be found under different given conditions

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

    Science.gov (United States)

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

    2014-09-01

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

  11. Solar active region display system

    Science.gov (United States)

    Golightly, M.; Raben, V.; Weyland, M.

    2003-04-01

    The Solar Active Region Display System (SARDS) is a client-server application that automatically collects a wide range of solar data and displays it in a format easy for users to assimilate and interpret. Users can rapidly identify active regions of interest or concern from color-coded indicators that visually summarize each region's size, magnetic configuration, recent growth history, and recent flare and CME production. The active region information can be overlaid onto solar maps, multiple solar images, and solar difference images in orthographic, Mercator or cylindrical equidistant projections. Near real-time graphs display the GOES soft and hard x-ray flux, flare events, and daily F10.7 value as a function of time; color-coded indicators show current trends in soft x-ray flux, flare temperature, daily F10.7 flux, and x-ray flare occurrence. Through a separate window up to 4 real-time or static graphs can simultaneously display values of KP, AP, daily F10.7 flux, GOES soft and hard x-ray flux, GOES >10 and >100 MeV proton flux, and Thule neutron monitor count rate. Climatologic displays use color-valued cells to show F10.7 and AP values as a function of Carrington/Bartel's rotation sequences - this format allows users to detect recurrent patterns in solar and geomagnetic activity as well as variations in activity levels over multiple solar cycles. Users can customize many of the display and graph features; all displays can be printed or copied to the system's clipboard for "pasting" into other applications. The system obtains and stores space weather data and images from sources such as the NOAA Space Environment Center, NOAA National Geophysical Data Center, the joint ESA/NASA SOHO spacecraft, and the Kitt Peak National Solar Observatory, and can be extended to include other data series and image sources. Data and images retrieved from the system's database are converted to XML and transported from a central server using HTTP and SOAP protocols, allowing

  12. Angiotensinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population

    DEFF Research Database (Denmark)

    Ravn, Lasse Steen; Benn, Marianne; Nordestgaard, Børge

    2008-01-01

    Objectives The renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin-angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding proteins...... in this system predict risk of atrial fibrillation. Methods and results We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism in the ACE gene...

  13. The activation system Easy 2007

    International Nuclear Information System (INIS)

    Forrest, R.A.; Kopecky, J.

    2007-01-01

    Full text of publication follows: Safety and waste management of materials for ITER, IFMIF and future power plants require detailed knowledge of the activation caused by irradiation with neutrons, or in the case of IFMIF, deuterons. The European Activation System (EASY) has been developed for such calculations and a new version (EASY-2007) was released earlier this year. This contains a large amount of nuclear data in the European Activation File (EAF-2007) covering neutron-, deuteron- and proton-induced cross sections (about 200,000 reactions have data extending up to 60 MeV), decay data (2,231 nuclides) and subsidiary data on e.g. biological hazards. These data are input to the FISPACT inventory code used to calculate the activation. Recent work has concentrated on the validation of EASY-2007 using integral and differential measurements; these studies are summarised showing examples of reactions agreeing with the experimental results and cases where the library data require further improvement. Integral data above 20 MeV are especially important in improving the library for IFMIF calculations. Using a previous version of EASY a study of the activation of all the elements enabled the identification of the reactions important in producing activation below 20 MeV. The list of 1,340 neutron-reactions producing the dominant radio-nuclides enables further studies to be focused on the important data. This study made extensive use of importance diagrams. This work has been extended to cover the energy region up to 60 MeV, and the new important radionuclides and reactions in this energy range are reported. Although the data above 20 MeV are important for IFMIF and are of interest because of their novelty, the traditional energy region below 20 MeV remains of great importance for most fusion applications. The testing of such large data libraries for reactions with no experimental data is necessary and results from the use of the recently developed method of Statistical

  14. Activity System Theory Approach to Healthcare Information System

    OpenAIRE

    Bai, Guohua

    2004-01-01

    Healthcare information system is a very complex system and has to be approached from systematic perspectives. This paper presents an Activity System Theory (ATS) approach by integrating system thinking and social psychology. First part of the paper, the activity system theory is presented, especially a recursive model of human activity system is introduced. A project ‘Integrated Mobile Information System for Diabetic Healthcare (IMIS)’ is then used to demonstrate a practical application of th...

  15. RETRACTED: Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population.

    Science.gov (United States)

    Zhong, Weiqiang; Jiang, Zongpei; Zhou, Tian-Biao

    2015-12-01

    This article has been included in a multiple retraction: Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10

  16. RETRACTED: Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression.

    Science.gov (United States)

    Yang, Chun-Hua; Zhou, Tian-Biao

    2015-12-01

    This article has been included in a multiple retraction: Chun-Hua Yang and Tian-Biao Zhou Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi: 10.1177/1470320314568521 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 Tian-Biao Zhou, Xue-Feng Guo, Zongpei

  17. RETRACTED: Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population.

    Science.gov (United States)

    Zhou, Tian-Biao; Guo, Xue-Feng; Jiang, Zongpei; Li, Hong-Yan

    2015-12-01

    The following article has been included in a multiple retraction: Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi: 10.1177/1470320314563425 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January

  18. Manually controlled neutron-activation system

    International Nuclear Information System (INIS)

    Johns, R.A.; Carothers, G.A.

    1982-01-01

    A manually controlled neutron activation system, the Manual Reactor Activation System, was designed and built and has been operating at one of the Savannah River Plant's production reactors. With this system, samples can be irradiated for up to 24 hours and pneumatically transferred to a shielded repository for decay until their activity is low enough for them to be handled at a radiobench. The Manual Reactor Activation System was built to provide neutron activation of solid waste forms for the Alternative Waste Forms Leach Testing Program. Neutron activation of the bulk sample prior to leaching permits sensitive multielement radiometric analyses of the leachates

  19. Systemic factors related to soluble (prorenin receptor in plasma of patients with proliferative diabetic retinopathy.

    Directory of Open Access Journals (Sweden)

    Keitaro Hase

    Full Text Available (Prorenin receptor [(PRR], a new component of the tissue renin-angiotensin system (RAS, plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR. In this study, we investigated systemic factors related to plasma levels of soluble form of (PRR [s(PRR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(PRR, prorenin, tumor necrosis factor (TNF-α, complement factor D (CFD, and leucine-rich α-2-glycoprotein 1 (LRG1 significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(PRR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s(PRR, but not prorenin, levels. Among the inflammatory molecules correlated with s(PRR in the plasma, TNF-α, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (PRR but not prorenin, while stimulation with high glucose enhanced both (PRR and prorenin expression. These findings suggested close relationships between plasma s(PRR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.

  20. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    Data.gov (United States)

    National Aeronautics and Space Administration — IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING ISAAC PERSING AND VINCENT NG Abstract. Active learning has been successfully applied to many natural language...

  1. Hybrid Active-Passive Radiation Shielding System

    Data.gov (United States)

    National Aeronautics and Space Administration — A radiation shielding system is proposed that integrates active magnetic fields with passive shielding materials. The objective is to increase the shielding...

  2. Liver cirrhosis and arterial hypertension

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren

    2006-01-01

    blood pressure. This review considers the alterations in systemic hemodynamics in patients with cirrhosis in relation to essential hypertension and arterial hypertension of the renal origin. Subjects with arterial hypertension (essential, secondary) may become normotensive during the development......Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counter-regulatory systems (renin-angiotensin-aldosterone system, sympathetic nervous system, release...... of cirrhosis, and arterial hypertension is rarely manifested in patients with cirrhosis, even in cases with renovascular disease and high circulating renin activity. There is much dispute as to the understanding of homoeostatic regulation in cirrhotic patients with manifest arterial hypertension. This most...

  3. RAS in the central nervous system: Potential role in neuropsychiatric disorders.

    Science.gov (United States)

    Rocha, Natalia Pessoa; Simões e Silva, Ana Cristina; Prestes, Thiago Ruiz Rodrigues; Feracin, Victor; Machado, Caroline Amaral; Ferreira, Rodrigo Novaes; Teixeira, Antonio Lucio; de Miranda, Aline Silva

    2018-02-25

    The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders of the modulation of RAS. We carried out an extensive literature search in PubMed central. Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and haemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Impact of glycaemic control on the effect of direct renin inhibition in the AVOID study

    DEFF Research Database (Denmark)

    Persson, Frederik; Lewis, Julia B; Lewis, Edmund J

    2012-01-01

    Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction ...

  5. Focus on Brain Angiotensin III and Aminopeptidase A in the Control of Hypertension

    Directory of Open Access Journals (Sweden)

    John W. Wright

    2012-01-01

    Full Text Available The classic renin-angiotensin system (RAS was initially described as a hormone system designed to mediate cardiovascular and body water regulation. The discovery of a brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins independent of the peripheral system significantly expanded the possible physiological and pharmacological functions of this system. This paper first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT1, AT2, and mas receptor subtypes. Recent evidence points to important contributions by brain angiotensin III (AngIII and aminopeptidases A (APA and N (APN in sustaining hypertension. Next, we discuss current approaches to the treatment of hypertension followed by novel strategies that focus on limiting the binding of AngII and AngIII to the AT1 receptor subtype by influencing the activity of APA and APN. We conclude with thoughts concerning future treatment approaches to controlling hypertension and hypotension.

  6. Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney disease

    DEFF Research Database (Denmark)

    Frimodt-Møller, Marie; Høj Nielsen, Arne; Strandgaard, Svend

    2010-01-01

    BACKGROUND: Dual blockade of the renin-angiotensin system (RAS) has been claimed to have a specific renal protective effect in chronic kidney disease (CKD). The present short-term study reports on the feasibility of dual blockade in a consecutive group of patients with CKD stage 3-5. METHODS: Forty...

  7. Blockade of AT1 receptors by losartan did not affect renin gene expression in kidney medulla

    Czech Academy of Sciences Publication Activity Database

    Tybitanclová, K.; Szabová, L.; Grima, M.; Ingert, C.; Železná, Blanka; Zórad, Š.

    2006-01-01

    Roč. 25, č. 1 (2006), s. 43-51 ISSN 0231-5882 Grant - others:VEGA(SK) 2/5090/25 Institutional research plan: CEZ:AV0Z50520514 Keywords : AT1 receptor * renin-angiotensin system * kidneys Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.771, year: 2006

  8. Sodium intake, RAAS-blockade and progressive renal disease

    NARCIS (Netherlands)

    de Borst, Martin H; Navis, Gerjan

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the

  9. Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy : a randomised clinical trial

    NARCIS (Netherlands)

    Kwakernaak, Arjan J.; Krikken, Jan A.; Binnenmars, S. Heleen; Visser, Folkert W.; Hemmelder, Marc H.; Woittiez, Arend-Jan; Groen, Henk; Laverman, Gozewijn D.; Navis, Gerjan

    Background Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added

  10. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  11. [Is this the end for double RAAS inhibition?

    NARCIS (Netherlands)

    Deinum, J.

    2014-01-01

    Recently, the VA NEPHRON-D study was stopped early due to insignificant effects and increased adverse events. This was the last in a series of trials on the value of dual versus single blockade of the renin-angiotensin-aldosterone system in patients at risk for renal or cardiovascular complications.

  12. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients : results from a phase 3 randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Anker, Stefan D.; Kosiborod, Mikhail; Zannad, Faiez; Pina, Ileana L.; McCullough, Peter A.; Filippatos, Gerasimos; van der Meer, Peter; Ponikowski, Piotr; Rasmussen, Henrik S.; Lavin, Philip T.; Singh, Bhupinder; Yang, Alex; Deedwania, Prakash

    2015-01-01

    AimsHyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract

  13. [Acute renal failure due to RAAS-inhibitors combined with dehydration].

    NARCIS (Netherlands)

    Scherpbier-de Haan, N.D.; Grauw, W.J.C. de; Wetzels, J.F.M.; Vervoort, G.M.M.

    2010-01-01

    Two men (61 and 81 years old) with mild impaired kidney function developed acute renal failure due to dehydration combined with the use of inhibitors of the renin-angiotensin-aldosterone system (RAAS). After rehydration, correction of hyperkalaemia and stopping RAAS-inhibition and diuretics, they

  14. Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors

    DEFF Research Database (Denmark)

    Andrésdóttir, Gudbjörg; Jensen, Majken; Carstensen, Bendix

    2014-01-01

    OBJECTIVE: To evaluate long-term survival, development of renal end points, and decline in glomerular filtration rate (GFR) in patients with type 2 diabetes and diabetic nephropathy (DN) after renin-angiotensin system (RAS) inhibition and multifactorial treatment of cardiovascular risk factors ha...

  15. Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy

    NARCIS (Netherlands)

    Siwy, Justyna; Schanstra, Joost P.; Argiles, Angel; Bakker, Stephan J. L.; Beige, Joachim; Boucek, Petr; Brand, Korbinian; Delles, Christian; Duranton, Flore; Fernandez-Fernandez, Beatriz; Jankowski, Marie-Luise; Al Khatib, Mohammad; Kunt, Thomas; Lajer, Maria; Lichtinghagen, Ralf; Lindhardt, Morten; Maahs, David M.; Mischak, Harald; Mullen, William; Navis, Gerarda; Noutsou, Marina; Ortiz, Alberto; Persson, Frederik; Petrie, John R.; Roob, Johannes M.; Rossing, Peter; Ruggenenti, Piero; Rychlik, Ivan; Serra, Andreas L.; Snell-Bergeon, Janet; Spasovski, Goce; Stojceva-Taneva, Olivera; Trillini, Matias; von der Leyen, Heiko; Winklhofer-Roob, Brigitte M.; Zuerbig, Petra; Jankowski, Joachim

    Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The 'Proteomic prediction and Renin angiotensin aldosterone system

  16. The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy

    DEFF Research Database (Denmark)

    Nielsen, Stine; Rossing, Kasper; Hess, Georg

    2012-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid......-binding protein (LFABP)....

  17. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction

    DEFF Research Database (Denmark)

    Solomon, Scott D; Shin, Sung Hee; Shah, Amil

    2011-01-01

    Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following...

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

    NARCIS (Netherlands)

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

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

  19. Safe use of NSAIDs and RAS-inhibitors at Agogo Presbyterian Hospital, Ghana

    NARCIS (Netherlands)

    Meulendijks, L.G.; Adomako, E.A.; Appiah, E.B.; Kramers, C.

    2016-01-01

    BACKGROUND: Preventable adverse events of medication are an important cause of hospital admissions in the developed world, in which non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system (RAS-) inhibitors are frequently involved. NSAIDs and RAS-inhibitors are also often used in

  20. Frontiers in Research

    DEFF Research Database (Denmark)

    Sumners, Colin; Horiuchi, Masatsugu; Widdop, Robert E

    2013-01-01

    In recent years it has been firmly established that apart from the classical renin-angiotensin-system (RAS) comprising angiotensin II (Ang II), angiotensin converting enzyme (ACE) - being responsible for Ang II generation - and the angiotensin type 1 receptor (AT1R), there also exist protective a...

  1. Telmisartan to prevent recurrent stroke and cardiovascular events

    NARCIS (Netherlands)

    Yusuf, Salim; Diener, Hans-Christoph; Sacco, Ralph L.; Cotton, Daniel; Ounpuu, Stephanie; Lawton, William A.; Palesch, Yuko; Martin, Renee H.; Albers, Gregory W.; Bath, Philip; Bornstein, Natan; Chan, Bernard P. L.; Chen, Sien-Tsong; Cunha, Luis; Dahlof, Bjorn; de Keyser, Jacques; Donnan, Geoffrey A.; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; VanderMaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2008-01-01

    Background: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood

  2. Long-term patterns of adherence to medication therapy among patients with type 2 diabetes mellitus in Denmark

    DEFF Research Database (Denmark)

    Jensen, Majken Linnemann; Jørgensen, Marit Eika; Hansen, Ebba Holme

    2017-01-01

    : Adherence to six medicine groups (metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, renin angiotensin system inhibitors, and statins) were analysed among 5,232 patients with type 2 diabetes at a tertiary referral hospital during 1998-2009. Rate-ratios of initiation of treatment, recurrent...

  3. Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients

    NARCIS (Netherlands)

    Slagman, Maartje C. J.; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D.

    Background. Renin angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both

  4. Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients

    NARCIS (Netherlands)

    Slagman, Maartje C. J.; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D.

    2012-01-01

    Background. Renin angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both

  5. Effects of short-term addition of NSAID to diuretics and/or RAAS-inhibitors on blood pressure and renal function

    NARCIS (Netherlands)

    Nygard, Peder; Jansman, Frank G. A.; Kruik-Kolloffel, Willemien J.; Barnaart, Alex F. W.; Brouwers, Jacobus R. B. J.

    Background The combined post-operative use of diuretics and/or renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of nonsteroidal anti-inflammatory drug (NSAID) associated renal failure because of a drug-drug interaction. Objective The aim of this study was to investigate

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may in...

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

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striki...

  8. CARDIOVASCULAR ENDOCRINOLOGY Dual RAAS blockade has dual effects on outcome

    NARCIS (Netherlands)

    Heerspink, Hiddo J. Lambers; de Zeeuw, Dick

    Makani and colleagues report that dual blockade of the renin-angiotensin-aldosterone system is associated with harm despite previous studies showing that this approach decreases blood pressure and albuminuria. Do these results imply that we should abandon surrogate markers? Or should we become more

  9. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

    DEFF Research Database (Denmark)

    Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

    2016-01-01

    BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemi...... pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit....

  10. The BEAUTIFUL study: randomized trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction - baseline characteristics of the study population

    DEFF Research Database (Denmark)

    NN, NN; Ferrari, R; Ford, I

    2008-01-01

    diabetes, and 40% had metabolic syndrome. Mean ejection fraction was 32% and resting heart rate was 71.6 bpm. Concomitant medications included beta-blockers (87%), renin-angiotensin system agents (89%), antithrombotic agents (94%), and lipid-lowering agents (76%). CONCLUSIONS: Main results from BEAUTIFUL...

  11. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy : A Randomized Clinical Trial

    NARCIS (Netherlands)

    Bakris, George L; Agarwal, Rajiv; Chan, Juliana C; Cooper, Mark E; Gansevoort, Ron T; Haller, Hermann; Remuzzi, Giuseppe; Rossing, Peter; Schmieder, Roland E; Nowack, Christina; Kolkhof, Peter; Joseph, Amer; Pieper, Alexander; Kimmeskamp-Kirschbaum, Nina; Ruilope, Luis M

    2015-01-01

    IMPORTANCE: Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events. OBJECTIVE: To evaluate the safety and efficacy of

  12. ENALAPRIL: PHARMACOKINETIC/DYNAMIC INFERENCES FOR COMPARATIVE DEVELOPMENTAL TOXICITY

    Science.gov (United States)

    Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the ...

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

    DEFF Research Database (Denmark)

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

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...

  15. The effect of liraglutide on renal function

    DEFF Research Database (Denmark)

    von Scholten, Bernt J; Persson, Frederik; Rosenlund, Signe

    2017-01-01

    (GLP-1) receptor agonist liraglutide on top of multifactorial care, including renin-angiotensin-system (RAS)-inhibition. MATERIALS AND METHODS: Randomized, double-blind, placebo-controlled, cross-over trial including patients with type 2 diabetes and persistent albuminuria (urinary albumin-to-creatinine...

  16. Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats

    Czech Academy of Sciences Publication Activity Database

    Jíchová, Š.; Kopkan, L.; Husková, Z.; Doleželová, Š.; Neckář, Jan; Kujal, P.; Vernerová, Z.; Kramer, H. J.; Sadowski, J.; Kompanowska; Jezierska, E.; Reddy, N. R.; Falck, J. R.; Imig, J. D.; Červenka, L.

    2016-01-01

    Roč. 34, č. 10 (2016), s. 2008-2025 ISSN 0263-6352 R&D Projects: GA ČR(CZ) GA15-07544S Institutional support: RVO:67985823 Keywords : epoxyeicosatrienoic acid analog * malignant hypertension * renal blood flow autoregulation * renin-angiotensin system * sodium excretion Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.085, year: 2016

  17. Telmisartan to prevent recurrent stroke and cardiovascular events

    DEFF Research Database (Denmark)

    Yusuf, Salim; Diener, Hans-Christoph; Sacco, Ralph L

    2008-01-01

    BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pres...

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

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Marcussen, Niels; Pedersen, Michael

    2010-01-01

    Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantifie...

  19. Dual blockade with candesartan cilexetil and lisinopril in hypertensive patients with diabetes mellitus

    DEFF Research Database (Denmark)

    Andersen, Niels H; Knudsen, Søren T; Poulsen, Per L

    2003-01-01

    BACKGROUND: Blood pressure (BP) reduction is the key to risk reduction of cardiovascular disease or renal failure in hypertensive patients with diabetes mellitus. Inhibition of the renin-angiotensin system by an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (...

  20. Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy.

    Directory of Open Access Journals (Sweden)

    Martha Trindade Manchini

    Full Text Available Low-level laser therapy (LLLT has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI. However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS and Kallikrein-Kinin System (KKS vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO generation.

  1. Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

    Science.gov (United States)

    Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

    2014-01-01

    Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation. PMID:24991808

  2. Hypertension and liver disease

    DEFF Research Database (Denmark)

    Henriksen, Jens H; Møller, Søren

    2004-01-01

    to increased arterial blood pressure. Subjects with established arterial hypertension (essential, secondary) may become normotensive during the development of cirrhosis, and arterial hypertension is rarely manifested in patients with cirrhosis, even in cases with renovascular disease and high circulating renin......Arterial hypertension is a common disorder with a frequency of 10% to 15% in subjects in the 40- to 60-year age group. Yet most reports find the prevalence of arterial hypertension in patients with chronic liver disease (cirrhosis) much lower. In this review, we consider the alterations in systemic...... hemodynamics in cirrhosis. The most characteristic findings in cirrhotic patients are vasodilatation with low systemic vascular resistance, increased cardiac output, high arterial compliance, secondary activation of counterregulatory systems (sympathetic nervous system, renin-angiotensin-aldosterone system...

  3. Arterial hypertension and chronic liver disease

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Møller, S

    2005-01-01

    , calcitonin gene-related peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This provides an effective (although relative) counterbalance to raised arterial blood pressure. Subjects with arterial hypertension (essential, secondary) may become normotensive during......This review looks at the alterations in the systemic haemodynamics of patients with chronic liver disease (cirrhosis) in relation to essential hypertension and arterial hypertension of renal origin. Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic...... vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counterregulatory systems (renin-angiotensin-aldosterone system, sympathetic nervous system, release of vasopressin), and resistance to vasopressors. The vasodilatory state is mediated through adrenomedullin...

  4. Insulin resistance and associated dysfunction of resistance vessels and arterial hypertension

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren

    2005-01-01

    , calcitonin gene-related peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This provides an effective (although relative) counterbalance to raised arterial blood pressure. Subjects with arterial hypertension (essential, secondary) may become normotensive during......This review looks at the alterations in the systemic haemodynamics of patients with chronic liver disease (cirrhosis) in relation to essential hypertension and arterial hypertension of renal origin. Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic...... vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counterregulatory systems (renin-angiotensin-aldosterone system, sympathetic nervous system, release of vasopressin), and resistance to vasopressors. The vasodilatory state is mediated through adrenomedullin...

  5. Vitamin D and its effects on cardiovascular diseases: a comprehensive review.

    Science.gov (United States)

    Pérez-Hernández, Nonanzit; Aptilon-Duque, Gad; Nostroza-Hernández, María Cristina; Vargas-Alarcón, Gilberto; Rodríguez-Pérez, José Manuel; Blachman-Braun, Ruben

    2016-11-01

    Vitamin D is a molecule that is actively involved in multiple metabolic pathways. It is mostly known for its implications related to calcium metabolism. It has also been determined that it actively participates in the cardiovascular system, influencing blood pressure, coronary artery disease and other vascular diseases, such as heart failure and atrial fibrillation. Furthermore, it has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. In this review, we present the different vitamin D metabolic pathways associated with the cardiovascular pathophysiology, and we include studies in animal and human models, as well as some of the controversies found in the literature. This review also incorporates an overview of the implications in the molecular biology and public health fields.

  6. Content Analysis in Systems Engineering Acquisition Activities

    Science.gov (United States)

    2016-04-30

    Acquisition Activities Karen Holness, Assistant Professor, NPS Update on the Department of the Navy Systems Engineering Career Competency Model Clifford...systems engineering toolkit . Having a common analysis tool that is easy to use would support the feedback of observed system performance trends from the

  7. Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA

    International Nuclear Information System (INIS)

    Milsted, A.; Barna, B.P.; Ransohoff, R.M.; Brosnihan, K.B.; Ferrario, C.M.

    1990-01-01

    The authors have identified human cultured cell lines that are useful for studying angiotensinogen gene expression and its regulation in the central nervous system. A model cell system of human central nervous system origin expressing angiotensinogen has not previously been available. Expression of angiotensinogen mRNA appears to be a basal property of noninduced human astrocytes, since astrocytic cell lines derived from human glioblastomas or nonneoplastic human brain tissue invariably produced angiotensinogen mRNA. In situ hybridization histochemistry revealed that angiotensinogen mRNA production was not limited to a subpopulation of astrocytes because >99% of cells in these cultures contained angiotensinogen mRNA. These cell lines will be useful in studies of the molecular mechanisms controlling angiotensin synthesis and the role of biologically active angiotensin in the human brain by allowing the authors to examine regulation of expression of the renin-angiotensin system in human astrocyte cultures

  8. A peripheral blood transcriptome biomarker test to diagnose functional recovery potential in advanced heart failure.

    Science.gov (United States)

    Deng, Mario C

    2018-05-08

    Heart failure (HF) is a complex clinical syndrome that causes systemic hypoperfusion and failure to meet the body's metabolic demands. In an attempt to compensate, chronic upregulation of the sympathetic nervous system and renin-angiotensin-aldosterone leads to further myocardial injury, HF progression and reduced O 2 delivery. This triggers progressive organ dysfunction, immune system activation and profound metabolic derangements, creating a milieu similar to other chronic systemic diseases and presenting as advanced HF with severely limited prognosis. We hypothesize that 1-year survival in advanced HF is linked to functional recovery potential (FRP), a novel clinical composite parameter that includes HF severity, secondary organ dysfunction, co-morbidities, frailty, disabilities as well as chronological age and that can be diagnosed by a molecular biomarker.

  9. Implementation of Business Game Activity Support System

    Institute of Scientific and Technical Information of China (English)

    TANABU Motonari

    2004-01-01

    Business game can be used not only as an educational tool for the development of decision making ability, but also can be used for supporting the knowledge creation activity in organizations. In this paper, some conceptual considerations to meanings of the business game in the knowledge creation activity by using the knowledge creation theory and other related theories are given,and business game activity concept which refers to game play and development is proposed. Then focusing on the business game activity as an instantiation of the knowledge creation activity, and a Web based gaming activity support system based on the former system called YBG that enables us to play and develop many business games through the standard web browser is proposed. This system also provides us a lot of opportunities to play and develop the business games over business game communities.

  10. Effects of tilting on central hemodynamics and homeostatic mechanisms in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Nørgaard, Annette; Henriksen, Jens H

    2004-01-01

    Patients with cirrhosis have a hyperdynamic circulation and an abnormal blood volume distribution with central hypovolemia, an activated sympathetic nervous system (SNS) as well as the renin-angiotensin-aldosterone system (RAAS). As the hyperdynamic circulation in cirrhosis may be present only...... in the supine patient, we studied the humoral and central hemodynamic responses to changes with posture. Twenty-three patients with alcoholic cirrhosis (Child-Turcotte-Pugh classes A/B/C: 2/13/8) and 14 healthy controls were entered. Measurements of central hemodynamics and activation of SNS and RAAS were taken......). Central circulation time increased only in the patients (+30% vs. -1%, P higher in the patients than in the controls (P

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

    Directory of Open Access Journals (Sweden)

    V. I. Podzolkov

    2017-01-01

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

  12. Proteinuric diseases with sodium retention: Is plasmin the link?

    DEFF Research Database (Denmark)

    Svenningsen, Per; Skøtt, Ole; Jensen, Boye L

    2012-01-01

    1. Sodium retention in disease states characterized by proteinuria, such as nephrotic syndrome, preeclampsia, and diabetic nephropathy, occurs through poorly understood mechanism(s). 2. In the nephrotic syndrome, data from experimental and clinical studies indicate that the sodium retention...... originates in the renal cortical collecting duct and involves hyper-activity of the epithelial sodium channel (ENaC). 3. The stimulus for the increased ENaC activity does not appear to involve any of the classical sodium retaining mechanisms, such as the renin-angiotensin-aldosterone system, arginine...... and diabetic nephropathy, which are also characterized by proteinuria and sodium retention. 7. In this review, we will examine the evidence for a role of urinary serine protease activity in the development of sodium and water retention in diseases characterised by proteinuria with a focus on the nephrotic...

  13. Design of an Active Automotive Safety System

    Directory of Open Access Journals (Sweden)

    Y. Wang

    2013-07-01

    Full Text Available With the development of the national economy, the people's standard of living got corresponding improvement, cars has been one of the indispensable traffic tools in many families. An active safety system is proposed, which can real-time detect the vehicle's running status and judge the security status of the vehicle. The system, which takes single-chip microcomputer as the controlling core and combines with millimeter-wave and ultrasonic distance measurement technology, can detect the distance from vehicle to vehicle and judge the security status of the vehicle. The hardware composition of the system and the data acquiring circuit are proposed, the mathematic model for different situation is established, and the controlling algorithm is completed. This system can accurately measure speed and distance between vehicles; the active safety control system can meet the relevant data measurement and transmission requirement; and can meet the functional requirement of the active safety control system

  14. Performance of Active Wave Absorption Systems

    DEFF Research Database (Denmark)

    Hald, Tue; Frigaard, Peter

    on a horisontal and vertical velocity are treated. All three systems are based on digital FIR-filters. For numerical comparison a performance function combining the frequency response of the set of filters for each system is derived enabling discussion on optimal filter design and system setup. Irregular wave......A comparison of wave gauge based on velocity meter based active absorption systems is presented discussing advantages and disadvantages of the systems. In detail one system based on two surface elevations, one system based on a surface elevation and a horisontal velocity and one system based...... tests with a highly reflective structure with the purely wave gauge based system and the wave gauge velocity meter based system are performed. The wave test depict the differences between the systems....

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

    DEFF Research Database (Denmark)

    Sumners, Colin; Isenberg, Jacob; Harmel, Allison

    2016-01-01

    OBJECTIVE: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2R). The selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exhibit neuroprotection and improve stroke outcomes...... in preclinical studies, effects that likely involve neurotropic actions. However, these beneficial actions of C21 have not been demonstrated to occur beyond 1 week post stroke. The objective of this study was to determine if systemic administration of C21 would exert sustained neuroprotective effects in aged...... min), 24 h, and 48 h after stroke. Infarct size was assessed by magnetic resonance imaging at 21 days post MCAO. Animals received blinded neurological exams at 4 h, 24 h, 72 h, 7d, 14d, and 21d post-MCAO. RESULTS: Systemic treatment with C21 after stroke significantly improved neurological function...

  16. Circumpolar Active-Layer Permafrost System (CAPS)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Circumpolar Active-Layer Permafrost System (CAPS) contains over 100 data sets pertaining to permafrost and frozen ground topics. It also contains detailed...

  17. Flight Activity and Crew Tracking System -

    Data.gov (United States)

    Department of Transportation — The Flight Activity and Crew Tracking System (FACTS) is a Web-based application that provides an overall management and tracking tool of FAA Airmen performing Flight...

  18. Factors influencing the cardiac MIBG accumulation

    International Nuclear Information System (INIS)

    Takatsu, Hisato; Fujiwara, Hisayoshi

    1997-01-01

    Following factors possibly influencing the cardiac MIBG accumulation were examined mainly in mice. 1. The specific activity of the MIBG (meta-iodo-benzyl guanidine) on the neuronal and non-neuronal fractions. 2. Motor restriction stress on MIBG accumulation and washout. 3. Loading and restriction of sodium chloride on the accumulation and effect of suppression of renin-angiotensin system. 4. Examinations in Dahl rats. 125I- or 131I-MIBG was intravenously administered to mice at 74 kBq. At 30 min or 4 hr after administration, mice were sacrificed and their left ventricles were dissected out for measurement of radioactivity in a liquid scintillation counter. Salt-sensitive and -resistant Dahl rats were given with 37 MBq of 123I-MIBG and cardiac radioactivity was measured externally for calculation of washout. Factors examined were found highly correlated with the accumulation of MIBG and measurement of its washout was considered useful for evaluating sympathetic activity. (K.H.)

  19. Overexpressed cyclophilin B suppresses aldosterone-induced proximal tubular cell injury both in vitro and in vivo.

    Science.gov (United States)

    Wang, Bin; Lin, Lilu; Wang, Haidong; Guo, Honglei; Gu, Yong; Ding, Wei

    2016-10-25

    The renin-angiotensin-aldosterone system (RAAS) is overactivated in patients with chronic kidney disease. Oxidative stress and endoplasmic reticulum stress (ERS) are two major mechanisms responsible for aldosterone-induced kidney injury. Cyclophilin (CYP) B is a chaperone protein that accelerates the rate of protein folding through its peptidyl-prolyl cis-trans isomerase (PPIase) activity. We report that overexpression of wild-type CYPB attenuated aldosterone-induced oxidative stress (evidenced by reduced production of reactive oxygen species and improved mitochondrial dysfunction), ERS (indicated by reduced expression of the ERS markers glucose-regulated protein 78 [GRP78] and C/-EBP homologous protein [CHOP]), and tubular cell apoptosis in comparison with aldosterone-induced human kidney-2 (HK-2) cells. The in vivo study also yielded similar results. Hence, CYPB performs a crucial function in protecting cells against aldosterone-induced oxidative stress, ERS, and tubular cell injury via its PPIase activity.

  20. Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria

    Science.gov (United States)

    de la Cuesta, Fernando; Baldan-Martin, Montserrat; Moreno-Luna, Rafael; Alvarez-Llamas, Gloria; Gonzalez-Calero, Laura; Mourino-Alvarez, Laura; Sastre-Oliva, Tamara; López, Juan A.; Vázquez, Jesús; Ruiz-Hurtado, Gema; Segura, Julian; Vivanco, Fernando; Ruilope, Luis M.; Barderas, Maria G.