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Sample records for angiotensin system inhibition

  1. 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....

  2. Inhibition of the renin-angiotensin system for lowering coronary artery disease risk.

    Science.gov (United States)

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects. PMID:23523606

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  4. New perspectives in the renin-angiotensin-aldosterone system (RAAS I: endogenous angiotensin converting enzyme (ACE inhibition.

    Directory of Open Access Journals (Sweden)

    Miklós Fagyas

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected enzyme activities significantly increased by dilution of human serum samples (23.2 ± 0.7 U/L at 4-fold dilution, 51.4 ± 0.3 U/L at 32-fold dilution, n = 3, p = 0.001, suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655 ± 145 U/L, 605 ± 42 U/L, n = 3, p = 0.715, respectively. FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4 ± 2.4 U/L, n = 4, control: 26.4 ± 0.7 U/L, n = 4, p<0.001. Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

  5. Aggressive versus Low Dose Inhibition of the Renin-Angiotensin System for the Treatment of Microalbuminuria in Type 2 Diabetic Patients: A Pilot Study

    OpenAIRE

    Davidson, M B; Tareen, N.; Duran, P.; V. Aguilar; M. L. Lee

    2011-01-01

    Objective. This study compares low dose versus aggressive inhibition of the renin angiotensin system (RAS) to treat microalbuminuria (MA). Methods. Patients with MA after a run-in period to control BP to

  6. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Wang, Fu-Xin [Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002 (China); Ren, Jun [Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071 (United States); Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Zhiming [Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, The Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-04-15

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.

  7. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    International Nuclear Information System (INIS)

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension

  8. Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease.

    Science.gov (United States)

    Komers, Radko; Plotkin, Horacio

    2016-05-15

    Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in treatment of chronic kidney diseases (CKD). However, reversal of the course of CKD or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. New treatments are needed to enhance protective actions of RAAS inhibitors (RAASis), such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and improve prognosis in CKD patients. Inhibition of endothelin (ET) system in combination with established RAASis may represent such an approach. There are complex interactions between both systems and similarities in their renal physiological and pathophysiological actions that provide theoretical rationale for combined inhibition. This view is supported by some experimental studies in models of both diabetic and nondiabetic CKD showing that a combination of RAASis with ET receptor antagonists (ERAs) ameliorate proteinuria, renal structural changes, and molecular markers of glomerulosclerosis, renal fibrosis, or inflammation more effectively than RAASis or ERAs alone. Practically all clinical studies exploring the effects of RAASis and ERAs combination in nephroprotection have thus far applied add-on designs, in which an ERA is added to baseline treatment with ACEIs or ARBs. These studies, conducted mostly in patients with diabetic nephropathy, have shown that ERAs effectively reduce residual proteinuria in patients with baseline RAASis treatment. Long-term studies are currently being conducted to determine whether promising antiproteinuric effects of the dual blockade will be translated in long-term nephroprotection with acceptable safety profile. PMID:27009050

  9. Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system.

    Science.gov (United States)

    Brown, L; Duce, B; Miric, G; Sernia, C

    1999-01-01

    Fibrosis impairs cardiac function. This project has determined the expression and deposition of collagens and fibronectin and cardiac function in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat after inhibition of the renin-angiotensin system. DOCA-salt hypertension was induced in 8-wk-old male Wistar rats by uninephrectomy and administration of DOCA (25 mg every fourth day, subcutaneously) and 1% NaCl in the drinking water for 4 wk. Starting 2 wk after surgery, rats were given either oral captopril (100 mg/kg), oral candesartan cilexetil (2 mg/kg), or subcutaneous spironolactone (50 mg/kg) daily for 2 wk (reversal protocol). DOCA-salt rats failed to gain weight with markedly increased water intake and decreased food intake; drug treatment did not alter these parameters. Systolic BP increased from 116+/-5 mmHg in uninephrectomized rats to 179+/-7 mmHg in DOCA-salt rats and was not decreased by treatment (captopril 172+/-1 mmHg; candesartan 187+/-2 mmHg; spironolactone 178+/-3 mmHg). Captopril, candesartan, and spironolactone reversed the increased collagen I mRNA in DOCA-salt rats; only candesartan reversed the increased collagen III mRNA. Collagen IV mRNA was unchanged in DOCA-salt rats and following treatment. Total fibronectin mRNA increased without changing the proportion of fibronectin mRNA as the fetal isoforms EIIIA and EIIIB. Captopril, candesartan, and spironolactone reversed the increased deposition of perivascular and interstitial collagen in DOCA-salt rats; the increased cardiac fibronectin deposition was reversed by candesartan and spironolactone. Captopril, candesartan, and spironolactone also attenuated or reversed the increased diastolic stiffness and the increased dP/dt but not the increased rate-pressure products in DOCA-salt rat hearts. Thus, inhibition of the renin-angiotensin system reverses cardiac fibrosis in DOCA-salt rats and returns some indices of myocardial function to normal. PMID:9892155

  10. Role of chymase in the local renin-angiotensin system in keloids: inhibition of chymase may be an effective therapeutic approach to treat keloids

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    Wang R

    2015-08-01

    Full Text Available Ru Wang, Junjie Chen, Zhenyu Zhang, Ying CenDepartment of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaBackground: Histologically, keloids contain excess fibroblasts and an overabundance of dermal collagen. Recently, it was reported that chymase induced a profibrotic response via transforming growth factor-β1 (TGF-β1/Smad activation in keloid fibroblasts (KFs. However, the role of chymase in the local renin-angiotensin system (RAS in keloids has not been elucidated. This study aims to determine whether chymase plays an important role in the local RAS in keloids.Methods: We compared the expression and activity of chymase in keloids and normal skin tissues using Western blotting and radioimmunoassay, and studied the expression of TGF-β1, interleukin-1β, collagen I, hydroxyproline, and angiotensin II in KFs after chymase and inhibitors’ treatment.Results: The results revealed an increased activity of chymase in keloid tissues, and that chymase enhanced the expression of angiotensin II, collagen I, TGF-β1, and interleukin-1β in KFs. Blockade of the chymase pathway involved in the local RAS lowered the expression of these signaling factors.Conclusion: This research suggests that inhibition of chymase might be an effective therapeutic approach to improve the clinical treatment of keloids.Keywords: pathological scar, chymase, angiotensin II, therapy

  11. New perspectives in the renin-angiotensin-aldosterone system (RAAS III: endogenous inhibition of angiotensin converting enzyme (ACE provides protection against cardiovascular diseases.

    Directory of Open Access Journals (Sweden)

    Miklós Fagyas

    Full Text Available ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151. ACE concentration was found to be in a wide range (47-288 ng/mL. ACE activity decreased with the increasing concentration of the serum albumin (HSA: ACE activity was 56 ± 1 U/L in the presence of 2.4 ± 0.3 mg/mL HSA, compared to 39 ± 1 U/L in the presence of 12 ± 1 mg/mL HSA (values are mean ± SEM. Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74-288 ng/mL, median, 155.2 ng/mL, n = 52 compared to patients with II genotype (range, 47-194 ng/mL, median, 94.5 ng/mL, n = 28 while the difference in ACE activities was only 32% (range, 27.3-59.8 U/L, median, 43.11 U/L, and range 15.6-55.4 U/L, median, 32.74 U/L, respectively in the presence of 12 ± 1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5 ± 0.5 mg/mL or other endogenous inhibitors. Main implications are that (1 physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2 angiotensin II elimination may have a significant role in angiotensin II related pathologies.

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

    International Nuclear Information System (INIS)

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

  13. 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.

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

    OpenAIRE

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

    1994-01-01

    Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the be...

  15. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure

    DEFF Research Database (Denmark)

    McMurray, John J V; Packer, Milton; Desai, Akshay S;

    2013-01-01

    AIMS: Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and...... natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor...

  16. 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.

  17. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    OpenAIRE

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.; Toto, Robert D.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We co...

  18. Advances in the Renin-Angiotensin-Aldosterone System: Relevance to Diabetic Nephropathy

    OpenAIRE

    Audrey Koitka; Christos Tikellis

    2008-01-01

    Hypertension is now recognized as a key contributory factor to the development and progression of kidney disease in both type 1 and type 2 diabetes. The renin angiotensin system (RAS) and its effector molecule angiotensin II, in particular, have a range of hemodynamic and nonhemodynamic effects that contribute not only to the development of hypertension, but also to renal disease. As a result, therapeutic inhibition of the RAS with angiotensin-converting enzyme inhibitors and/or selective ang...

  19. The Renin-Angiotensin System Modulates Inflammatory Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies

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    Fabrizio Montecucco

    2009-01-01

    Full Text Available Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. The regulation of arterial blood pressure was considered from its first description of the main mechanism involved. Vasoconstriction (mediated by angiotensin II and salt and water retention (mainly due to aldosterone were classically considered as pivotal proatherosclerotic activities. However, basic research and animal studies strongly support angiotensin II as a proinflammatory mediator, which directly induces atherosclerotic plaque development and heart remodeling. Furthermore, angiotensin II induces proatherosclerotic cytokine and chemokine secretion and increases endothelial dysfunction. Accordingly, the pharmacological inhibition of the renin-angiotensin system improves prognosis of patients with cardiovascular disease even in settings of normal baseline blood pressure. In the present review, we focused on angiotensin-convertingenzyme (ACE inhibitors, angiotensin II receptor blockers (ARBs, and renin inhibitors to update the direct activities of the renin-angiotensin system in inflammatory processes governing atherosclerosis.

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

    NARCIS (Netherlands)

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

    2004-01-01

    OBJECTIVE: The heptapeptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a versatile, endogenous inhibitor of the renin-angiotensin system (RAS). As the therapeutic response to exogenous RAS inhibitors, such as AT1 receptor antagonists, is altered by changes in salt intake, we investigated t

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

    NARCIS (Netherlands)

    Roks, AJM; Nijholt, J; van Buiten, A; van Gilst, WH; de Zeeuw, D; Henning, RH

    2004-01-01

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

  2. Mechanisms of fetal and neonatal renal impairment by pharmacologic inhibition of angiotensin.

    Science.gov (United States)

    Chevalier, Robert L

    2012-01-01

    The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease. PMID:22876894

  3. 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

    trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to......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 in...... normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify...

  4. The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

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    Hart Meaghan

    2009-11-01

    Full Text Available Abstract Background Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC, to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments. Methods/Design The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control" for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP 20 and without clinical diagnosis of dementia or Alzheimer's disease. Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives, 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory, cerebral blood flow, and carbon dioxide cerebral vasoreactivity. Discussion The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the

  5. The Renin-Angiotensin System in the Endocrine Pancreas

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    Carlsson PO

    2001-01-01

    Full Text Available Experimental data suggest that a tissue renin-angiotensin system is present in the pancreatic islets of several species, including man. However, the physiological role for this local renin-angiotensin system remains largely unknown. In vitro findings argue against a direct effect of angiotensin II on alpha- and beta-cells. In contrast, when the influence of angiotensin II on the pancreatic islets has been evaluated in the presence of an intact vascular system either in vivo or in the perfused pancreas, a suppression of insulin release has been observed, also in man. These discrepancies may be explained by the profound effects of the renin-angiotensin system on pancreatic islet blood perfusion. Alterations in the systemic renin-angiotensin system and an increased vascular sensitivity for its components have been observed in diabetes mellitus and hypertension. Whether changes occur also in the pancreatic islet renin-angiotensin system during these conditions remains unknown. Future research may help to provide an answer to this question, and to elucidate to what extent the renin-angiotensin system may contribute to beta-cell dysfunction in these diseases.

  6. Brain renin angiotensin system in cardiac hypertrophy and failure

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    MichaelBader

    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.

  7. Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Zhu-zhi Wen

    Full Text Available The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS-induced podocyte injury. Sprague-Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16(ink4a, decreased immunostaining for Wilms' tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1 and decreased expressions of IGF-1 receptor (IGF-1R protein and mRNA and phosphorylated(p-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2'-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16(ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.

  8. Renin-angiotensin system in ventilator-induced diaphragmatic dysfunction: Potential protective role of Angiotensin (1-7).

    Science.gov (United States)

    Sigurta', Anna; Zambelli, Vanessa; Bellani, Giacomo

    2016-09-01

    Ventilator-induced diaphragmatic dysfunction is a feared complication of mechanical ventilation that adversely affects the outcome of intensive care patients. Human and animal studies demonstrate atrophy and ultrastructural alteration of diaphragmatic muscular fibers attributable to increased oxidative stress, depression of the anabolic pathway regulated by Insulin-like growing factor 1 and increased proteolysis. The renin-angiotensin system, through its main peptide Angiotensin II, plays a major role in skeletal muscle diseases, mainly increasing oxidative stress and inducing insulin resistance, atrophy and fibrosis. Conversely, its counter-regulatory peptide Angiotensin (1-7) has a protective role in these processes. Recent data on rodent models show that renin-angiotensin system is activated after mechanical ventilation and that infusion of Angiotensin II induces diaphragmatic skeletal muscle atrophy. Given: (A) common pathways shared by ventilator-induced diaphragmatic dysfunction and skeletal muscle pathology induced by renin-angiotensin system, (B) evidences of an involvement of renin-angiotensin system in diaphragm atrophy and dysfunction, we hypothesize that renin-angiotensin system plays an important role in ventilator-induced diaphragmatic dysfunction, while Angiotensin (1-7) can have a protective effect on this pathological process. The activation of renin-angiotensin system in ventilator-induced diaphragmatic dysfunction can be demonstrated by quantification of its main components in the diaphragm of ventilated humans or animals. The infusion of Angiotensin (1-7) in an established rodent model of ventilator-induced diaphragmatic dysfunction can be used to test its potential protective role, that can be further confirmed with the infusion of Angiotensin (1-7) antagonists like A-779. Verifying this hypothesis can help in understanding the processes involved in ventilator-induced diaphragmatic dysfunction pathophysiology and open new possibilities for its

  9. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    Science.gov (United States)

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. PMID:19926893

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Comparative Effects of Angiotensin Receptor BlockadeandACE Inhibition on the Fibrinolytic and Inflammatory Responses to Cardiopulmonary Bypass

    OpenAIRE

    Billings, Frederic T.; Balaguer, Jorge M.; Yu, Chang; Wright, Patricia; Petracek, Michael R.; Byrne, John G; Brown, Nancy J.; Pretorius, Mias

    2012-01-01

    The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation following cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to greater extent than ARB in patients undergoing CPB.One week to five days prior to surgery, patients were randomized to ramipril 5mg/day,candesartan 16mg/day or placebo.ACE inhibition increased intraopera...

  12. Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

    Science.gov (United States)

    Bertagnolli, Mariane; Dios, Anne; Béland-Bonenfant, Sarah; Gascon, Gabrielle; Sutherland, Megan; Lukaszewski, Marie-Amélie; Cloutier, Anik; Paradis, Pierre; Schiffrin, Ernesto L; Nuyt, Anne Monique

    2016-04-01

    Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions. PMID:26857347

  13. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2002-03-01

    more sensitive than valsartan renography in detecting a clinically significant renal artery stenosis. Furthermore, our data suggest that other effects, such as that on the prostaglandin-bradykinin system, are of at least similar importance to ACE inhibition for the high diagnostic sensitivity of captopril renography regarding renovascular hypertension. (orig.)

  15. Angiotensin-converting enzyme inhibition increases glucose-induced insulin secretion in response to acute restraint.

    Science.gov (United States)

    Schweizer, Júnia R O L; Miranda, Paulo A C; Fóscolo, Rodrigo B; Lemos, Joao P M; Paula, Luciano F; Silveira, Warley C; Santos, Robson A S; Pinheiro, Sérgio V B; Coimbra, Candido C; Ribeiro-Oliveira, Antônio

    2012-12-01

    There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint. PMID:23734984

  16. Orphan nuclear receptor small heterodimer partner inhibits angiotensin II-stimulated PAI-1 expression in vascular smooth muscle cells

    OpenAIRE

    Lee, Kyeong-Min; Seo, Hye-Young; Kim, Mi-Kyung; Min, Ae-Kyung; Ryu, Seong-Yeol; Kim, Yoon-Nyun; Park, Young Joo; Choi, Hueng-Sik; Lee, Ki-Up; Park, Wan-Ju; Park, Keun-Gyu; Lee, In-Kyu

    2009-01-01

    Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-β signaling pathways. Here, we investigated whether SHP inhibite...

  17. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    OpenAIRE

    Ligia Guerrero; Julián Castillo; Mar Quiñones; Santiago Garcia-Vallvé; Lluis Arola; Gerard Pujadas; Begoña Muguerza

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric metho...

  18. Post-exercise reduction in blood pressure in hypertensive subjects: effects of angiotensin converting enzyme inhibition.

    OpenAIRE

    Beaulieu, M.; Nadeau, A.; Lacourcière, Y; Cléroux, J

    1993-01-01

    1. Much attention has been given to the effects of various classes of antihypertensive drugs on blood pressure and haemodynamics. The effects of a single bout of exercise on post-exercise blood pressure have also been studied by several investigators. However, the combined effects of prior exercise and antihypertensive medication has drawn less attention. 2. We examined the separate and combined effects of a single bout of exercise and of angiotensin converting enzyme (ACE) inhibition with a ...

  19. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.

    Science.gov (United States)

    Simões E Silva, Ana Cristina; Teixeira, Mauro Martins

    2016-05-01

    The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases. PMID:26995300

  20. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    OpenAIRE

    Suyeon Kim; Morvarid Soltani-Bejnood; Annie Quignard-Boulange; Florence Massiera; Michele Teboul; Gerard Ailhaud; Jung Han Kim; Naima Moustaid-Moussa; Voy, Brynn H.

    2006-01-01

    Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating...

  1. Angiotensin II Inhibits Insulin Binding to Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Su-Jin Oh

    2011-06-01

    Full Text Available BackgroundInsulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance.MethodsAfter treating bovine aortic endothelial cells with angiotensin II (ATII, we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR on the cell membranes and in the cytosol.ResultsAfter treatment of 10-7M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05. ATII receptor blocker (eprosartan dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05. At 200 µM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol.ConclusionATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

  2. Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin II on lung function.

    OpenAIRE

    Millar, E. A.; Angus, R. M.; Hulks, G.; Morton, J J; Connell, J M; Thomson, N C

    1994-01-01

    BACKGROUND--The activity of the renin-angiotensin system in asthma has not been studied previously and the effect of angiotensin II (AII) on bronchomotor tone in vivo is unknown. METHODS--Plasma levels of renin and AII levels were measured in 20 patients with acute severe asthma, nine with mild asthma, 10 with severe chronic asthma, and 16 normal volunteers. The effect of AII, given as an intravenous infusion, on bronchomotor tone was also investigated in eight mild asthmatic patients. RESULT...

  3. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    OpenAIRE

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1–7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtype...

  4. Expression of the Components of the Renin–Angiotensin System in Venous Malformation

    OpenAIRE

    Siljee, Sam; Keane, Emily; Marsh, Reginald; Brasch, Helen D.; Tan, Swee T.; Itinteang, Tinte

    2016-01-01

    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, (pro)renin 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 ...

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

    Science.gov (United States)

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

    2006-12-15

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

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

    Science.gov (United States)

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

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

  7. African Americans, hypertension and the renin angiotensin system.

    OpenAIRE

    Williams, SF; Nicholas, SB; Vaziri, ND; Norris, KC

    2014-01-01

    African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system (RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovas...

  8. 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.

  9. The Pancreatic Renin-Angiotensin System: Does It Play a Role in Endocrine Oncology?

    OpenAIRE

    Lam KY

    2001-01-01

    The characterization of a local renin-angiotensin system in the pancreas has attracted much attention because of its potential clinical applications. A pancreatic renin-angiotensin system may be present in humans and may interact with islet cells. Nevertheless, our knowledge of the renin-angiotensin system in the human pancreas is still in its infancy, especially in the field of endocrine oncology. Much of our knowledge stems from the study of the pancreas and pancreatic endocrine tumors of r...

  10. Inhibition of central angiotensin-converting enzyme with enalapril protects the brain from ischemia/reperfusion injury in normotensive rat

    Directory of Open Access Journals (Sweden)

    H Panahpour

    2010-03-01

    Full Text Available "n  Background and the Purpose of the study: Central Angiotensin Converting Enzyme (ACE has an important role on cerebral microcirculation and metabolism. However, its role in terms of protecting the brain from ischemic/reperfusion (I/R injury are debatable. This study evaluated the role of ACE, using enalapril as ACE inhibitor, in protection of the brain from I/R injury during transient focal cerebral ischemia (TFCI in normotensive rat. Method: Male Sprague Dawley rats (280-320g randomly assigned to control ischemic and enalapril pre-treated ischemic groups. Enalapril was injected intraperitoneally 1 h before middle cerebral artery occlusion (MCAO at the dose of 0.03 or 0.1 mg/kg. Cerebral ischemia was induced by 60 min MCAO followed by 24 hrs reperfusion. After evaluation of neurological deficit scores (NDS the animal was sacrificed for assessment of cerebral infarction and edema. Results: TFCI induced cerebral infarctions (283±18 mm3, brain edema (4.1±0.4% and swelling (9.8±1.5% with NDS of 3.11±0.36. Non-hypotensive dose of enalapril (0.03 mg/kg improved NDS (1.37±0.26, reduced cerebral infarction (45%, brain edema (54% and swelling of the lesioned hemispheres (34% significantly. However, hypotensive dose of enalapril (0.1 mg/kg could improve neurological activity (1.67±0.31 and failed to reduce cerebral infarction (276±39mm3 and swelling (10.4±1.4%. Conclusion: In the rat model of transient focal cerebral ischemia, inhibition of angiotensin converting enzyme with non-hypotensive doses of enalapril has the benefit of improving neurological activity, reducing cerebral infarction, brain swelling and edema of acute ischemic stroke. Therefore, it is reasonable to conclude that central renin-angiotensin system may participate in ischemic/reperfusion injury of the cerebral cortex.

  11. 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 ostatní: 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

  12. 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

    Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte and water balance. Here we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of ACE2 angiotensin A, or directly from angiotensin-(1......, provides new insights for the understanding of the physiological and pathophysiological role of the RAS, and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders....

  13. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats.

    Science.gov (United States)

    Husková, Zuzana; Kopkan, Libor; Červenková, Lenka; Doleželová, Šárka; Vaňourková, Zdeňka; Škaroupková, Petra; Nishiyama, Akira; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kramer, Herbert J; Červenka, Luděk

    2016-04-01

    The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis. PMID:26833491

  14. Renin-angiotensin-aldosterone system blockade in chronic kidney disease: current strategies and a look ahead.

    Science.gov (United States)

    Viazzi, Francesca; Bonino, Barbara; Cappadona, Francesca; Pontremoli, Roberto

    2016-08-01

    The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition. PMID:26984204

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

    International Nuclear Information System (INIS)

    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

  16. Activation of the Renin-Angiotensin System Promotes Colitis Development

    OpenAIRE

    Yongyan Shi; Tianjing Liu; Lei He; Urszula Dougherty; Li Chen; Sarbani Adhikari; Lindsay Alpert; Guolin Zhou; Weicheng Liu; Jiaolong Wang; Deb, Dilip K.; John Hart; Liu, Shu Q.; John Kwon; Joel Pekow

    2016-01-01

    The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type cont...

  17. [STUDIES IN VITRO INHIBITION OF THE ANGIOTENSIN-CONVERTING ENZYME-I, HYPOTENSIVE AND ANTIHYPERTENSIVE EFFECTS OF PEPTIDE FRACTIONS OF V. UNGUICULATA].

    Science.gov (United States)

    Cú-Cañetas, Trinidad; Betancur Ancona, David; Gallegos Tintoré, Santiago; Sandoval Peraza, Mukthar; Chel Guerrero, Luis

    2015-01-01

    Inhibition of angiotensin-converting enzyme I (ACE-I) in vitro and in vivo from peptide fractions by enzymatic hydrolysis of the Vigna unguiculata protein concentrate was evaluated. Hydrolysis was done with Pepsin-Pancreatin and Flavourzima in two separate systems. The resulting hidrolysates were ultrafiltrated to obtain fractions with different molecular weight. The fractions with better inhibition Flavourzima were size > 1 kDa (> 1 kDa-F) and < 1 kDa (< 1 kDa-F), with an IC50 of 1222.84 and 1098.6 μg/ml respectively. Pepsin-Pancreatin fraction. PMID:26545668

  18. Local Angiotensin Pathways in Human Carotid Atheroma: Towards a Systems Biology Approach

    OpenAIRE

    Bricca, Giampiero; Legedz, Liliana; Nehme, Ali; Ayari, Hanène; Paultre, Christian; Hodroj, Wassim; Li, Jacques-Yuan; Randon, Jacques; Lohez, Olivier; Dhaouadi, Nedra; Gustin, Marie Paule; Cerutti, Catherine

    2015-01-01

    We will summarize the data we have obtained in human carotid artery concerning the organization of an extended local renin angiotensin aldosterone system and its variations at different stages of atheroma. In a system view, we propose a model where concomitant increase in angiotensin and glucocorticoid signaling is induced and amplified in VSMC while vascular smooth muscle cells transdifferentiate toward a lipid storing phenotype.

  19. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    Kazim; Husain; Wilfredo; Hernandez; Rais; A; Ansari; Leon; Ferder

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.

  20. 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.

  1. Chinese medicinal formula Fufang Xueshuantong capsule could inhibit the activity of angiotensin converting enzyme

    Science.gov (United States)

    Sheng, Shujing; Wang, Yonggang; Long, Chaofeng; Su, Weiwei; Rong, Xia

    2014-01-01

    Fufang Xueshuantong (FXST) capsule, a Chinese medicinal formula composed of four herbals – Panax notoginseng, Radix Astragali, Radix Salvia Miltiorrhizae and Radix Scrophulariaceae, has been used to treat cardiovascular diseases for many years, but the pharmacological mechanisms underlying its effects has not been clarified. This study investigates if a connection between FXST and angiotensin converting enzyme (ACE) might be an explanation for its pharmacological effects. ACE inhibition assay was performed on FXST capsule, 50% ethanol extracts from the four herbals and three selected saponins most abundant in P. notoginseng (Ginsenoside Rg1, Ginsenoside Rb1 and Notoginsenoside R1) using a biochemical test. Reversed-phase high-performance liquid chromatography of liberated hippuric acid from the ACE assay was conducted to determine the inhibitory effect. As a result, FXST and extracts from P. notoginseng showed a significant and dose-dependent inhibition on ACE activity with the IC50 values of 115 μg/ml and 179 μg/ml, respectively. But extracts from the other three herbals and the three selected saponins had no significant effect on ACE inhibition. Compared to other reported plant extracts, FXST could be considered as an effective ACE inhibitor. The inhibition of ACE activity supports the traditional use of FXST on blood circulation and the inhibitory property of FXST is mainly caused by P. notoginseng. PMID:26019516

  2. Renin-Angiotensin-Aldosteron-System und Linksventrikelfunktion

    Directory of Open Access Journals (Sweden)

    Stanek B

    2002-01-01

    Full Text Available Der ungünstige Einfluß der neurohumoralen Systeme auf die Hämodynamik bei Patienten mit Herzinsuffizienz ist seit langem bekannt. Neueren Studien zufolge ist das Reninsystem auch an den pathologischen Strukturveränderungen des Herz-Kreislauf-Systems wesentlich beteiligt. Daher sind es nicht unbedingt die vasodilatierenden Wirkungen der Antagonisten im Reninsystem, die zu den Langzeiterfolgen bei der Behandlung kardiovaskulärer Erkrankungen, insbesondere der chronischen Herzinsuffizienz, führen. Vielmehr dürfte die Verzögerung oder die Regression der ungünstigen Umbauvorgänge des linken Ventrikels ursächlich beteiligt sein. Sequentielle Blockade des Reninsystems mit ACE-Hemmern in Kombination mit Angiotensinrezeptorblockern scheint noch weitere günstige Effekte auf die Progression der Herzinsuffizienz, gemessen an der verbesserten Linksventrikelfunktion, zu erbringen. Über die Wertigkeit der Angiotensinrezeptorblocker in Hinblick auf die Lebensverlängerung - insbesondere bei gleichzeitiger Betablockade - herrscht noch keine endgültige Klarheit. Zukünftige Vergleichsstudien werden zeigen, ob Angiotensinrezeptorblocker bei der Herzinsuffizienz ihr Potential als eigenständige Therapieklasse gegenüber den ACE-Hemmern behaupten können.

  3. Enkephalin inhibition of angiotensin-stimulated release of oxytocin and vasopressin

    Science.gov (United States)

    Keil, L. C.; Chee, O.; Rosella-Dampman, L. M.; Emmert, S.; Summy-Long, J. Y.

    1984-01-01

    The effect of intracerebroventricular (ICV) pretreatment with 100 ng/5 microliter leucine(5)-enkephalin (LE) on the increase in plasma oxytocin (OT) and vasopressin (VP) caused by ICV injection of 10, 50, or 100 ng/5 microliter of angiotensin II (AII) is investigated experimentally in conscious adult male Sprague-Dawley rats; the effects of water-deprivation dehydration and lactation/suckling (in female rats) are also studied. An OT radioimmunoassay (RIA) with a sensitivity of 800 fg/ml (described in detail) and the VP RIA technique of Keil and Severs (1977) are employed. Administration of AII or dehydration for 48 or 72 h cause a significant increase in OT and VP without affecting the ratio, while lactation and suckling increase OT only. LE pretreatment inhibits significantly but does not suppress the AII-stimulated OT-VP response.

  4. INTERLEUKIN 10 INHIBITS THE RAT VSMC PROLIFERATION AND COLLAGEN SECRETION STIMULATED BY ANGIOTENSIN

    Institute of Scientific and Technical Information of China (English)

    夏春芳; 霍勇; 尹航; 朱国英; 唐朝枢

    2001-01-01

    Objective. To study the effect of interleukin 10 (IL-10) on the angiotensin Ⅱ(AngⅡ) stimulated rat VSMC proliferation and collagen secretion, and furthermore, explore its mechanism. Methods. On cultured VSMC of rat, 3H-thymine (3H-TdR) and 3H-proline incorporations were used to evaluate the DNA and collagen synthesis, respectively. Western blot and immunoprecipitation were applied to assay the expression and activity of focal adhesion kinase (FAK), respectively. Results. IL-10 (10-8 -10-10g/ml) inhibited the increase of 3H-TdR and 3H-proline incorporation as wellas FAK activity, which was induced by 10-Tmol/L AngⅡ (P 0.05). Conclusion. IL-10 antagonizes the VSMC proliferation and collagen synthesis by regulating FAK activity stimulated by AngⅡ.

  5. The influence of angiotensin-converting enzyme inhibition on renal tubular function in progressive chronic nephropathy

    DEFF Research Database (Denmark)

    Kamper, A L; Holstein-Rathlou, N H; Leyssac, P P; Strandgaard, S

    1996-01-01

    The influence of angiotensin-converting enzyme (ACE) inhibition on renal tubular function in progressive chronic nephropathy was investigated in 69 patients by the lithium clearance (C(Li)) method. Studies were done repeatedly for up to 2 years during a controlled trial on the effect of enalapril...... on progression of renal failure. The pattern of proteinuria was followed over the first 9 months. At baseline, the glomerular filtration rate (GFR) was 5 to 68 mL/min. Absolute proximal tubular reabsorption rate of fluid (APR), estimated as the difference between GFR and C(Li), was 1 to 54 m......L/min. Calculated fractional proximal reabsorption (FPR) was moderately subnormal. During the study, GFR decreased and sodium clearance was unchanged; fractional excretion of sodium therefore increased. In the group of patients randomized to treatment with enalapril (n = 34), GFR at 1 month was 83% (P < 0.001) and...

  6. Autonomic dysregulation in ob/ob mice is improved by inhibition of angiotensin-converting enzyme

    OpenAIRE

    Hilzendeger, A.M.; da Costa Goncalves, A.C.; Plehm, R.; Diedrich, A.; Gross, V; J.B. Pesquero; Bader, M

    2010-01-01

    The leptin-deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and of the renin-angiotensin system in the cardiovascular abnormalities observed in obesity using a model lacking leptin. To this purpose, we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril tr...

  7. 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.

  8. Local and systemic effects of angiotensin receptor blockade in an emphysema mouse model

    OpenAIRE

    Raupach, Tobias; Lüthje, Lars; Kögler, Harald; de Duve, Christian; Schweda, Frank; Hasenfuß, Gerd; Andreas, Stefan

    2011-01-01

    Abstract Objectives COPD with emphysema causes marked neurohumoral activation. Angiotensin II receptors are highly expressed within the lung and interfere with mechanisms involved in the progression of emphysema. This study examined the effects of an angiotensin II receptor blocker (ARB) on pulmonary and systemic manifestations of emphysema in a mouse model. Methods Female NMRI mice received five intratracheal instillations of porcine pancreatic ela...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-03-27

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

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

    International Nuclear Information System (INIS)

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

  11. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    Directory of Open Access Journals (Sweden)

    Suyeon Kim

    2006-01-01

    Full Text Available Background. The adipose tissue renin-angiotensin system (RAS contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO, mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO, and mice overexpressing Agt in adipose tissue (aP2-Agt was studied. 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. aP2-Agt mice exhibited 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 elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

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

    NARCIS (Netherlands)

    Laverman, Ger Jan; Navis, Ger Jan; de Zeeuw, Dick

    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, promp

  13. 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, promp

  14. SIRT1 inhibits angiotensin Ⅱ-induced vascular smooth muscle cell hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Li Li; Chihchuan Liang; Peng Gao; Huina Zhang; Houzao Chen; Wei Zheng; Xiang Lv; Tingting Xu; Yusheng Wei; Depei Liu

    2011-01-01

    Angiotensin Ⅱ (Ang Ⅱ) stimulates vascular smooth muscle cell (VSMC) hypertrophy as a critical event in the development of vascular diseases such as atherosclerosis.Sirtuin (SIRT) 1, a nicotinamide adenine dinucleotide dependent deacetylase, has been demonstrated to exert protective effects in atherosclerosis by promoting endo-thelium-dependent vascular relaxation and reducing macrophage foam cell formation, but its role in VSMC hypertrophy remains unknown. In this study, we tried to investigate the effect of SIRTI on Ang Ⅱ-induced VSMC hypertrophy. Results showed that adenoviral-mediated over-expression of SIRT1 significantly inhibited Ang Ⅱ-induced VSMC hypertrophy, while knockdown of SIRT1 by RNAi resulted in an increased [3H]-leucine incorpor-ation of VSMC. Accordingly, nicotinamide adenine dinu-cleotide phosphate oxidase 1 (Nox1) expression induced by Ang Ⅱ was inhibited by SIRT1 in VSMCs. SIRT1 acti-vator resveratrol decreased, whereas endogenous SIRT1 inhibitor nicotinamide increased Nox1 expression in A7r5 VSMCs. Furthermore, transcription factor GATA-6 was involved in the down-regulation of Nox1 expression by SIRT1. These results provide new insight into SIRTI's anti-atherogenic properties by suppressing Ang Ⅱ-induced VSMC hypertrophy.

  15. African Americans,hypertension and the renin angiotensin system

    Institute of Scientific and Technical Information of China (English)

    Sandra; F; Williams; Susanne; B; Nicholas; Nosratola; D; Vaziri; Keith; C; Norris

    2014-01-01

    African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system(RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovascular and chronic kidney disease makes treatment with RAS inhibitors more compelling. Despite lower circulating renin levels and a less significant fall in blood pressure in response to RAS inhibitors in African Americans, numerous clinical trials support the efficacy of RAS inhibitors to improve clinical outcomes in this population, especially in those with hypertension and risk factors for cardiovascular and related diseases. Here, we discuss the rationale of RAS blockade as part of a comprehensive approach to attenuate the high rates of premature morbidity and mortality associated with hypertension among African Americans.

  16. 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 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....... 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...

  17. Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner.

    Science.gov (United States)

    Akhtar, Saghir; El-Hashim, Ahmed Z; Chandrasekhar, Bindu; Attur, Sreeja; Benter, Ibrahim F

    2016-05-01

    The effects of naked polyamidoamine (PAMAM) dendrimers on renin-angiotensin system (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic fifth-generation (G5) PAMAM dendrimer dose- and time-dependently inhibited Ang II/AT1 receptor-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at noncytotoxic concentrations at short (1 h) exposure times and was dependent on dendrimer generation (G7 > G6 > G5 > G4) and surface group chemistry (amino > carboxyl > hydroxyl). Mechanistically, the cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the nonreceptor tyrosine kinase Src. This novel, early onset, intrinsic biological action of PAMAM dendrimers as inhibitors of the Ang II/AT1/Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications. PMID:26985693

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

    International Nuclear Information System (INIS)

    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

  19. 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

    2015-01-01

    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. PMID:26068176

  20. Luteolin Inhibits Angiotensin II-Stimulated VSMC Proliferation and Migration through Downregulation of Akt Phosphorylation

    Directory of Open Access Journals (Sweden)

    Tongda Xu

    2015-01-01

    Full Text Available Luteolin is a naturally occurring flavonoid found in many plants that possesses cardioprotective properties. The purpose of this study was to elucidate the effect of luteolin on vascular smooth muscle cells (VSMCs proliferation and migration induced by Angiotensin II (Ang II and to investigate the mechanism(s of action of this compound. Rat VSMCs were cultured in vitro, and the proliferation and migration of these cells following Ang II stimulation were monitored. Different doses of luteolin were added to VSMC cultures, and the proliferation and migration rate were observed by MTT and Transwell chamber assays, respectively. In addition, the expressions of p-Akt (308, p-Akt (473, and proliferative cell nuclear antigen (PCNA in VSMCs were monitored by Western blotting. This study demonstrated that luteolin has an inhibitory effect on Ang II-induced VSMC proliferation and migration. Further, the levels of p-Akt (308, p-Akt (473, and PCNA were reduced in VSMCs treated with both Ang II and luteolin compared to VSMCs treated with only Ang II. These findings strongly suggest that luteolin inhibits Ang II-stimulated proliferation and migration of VSMCs, which is partially due to downregulation of the Akt signaling pathway.

  1. INTERLEUKIN 10 INHIBITS THE RAT VSMC PROLIFERATION AND COLLAGEN SECRETION STIMULATED BY ANGIOTENSIN

    Institute of Scientific and Technical Information of China (English)

    夏春芳; 霍勇; 尹航; 朱国英; 唐朝枢

    2001-01-01

    Objective. To study the effect of interleukin 10 (IL-10) on the angiotensin II (AagII) stimulated rat VSMC proliferation and collagen secretion, and furthermore, explore its mechanism.Methods. On cultured VSMC of rat, 3H-thymine (3H-TdR) and 3H-proline incorporations were used to evaluate the DNA and collagen synthesis, respectively. Western blot and immunoprecipitation were applied to assay the expression and activity of focal adhesion kinase (FAK), respectively.Results. IL-10 (10-8 ~ 10-10g/ml) inhibited the increase of 3H-TdR and 3H-proline incorporation as well as FAK activity, which was induced by 10-7mol/L AngI ( P < 0. 05 or P < 0. 01 ). IL-10 also obviously downregulated the synthesis and secretion of collagen by AngII stimulated VSMC. But there was no difference in the protein expression of FAK among all the groups ( P > 0. 05).Conclusion. IL-10 antagonizes the VSMC proliferation and collagen synthesis by regulating FAK activity stimulated by AngII.

  2. Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

    Science.gov (United States)

    Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

    2014-10-01

    Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI. PMID:25119854

  3. Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction

    NARCIS (Netherlands)

    Oosterga, M; Anthonio, RL; de Kam, PJ; Kingma, JH; Crijns, HJGM; van Gilst, WH

    1998-01-01

    There are conflicting reports on the interaction of aspirin with angiotensin-converting enzyme inhibitors in heart failure and systemic hypertension. A past hoc analysis of the Captopril and Thrombolysis Study (CATS) study was conducted. At randomization, 94 patients (31.5%) took aspirin. In patient

  4. Somatostatin analog (SMS 201-995) inhibits the basal and angiotensin II-stimulated 3H-thymidine uptake by rat adrenal glands

    International Nuclear Information System (INIS)

    The effects of a long-acting somatostatin analog SMS 201-995 injections on the basal and angiotensin II-stimulated [3H]-thymidine uptake by the rat adrenal glands incubated in vitro were examined. It was shown that SMS 201-995 significantly inhibited the [3H]-thymidine uptake and, additionally, suppressed the stimulatory effect of a single angiotensin II injection

  5. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide

    Directory of Open Access Journals (Sweden)

    Shumin Li

    2014-01-01

    Full Text Available Angiotensin II (AngII is the main effector peptide of the renin–angiotensin system (RAS, and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2·−. Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2·−. We have previously reported that over-expression of manganese superoxide dismutase (MnSOD, a mitochondrial matrix-localized O2·− scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD, which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2·−. Using a neuronal cell culture model (CATH.a neurons, we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2·− levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2·−, and inhibits AngII intra-neuronal signaling.

  6. Renin-angiotensin-aldosterone system in the elderly: rational use of aliskiren in managing hypertension

    Directory of Open Access Journals (Sweden)

    Karl Andersen

    2009-03-01

    Full Text Available Karl AndersenDepartment of Medicine, Division of Cardiology, Landspitali University Hospital, University of Iceland, Reykjavik, IcelandAbstract: The overall purpose of hypertension treatment is 2-fold. First, patients often have symptoms that are related to their high blood pressure and although subtle in many instances may be improved dramatically by blood pressure control. The main reason for blood pressure treatment, however, is to reduce the burden of cardiovascular complications and end organ damage related to the condition. This may be considered the ultimate goal of blood pressure treatment. In this respect, actual blood pressure measurements may be seen as surrogate end points as the organ protective effects of two antihypertensive agents may differ significantly even though their blood pressure lowering effects are similar. Thus beta-blockers, once seen as first-line treatment of hypertension for most patients, now are considered as third- or fourth-line agents according to the latest NICE guidelines (National Institute for Health and Clinical Excellence, www.nice.org.uk/CG034. On the other hand, agents that inhibit the activity of the renin-angiotensin-aldosterone system (RAAS are being established as safe, effective and end organ protective in numerous clinical trials, resulting in their general acceptance as first-line treatment in most patients with stage 2 hypertension. This shift in emphasis from beta-blockers and thiazide diuretics is supported by numerous clinical trials and has proven safe and well tolerated by patients. The impact of this paradigm shift will have to be established in future long-term randomized clinical trials. The optimal combination treatment with respect to end organ protection has yet to be determined. Most combinations will include either a RAAS active agent and calcium channel blocker or two separate RAAS active agents working at different levels of the cascade. In this respect direct renin inhibitors

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

    Directory of Open Access Journals (Sweden)

    V S Nade

    2015-01-01

    Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.

  8. Drug discovery in renin-angiotensin system intervention: past and future.

    Science.gov (United States)

    Williams, Bryan

    2016-06-01

    The renin-angiotensin system (RAS) plays a central role in the control of blood pressure in the body and the way this interacts with other systems is widely recognized. This has not always been the case and this review summarizes how our knowledge has evolved from the initial discovery of renin by Tigerstedt and Berman in 1898. This includes the identification of angiotensin in the 1950s to the proposed relationship between this system, hypertension and ultimately cardiovascular disease. While the RAS is far more complex than originally thought, much is now known about this system and the wide ranging effects of angiotensin in the body. This has enabled the development of therapies that target the various proteins in this pathway and hence are implicated in disease. The first of these treatments was the angiotensin converting enzyme inhibitors (ACE-Is), followed by the angiotensin receptor blockers (ARBs), and more recently the direct renin inhibitors (DRIs). Clinical outcome trials have shown these drugs to be effective, but as they act at contrasting points in the RAS, there are differences in their efficacy and safety profiles. RAS blockade is the foundation of modern combination therapy with a calcium channel blocker and/or a diuretic given to reduce blood pressure and limit the impact of RAS activation. Other options that complement these treatments may be available in the future and will offer more choice to clinicians. PMID:27126389

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

    NARCIS (Netherlands)

    B. Tom (Beril)

    2003-01-01

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

  10. INHIBITION OF KIDNEY DISORDERS IN CARDIOVASCULAR DISEASES: THE ROLE OF ANGIOTENSIN II RECEPTOR BLOCKERS

    Directory of Open Access Journals (Sweden)

    V. V. Fomin

    2016-01-01

    Full Text Available Mechanisms of renal disorders in cardiovascular diseases are presented. The main of these mechanisms is an endothelium dysfunction. It is related with some factors: arterial hypertension, insulin resistance syndrome, diabetes type 2, dyslipidemia, obesity. Approaches to prevention of kidney disorder and cardiovascular complications are discussed with focus on usage of angiotensin II receptor blockers.

  11. The Impact of Age-Related Dysregulation of the Angiotensin System on Mitochondrial Redox Balance

    Directory of Open Access Journals (Sweden)

    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.

  12. The Pancreatic Renin-Angiotensin System: Does It Play a Role in Endocrine Oncology?

    Directory of Open Access Journals (Sweden)

    Lam KY

    2001-01-01

    Full Text Available The characterization of a local renin-angiotensin system in the pancreas has attracted much attention because of its potential clinical applications. A pancreatic renin-angiotensin system may be present in humans and may interact with islet cells. Nevertheless, our knowledge of the renin-angiotensin system in the human pancreas is still in its infancy, especially in the field of endocrine oncology. Much of our knowledge stems from the study of the pancreas and pancreatic endocrine tumors of rodents. Thus, the direction of future research should be based on in-depth and collaborative efforts between researchers in the various disciplines in order to apply the newly acquired scientific knowledge to the patient.

  13. Possible Involvement of the Local Renin-Angiotensin System in Exocrine Pancreas Responses to Food Components

    Directory of Open Access Journals (Sweden)

    Grant G

    2001-01-01

    Full Text Available The functioning of the exocrine and endocrine pancreas is strictly co-ordinated through an interdependent array of neural and endocrine, paracrine and autocrine hormonal factors. The responses of the exocrine pancreas to food are primarily initiated via hormones secreted by neuroendocrine cells in the gut. No role for the pancreatic renin-angiotensin system in these mechanisms has so far been established. However, because of its distribution throughout the pancreas, the renin-angiotensin system could have a function in fine-tuning of secretory responses or in integrating some of the actions of the endocrine and exocrine pancreas. In the normal diet, we are exposed to an array of bioactive (lectins, protease inhibitors, hormone-mimics, tannins, etc. Some can profoundly alter pancreas metabolism both in a beneficial or detrimental manner. Others could have beneficial effects on the pancreas renin-angiotensin system. The effects of these compounds need to be evaluated.

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

    OpenAIRE

    van der Harst, Pim

    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 both angiotensin converting enzyme inhibitors and the HMG-CoA reductase inhibitors on improving vascular function. Despite the extensive experimental evidence and some clinical trials studies using qu...

  15. Renin angiotensin system: A novel target for migraine prophylaxis

    Directory of Open Access Journals (Sweden)

    Ruchika Nandha

    2012-01-01

    Full Text Available Migraine constitutes 16% of primary headaches affecting 10-20% of general population according to International Headache Society. Till now nonsteroidalanti-inflammatory drugs (NSAIDS, opioids and triptans are the drugs being used for acute attack of migraine. Substances with proven efficacy for prevention include β-blockers, calcium channel blockers, antiepileptic drugs and antidepressants. All the already available drugs have certain limitations. Either they are unable to produce complete relief or 30-40% patients are no responders or drugs produce adverse effects. This necessitates the search for more efficacious and well-tolerated drugs. A new class of drugs like angiotensin-converting enzyme inhibitors (ACE inhibitors and angiotensin II receptor antagonists have recently been studied for their off label use in prophylaxis of migraine. Studies, done so far, have shown results in favour of their clinical use because of the ability to reduce number of days with headache, number of days with migraine, hours with migraine, headache severity index, level of disability, improved Quality of life and decrease in consumption of specific or nonspecific analgesics. This article reviews the available evidence on the efficacy and safety of these drugs in prophylaxis of migraine and can give physician a direction to use these drugs for chronic migraineurs. Searches of pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made using terms like ACE inhibitors, angiotensin II receptor antagonists and migraine. Relevant journal articles were chosen to provide necessary information.

  16. Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned?

    Science.gov (United States)

    Mochel, Jonathan P; Danhof, Meindert

    2015-01-01

    Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides

  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. PMID:25631218

  18. 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

    renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with severe hypoglycaemia, and by including these factors in a common model...... 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...... needs to be confirmed by case-control studies. We identified elevated renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with...

  19. A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system

    Directory of Open Access Journals (Sweden)

    MichaelBlock

    2013-02-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically-based pharmacokinetic (wb PBPK model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting enzyme (ACE. To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE , angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK and pharmacodynamics (PD of enalapril and enalaprilat in an accurate manner. The full set of RAAS hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement to literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD model including the PK and the mode of action (MoA of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure.

  20. Luteolin Inhibits Angiotensin II-Stimulated VSMC Proliferation and Migration through Downregulation of Akt Phosphorylation

    OpenAIRE

    Tongda Xu; Hong Zhu; Dongye Li; Yasong Lang; Lijuan Cao; Yang Liu; Wanling Wu; Dan Chen

    2015-01-01

    Luteolin is a naturally occurring flavonoid found in many plants that possesses cardioprotective properties. The purpose of this study was to elucidate the effect of luteolin on vascular smooth muscle cells (VSMCs) proliferation and migration induced by Angiotensin II (Ang II) and to investigate the mechanism(s) of action of this compound. Rat VSMCs were cultured in vitro, and the proliferation and migration of these cells following Ang II stimulation were monitored. Different doses of luteol...

  1. Effects of angiotensin-converting enzyme inhibition and bradykinin peptides in rats with myocardial infarction

    OpenAIRE

    Qu, Zhe; Xu, Hongxin; Tian, Yihao

    2015-01-01

    Background and objective: Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease myocardial remodeling and faciliate cardiac function improvement in the setting myocardial infarction by affecting bradykinin. The purpose of this study was to evaluate the combination effects of perindopril and bradykinin (BK) in rats with myocardial infarction. Methods: Wistar Rats underwent to left anterior descending (LAD) coronary artery ligation were allocated into MI group (n = 6); P...

  2. Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

    OpenAIRE

    Rai, Partab; Lederman, Rivka; Haque, Shabirul; Rehman, Shabina; Kumar, Viki; Sataranatrajan, Kavithalakshmi; Malhotra, Ashwani; Kasinath, Balakuntalam S.; Singhal, Pravin C.

    2014-01-01

    Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIV...

  3. Optimal antagonism of the Renin-Angiotensin-aldosterone system: do we need dual or triple therapy?

    Science.gov (United States)

    Werner, Christian; Pöss, Janine; Böhm, Michael

    2010-07-01

    The cardiovascular and cardiorenal disease continuum comprises the transition from cardiovascular risk factors to endothelial dysfunction and atherosclerosis, to clinical complications such as myocardial infarction (MI) and stroke, to the development of persistent target-organ damage and, ultimately, to chronic congestive heart failure (CHF), end-stage renal disease or premature death. The renin-angiotensin-aldosterone system (RAAS) is involved in all steps along this pathway, and RAAS blockade with ACE inhibitors or angiotensin AT(1)-receptor antagonists (angiotensin receptor blockers; ARBs) has turned out to be beneficial for patient outcomes throughout the disease continuum. Both ACE inhibitors and ARBs can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. These drugs have further been shown to reduce end-organ damage in the heart, kidneys and brain. Aldosterone antagonists such as spironolactone and eplerenone are increasingly recognized as a third class of RAAS inhibitor with potent risk-reducing properties, especially but not solely with respect to the inhibition of cardiac remodelling and the possible prevention of heart failure. In secondary prevention, head-to-head comparisons of ACE inhibitors and ARBs, such as the recent ONTARGET study, provided evidence that, in addition to better tolerability, ARBs are non-inferior to ACE inhibitors in the prevention of clinical endpoints such as MI and stroke in cardiovascular high-risk patients. However, the combination of both ramipril and telmisartan at the maximally tolerated dosage achieved no further benefits and was associated with more adverse events such as symptomatic hypotension and renal dysfunction. In acute MI complicated by heart failure, the VALIANT trial has shown similar effects of ACE inhibition with captopril and ARB treatment with valsartan, but dual RAAS blockade did not further reduce events. In CHF, meta-analyses of RESOLVD, Val

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

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

    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 ofmonotherapy, 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 evidence-based practice.

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

    Directory of Open Access Journals (Sweden)

    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

  6. Clinical significance of renin-angiotensin-aldosterone system, endothelin and nitric oxide in renal hypertension and adrenocorticoadenomas

    International Nuclear Information System (INIS)

    Objective: To investigate the roles of renin-angiotensin system (RAS) and aldosterone (ALD), endothelin (ET), nitric oxide (NO) in patients with renal hypertension (30 cases) and adrenocorticoadenomas (35 cases), 30 normal subjects were included in the study as controls. Methods: Radioimmunoassay (RIA) was used to determine the plasma concentrations of the renin, angiotensin II, aldosterone, endothelin (ET) in the above cases. Enzymic assay was adopted to examine the plasma concentration of the nitric oxide synthase (NOS). Results: The plasma concentrations of renin, angiotensin II, aldosterone, endothelin, NOS in control group were 1.04 +- 0.90 ng/ml/h, 71.06 +- 16.18 pg/ml, 144.77 +- 32.57 pg/ml, 45.86 +- 20.85 pg/ml, 32.2 +- 4.61 U/ml respectively. The concentration in renal hypertension patients were 7.53 +- 2.23 ng/ml/h, 144.77 +- 68.45 pg/ml, 261.07 +- 73.03 pg/ml, 96.72 +- 31.36 pg/ml, 28.8 +- 6.14 U/ml, respectively, all of the above items were significantly higher than those in the control group (p<0.01) except with the concentration of NOS , which were lower than that in controls (p<0.05). The plasma concentrations of the renin, angiotensin II, ALD, ET, NOS in the patients with adrenocorticoadenomas were 0.55 +- 0.47 ng/ml/h, 71.85 +- 17.85 pg/ml, 247.03 +- 84.03 pg/ml, 81.83 +- 28.38 pg/ml, 32.34 +- 9.02 U/ml, respectively the ALD, ET were higher than those in controls (p<0.01) but renin all AII were lower (p<0.05). Conclusion: The plasma concentrations of renin, angiotensin II, aldosterone in the patients with renal hypertension were higher than those in the controls. The patients with adrenocortical adenoma secreted a lot of ALD, thereby feedback inhibited secretion of the renin all AII. The aldosterone played an important role in the renal adenoma and renal hypertension. Determination of the plasma renin, angio-tension, aldosterone and NO might be able to and NO diagnose renal hypertension and adrenocorticoadenoma earlier

  7. Interaction of the renin angiotensin and cox systems in the kidney.

    Science.gov (United States)

    Quadri, Syed S; Culver, Silas A; Li, Caixia; Siragy, Helmy M

    2016-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in mediating actions of the renin-angiotensin system (RAS). This review sheds light on the recent developments regarding the complex interactions between components of RAS and COX-2; and their implications on renal function and disease. COX-2 is believed to counter regulate the effects of RAS activation and therefore counter balance the vasoconstriction effect of Ang II. In kidney, under normal conditions, these systems are essential for maintaining a balance between vasodilation and vasoconstriction. However, recent studies suggested a pivotal role for this interplay in pathology. COX-2 increases the renin release and Ang II formation leading to increase in blood pressure. COX-2 is also associated with diabetic nephropathy, where its upregulation in the kidney contributes to glomerular injury and albuminuria. Selective inhibition of COX-2 retards the progression of renal injury. COX-2 also mediates the pathologic effects of the (Pro)renin receptor (PRR) in the kidney. In summary, this review discusses the interaction between the RAS and COX-2 in health and disease. PMID:27100703

  8. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  9. Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, Rikke; Høi-Hansen, Thomas; Larroude, Charlotte Ellen; Olsen, Niels Vidiendal; Kanters, Jørgen Kim; Boomsma, Frans; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2008-01-01

    AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS...

  10. 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; Larroude, Charlotte Ellen; Kanters, Jørgen Kim; Boomsma, Frans; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2008-01-01

    AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with...

  11. 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

  12. Optimization of angiotensin I-converting enzyme (ACE) inhibition by rice dregs hydrolysates using response surface methodology

    Institute of Scientific and Technical Information of China (English)

    HE Guo-qing; XUAN Guo-dong; RUAN Hui; CHEN Qi-he; XU Ying

    2005-01-01

    Angiotensin I-converting enzyme (ACE) inhibitory peptides have been shown to have antihypertensive effects and have been utilized for physiologically functional foods and pharmaceuticals. The ACE inhibitory ability of a hydrolysate is determined by its peptide composition. However, the peptide composition of a hydrolysate depends on proteolytic enzyme and the hydrolysis conditions. In this study, the effect of process conditions on the ACE inhibitory activity of rice dregs hydrolyzed with a trypsin was investigated systematically using response surface methodology. It was shown that the ACE inhibitory activity of rice dregs hydrolysates could be controlled by regulation of five process conditions. Hydrolysis conditions for optimal ACE inhibition were defined using the response surface model of fractional factorial design (FFD), steepest ascent design, and central composite design (CCD).

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

    Science.gov (United States)

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

    2014-05-15

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

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

    Science.gov (United States)

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

    2016-01-01

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

  15. In vitro inhibition of [3H]-angiotensin II binding on the human AT1 receptor by proanthocyanidins from Guazuma ulmifolia bark.

    Science.gov (United States)

    Caballero-George, Catherina; Vanderheyden, Patrick M L; De Bruyne, Tess; Shahat, Abdel-Atty; Van den Heuvel, Hilde; Solis, Pablo N; Gupta, Mahabir P; Claeys, Magda; Pieters, Luc; Vauquelin, Georges; Vlietinck, Arnold J

    2002-12-01

    A bioassay-guided fractionation of the 70% acetone extract of the bark of Guazuma ulmifolia Lam. on the inhibition of angiotensin II binding to the AT 1 receptor led to the isolation and identification of bioactive oligomeric and polymeric proanthocyanidins consisting mainly of (-)-epicatechin units. The displacement of [3H]-angiotensin II binding was dose-dependent and correlated with the degree of polymerization of the different fractions containing proanthocyanidins. A strong displacement was seen for the residual fraction suggesting that the most active substances corresponding to the highly polymerized proanthocyanidins. Angiotensin II AT 1 receptor binding might be considered as a potentially interesting biological activity of proanthocyanidins contributing to the very broad spectrum of biological activities of the condensed tannins. PMID:12494331

  16. Probiotics (VSL#3 prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

    Directory of Open Access Journals (Sweden)

    Sherzad K Rashid

    Full Text Available AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO and endothelium-dependent hyperpolarization (EDH has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹ for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS. In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

  17. Propofol protects against angiotensin II-induced mouse hippocampal HT22 cells apoptosis via inhibition of p66Shc mitochondrial translocation.

    Science.gov (United States)

    Zhu, Minmin; Chen, Jiawei; Wen, Meilin; Sun, Zhirong; Sun, Xia; Wang, Jing; Miao, Changhong

    2014-12-01

    Hippocampal neuronal oxidative stress and apoptosis have been reported to be involved in cognitive impairment, and angiotensin II could induce hippocampal oxidative stress and apoptosis. Propofol is a widely used intravenous anesthetic agent in clinical practice, and it demonstrates significant neuroprotective activities. In this study, we investigated the mechanism how propofol protected mouse hippocampal HT22 cells against angiotensin II-induced oxidative stress and apoptosis. Cell viability was evaluated with CCK8 kit. Protein expressions of active caspase 3, cytochrome c, p66(Shc), p-p66(shc)-Ser(36), protein kinase C βII (PKCβII), Pin-1 and phosphatase A2 (PP2A) were measured by Western blot. Superoxide anion (O2(.-)) accumulation was measured with the reduction of ferricytochrome c. Compared with the control group, angiotensin II up-regulated expression of PKCβII, Pin-1 and PP2A, induced p66(Shc)-Ser(36) phosphorylation, and facilitated p66(Shc) mitochondrial translocation, resulting in O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, and the inhibition of cell viability. Importantly, we found propofol inhibited angiotensin II-induced PKCβII and PP2A expression and improved p66(Shc) mitochondrial translocation, O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, inhibition of cell viability. On the other hand, propofol had no effects on angiotensin II-induced Pin-1 expression and p66(Shc)-Ser(36) phosphorylation. Moreover, the protective effects of propofol on angiotensin II-induced HT22 apoptosis were similar with calyculin A, an inhibitor of PP2A and CGP53353, an inhibitor of PKCβII. However, the protective effect of propofol could be reversed by FTY720, an activator of PP2A, rather than PMA, an activator of PKCβII. Our data indicated that propofol down-regulated PP2A expression, inhibiting dephosphorylation of p66(Shc)-Ser(36) and p66(Shc) mitochondrial translocation, decreasing O2

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

    Science.gov (United States)

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

    2016-04-29

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

  19. The prevalence of unique SNPs in the renin-angiotensin system highlights the need for pharmacogenetics in Indigenous Australians.

    Science.gov (United States)

    Grimson, Steven; Cox, Amanda J; Pringle, Kirsty G; Burns, Christine; Lumbers, Eugenie R; Blackwell, C Caroline; Scott, Rodney J

    2016-02-01

    Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines. PMID:26667052

  20. Myocardial perfusion in type 2 diabetes with left ventricular hypertrophy: normalisation by acute angiotensin-converting enzyme inhibition

    International Nuclear Information System (INIS)

    The purpose of this study was to assess whether acute angiotensin-converting enzyme (ACE) inhibition would improve myocardial perfusion and perfusion reserve in a subpopulation of normotensive patients with diabetes and left ventricular hypertrophy (LVH), both independent risk factors of coronary disease. Using positron emission tomography (PET), we investigated the response of regional myocardial perfusion to acute ACE inhibition with i.v. infusion of perindoprilat (vs saline infusion as control, minimum interval 3 days) in 12 diabetic patients with LVH. Myocardial perfusion was quantified with PET using nitrogen-13 ammonia infused at rest and during dipyridamole hyperaemia. Twelve healthy control subjects were included in the study, five of whom were also studied with perindoprilat. Mean blood pressure in normo-albuminuric, asymptomatic patients was 123±7/65±9 mmHg. Compared with controls, maximal perfusion was reduced in patients (1.8±0.6 vs 2.5±1.0 ml min-1 g-1; P-1 g-1, P<0.01). In the five control subjects both resting and hyperaemic perfusion remained unchanged during perindoprilat infusion. It is concluded that acute ACE inhibition with perindoprilat improves maximal achieved myocardial perfusion in non-hypertensive patients with diabetes and LVH. (orig.)

  1. [Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure].

    Science.gov (United States)

    Bruhn, Claudia

    2016-01-01

    The molecular combination of sacubitril and valsartan (Entresto) is a new drug for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, instead of an ACE inhibitor or an angiotensin-receptor blocker (ARB). In studies, sacubitril/ valsartan was superior to enalapril in reducing the risks of death and hospitalization for heart failure. Possible side effects of sacubitril/valsartan are hypotension, angioedema, impaired renal function and elevation in serum potassium levels. The drug should not be used in times of pregnancy and breast feeding, in patients with servere hepatic impairment (Child-Pugh C) and in combination with aliskiren in patients with diabetes. PMID:26975167

  2. Association between the intrarenal renin-angiotensin system and renal injury in chronic kidney disease of dogs and cats.

    Science.gov (United States)

    Mitani, Sawane; Yabuki, Akira; Taniguchi, Kazuyuki; Yamato, Osamu

    2013-02-01

    The association of renin and angiotensin II, which are potent components of the renin-angiotensin system, with the severity of chronic renal disease was investigated immunohistochemically in dogs and cats. Immunoreactivities of renin and angiotensin II were evaluated quantitatively, and their correlations with the degrees of glomerulosclerosis, glomerular hypertrophy, interstitial cell infiltration and interstitial fibrosis were statistically analyzed. Immunoreactivities for renin were detected in afferent arteries in both dogs and cats. The score of renin-positive signals showed no correlation with plasma creatinine concentration or any of the histopathological parameters, except for the diameter of glomeruli in dogs. Immunoreactivities for angiotensin II were detected in tubules (primarily proximal tubules) and interstitial mononuclear cells in both dogs and cats. The score of tubular angiotensin II correlated with glomerulosclerosis and cell infiltration in cats but not in dogs. The score of interstitial angiotensin II correlated with plasma creatinine concentration, glomerulosclerosis, cell infiltration and fibrosis in dogs and with glomerulosclerosis and cell infiltration in cats. In conclusion, the results of the study suggest that intrarenal renin-angiotensin system is correlated with the severity of kidney disease, with the underlying mechanism differing between dogs and cats. PMID:22986274

  3. Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis.

    Science.gov (United States)

    Pan, Zhijian; Feng, Ling; Long, Haocheng; Wang, Hui; Feng, Jiarui; Chen, Feixiang

    2015-07-01

    Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis. PMID:26170733

  4. Inhibition of tissue angiotensin converting enzyme by perindopril: in vivo assessment in the rat using radioinhibitor binding displacement

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, B.; Cubela, R.B.; Johnston, C.I.

    1988-06-01

    Changes in angiotensin converting enzyme (ACE) derived from plasma, lung, aorta, brain, kidney and testis were measured in rats treated with perindopril. Angiotensin converting enzyme was measured by a radio inhibitor binding method using 125I351A. Rats were gavage fed perindopril (1, 4 and 8 mg/kg) and changes followed over 48 hr. Plasma and kidney ACE were both affected acutely with reduction of 125I351A binding to less than 5% of that in control animals 1 and 2 hr after gavage. Ligand binding to ACE in plasma and kidney returned to control levels after 24 hr. Ligand binding to ACE in lung, aorta and brain also was displaced after perindopril treatment. Changes were of a lesser degree than in plasma or kidney. Maximal effect was 1 to 4 hr after treatment and persisted through 24 hr postgavage. Ligand binding to ACE from testis was little altered over the time period of study. In a dose varying study rats were gavage fed perindopril (0-32 mg/kg) and tissues were studied 4 hr later. Ligand binding to plasma and kidney ACE was displaced by 50% at a dose of 1 mg/kg or less, whereas a dose of 16 to 32 mg/kg was required for a similar effect on ACE in lung, aorta and brain. ACE in testis was only affected to a small degree at a dose of 32 mg/kg. ACE is tissues was inhibited differentially after oral treatment with perindopril. Although differing in bioavailability, bioactivation of the drug or different binding properties of the enzyme could all account for the results, the most likely explanation is that there is variation in tissue penetration of the drug.

  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

    renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with severe hypoglycaemia, and by including these factors in a common model...... 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...... 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...

  6. Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition.

    Science.gov (United States)

    Goel, Ruby; Bhat, Shahnawaz Ali; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2015-06-01

    Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition. PMID:25869103

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

    Directory of Open Access Journals (Sweden)

    Shan-Shan Liu

    2013-12-01

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

  8. Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes

    OpenAIRE

    Çizmeci, Deniz; Arkun, Yaman

    2013-01-01

    Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes Deniz Cizmeci, Yaman Arkun* Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey Abstract The cross-talk between insulin and angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. We developed a mathematical model of the system of ...

  9. 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

  10. A systematic review: effect of angiotensin converting enzyme inhibition on left ventricular volumes and ejection fraction in patients with a myocardial infarction and in patients with left ventricular dysfunction

    DEFF Research Database (Denmark)

    Abdulla, Jawdat; Barlera, Simona; Latini, Roberto;

    2006-01-01

    BACKGROUND AND AIM: To summarize and quantify results of echocardiographic studies examining the effect of angiotensin converting enzyme (ACE) inhibition on left ventricular remodelling in patients with acute myocardial infarction (MI) and in patients with left ventricular systolic dysfunction (L...

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

    Directory of Open Access Journals (Sweden)

    Wolfgang Wurst

    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.

  12. Cholinergic signal activated renin angiotensin system associated with cardiovascular changes in the ovine fetus

    OpenAIRE

    Geng, Chunsong; Mao, Caiping; Wu, Lei; Cheng, Yu; Liu, Rulu; Chen, Bingxin; Chen, Ling; Zhang, Lubo; Xu, Zhice

    2010-01-01

    Aim: Cholinergic regulation is important in the control of cardiovascular and endocrine responses. The mechanisms behind cardiovascular responses induced by cholinergic activation are explored by studying hormonal systems, including renin-angiotensin and vasopressin (VP). Results: In chronically prepared fetal sheep, intravenous infusion of the cholinergic agonist carbachol increased fetal systolic, diastolic, and mean arterial pressure accompanied with bradycardia at near-term. Although int...

  13. 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.

  14. Therapeutic potential of targeting the renin angiotensin system in portal hypertension

    OpenAIRE

    2013-01-01

    Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesen...

  15. Inhibition of angiotensin II-induced contraction by losartan in human coronary arteries

    DEFF Research Database (Denmark)

    Holmgren, A; Pantev, E; Erlinge, D;

    1998-01-01

    II on human coronary arteries and to study the effects of angiotensin II type 1 receptor blockade with losartan. The setting was contractile experiments with ring segments of coronary arteries. We observed that Ang II is a vasoconstrictor of human coronary arteries, with a pEC50 value of 9.26 +/- 0.......22 and Emax of 68.7 +/- 9.61% of potassium-induced contraction. Losartan (10-100 nM) shifted the concentration-response curve of Ang II to the right, with pEC50 values of 7.64 +/- 0.10 and 7.00 +/- 0.15, respectively (p = 0.001), demonstrating the antagonistic properties of losartan. We also noted a...... decreased maximal response to Ang II after incubation of losartan, with Emax of 51.1 +/- 7.08% and 41.9 +/- 4.70% (p = 0.05), respectively. In conclusion, this is the first report describing the contractile effect of Ang II and the antagonizing effects of losartan in isolated human coronary arteries....

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  17. Angiotensin-converting enzyme inhibition in patients with coronary artery disease and preserved left ventricular function : Ischemia Management with Accupril post-bypass graft via inhibition of angiotensin-converting enzyme (IMAGINE) compared with the other major trials in coronary- artery disease

    NARCIS (Netherlands)

    van Gilst, WH; Warnica, JW; Baillot, R; Johnstone, D; Calciu, CD; Block, P; Myers, MG; Chocron, S; Rouleau, JL

    2006-01-01

    It has been hypothesized that angiotensin-converting enzyme (ACE) inhibition, independent from its effect on ventricular function and blood pressure, could affect the atherosclerotic process and reduce the incidence of ischemic events and its complications. Several large clinical outcome trials were

  18. Renin-angiotensin system expression and secretory function in cultured human ciliary body non-pigmented epithelium

    OpenAIRE

    Cullinane, A B; Leung, P S; Ortego, J.; Coca-Prados, M; Harvey, B J

    2002-01-01

    Background: Renin-angiotensin system (RAS) components have been identified in human ciliary body and aqueous humour, pointing to a role for the RAS in the regulation of aqueous humour dynamics. Here, the authors examine the functional expression of a RAS and the effects of angiotensin II (AII) on a signal transduction pathway and ion secretion mechanism in cultured human ciliary body non-pigmented epithelium (HNPE).

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

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2012-01-01

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

  20. Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

    OpenAIRE

    Liu, Chun Xi; Hu, Qin; Yan WANG; Zhang, Wei; Ma, Zhi Yong; Feng, Jin Bo; Wang, Rong; Wang, Xu Ping; Dong, Bo; Gao, Fei; Zhang, Ming Xiang; Zhang, Yun

    2010-01-01

    The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 ...

  1. 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.

  2. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    Science.gov (United States)

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

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. RESULTS: PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under β-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio. PMID:19058308

  3. Renin-angiotensin system gene polymorphisms as risk factors for multiple sclerosis.

    Science.gov (United States)

    Živković, Maja; Kolaković, Ana; Stojković, Ljiljana; Dinčić, Evica; Kostić, Smiljana; Alavantić, Dragan; Stanković, Aleksandra

    2016-04-15

    The components of renin-angiotensin system, such as angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II receptor type 1 and 2 (AT1R and AT2R), are expressed in the central nervous system and leukocytes and proposed to be involved in the inflammation and pathogenesis of multiple sclerosis (MS). ACE I/D, AT1R 1166A/C and AT2R -1332A/G are functional polymorphisms associated with phenotypes of diverse chronic inflammatory diseases. The aim of this study was to investigate the association between ACE I/D, AT1R 1166A/C and AT2R -1332A/G gene polymorphisms and MS in Serbian population. A total of 470 MS patients and 478 controls participated in the study. Allele-specific polymerase chain reaction (PCR) was performed for genotyping of the ACE polymorphism. The AT1R and AT2R genotyping was done by duplex PCR and restriction fragment length polymorphism analysis. Both ACE homozygotes, II and DD, were significantly overrepresented in MS patients, compared to controls (χ(2) test p=0.03). Neither genotype nor allele frequencies of AT1R 1166A/C polymorphism were significantly different between patients and controls. Significant overrepresentation of AT2R -1332 AA genotype in female patients, compared to female controls, was detected (OR=1.67, 95%CI=1.13-2.49, χ(2) test p=0.01), suggesting that this genotype could be a gender-specific genetic risk factor for MS. PMID:27000216

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

    Science.gov (United States)

    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. PMID:24040205

  5. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Walkiria Wingester Vilas-Boas; Ant(o)nio Ribeiro-Oliveira Jr; Renata da Cunha Ribeiro; Renata Lúcia Pereira Vieira; Jerusa Almeida; Ana Paula Nadu; Ana Cristina Sim(o)es e Silva; Robson Augusto Souza Santos

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) Ⅰ, Ang Ⅱ, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components.RESULTS: PRA, Ang Ⅰ, Ang Ⅱ and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang Ⅰ levels and between Ang Ⅱ and Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under 13-blockade, whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup.CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

  6. 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.

  7. RAMP1 Augments Cerebrovascular Responses to CGRP And Inhibits Angiotensin II-Induced Vascular Dysfunction

    Science.gov (United States)

    Chrissobolis, Sophocles; Zhang, Zhongming; Kinzenbaw, Dale A.; Lynch, Cynthia M.; Russo, Andrew F.; Faraci, Frank M.

    2010-01-01

    Background and Purpose Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1). Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in hRAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro following overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by ∼50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in hRAMP1 transgenic mice. Conclusions RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states where Ang II plays a major role. PMID:20814003

  8. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide ☆

    OpenAIRE

    Shumin Li; Adam J. Case; Rui-Fang Yang; Schultz, Harold D.; Zimmerman, Matthew C

    2013-01-01

    Angiotensin II (AngII) is the main effector peptide of the renin–angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 •−). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 •−. We have previously reported...

  9. New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension.

    Science.gov (United States)

    Monge, Matthieu; Lorthioir, Aurélien; Bobrie, Guillaume; Azizi, Michel

    2013-12-01

    There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension. PMID:24222656

  10. Transdermal contraception and the renin-angiotensin-aldosterone system in premenopausal women.

    Science.gov (United States)

    Odutayo, Ayodele; Cherney, David; Miller, Judith; Ahmed, Sofia B; Lai, Vesta; Dunn, Sheila; Pun, Nicole; Moineddin, Rahim; Hladunewich, Michelle A

    2015-03-15

    The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P versus control subjects only (P < 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P < 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P < 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease. PMID:25587124

  11. Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.

    Science.gov (United States)

    Abd El-Aziz, Tarek A; Hussein, Yousri M; Mohamed, Randa H; Shalaby, Sally M

    2012-05-01

    Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients. PMID:22387727

  12. Gene polymorphisms of renin-angiotensin-aldosterone system components and the progression of chronic kidney diseases

    Directory of Open Access Journals (Sweden)

    Agata Kujawa-Szewieczek

    2010-08-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS plays an important role in the pathogenesis of hypertension as well as cardiovascular diseases and chronic kidney diseases. Among the most frequently studied RAAS gene polymorphisms are the angiotensin-converting enzyme insertion/deletion (I/D, angiotensinogen M235T and angiotensin II receptor type 1 A1166C polymorphisms.A significant correlation was found between the I/D polymorphism and cardiovascular morbidity and mortality rates. However, there was no significant correlation between I/D, M235T, A1166C polymorphism and arterial hypertension. The role of I/D polymorphism in the development and progression of chronic kidney disease is also non-conclusive. However, DD genotype has been identified as relevant for loss of renal function both in patients with IgA nephropathy and in patients of Asian origin with diabetic nephropathy.The relationship between RAAS gene polymorphism and transplanted kidney function has not been confirmed in large prospective and retrospective studies. Conclusion: there is no clear opinion concerning the influence of RAAS genotypes on the prevalence of post-transplant hypertension or erythrocytosis.Although a role of RAAS gene polymorphism in kidney function deterioration could not be ruled out, it is more likely that a variety of genetic and environmental factors influence the progression of chronic kidney diseases.

  13. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    Directory of Open Access Journals (Sweden)

    Siew Mei Joyce-Tan

    2016-01-01

    Full Text Available Genome-wide association studies (GWAS have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM. However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE, angiotensinogen (AGT, and angiotensin II type 1 receptor (AGTR1. There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05 but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012; however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

  14. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen.

    Science.gov (United States)

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  15. Leptin Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by Angiotensin II through Nitric Oxide-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Amaia Rodríguez

    2010-01-01

    Full Text Available Objective. This study was designed to investigate whether leptin modifies angiotensin (Ang II-induced proliferation of aortic vascular smooth muscle cells (VSMCs from 10-week-old male Wistar and spontaneously hypertensive rats (SHR, and the possible role of nitric oxide (NO. Methods. NO and NO synthase (NOS activity were assessed by the Griess and 3H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Results. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Conclusion. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.

  16. Inhibition of oxytocin-induced but not angiotensin-induced rat uterine contractions following exposure to sodium sulfide

    Energy Technology Data Exchange (ETDEWEB)

    Hayden, L.J.; Franklin, K.J.; Roth, S.H.; Moore, G.J. (Univ. of Calgary, Alberta (Canada))

    1989-01-01

    Low concentrations of sodium sulfide reversibly attenuate the contractile response of the isolate rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low level of H{sub 2}S delay parturition in rats.

  17. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis

    OpenAIRE

    Harel, Ziv; Gilbert, Cameron; Wald, Ron; Bell, Chaim; Perl, Jeff; Juurlink, David; Beyene, Joseph; Shah, Prakesh S.

    2012-01-01

    Objective To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011. Study selection Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers w...

  18. Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension.

    Science.gov (United States)

    Csongradi, Eva; Storm, Megan V; Stec, David E

    2012-01-01

    The goal of this study was to test the hypothesis that renal medullary heme oxygenase (HO) acts as a buffer against Ang-II dependent hypertension. To test this hypothesis, renal medullary HO activity was blocked using QC-13, an imidazole-dioxolane HO-1 inhibitor, or SnMP, a classical porphyrin based HO inhibitor. HO inhibitors were infused via IRMI catheters throughout the study starting 3 days prior to implantation of an osmotic minipump which delivered Ang II or saline vehicle. MAP was increased by Ang II infusion and further increased by IRMI infusion of QC-13 or SnMP. MAP averaged 113 ± 3, 120 ± 7, 141 ± 2, 153 ± 2, and 154 ± 3 mmHg in vehicle, vehicle + IRMI QC-13, Ang II, Ang II + IRMI QC-13, and Ang II + IRMI SnMP treated mice, respectively (n = 6). Inhibition of renal medullary HO activity with QC-13 in Ang II infused mice was also associated with a significant increase in superoxide production as well as significant decreases in antioxidant enzymes catalase and MnSOD. These results demonstrate that renal inhibition of HO exacerbates Ang II dependent hypertension through a mechanism which is associated with increases in superoxide production and decreases in antioxidant enzymes. PMID:22164328

  19. Angiotensin IV protects cardiac reperfusion injury by inhibiting apoptosis and inflammation via AT4R in rats.

    Science.gov (United States)

    Park, Byung Mun; Cha, Seung Ah; Lee, Sun Hwa; Kim, Suhn Hee

    2016-05-01

    Angiotensin IV (Ang IV) is formed by aminopeptidase N from Ang III by removing the first N-terminal amino acid. Previously, we reported that Ang III has some cardioprotective effects against global ischemia in Langendorff heart. However, it is not clear whether Ang IV has cardioprotective effects. The aim of the present study was to evaluate the effect of Ang IV on myocardial ischemia-reperfusion (I/R) injury in rats. Before ischemia, male Sprague-Dawley rats received Ang IV (1mg/kg/day) for 3 days. Anesthetized rats were subjected to 45min of ischemia by ligation of left anterior descending coronary artery followed by reperfusion and then, sacrificed 1 day or 1 week after reperfusion. Plasma creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations, and infarct size were measured. Quantitative analysis of apoptotic and inflammatory proteins in ventricles were performed using Western blotting. Pretreatment with Ang IV attenuated I/R-induced increases in plasma CK and LDH levels, and infarct size, which were blunted by Ang IV receptor (AT4R) antagonist and but not by antagonist for AT1R, AT2R, or Mas receptor. I/R increased Bax, caspase-3 and caspase-9 protein levels, and decreased Bcl-2 protein level in ventricles, which were blunted by Ang IV. I/R-induced increases in TNF-α, MMP-9, and VCAM-1 protein levels in ventricles were also blunted by Ang IV. Ang IV increased the phosphorylation of Akt and mTOR. These effects were attenuated by co-treatment with AT4R antagonist or inhibitors of downstream signaling pathway. Myocardial dysfunction after reperfusion was improved by Ang IV. These results suggest that Ang IV has cardioprotective effect against I/R injury by inhibiting apoptosis via AT4R and PI3K-Akt-mTOR pathway. PMID:27038740

  20. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

    International Nuclear Information System (INIS)

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of LmnaH222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in LmnaH222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male LmnaH222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of LmnaH222P/H222P mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional

  1. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

    Energy Technology Data Exchange (ETDEWEB)

    Muchir, Antoine, E-mail: a.muchir@institut-myologie.org [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Wu, Wei [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Sera, Fusako; Homma, Shunichi [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Worman, Howard J., E-mail: hjw14@columbia.edu [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States)

    2014-10-03

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left

  2. Emergence and evolution of the renin-angiotensin-aldosterone system

    OpenAIRE

    Fournier, D.; Luft, F C; Bader, M.; Ganten, D; Andrade-Navarro, M A

    2012-01-01

    The renin–angiotensin–aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first...

  3. 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.

  4. Hyponatremia in a patient with scleroderma renal crisis: a potential role of activated renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    Fukasawa Hirotaka

    2012-06-01

    Full Text Available Abstract Background Scleroderma renal crisis is an important complication of scleroderma (systemic sclerosis that is associated with significant morbidity and mortality. On the other hand, hyponatremia has never been reported in patients with scleroderma renal crisis. Case presentation A 66-year-old man with scleroderma was admitted to our hospital for an evaluation of renal dysfunction and extreme hypertension. The laboratory evaluation revealed remarkably high plasma renin activity in association with microangiopathic hemolytic anemia, and the anti-RNA polymerase III antibody assessment was positive. The patient was diagnosed with scleroderma renal crisis and was started treatment with enalapril maleate, an angiotensin-converting enzyme inhibitor. During hospitalization, the patient developed symptomatic hyponatremia three times and each laboratory analysis revealed improperly high levels of antidiuretic hormone without signs of extracellular fluid volume depletion as well as remarkably high plasma renin activities and angiotensin levels. However, hyponatremia has not been demonstrated to occur as a result of combined therapy with candesartan cilexetil, an angiotensin II receptor blocker, and aliskiren fumarate, a direct renin inhibitor. The plasma renin activities and angiotensin levels were normalized and the renal function was maintained after treatment. Conclusions To our best knowledge, this is the first documented case of scleroderma renal crisis complicated with hyponatremia. This report also suggests that the activated renin-angiotensin system may play a role in the development of hyponatremia and that hyponatremia should be taken into consideration as a rare but possible complication associated with screloderma renal crisis.

  5. 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. PMID:26328531

  6. Expression of Astrocytic Type 2 Angiotensin Receptor in Central Nervous System Inflammation Correlates With Blood-Brain Barrier Breakdown

    DEFF Research Database (Denmark)

    Füchtbauer, Laila; Toft-Hansen, Henrik; Khorooshi, Reza;

    2010-01-01

    The blood-brain barrier (BBB), a complex of endothelial and glial barriers, controls passage of cells and solutes between the blood and central nervous system (CNS). Blood-brain barrier breakdown refers to entry of cells and/or solutes. We were interested whether the renin-angiotensin system is...... involved during BBB breakdown. We studied the type 2 angiotensin receptor AT(2) because of its suggested neuroprotective role. Two models of brain inflammation were used to distinguish solute versus cellular barrier functions. Both leukocytes and horseradish peroxidase (HRP) accumulated in the perivascular...

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

    Science.gov (United States)

    Bali, Anjana; Jaggi, Amteshwar Singh

    2016-04-01

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

  8. Influence of a history of arterial hypertension and pretreatment blood pressure on the effect of angiotensin converting enzyme inhibition after acute myocardial infarction. Trandolapril Cardiac Evaluation Study

    DEFF Research Database (Denmark)

    Gustafsson, F; Køber, L; Torp-Pedersen, C;

    1998-01-01

    inhibition after AMI complicated by left ventricular dysfunction may be of particular importance in patients with a history of arterial hypertension or a relatively high pretreatment blood pressure. However, further investigations are necessary to establish the clinical impact of these results.......OBJECTIVE: To evaluate the influence of a history of arterial hypertension and the level of pretreatment blood pressure on the efficacy of the angiotensin converting enzyme (ACE) inhibitor trandolapril on mortality and morbidity in patients with acute myocardial infarction (AMI) and left...... broad spectrum of potential confounders. Also, benefit from ACE inhibition increased with increasing blood pressure at the time of randomization. Significant interactions between benefit from ACE inhibition and hypertension history, and systolic and diastolic blood pressure were found. CONCLUSION: ACE...

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Angiotensin Ⅱ type 2 receptor gene mediated by the tetracycline-regulatable system inhibits neointimal hyperplasia in rat carotid arteries after balloon angioplasty%血管紧张素Ⅱ2型受体在体可调控表达对大鼠颈动脉新生内膜增生的影响

    Institute of Scientific and Technical Information of China (English)

    苗莉; 罗先润; 景涛; 张辉; 刘安丰; 娄云霄; 何国祥

    2011-01-01

    Objective Transducing the angiotensin Ⅱ type 2 receptor (AT2R) gene into rat balloon injury carotid arteries can attenuate neointimal hyperplasia, but how to regulate the expression of the AT2.R gene according to our need is very important in utilizing transgenie technology. The purpose of the current study is to investigate the effects of the AT2R gene medicated by the tetracy-cline regulatable system on neointimal hyperplasia in rat carotid arteries after balloon angioplasty. Methods After establishment of the rat model of carotid balloon injury restenosis, we locally perfused into the rat carotid arteries PBS (the control group), mesenchy-mal stem cells (the MSC group) or MSC/AT2R (the MSC/AT2R group) with AT2R medicated by the tetracycline regulatable system, the latter again subdivided into a doxycycline administration (Dox) and non-doxycycline Dox administration (non-Dox) group. At 14 and 28 days after the operation, we evaluated the expression of AT2R by immunohistochemistry and RT-PCR and measured the neointi-ma/media (I/M) area ratio was by morphometric analysis. Results In the MSC/AT2R + Dox group, the expressions of AT2R mRNA and protein in the neointima were significantly up-regulated from day 14 to 28 after injury (P <0.01), and the I/M ratio significantly reduced (P<0.01). The transplanted MSC showed no obvious effect on the neointimal hyperplasia. Conclusion The expression of the AT2R gene can be regulated efficiently in vivo by local delivery of MSC with dual-stable expression of the AT2R gene, and thus inhibit neointimal hyperplasia.%目的 血管紧张素Ⅱ2型受体(angiotensinⅡtype 2 receptor,AT2R)基因转染可减轻血管损伤后新生内膜的过度增生,但如何主动调控转入体内基因的表达有着重要的临床意义.文中以四环素可调控系统下的AT2R基因转染的骨髓间充质干细胞(mesenchymal stem cell,MSC)为载体,探讨AT2R在体可调控表达及对大鼠颈动脉新生内膜的影响.方法 大鼠

  11. Lactic acid bacteria: inhibition of angiotensin converting enzyme in vitro and in vivo

    DEFF Research Database (Denmark)

    Fuglsang, Anders; Rattray, Fergal; Nilsson, Dan;

    2003-01-01

    A total of 26 strains of wild-type lactic acid bacteria, mainly belonging to Lactococcus lactis and Lactobacillus helveticus , were assayed in vitro for their ability to produce a milk fermentate with inhibitory activity towards angiotensin converting enzyme (ACE). It was clear that the test...

  12. Angiotensin converting enzyme and vascular endothelial growth factor responses to exercise training in claudicants: the role of ace inhibition

    OpenAIRE

    Ng, P

    2009-01-01

    Exercise training is well recognised as an effective treatment for intermittent claudication. The mechanism underlying exercise induced improvements is multi-factorial but remains poorly understood. Low angiotensin-converting enzyme (ACE) activity has been associated with enhanced responses to endurance training. Specifically, low ACE activity has been associated with improved muscle metabolism, endothelial function, and suppressed inflammatory responses; processes linked with exercise traini...

  13. EFFECTS OF EARLY ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN A PIG MODEL OF MYOCARDIAL-ISCHEMIA AND REPERFUSION

    NARCIS (Netherlands)

    VANWIJNGAARDEN, J; TOBE, TJM; WEERSINK, EGL; BEL, KJ; DEGRAEFF, PA; DELANGEN, CDJ; VANGILST, WH; WESSELING, H

    1992-01-01

    In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infraction. In anesthetized pigs, my ocardinal ischemia and reperfusion were induced by in

  14. Comparative study of Mg/Al- and Zn/Al-layered double hydroxide-perindopril erbumine nanocomposites for inhibition of angiotensin-converting enzyme

    Directory of Open Access Journals (Sweden)

    Hussein Al Ali SH

    2012-08-01

    Full Text Available Samer Hasan Hussein Al Ali,1 Mothanna Al-Qubaisi,2 Mohd Zobir Hussein,1,3 Maznah Ismail,2,4 Zulkarnain Zainal,1 Muhammad Nazrul Hakim51Department of Chemistry, Faculty of Science, 2Laboratory of Molecular Biomedicine, Institute of Bioscience, 3Advanced Materials and Nanotechnology Laboratory, Institute of Advanced Technology, 4Department of Nutrition and Health Science, 5Department of Biomedical Science, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Selangor, MalaysiaAbstract: The intercalation of a drug active, perindopril, into Mg/Al-layered double hydroxide for the formation of a new nanocomposite, PMAE, was accomplished using a simple ion exchange technique. A relatively high loading percentage of perindopril of about 36.5% (w/w indicates that intercalation of the active took place in the Mg/Al inorganic interlayer. Intercalation was further supported by Fourier transform infrared spectroscopy, and thermal analysis shows markedly enhanced thermal stability of the active. The release of perindopril from the nanocomposite occurred in a controlled manner governed by pseudo-second order kinetics. MTT assay showed no cytotoxicity effects from either Mg/Al-layered double hydroxide or its nanocomposite, PMAE. Mg/Al-layered double hydroxide showed angiotensin-converting enzyme inhibitory activity, with 5.6% inhibition after 90 minutes of incubation. On incubation of angiotensin-converting enzyme with 0.5 µg/mL of the PMAE nanocomposite, inhibition of the enzyme increased from 56.6% to 70.6% at 30 and 90 minutes, respectively. These results are comparable with data reported in the literature for Zn/Al-perindopril.Keywords: magnesium, aluminum, layered double hydroxide, perindopril erbumine, ion exchange, angiotensin-converting enzyme, Chang cells line

  15. 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

  16. Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: A feasible strategy?

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Ger Jan; de Zeeuw, Dick

    2005-01-01

    Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strat

  17. Effects of cilazapril on endothelial cell function and fibrinolysis system in atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    HAN Wei; LI Wei-min; XIE Bao-dong; LI Yue; ZHAO Ji-yi; HUANG Yong-lin

    2005-01-01

    @@ Recently, it has been found that atrial fibrillation (AF) is associated with renin angiotensin aldosterone system (RAAS) activation and that angiotensin converting enzyme inhibition (ACEI) reduces incidence of AF in hypertensive patients.

  18. Angiotensin 2 directly increases rabbit renal brush-border membrane sodium transport: Presence of local signal transduction system

    International Nuclear Information System (INIS)

    In the present study, the authors have examined the direct actions of angiotensin II (AII) in rabbit renal brush border membrane (BBM) where binding sites for AII exist. Addition of AII (10(-11)-10(-7) M) was found to stimulate 22Na+ uptake by the isolated BBM vesicles directly. All did not affect the Na(+)-dependent BBM glucose uptake, and the effect of AII on BBM 22Na+ uptake was inhibited by amiloride, suggesting the involvement of Na+/H+ exchange mechanism. BBM proton permeability as assessed by acridine orange quenching was not affected by AII, indicating the direct effect of AII on Na+/H+ antiport system. In search of the signal transduction mechanism, it was found that AII activated BBM phospholipase A2 (PLA) and that BBM contains a 42-kDa guanine nucleotide-binding regulatory protein (G-protein) that underwent pertussis toxin (PTX)-catalyzed ADP-ribosylation. Addition of GTP potentiated, while GDP-beta S or PTX abolished, the effects of AII on BBM PLA and 22Na+ uptake, suggesting the involvement of G-protein in AII's actions. On the other hand, inhibition of PLA by mepacrine prevented AII's effect on BBM 22Na+ uptake, and activation of PLA by mellitin or addition of arachidonic acid similarly enhanced BBM 22Na+ uptake, suggesting the role of PLA activation in mediating AII's effect on BBM 22Na+ uptake. In summary, results of the present study show a direct stimulatory effect of AII on BBM Na+/H+ antiport system, and suggest the presence of a local signal transduction system involving G-protein mediated PLA activation

  19. Sex differences in hypertension: contribution of the renin-angiotensin system.

    Science.gov (United States)

    Maric-Bilkan, Christine; Manigrasso, Michaele B

    2012-08-01

    Numerous studies have shown that female human beings exhibit lower blood pressure levels over much of their life span compared with their age-matched counterparts. This sexual dimorphism is apparent in human beings as well as most, if not all, mammals. However, after the onset of menopause blood pressure levels in women increase and become similar to those in men, suggesting an important role of sex hormones in the regulation of blood pressure. The lower blood pressure levels in premenopausal women are associated with a lower risk of development and progression of cardiovascular disease and hypertension compared with age-matched men. This clear female advantage with respect to lower incidence of cardiovascular disease no longer exists after menopause, again highlighting the importance of sex hormones in the pathophysiology of cardiovascular disease in both men and women. In fact, both estrogens and androgens have been implicated in the development of cardiovascular disease and hypertension, with estrogens, in general, being protective and androgens being detrimental. Although the exact mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated, there is increasing evidence that modulating the activity of locally active hormonal systems is one of the major mechanisms of sex hormone actions in target organs, including the vasculature and kidneys. Indeed, several studies have demonstrated the importance of the interaction between sex hormones and the renin-angiotensin system in regulating cardiovascular function and blood pressure. Furthermore, the differential effects of estrogens and androgens on the expression and activity of the components of the renin-angiotensin system could possibly explain the sex differences in blood pressure levels and the development and progression of cardiovascular disease and hypertension. PMID:22795464

  20. Renin-angiotensin system in thyroidectomized rats at different periods of development.

    Science.gov (United States)

    Jiménez, E; Ruiz, M; Montiel, M; Narvaez, J A; Dieguez, J L; Morell, M

    1991-12-01

    The relationship between the renal function and some components of the renin-angiotensin system has been studied in hypothyroid rats thyroidectomized surgically at different periods of their life. Changes in plasma renin concentration (PRC) depending on the period hypothyroidism were induced. Results showed that the renin release control could result from an equilibrium between the reduced beta-adrenergic activity and the marked natriuresis observed in hypothyroidism. A reduction in plasma angiotensinogen concentration (PAC), due to a decrease in its hepatic production, was observed in thyroidectomized animals. PAC reduction was independent of the hypothyroidism induction period. Alterations in plasma renin activity (PRA) were a consequence of PRC and PAC changes in thyroidectomized animals, as an increase in fractional sodium excretion (FENa) time course dependent, was found in these rats. PMID:1725739

  1. 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

    Adverse events during fetal development can predispose the individual for cardiovascular disease later in life, a correlation known as fetal programming of adult hypertension. The "programming" events are not known but might reside in the kidneys due to these organs significant role in...... 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...... 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...

  2. Renin-angiotensin system and its role in hyperoxic acute lung injury.

    Science.gov (United States)

    Zhang, P X; Han, C H; Zhou, F J; Li, L; Zhang, H M; Liu, W W

    2016-01-01

    Oxygen is essential to sustain life, but at a high partial pressure oxygen may cause toxicity to the human body. These injuries to the lung are known as hyperoxic acute lung injury [HALI]). To date, numerous studies have been conducted to investigate the pathogenesis of HALI, for which some hypotheses have been proposed. Accumulating evidence indicates that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of some lung diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD) and HALI. In this review, we briefly introduce the classic RAS, local (tissue) RAS and intracellular RAS, and we summarize findings on the relationship between local/classic RAS and HALI. The importance--and ambiguity--of the results of these studies indicate a need for further investigations of the RAS and its role in the patho- genesis of HALI. PMID:27416692

  3. Current aspects of the interactions between dementia, the brain renin-angiotensin system and oxidative stress

    Directory of Open Access Journals (Sweden)

    Serban Dragomir

    2015-01-01

    Full Text Available There is increased interest in the interactions between vascular disorders and Alzheimer’s disease (AD. While initially these interactions were explained by the fact that these are both very common disorders, particularly later in life, recently, the possibility that these deficiencies might actually coexist is increasingly being questioned. This review attempts to present modern aspects and current reports regarding the interactions between AD, the renin-angiotensin system (RAS and hypertension, while also describing the relevance of antihypertensive drug use acting via the RAS in the treatment and prevention of AD, as well as the importance of oxidative stress, the alteration of the balance between antioxidants and pro-oxidants, in the interaction between AD and the RAS.

  4. 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.

  5. Renin-angiotensin system in ureteric bud branching morphogenesis: implications for kidney disease.

    Science.gov (United States)

    Yosypiv, Ihor V

    2014-04-01

    Failure of normal branching morphogenesis of the ureteric bud (UB), a key ontogenic process that controls organogenesis of the metanephric kidney, leads to congenital anomalies of the kidney and urinary tract (CAKUT), the leading cause of end-stage kidney disease in children. Recent studies have revealed a central role of the renin-angiotensin system (RAS), the cardinal regulator of blood pressure and fluid/electrolyte homeostasis, in the control of normal kidney development. Mice or humans with mutations in the RAS genes exhibit a spectrum of CAKUT which includes renal medullary hypoplasia, hydronephrosis, renal hypodysplasia, duplicated renal collecting system and renal tubular dysgenesis. Emerging evidence indicates that severe hypoplasia of the inner medulla and papilla observed in angiotensinogen (Agt)- or angiotensin (Ang) II AT 1 receptor (AT 1 R)-deficient mice is due to aberrant UB branching morphogenesis resulting from disrupted RAS signaling. Lack of the prorenin receptor (PRR) in the UB in mice causes reduced UB branching, resulting in decreased nephron endowment, marked kidney hypoplasia, urinary concentrating and acidification defects. This review provides a mechanistic rational supporting the hypothesis that aberrant signaling of the intrarenal RAS during distinct stages of metanephric kidney development contributes to the pathogenesis of the broad phenotypic spectrum of CAKUT. As aberrant RAS signaling impairs normal renal development, these findings advocate caution for the use of RAS inhibitors in early infancy and further underscore a need to avoid their use during pregnancy and to identify the types of molecular processes that can be targeted for clinical intervention. PMID:24061643

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

    Directory of Open Access Journals (Sweden)

    Lee Robert E

    2006-01-01

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

  7. Acute lead exposure increases arterial pressure: role of the renin-angiotensin system.

    Directory of Open Access Journals (Sweden)

    Maylla Ronacher Simões

    Full Text Available BACKGROUND: Chronic lead exposure causes hypertension and cardiovascular disease. Our purpose was to evaluate the effects of acute exposure to lead on arterial pressure and elucidate the early mechanisms involved in the development of lead-induced hypertension. METHODOLOGY/PRINCIPAL FINDINGS: Wistar rats were treated with lead acetate (i.v. bolus dose of 320 µg/Kg, and systolic arterial pressure, diastolic arterial pressure and heart rate were measured during 120 min. An increase in arterial pressure was found, and potential roles of the renin-angiotensin system, Na(+,K(+-ATPase and the autonomic reflexes in this change in the increase of arterial pressure found were evaluated. In anesthetized rats, lead exposure: 1 produced blood lead levels of 37±1.7 µg/dL, which is below the reference blood concentration (60 µg/dL; 2 increased systolic arterial pressure (Ct: 109±3 mmHg vs Pb: 120±4 mmHg; 3 increased ACE activity (27% compared to Ct and Na(+,K(+-ATPase activity (125% compared to Ct; and 4 did not change the protein expression of the α1-subunit of Na(+,K(+-ATPase, AT(1 and AT(2. Pre-treatment with an AT(1 receptor blocker (losartan, 10 mg/Kg or an ACE inhibitor (enalapril, 5 mg/Kg blocked the lead-induced increase of arterial pressure. However, a ganglionic blockade (hexamethonium, 20 mg/Kg did not prevent lead's hypertensive effect. CONCLUSION: Acute exposure to lead below the reference blood concentration increases systolic arterial pressure by increasing angiotensin II levels due to ACE activation. These findings offer further evidence that acute exposure to lead can trigger early mechanisms of hypertension development and might be an environmental risk factor for cardiovascular disease.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Effects of Aerobic Exercise Training on Cardiac Renin-Angiotensin System in an Obese Zucker Rat Strain

    OpenAIRE

    Diego Lopes Mendes Barretti; Flávio de Castro Magalhães; Tiago Fernandes; Everton Crivoi do Carmo; Kaleizu Teodoro Rosa; Maria Claudia Irigoyen; Carlos Eduardo Negrão; Edilamar Menezes Oliveira

    2012-01-01

    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 Zu...

  10. The response of tumour vasculature to angiotensin II revealed by its systemic and local administration to 'tissue-isolated' tumours.

    OpenAIRE

    Tozer, G M; Shaffi, K. M.

    1995-01-01

    A tissue-isolated preparation of the P22 rat carcinosarcoma was used to investigate the tumour vascular response to angiotensin II (ATII). In particular, the relative importance of systemic and local tumour factors was assessed by comparing tumour vascular resistance during systemic administration of ATII and during administration directly into the tumour-supplying artery. The effect of hypervolaemia on tumour vascular resistance was determined as well as the effect of ATII on oxygen metaboli...

  11. Long-Term Regulation of the Local Renin-Angiotensin System in the Myocardium of Spontaneously Hypertensive Rats by Feeding Bioactive Peptides Derived from Spirulina platensis.

    Science.gov (United States)

    Pan, Huanglei; She, Xingxing; Wu, Hongli; Ma, Jun; Ren, Difeng; Lu, Jun

    2015-09-01

    This study investigated the long-term (8 weeks) anti-hypertensive effects of 10 mg/kg tripeptides isolated from Spirulina platensis, Ile-Gln-Pro (IQP) and Val-Glu-Pro (VEP), and S. platensis hydrolysates (SH) on spontaneously hypertensive rats. The treatment period was 6 weeks, and observation continued for another 2 weeks. After treatment, weighted systolic blood pressure, weighted diastolic blood pressure, left ventricular mass index, and right ventricular mass index of groups treated with IQP, VEP, and SH were significantly lower than those of the group treated with distilled water, even when the treatments had been withdrawn for 2 weeks. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting showed the mRNA expression levels and protein/peptide concentrations of the main components of the renin angiotensin system in myocardium were significantly affected by treatment: angiotensin converting enzyme, angiotensin II, and angiotensin type 1 receptor were down-regulated, whereas angiotensin type 2 receptor, angiotensin converting enzyme 2, angiotensin-(1-7), and Mas receptor were up-regulated. PMID:26245714

  12. Importance of the Brain Angiotensin System in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    John W. Wright

    2012-01-01

    Full Text Available Parkinson’s disease (PD has become a major health problem affecting 1.5% of the world’s population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson’s disease.

  13. Effect of a cheese rich in angiotensin-converting enzyme-inhibiting peptides (Gamalost®) and a Gouda-type cheese on blood pressure: results of a randomised trial

    OpenAIRE

    Nilsen, Rita; Pripp, Are H; Arne T. Høstmark; Haug, Anna; Skeie, Siv

    2016-01-01

    Background: High blood pressure (BP) is the leading risk factor for global disease burden, contributing to 7% of global disability adjusted life years. Angiotensin converting enzyme (ACE)-inhibiting bioactive peptides have the potential to reduce BP in humans. These peptides have been identified in many dairy products and have been associated with significant reductions in BP.Objective: The objective of this trial was to examine whether a cheese rich in ACE-inhibiting peptides (Gamalost®), or...

  14. Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering.

    Science.gov (United States)

    Düsing, Rainer

    2016-06-01

    Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin-angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro-protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering. PMID:27122491

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

    OpenAIRE

    Sabharwal, Rasna; Chapleau, MarkW.

    2013-01-01

    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 defi...

  16. Atlas of tissue renin-angiotensin-aldosterone system in human: A transcriptomic meta-analysis.

    Science.gov (United States)

    Nehme, Ali; Cerutti, Catherine; Dhaouadi, Nedra; Gustin, Marie Paule; Courand, Pierre-Yves; Zibara, Kazem; Bricca, Giampiero

    2015-01-01

    Tissue renin-angiotensin-aldosterone system (RAAS) has attracted much attention because of its physiological and pharmacological implications; however, a clear definition of tissue RAAS is still missing. We aimed to establish a preliminary atlas for the organization of RAAS across 23 different normal human tissues. A set of 37 genes encoding classical and novel RAAS participants including gluco- and mineralo-corticoids were defined as extended RAAS (extRAAS) system. Microarray data sets containing more than 10 normal tissues were downloaded from the GEO database. R software was used to extract expression levels and construct dendrograms of extRAAS genes within each data set. Tissue co-expression modules were then extracted from reproducible gene clusters across data sets. An atlas of the maps of tissue-specific organization of extRAAS was constructed from gene expression and coordination data. Our analysis included 143 data sets containing 4933 samples representing 23 different tissues. Expression data provided an insight on the favored pathways in a given tissue. Gene coordination indicated the existence of tissue-specific modules organized or not around conserved core groups of transcripts. The atlas of tissue-specific organization of extRAAS will help better understand tissue-specific effects of RAAS. This will provide a frame for developing more effective and selective pharmaceuticals targeting extRAAS. PMID:25992767

  17. 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; Parsons-Wingerter, Patricia; Oudit, Gavin Y.; Grant, Maria B.

    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

  18. Human in vivo study of the renin-angiotensin-aldosterone system and the sympathetic activity after 8 weeks daily intake of fermented milk

    DEFF Research Database (Denmark)

    Usinger, Lotte; Ibsen, Hans; Linneberg, Allan; Azizi, Michel; Flambard, Bénédicte; Jensen, Lars T

    2010-01-01

    Milk fermented by lactic acid bacteria is suggested to have antihypertensive effect in humans. In vitro and animal studies have established an angiotensin-converting enzyme (ACE) inhibitor effect of peptides in fermented milk. However, other modes of action must be considered, because until today...... no human studies have confirmed an ACE inhibition in relation to the intake of fermented milk....

  19. 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

    OpenAIRE

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

    2015-01-01

    Objectives: 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. Materials and Methods: A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreate...

  20. Vascular hypothesis revisited: Role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis.

    Science.gov (United States)

    Cabral-Marques, Otavio; Riemekasten, Gabriela

    2016-07-01

    Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology characterized by the presence of multiple autoantibodies, including those against angiotensin and endothelin receptors. Patients with SSc can develop heterogeneous clinical manifestations including microvascular damage, the dysregulation of innate and adaptive immunity, and generalized fibrosis of multiple organs. Autoantibodies against angiotensin II type I receptor (AT1R) and endothelin-1 type A receptor (ETAR) play important roles in the pathogenesis of SSc. These autoantibodies regulate physiological processes ranging from production of collagen by skin fibroblasts to angiogenesis modulation. Understanding the mechanisms behind autoantibodies against AT1R and ETAR could provide insight to future novel therapies for SSc patients. In this review, we focus on elucidating the immunopathological mechanisms triggered by anti-AT1R and anti-ETAR autoantibodies to summarize current knowledge about vascular abnormalities resulting in progressive damage of organs seen in patients with SSc. PMID:26970493

  1. 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

    . lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis......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...... angiotensinogen concentration and serum ACE activity. RESULTS: Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs...

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

    Directory of Open Access Journals (Sweden)

    Tojo A

    2016-01-01

    Full Text Available Akihiro Tojo,1 Satoshi Kinugasa,1 Toshiro Fujita,2 Christopher S Wilcox3 1Division of Nephrology and Endocrinology, 2Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 3Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Research, Georgetown University, Washington, DC, USA Abstract: 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. Keywords: renal renin–angiotensin system, prorenin, angiotensinogen, diabetic nephropathy, microalbuminuria

  3. Renal uptake of dimercaptosuccinic acid and glomerular filtration rate in chronic nephropathy at angiotensin converting enzyme inhibition

    DEFF Research Database (Denmark)

    Kamper, A L; Thomsen, H S; Nielsen, S L; Strandgaard, S

    1990-01-01

    function. Scintigrams of the kidneys showed an unaltered distribution of DMSA during treatment. GFR estimated by 51Cr-EDTA plasma clearance fell by 14% (P less than 0.01), but renal uptake of 99mTc-DMSA increased by 10% (P less than 0.01). It is concluded that DMSA in chronic renal failure is mainly taken......Glomerular filtration rate (GFR) and renal uptake of dimercaptosuccinic acid (DMSA) were measured in 31 patients with progressive chronic nephropathy before and immediately after the start of treatment with angiotensin converting enzyme (ACE) inhibitor in order to control adverse effects on kidney...... up by the tubular cells from the peritubular capillaries since the uptake was unaffected by the acute decrease in GFR....

  4. Use of renin angiotensin system inhibitors in patients with chronic kidney disease.

    Science.gov (United States)

    Adam, W R; Wright, J R

    2016-05-01

    Current guidelines recommend renin angiotensin system inhibitors (RASI) as key components of treatment of hypertension in patients with chronic kidney disease (CKD), because of their effect on reducing the future rate of loss of glomerular filtration rate (GFR). A common risk of RASI in CKD is a haemodynamically mediated, and reversible, fall in GFR of varying severity and duration, any time after commencement of the Inhibitors. A benefit of the acute reduction in filtration rate with RASI may be a reduction in the future rate of loss in GFR: the greatest benefit likely to be in those patients with a greater rate of loss of GFR prior to, and a lesser acute loss of GFR after, introduction of RASI; and in those patients with significant proteinuria. An acute loss of GFR of >25% following the introduction of RASI is an indication to cease the RASI. An acute loss of GFR Hyperkalaemia in patients with CKD on RASI is more common with more severe disease, potassium retaining diuretics and hypoaldosteronism. Treatment should be modified to maintain a plasma potassium <6 mmol/L. PMID:27170242

  5. 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.

  6. Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity.

    Science.gov (United States)

    Feraco, Alessandra; Armani, Andrea; Mammi, Caterina; Fabbri, Andrea; Rosano, Giuseppe M C; Caprio, Massimiliano

    2013-09-01

    The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'. PMID:23454117

  7. Angiotensin Converting Enzyme Gene Polymorphism in Egyptian Patients with Systemic Lupus Erythematosus

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    El-Shafeey M.M., El-Shayeb M., Othman E. and Elfawy N

    2005-12-01

    Full Text Available Systemic lupus erythematosus (SLE shows various clinical manifestations with various immunological abnormalities. The development of lupus nephritis and vasculitis is common in patients with SLE. As angiotensin I-converting enzyme (ACE has been reported to be associated with various immunological phenomena, we investigated the correlation between insertion(I / deletion(D polymorphism of the ACE gene and SLE. Fifty Egyptian patients with SLE and thirty healthy control persons were involved in this study. ACE gene was detected by the polymerase chain reaction (PCR. In SLE patients, there is a significant difference when comparing DD and II genotypes (P<0.05,being higher in the DD genotype. And a highly significant difference when comparing ID and II genotypes (P=0.001, being much higher in ID genotype than II genotype. According to vasculitis, there is a significant relationship between vasculitis and patients genotypes when comparing ID genotype with both II and DD genotypes (P<0.05, being highest in ID genotype. There is a significant relationship found when comparing ID genotype with both II and DD genotypes, being highest in ID genotype in patients with score 21. These results suggest that the ACE genotype could be associated with SLE.

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

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    Kosuke Nagayama

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

  9. A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy

    Directory of Open Access Journals (Sweden)

    Zohreh Rahimi

    2014-01-01

    Full Text Available Background: The renin angiotensin aldosterone system (RAAS plays a vital role in regulating glucose metabolism and blood pressure, electrolyte and fluid homeostasis. The aim of this systematic review is to assess the association of the RAAS genes with diabetes mellitus (DM and its complications of retinopathy, neuropathy and cardiovascular disease (CVD. Materials and Methods: The relevant English-language studies were identified using the key words of DM, type 1 diabetes mellitus (T1DM, T2DM, renin angiotensin aldosterone polymorphisms or genotypes and RAAS from the search engines of MEDLINE/PubMed, and Scopus from January 1, 1995 to July 30, 2014. Inclusion criteria for selecting relevant studies were reporting the role of RAAS gene variants in the pathogenesis of T1DM or T2DM, diabetic retinopathy (DR, diabetic neuropathy and cardiovascular complication of DM. Results: The reviewers identified 204 studies of which 73 were eligible for inclusion in the present systematic review. The review indicates the angiotensinogen (AGT M235T polymorphism might not affect the risk of DM. The role of angiotensin converting enzyme insertion/deletion (ACE I/D and angiotensin II type 1 receptor gene (AT1R A1166C polymorphisms in the pathogenesis of DM could not be established. Studies indicate the absence of an association between three polymorphisms of AGT M235T, ACE I/D and AT1R A1166C and DR in DM patients. A protective role for ACE II genotype against diabetic peripheral neuropathy has been suggested. Also, the ACE I/D polymorphism might be associated with the risk of CVD in DM patients. Conclusion: More studies with adequate sample size that investigate the influence of all RAAS gene variants together on the risk of DM and its complications are necessary to provide a more clear picture of the RAAS genes polymorphisms involvement in the pathogenesis of DM and its complications.

  10. The Renin-Angiotensin-Aldosterone System in Smokers and Non-Smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

    Science.gov (United States)

    Delgado, Graciela E; Siekmeier, Rüdiger; Krämer, Bernhard K; Grübler, Martin; Tomaschitz, Andreas; März, Winfried; Kleber, Marcus E

    2016-01-01

    High concentrations of renin and aldosterone are risk factors for cardiovascular diseases (CVD) which are the leading cause of morbidity and mortality worldwide. Enhanced activation of the renin-angiotensin-aldosterone system (RAAS) by cigarette smoking has been reported. The aim of our study was to analyze the effect of cigarette smoking on parameters of the RAAS in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study as well as the utility of RAAS parameter for risk prediction. We determined the concentration of aldosterone, renin, angiotensin-I and angiotensin-II in participants of the LURIC study. Smoking status was assessed by a questionnaire and the measurement of plasma cotinine concentration. Parameters were log transformed before entering analyses, where appropriate. We used a multivariate Cox regression analysis to assess the effect of parameters on mortality. From the 3316 LURIC participants 777 were AS and 1178 NS. Within a median observation period of 10 years 221 (28.4 %) AS and 302 (25.6 %) NS died. After adjustment for age, gender, and the use of anti-hypertensive medication, only angiotensin-I was significantly different in AS compared to NS with an estimated marginal mean (95 % CI) of 1607 (1541-1673) ng/L and 1719 (1667-1772) ng/L, respectively. For both NS and AS renin and angiotensin-II were directly associated with mortality in the multivariate Cox regression analysis. Angiotensin-I was only associated with increased risk for mortality in NS (HR (95 % CI) of 0.69 (0.53-0.89)). We conclude that increased renin and angiotensin-II are independent predictors of mortality in AS and NS, while angiotensin-I was associated with reduced risk of death in NS only. PMID:27334735

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

    Directory of Open Access Journals (Sweden)

    Edwin Roger Parra

    2014-01-01

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

  12. Pengaruh Pemberian Ekstrak Etanol Buah Mengkudu terhadap Aktivitas Angiotensin Converting Enzyme (ACE) pada Tikus Wistar yang Mendapat Diet Natrium

    OpenAIRE

    Syahreza, Adri

    2012-01-01

    Hypertension is now a global problem because of the prevalence continues to increase in line with lifestyle changes. One of hypertension cause is excess intake of sodium thus will increase the fluid volume in the body. One of regulates the fluid balance in the body is mechanism of renin angiotensin aldosterone system (RAAS). Increasing activity of angiotensin converting enzyme (ACE) in the body will lead to hypertension through RAAS. ACE activation can be inhibited by ACE In...

  13. 25-Hydroxyvitamin D status, arterial stiffness and the renin-angiotensin system in healthy humans.

    Science.gov (United States)

    Abdi-Ali, Ahmed; Nicholl, David D M; Hemmelgarn, Brenda R; MacRae, Jennifer M; Sola, Darlene Y; Ahmed, Sofia B

    2014-01-01

    Vitamin D deficiency is associated with increased arterial stiffness. We sought to clarify the influence of vitamin D in modulating angiotensin II-dependent arterial stiffness. Thirty-six healthy subjects (33 ± 2 years, 67% female, mean 25-hydroxyvitamin D 69 ± 4 nmol/L) were studied in high salt balance. Arterial stiffness, expressed as brachial pulse wave velocity (bPWV) and aortic augmentation index (AIx), was measured by tonometry at baseline and in response to angiotensin II infusion (3 ng/kg/min × 30 min then 6 ng/kg/min × 30 min). The primary outcome was change in bPWV after an angiotensin II challenge. Results were analyzed according to plasma 25-hydroxyvitamin D status: deficient (nmol/L) and sufficient (≥ 50 nmol/L). There were no differences in baseline arterial stiffness between vitamin D deficient (25-hydroxyvitamin D 40 ± 2 nmol/L) and sufficient (25-hydroxyvitamin D 80 ± 4 nmol/L) groups. Compared with sufficient vitamin D status, vitamin D deficiency was associated with a decreased arterial response to angiotensin II challenge (Δbrachial pulse wave velocity: 0.48 ± 0.44 m/s versus 1.95 ± 0.22 m/s, p=0.004; Δaortic augmentation index: 9.4 ± 3.4% versus 14.2 ± 2.7%, p=0.3), which persisted for brachial pulse wave velocity response after adjustment for covariates (p=0.03). Vitamin D deficiency is associated with increased arterial stiffness in healthy humans, possibly through an angiotensin II-dependent mechanism. PMID:24164282

  14. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.

    Science.gov (United States)

    Weber, Michael A; Mansfield, Traci A; Alessi, Federica; Iqbal, Nayyar; Parikh, Shamik; Ptaszynska, Agata

    2016-04-01

    Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 10 mg (n = 302) or placebo (n = 311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p < 0.0001), mean seated SBP (-10.4 vs -7.3 mmHg, p = 0.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.7 mmHg, p = 0.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.3 kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension. PMID:26623980

  15. Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

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    Li-Qun Zhao

    Full Text Available Atrial fibrillation(AF is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene.A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097 were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study.In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678, compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF.Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

  16. Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats

    NARCIS (Netherlands)

    Hamming, I.; van Goor, H.; Turner, A. J.; Rushworth, C. A.; Michaud, A. A.; Corvol, P.; Navis, G.

    2008-01-01

    Angiotensin-converting enzyme (ACE) 2 is thought to counterbalance ACE by breakdown of angiotensin (Ang) II and formation of Ang(1-7). Both enzymes are highly expressed in the kidney, but reports on their regulation differ. To enhance our understanding of the regulation of renal ACE and ACE2, we inv

  17. Association of Free Radicals and the Tissue Renin-Angiotensin System: Prospective Effects of Rhodiola, a Genus of Chinese Herb, on Hypoxia-Induced Pancreatic Injury

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    Ip SP

    2001-01-01

    Full Text Available The renin-angiotensin system has long been recognized as crucial factor in the regulation of the systemic blood pressure and renal electrolyte homeostasis. Numerous studies have demonstrated the presence of a local renin-angiotensin system in a variety of organs. A recent study of the pancreatic renin-angiotensin system showed that chronic hypoxia significantly increased the mRNA expression for angiotensinogen II receptor subtypes AT1b and AT2. The activation of the renin-angiotensin system may play an important role in cellular pathophysiological processes. Angiotensin II enhances the formation of reactive oxygen species via the activation of xanthine oxidase or NAD(PH oxidase. The reactive oxygen species can cause oxidative damage in the pancreas and other tissues either directly or indirectly via the formation of other radicals such as reactive nitrogen species. Rhodiola therapy may protect hypoxia-induced pancreatic injury in two ways. It prevents hypoxia-induced biological changes by increasing intracellular oxygen diffusion and efficiency of oxygen utilization. Alternatively, it reduces hypoxia-induced oxidative damage by its antioxidant activities. Additional experimental data are required to fully elucidate the mode of action of this herbal drug.

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

    Science.gov (United States)

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

    2016-04-01

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

  19. 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.

  20. Vitamin D receptor activation and downregulation of renin-angiotensin system attenuate morphine-induced T cell apoptosis

    OpenAIRE

    Chandel, Nirupama; Sharma, Bipin; Salhan, Divya; Husain, Mohammad; Malhotra, Ashwani; Buch, Shilpa; Singhal, Pravin C.

    2012-01-01

    Opiates have been reported to induce T cell loss. We evaluated the role of vitamin D receptor (VDR) and the activation of the renin-angiotensin system (RAS) in morphine-induced T cell loss. Morphine-treated human T cells displayed downregulation of VDR and the activation of the RAS. On the other hand, a VDR agonist (EB1089) enhanced T cell VDR expression both under basal and morphine-stimulated states. Since T cells with silenced VDR displayed the activation of the RAS, whereas activation of ...

  1. Heparin inhibits Angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways

    Science.gov (United States)

    Xie-Zukauskas, Hui; Das, Jharna; Short, Billie Lou; Gutkind, J. Silvio; Ray, Patricio E.

    2013-01-01

    Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistances arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PKA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PKA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways. PMID:23268358

  2. 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

  3. Influence of the renin-angiotensin system on human forearm blood flow

    DEFF Research Database (Denmark)

    Stadeager, C; Hesse, B; Henriksen, O; Bonde-Petersen, F; Mehlsen, J; Rasmussen, S

    1990-01-01

    Although angiotensin II is a potent vasoconstrictor agent in all tissues, including the human forearm, equivocal effects on forearm blood flow (FBF) have been found after angiotensin blockade. In 13 healthy Na(+)-depleted subjects FBF was measured by the 133Xe washout technique; subcutaneous and...... muscle blood flows were determined separately. FBF was measured during supine rest, after the arm was lowered, and during lower body negative pressure (LBNP). The measurements were repeated during intra-arterial saralasin infusion in six subjects and after intravenous administration of enalapril in seven...... subjects. FBF decreased and forearm vascular resistance (FVR) increased during arm lowering and LBNP, as the result of local and central adrenergic reflexes, respectively. We observed similar FBF and FVR values after both saralasin and enalapril, except for a decrease in FVR at rest after enalapril. It is...

  4. 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 to...... been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although 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. The...

  5. Saga of renin-angiotensin system and calcium channels in hypertensive diabetics: does it have a therapeutic edge?

    Science.gov (United States)

    Kumar, Arun H S; Ramarao, P

    2005-01-01

    Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in the development of micro- and macro-vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT1 receptors, whereas the AT2 receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT1 receptor blockers (ARBs) should provide additional end organ protection via AT2 receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs. Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT1 receptor blocker, or a hypothetical dual blocker of AT1 receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive clinical evidence to support the combined use of these drugs. This review highlights the available experimental data that support the therapeutic benefits of this combination. PMID:16007228

  6. 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: 1.293, year: 2014

  7. Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

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    Kazuma Izawa

    Full Text Available BACKGROUND: Angiotensin II (AII plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH redox status in cardiovascular remodeling remains unknown. METHODS: In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs. RESULTS: BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (p<0.01, which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, p<0.05. Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. CONCLUSIONS: We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical

  8. Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensin-aldosterone system

    Science.gov (United States)

    Jin, Ze-Ning; Wei, Yong-Xiang

    2016-01-01

    Background Obstructive sleep apnea (OSA) is the most common cause of resistant hypertension, which has been proposed to result from activation of the renin–angiotensin–aldosterone system (RAAS). We meta-analyzed the effects of OSA on plasma levels of RAAS components. Methods Full-text studies published on MEDLINE and EMBASE analyzing fasting plasma levels of at least one RAAS component in adults with OSA with or without hypertension. OSA was diagnosed as an apnea-hypopnea index or respiratory disturbance index ≥ 5. Study quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity was assessed using the I2 statistic. Results from individual studies were synthesized using inverse variance and pooled using a random-effects model. Subgroup analysis, sensitivity analysis, and meta-regression were performed, and risk of publication bias was assessed. Results The meta-analysis included 13 studies, of which 10 reported results on renin (n = 470 cases and controls), 7 on angiotensin II (AngII, n = 384), and 9 on aldosterone (n = 439). AngII levels were significantly higher in OSA than in controls [mean differences = 3.39 ng/L, 95% CI: 2.00–4.79, P < 0.00001], while aldosterone levels were significantly higher in OSA with hypertension than OSA but not with hypertension (mean differences = 1.32 ng/dL, 95% CI: 0.58–2.07, P = 0.0005). Meta-analysis of all studies suggested no significant differences in aldosterone between OSA and controls, but a significant pooled mean difference of 1.35 ng/mL (95% CI: 0.88–1.82, P < 0.00001) emerged after excluding one small-sample study. No significant risk of publication bias was detected among all included studies. Conclusions OSA is associated with higher AngII and aldosterone levels, especially in hypertensive patients. OSA may cause hypertension, at least in part, by stimulating RAAS activity.

  9. Safety and efficacy of rennin-angiotensin system inhibitors in heart failure with preserved ejection fraction '

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    Mukesh Singh

    2011-04-01

    Full Text Available Background: Approximately half of the patients with chronic heart failure have preserved left ventricular systolic function. The trials of rennin-angiotensin system inhibitors (RASIs in this population have yielded mixed results. We performed a meta-analysis of these trials to evaluate the safety and efficacy of RASIs in heart failure with preserved ejection fraction patients.Methods: A total of 8425 patients from six prospective randomized controlled trials were analyzed. The end points extracted were total mortality, cardiovascular mortality, hospitalization for heart failure, worsening of heart failure, worsening of renal failure, hyperkalemia, hypotension, six minute walk test, quality of life score. RASIs evaluated were perindopril, enalapril, ramipril, valsartan, candesartan and irbesartan. Combined odds ratios (OR across all the studies and 95% confidence intervals (CI were computed. A two-sided alpha error <0.05 was considered to be statistically significant. All studies were homogeneous for outcomes studied, so fixed effect model was used for this meta- analysis.Results: Both groups share similar baseline characteristics. There was significant reduction in worsening of heart failure events [OR: 1.16, CI: 1.03-1.31; p<0.05] with RASIs compared to placebo group. This was associated with a tendency toward reduced hospitalizations due to heart failure [OR: 1.11, CI: 0.99-1.24; p=0.052] but it could not achieve statistical significance. RASIs also failed to show any benefit in total mortality [OR: 1.07, CI: 0.96-1.19; p=0.19] or cardiovascular mortality [OR: 1.01, CI: 0.89-1.15; p= 0.84] [Figure 1]. However, treatment with RASI lead to significant improvement in six minute walking distance [p<0.05] and quality of life score in RASIs group [p=0.002] [Figure 1]. Safety analysis, as expected, revealed significantly more hyperkalemic events [OR: 0.53, CI: 0.29-0.95; p<0.05] and worsening of renal failure [OR: 0.65, CI: 0.50-0.85; p<0.05] in RASI

  10. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution.

    Science.gov (United States)

    Itinteang, Tinte; Brasch, Helen D; Tan, Swee T; Day, Darren J

    2011-06-01

    Infantile haemangioma is a benign tumour of the microvasculature characterised by excessive proliferation of immature endothelial cells. It typically undergoes rapid proliferation during infancy followed by spontaneous slow involution during childhood often leaving a fibro-fatty residuum. In 2008, propranolol, a non-selective β-blocker, was serendipitously discovered to induce accelerated involution of a proliferating infantile haemangioma. However, the mechanism by which propranolol causes this dramatic effect is unclear. Using immunohistochemical staining, we show that the CD34+ endothelial progenitor cells of the microvessels in proliferating infantile haemangioma express angiotensin-converting enzyme and angiotensin II receptor-2, but not angiotensin II receptor-1. We have also shown using our in vitro explant model that the cells emanating from proliferating haemangioma biopsies form blast-like structures that proliferate in the presence of angiotensin II. We present here a plausible model involving the renin-angiotensin system that may account for the propranolol-induced accelerated involution of proliferating infantile haemangioma. PMID:20870476

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

    Science.gov (United States)

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

    2016-05-18

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

  12. Long-term Angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARγ.

    OpenAIRE

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

    2006-01-01

    To clarify the mechanism of the effects of angiotensin II AT1 receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT1 receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum ...

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

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    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.

  14. Angiotensin-converting enzyme inhibition prevents myocardial infarction-induced increase in renal cortical cGMP and cAMP phosphodiesterase activities.

    Science.gov (United States)

    Clauss, François; Charloux, Anne; Piquard, François; Doutreleau, Stéphane; Talha, Samy; Zoll, Joffrey; Lugnier, Claire; Geny, Bernard

    2015-08-01

    We investigated whether myocardial infarction (MI) enhances renal phosphodiesterases (PDE) activities, investigating particularly the relative contribution of PDE1-5 isozymes in total PDE activity involved in both cGMP and cAMP pathways, and whether angiotensin-converting enzyme inhibition (ACEi) decreases such renal PDE hyperactivities. We also investigated whether ACEi might thereby improve atrial natriuretic peptide (ANP) efficiency. We studied renal cortical PDE1-5 isozyme activities in sham (SH)-operated, MI rats and in MI rats treated with perindopril (ACEi) 1 month after coronary artery ligation. Circulating atrial natriuretic peptide (ANP), its second intracellular messenger cyclic guanosine monophosphate (cGMP) and cGMP/ANP ratio were also determined. Cortical cGMP-PDE2 (80.3 vs. 65.1 pmol/min/mg) and cGMP-PDE1 (50.7 vs. 30.1 pmol/min/mg), and cAMP-PDE2 (161 vs. 104.1 pmol/min/mg) and cAMP-PDE4 (307.5 vs. 197.2 pmol/min/mg) activities were higher in MI than in SH rats. Despite increased ANP plasma level, ANP efficiency tended to be decreased in MI compared to SH rats. Perindopril restored PDE activities and tended to improve ANP efficiency in MI rats. One month after coronary ligation, perindopril treatment of MI rats prevents the increase in renal cortical PDE activities. This may contribute to increase renal ANP efficiency in MI rats. PMID:25939307

  15. All-trans retinoic acid inhibited angiotensin Ⅱ-induced increase in cell growth and collagen secretion of neonatal cardiac fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Yan HE; Ying HUANG; Li ZHOU; Li-min LU; Yi-chun ZHU; Tai YAO

    2006-01-01

    Aim:To determine whether all-trans retinoic acid (atRA) acts to modulate angiotensin Ⅱ (Ang Ⅱ) -induced cardiac fibroblast cell growth and collagen secretion.Methods:Cultured neonatal rat cardiac fibroblasts (CF) were used in the experiment.A 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) assay was used to detect cell growth of the CF;and immunocytochemistry and Western blotting were used to measure the production and secretion of collagen and the expression of transforming growth factor-β1 (TGF-β1) by the CF.Results:atRA (1×10-7 to 1×10-5mol/L) inhibitedtheAngⅡ-induced increase in cell growth of CF (P<0.05).Ang Ⅱ stimulated the secretion of collagen types Ⅰ and Ⅲ by the CF. This eflfect was blocked by AT1 receptor antagonist losartan (1×10-6 mol/L) ,but notbyAT2 receptorantagonistPDl23319 (upto 1×10-6mol/L).Exposure of CF to atRA (1×10-5mol/L) attenuated the Ang Ⅱ-induced increase in the secretion of collagen types I and Ⅲ (P<0.05).atRA (1×10-5mol/L) also blocked the Ang Ⅱ-induced increase in the expression of TGF-β1.Conclusion:atRA inhibits the Ang Ⅱ-induced increase in cell growth and collagen secretion of neonatal rat CF.The effect of atRA is possibly mediated by lowering the TGF-β1 level.These observations support the notion that atRA is a potential candidate for the prevention and therapy of cardiac remodeling.

  16. Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity

    Science.gov (United States)

    Blanke, Katja; Schlegel, Franziska; Raasch, Walter; Bader, Michael; Dähnert, Ingo; Dhein, Stefan; Salameh, Aida

    2015-01-01

    Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats. Methods:Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically. Results:After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7). Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function. PMID:26733884

  17. 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; Zappe, Dion H; Meng, Xiangyi; Parving, Hans-Henrik

    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 i...

  18. 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

    2007-01-01

    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 tot

  19. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring

    Science.gov (United States)

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  20. 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.

  1. Effect of post-myocardial infarction exercise training on the renin-angiotensin-aldosterone system and cardiac function.

    Science.gov (United States)

    Wan, Wenhan; Powers, Anthony S; Li, Ji; Ji, Lisa; Erikson, John M; Zhang, John Q

    2007-10-01

    After a myocardial infarction (MI), the injured heart undergoes intensive remodeling characterized by activation of the circulating renin-angiotensin-aldosterone system (RAAS), left ventricular (LV) dilation, and contractile dysfunction. Exercise training may attenuate activation of the RAAS and improve myocardial remodeling. In this study, we investigated whether starting exercise training early or late after MI would have different effect on circulating RAAS and LV dilation and function. Male Sprague-Dawley rats (7 weeks old) underwent surgically induced MI. After surgery, rats were matched for similar infarct sizes and assigned into two major groups, based on the designated starting time of exercise training. Exercise groups started exercise at either 1 or 6 weeks after MI and exercised on a treadmill for 8 weeks. Groups starting exercise 1 week after MI included sham-operated control (1Wk-Sham), MI-ksedentary (1Wk-MI-Sed), and MI-exercise (1Wk-MI-Ex). Groups starting exercise 6 weeks after MI included sham-operated control (6Wk-Sham), MI-sedentary (6Wk-MI-Sed), and MI-exercise (6Wk-MI-Ex). An echocardiogram was performed before and after exercise training. Blood samples were obtained at the end of experiments. The results showed that compared with sedentary rats with MI, exercise training significantly attenuated circulating renin, angiotensin converting enzyme, angiotensin II, and aldosterone. Rats in exercise groups had similar LV end-diastolic diameters compared with their sedentary counterparts and tended to have smaller LV end-systolic diameters, and percent fractional shortening in exercise rats was significantly higher than in sedentary rats. These findings suggest that exercise training does not cause LV dilation and preserves LV function. Post-MI exercise training also normalizes the circulating RAAS, and this effect is independent of timing of post-MI exercise. Exercise starting early or late after MI affects myocardial remodeling and function

  2. Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis

    DEFF Research Database (Denmark)

    Dalsgaard, Morten; Iversen, Kasper; Kjaergaard, Jesper;

    2014-01-01

    of 8 weeks, when exercise echocardiography was repeated. RESULTS: Compared with placebo, systolic blood pressure and systemic arterial compliance significantly changed at day 3 (-14 ± 11 vs -5 ± 13 mm Hg, P = .02, and 0.08 ± 0.16 vs -0.05 ± 0.86 mL/m(2) per mm Hg, P = .03, respectively). Changes in...

  3. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants.

    Science.gov (United States)

    Lacaille-Dubois; Franck, U; Wagner, H

    2001-01-01

    MeOH extracts, fractions and pure substances from Musanga cecropioides, Cecropia species and Crataegus oxyacantha /C. monogyna were screened by using an in vitro bio-assay based on the inhibition of Angiotensin Converting Enzyme (ACE), as measured from the enzymatic cleavage of the chromophore-fluorophore-labelled substrate dansyltriglycine into dansylglycine and diglycine. Phenolic acids showed no significant ACE-inhibition whereas flavonoids and proanthocyanidins demonstrated inhibitory activity at 0.33 mg/ml using this test system. PMID:11292239

  4. Grape-derived polyphenols improve aging-related endothelial dysfunction in rat mesenteric artery: role of oxidative stress and the angiotensin system.

    Directory of Open Access Journals (Sweden)

    Noureddine Idris Khodja

    Full Text Available Aging is characterized by the development of an endothelial dysfunction, which affects both the nitric oxide (NO- and the endothelium-derived hyperpolarizing factor (EDHF-mediated relaxations, associated with vascular oxidative stress and the activation of the angiotensin system. This study investigated whether red wine polyphenols (RWPs, antioxidants and potent stimulators of NO- and EDHF-mediated relaxations improve aging-related endothelial dysfunction, and, if so, examined the underlying mechanism. Mesenteric artery reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine and MitoSOX staining, and expression of target proteins by immunohistochemical staining. Control young rats (16 weeks received solvent (ethanol, 3% v/v, and middle-aged rats (46 weeks either solvent or RWPs (100 mg/kg/day in the drinking water. The acetylcholine-induced endothelium-dependent NO component was slightly reduced whereas the EDHF component was markedly blunted in rings of middle-aged rats compared to young rats. The endothelial dysfunction was associated with oxidative stress, an upregulation of angiotensin II and AT1 receptors and a down-regulation of SK(Ca, IK(Ca, and angiotensin converting enzyme. Intake of RWPs for either one or two weeks improved the NO and the EDHF components of the relaxation, and normalized oxidative stress, the expression of SK(Ca, IK(Ca and the components of the angiotensin system. The protective effect of the 2-week RWPs treatment persisted for one and two weeks following stopping intake of RWPs. Thus, intake of RWPs caused a persistent improvement of the endothelial function, particularly the EDHF component, in middle-aged rats and this effect seems to involve the normalization of the expression of SK(Ca, IK(Ca and the angiotensin system.

  5. A systematic review on randomized control trials on rennin angiotensin aldosterone system inhibitors role in managing hypertension among hemodialysis patients.

    Science.gov (United States)

    Aftab, Raja Ahsan; Khan, Amer Hayat; Adnan, Azreen Syazril; Jannah, Nurul

    2016-01-01

    Randomized control trials (RCTs) are considered as most rigors way of determining the cause-effect relationship of a treatment and outcome. Activation of rennin angiotensin aldosterone system (RAAS) is an important contributor to hypertension in hemodialysis patients. The prevalence of hypertension in hemodialysis patients varies from 60% to 80% and hypertension management alone with conventional hemodialysis is insufficient. Hence, the current review was aimed to investigate the effect of RAAS inhibitors in managing hypertension among hemodialysis patients in a randomized control trial. Using PUBMED and EMBASE databases, randomized control trial with primary or secondary outcomes related to the effect of RAAS inhibitors on blood pressure among hemodialysis patients were included for analysis. The current review also assessed the quality of reporting of RCT. A total of eight RCT met inclusion criteria for current review. According to modified jaded scale, one (12.5%) study scored four points for quality reporting, whereas two (25%) studies scored one point that was the least score. The mean score for all included studies was 2.25. Six (75%) of the eight RCT included, involved ARB in hypertension management among hemodialysis patients, whereas two (25%) studies involved angiotensin-converting enzyme (ACE) inhibitors. Of the siz RCT involving ARB, two (33.3%) RCT also included ACE inhibitors comparison group. Altogether six (75%) studies report a reduction in blood pressure with the use of RAAS inhibitors compared to control group; however, of the six studies, two (33.3%) reported that the reduction in blood pressure was not significant. Whereas, two (25%) studies reported no reduction in blood pressure compared to the control group. The findings from current review do not indicate a clear pattern for a role of RAAS inhibitors for hypertension control among hemodialysis patients. PMID:26853680

  6. Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats.

    Science.gov (United States)

    Kim, Yang Gyun; Lee, Sang Ho; Kim, Se-Yun; Lee, Arah; Moon, Ju Young; Jeong, Kyung-Hwan; Lee, Tae Won; Lim, Sung Jig; Sohn, Il Suk; Ihm, Chun-Gyoo

    2016-07-01

    The intrarenal renin-angiotensin system (RAS) has an important role in generating and maintaining hypertension in two-kidney, one-clip (2K1C) rats. This study evaluated how various intrarenal RAS components contributed to hypertension not only in the maintenance period (5w; 5 wk after operation) but also earlier (2w; 2 wk after operation). We inserted a 2.5-mm clip into the left renal artery of Sprague-Dawley rats and euthanized them at 2w and 5w following the operation. Systolic blood pressure increased within 1 wk after the operation, and left ventricular hypertrophy occurred in 2K1C rats. At 2w, juxtaglomerular apparatus (JGA) and collecting duct (CD) renin increased in clipped kidney (CK) of 2K1C rats. The tubular angiotensin I-converting enzyme (ACE) was not changed, but peritubular ACE2 decreased in nonclipped kidney (NCK) and CK of 2K1C rats. At 5w, ACE and CD renin were enhanced, and ACE2 was still lessened in both kidneys of 2K1C rats. However, plasma renin activity (PRA) was not different from that in sham rats. In proximal tubules of CK, the ANG II type 1 receptor (AT1R) was not suppressed, but the Mas receptor (MasR) was reduced; thus the AT1R/MasR ratio was elevated. Although hypoxic change in CK could not be excluded, the JGA renin of CK and CD renin in both kidneys was highly expressed independent of time. Peritubular ACE2 changed in the earlier period, and uninhibited AT1R in proximal tubules of CK was presented in the maintenance period. In 2K1C rats, attenuated ACE2 seems to contribute to initiating hypertension while upregulated ACE in combination with unsuppressed AT1R may have a key role in maintaining hypertension. PMID:26823279

  7. Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition.

    Directory of Open Access Journals (Sweden)

    Chiao-Yin Sun

    Full Text Available BACKGROUND: Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin-angiotensin-aldosterone system (RAAS and renal tubular epithelial-to-mesenchymal transition (EMT in kidney fibrosis induced by (indoxyl sulfate IS and (p-cresol sulfate PCS. METHODS: Mouse proximal renal tubular cells (PKSV-PRs treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks. RESULTS: IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1 receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-β1 (TGF-β1 expression and activated the TGF-β pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo. CONCLUSION: Activating the renal RAAS/TGF-β pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.

  8. 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.

  9. Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

    OpenAIRE

    Venegas-Pont, Marcia; Mathis, Keisa W.; Iliescu, Radu; Ray, William H.; Glover, Porter H.; Ryan, Michael J.

    2011-01-01

    Inflammation and immune system dysfunction contributes to the development of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that carries a high risk for both renal and cardiovascular disease. While hemodynamic changes that may contribute to increased cardiovascular risk have been reported in humans and animal models of SLE, renal hemodynamics have not been widely studied. The renin-angiotensin system (RAS) plays a central rol...

  10. Effect of angiotensin-converting enzyme inhibition on functional class in patients with left ventricular systolic dysfunction--a meta-analysis

    DEFF Research Database (Denmark)

    Abdulla, Jawdat; Pogue, Janice; Abildstrøm, Steen Z;

    2005-01-01

    BACKGROUND: The effect of angiotensin converting enzyme (ACE) inhibitors on symptoms in patients with left ventricular systolic dysfunction (LVSD) is controversial. AIMS: To perform a meta-analysis of studies evaluating effect of ACE inhibitors on New York Heart Association (NYHA) class in patien...

  11. 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

  12. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action.

    Directory of Open Access Journals (Sweden)

    Hong Wang

    Full Text Available ACE inhibitors and ARBs (angiotensin receptor blockers have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I, an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p. that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia, and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA

  13. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

    Science.gov (United States)

    Wang, Hong; Sethi, Gautam; Loke, Weng-Keong; Sim, Meng-Kwoon

    2015-01-01

    ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely

  14. Upregulation of Renin-Angiotensin System in Bone Marrow Mesenchymal Stem Cells Under Hypoxia Conditions

    Institute of Scientific and Technical Information of China (English)

    XIAO Rong-rong; GAO Jing-hong; LI Qing-ping

    2014-01-01

    Objective:To investigate the expressions of AT1-R, AT2-R and angiotensin converting enzyme (ACE) in mesenchymal stem cells (MSCs) under hypoxia and serum deprivation condition. Methods:Bone MSCs were isolated, cultured and identiifed by anti-CD29 and anti-CD11b/c with flow cytometry. The ischemic injury model was established by exposing MSCs to hypoxia and serum deprivation (Hypoxia/SD). Cell viability and apoptotic rate were detected by trypan blue staining, CCK8 assays and Annexin V-FITC staining. The mRNA expressions of AT1-R, AT2-R and ACE were determined by Reverse Transcription-PCR and Real-time Quantitative PCR, The expression of AT1-R, AT2-R and ACE protein were measured by Western-blot. Results:MSCs expressed CD29, but not the CD11b/c. The purity of MSCs employed was up to 97%. The results of trypan blue staining along with CCK8 and Annexin V-FITC staining proved that the injury model induced by Hypoxia/SD was successfully established. MSCs under hypoxia and serum deprivation for 24 h induced a rapid increase in mRNA expression of AT1-R, AT2-R and ACE as well as their protein expressions. Conclusion:The local RAS in MSCs is activated by Hypoxia/SD stimulation and the mRNA and protein expressions of AT1-R, AT2-R and ACE are up-regulated.

  15. Polymorphisms of Renin-angiotensin System in Essential Hypertension in Chinese Tibetans

    Institute of Scientific and Technical Information of China (English)

    BEI SUN; TSERING DRONMA; WEI-JUN QIN; CHAO-YING CUI; DAN TSE; TASHI PINGTSO; YING LIU; CHANG-CHUN QIU

    2004-01-01

    Objective To evaluate the potential implications of the genetic variability of angiotensin converting enzyme, angiotensinogen and angiotensinⅡtype 1 receptor gene for essential hypertension in Tibetan. Methods A case-control study was conducted in 173 hypertensive individuals and 193 individuals with normal blood pressure. Multiple logistic regression analyses were used to estimate the risks of developing hypertension for different genotypes, and haplotype analyses of the angiotensinogen gene were used to determine the association between two-locus angiotensinogen gene polymorphisms and hypertension. Results As to the risk to high blood pressure and high systolic pressure, women with MM genotype were 7.7 (95% CI: 1.3-20.5) and 8.7 (95% CI: 1.8-20.1) times higher than those with TT genotype after adjustment for age and body mass index. Haplotype frequencies for M235T and G-6A were significantly different between hypertensive individuals and controls, which indicated an association of angiotensinogen gene haplotypes with hypertension, and a significant association of 235T/-6A haplotype with hypotensive effect. Conclusion Our results suggest that angiotensinogen gene 235MM is a predictor for hypertension development in Tibetan women but not in men, and may exert its hypertensive effect on linkage disequilibrum with a possible function locus of G-6A.

  16. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    OpenAIRE

    MacLean Charles D; Ramos-Nino Maria E; Littenberg Benjamin

    2008-01-01

    Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly sele...

  17. Effect of angiotensin II, catecholamines and glucocorticoid on corticotropin releasing factor (CRF-induced ACTH release in pituitary cell cultures.

    Directory of Open Access Journals (Sweden)

    Murakami,Kazuharu

    1984-08-01

    Full Text Available The effects of angiotensin II, catecholamines and glucocorticoid on CRF-induced ACTH release were examined using rat anterior pituitary cells in monolayer culture. Synthetic ovine CRF induced a significant ACTH release in this system. Angiotensin II produced an additive effect on CRF-induced ACTH release. The ACTH releasing activity of CRF was potentiated by epinephrine and norepinephrine. Dopamine itself at 0.03-30 ng/ml did not show any significant effect on ACTH release, but it inhibited CRF-induced ACTH release. Corticosterone at 10(-7 and 10(-6M inhibited CRF-induced ACTH release. These results indicate that angiotensin II, catecholamines and glucocorticoid modulate ACTH release at the pituitary level.

  18. p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling.

    Science.gov (United States)

    Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2016-09-01

    The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart. PMID:27486069

  19. Heparin inhibits Angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways

    OpenAIRE

    Xie-Zukauskas, Hui; Das, Jharna; Short, Billie Lou; Gutkind, J Silvio; Ray, Patricio E.

    2012-01-01

    Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistances arteries through modulating the Rho-A/Rho kinase pathway....

  20. Angiotensin and insulin resistance: conspiracy theory.

    Science.gov (United States)

    Townsend, Raymond R

    2003-04-01

    Resistance to the metabolic effects of insulin is a contender for the short list of major cardiovascular risk factors. Since the elements of the syndrome of insulin resistance were first articulated together in 1988, numerous epidemiologic investigations and treatment endeavors have established a relationship between the metabolic disarray of impaired insulin action and cardiovascular disease. Angiotensin II, the primary effector of the renin-angiotensin system, has also achieved a place in the chronicles of cardiovascular risk factors. Conspiracy mechanisms by which angiotensin II and insulin resistance interact in the pathogenesis of cardiovascular disease are reviewed, with particular attention to recent developments in this engaging area of human research. PMID:12642009

  1. Effects of the angiotensin type I receptor antagonist, losartan, on systemic and regional vascular responses to lower body negative pressure in healthy volunteers.

    OpenAIRE

    Duranteau, J; Pussard, E; Berdeaux, A; Giudicelli, J. F.

    1995-01-01

    1. The effects of a single oral dose (50 mg) of the angiotensin II AT1-receptor antagonist, losartan, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in nine healthy volunteers, in a double-blind, placebo-controlled crossover study. 2. Arterial blood pressure remained unchanged throughout the study. Three hours after its administration and before LBNP, losartan selectively increased renal bl...

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

    OpenAIRE

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

    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 cardiop...

  3. Angiotensin Converting Enzyme Activity in Alopecia Areata

    OpenAIRE

    Mohammad Reza Namazi; Armaghan Ashraf; Farhad Handjani; Ebrahim Eftekhar; Amir Kalafi

    2014-01-01

    Background. Alopecia areata (AA) is a chronic inflammatory disease of the hair follicle. The exact pathogenesis of AA remains unknown, although recent studies support a T-cell mediated autoimmune process. On the other hand, some studies have proposed that the renin-angiotensin-aldosterone system (RAAS) may play a role in autoimmunity. Therefore, we assessed serum activity of angiotensin converting enzyme (ACE), a component of this system, in AA. Methods. ACE activity was measured in the sera ...

  4. Renin-angiotensin system activity in vitamin D deficient, obese individuals with hypertension: An urban Indian study

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Kota

    2011-01-01

    Full Text Available Background: Elevated renin-angiotensin-aldosterone system (RAAS activity is an important mechanism in the development of hypertension. Both obesity and 25-hydroxy vitamin D [25(OHD] deficiency have been associated with hypertension and augmented renin-angiotensin system (RAS activity. We tried to test the hypothesis that vitamin D deficiency and obesity are associated with increased RAS activity in Indian patients with hypertension. Materials and Methods: Fifty newly detected hypertensive patients were screened. Patients with secondary hypertension, chronic kidney disease, or coronary artery disease were excluded. Patients underwent measurement of vitamin D and plasma renin and plasma aldosterone concentrations. They were divided into three groups according to their baseline body mass index (BMI; normal <25 kg/m 2 , overweight 25-29.9 kg/m 2 and obese ≥30 kg/m 2 and 25(OHD levels (deficient <20 ng/ml, insufficient 20-29 ng/ml and optimal ≥30 ng/ml. Results: A total of 50 (male:female = 32:18 patients were included, with a mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m 2 and a mean 25(OHD concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure (SBP was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP was 100.2 ± 11.2 mm Hg. All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP] were significantly higher among individuals with lower 25(OHD levels. The P values for trends in SBP, DBP and MAP were 0.009, 0.01 and 0.007, respectively. Though all the three blood pressure parameters (SBP, DBP and MAP were higher among individuals with higher BMIs, they were not achieving statistical significance. Increasing trends in PRA and PAC were noticed with lower 25(OHD and higher BMI levels. Conclusion: Vitamin D deficiency and obesity are associated with stimulation of RAAS activity. Vitamin D supplementation along with weight loss may be studied as a therapeutic strategy to reduce tissue RAS

  5. Review: Novel roles of nuclear angiotensin receptors and signaling mechanisms

    OpenAIRE

    Gwathmey, TanYa M.; Alzayadneh, Ebaa M.; Karl D. Pendergrass; Chappell, Mark C.

    2011-01-01

    The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists is an effective therapy to attenuate hype...

  6. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  7. Neonatal ACE inhibition in rats interferes with lung development.

    OpenAIRE

    Lasaitiene, Daina; Chen, Yun; Nannmark, Ulf; Wollmer, Per; Friberg, Peter

    2004-01-01

    The renin-angiotensin system (RAS) is developmentally up-regulated and it is essential for kidney development in several species. Given the fact that the rat lung undergoes postnatal development, the mammalian lung possesses the highest angiotensin-converting enzyme (ACE) levels and ACE activity increases during the first weeks postpartum, we tested the hypothesis that ACE inhibition influences postnatal lung development. Rats were given the ACE inhibitor enalapril (10 mg kg-1) from 0 to 9 da...

  8. Proopiomelanocortin but not vasopressin or renin-angiotensin system induces resuscitative effects of central 5-HT1A activation in haemorrhagic shock in rats.

    Science.gov (United States)

    Sowa, P; Adamczyk-Sowa, M; Zwirska-Korczala, K; Pierzchala, K; Adamczyk, D; Paluch, Z; Misiolek, M

    2014-10-01

    The aim of this study was to determine the effectory mechanisms: vasopressin, renin-angiotensin system and proopiomelanocortin-derived peptides (POMC), partaking in the effects of serotonin through central serotonin 1A receptor (5-HT1A) receptors in haemorrhagic shock in rats. The study was conducted on male Wistar rats. All experimental procedures were carried out under full anaesthesia. The principal experiment included a 2 hour observation period in haemorrhagic shock. Drugs used - a selective 5-HT1A agonist 8-OH-DPAT (5 μg/5 μl); V1a receptor antagonist [β-mercapto-β, β-cyclo-pentamethylenepropionyl(1),O-me-Tyr(2),Arg(8)]AVP (10 μg/kg); angiotensin type I receptor antagonist (AT1) ZD7155 (0.5 mg/kg, i.v.); angiotensin-converting-enzyme inhibitor captopril (30 mg/kg, i.v.); melanocortin type 4 (MC4) receptor antagonist HS014 (5 μg, i.c.v.). There was no influence of ZD715, captopril or blocking of the V1a receptors on changes in the heart rate (HR), mean arterial pressure (MAP), peripheral blood flow or resistance caused by the central stimulation of 5-HT1A receptors (P≥0.05). However, selective blocking of central MC4 receptors caused a slight, but significant decrease in HR and MAP (Pvasopressin systems do not participate in these actions. PMID:25371525

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

    Institute of Scientific and Technical Information of China (English)

    Wei SHI; J Gary MESZAROS; Shao-ju ZENG; Ying-yu SUN; Ming-xue ZUO

    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 reninangiotensin system in rats.Methods:Adult male SD rats were randomly assigned into 4 groups,and trained on living low-sedentary (LLS,control),living lowtraining 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 regionspecific expression of renin-angiotensin system components.

  10. Local Renin-Angiotensin System in the Pancreas: The Significance of Changes by Chronic Hypoxia and Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Leung PS

    2001-01-01

    Full Text Available The circulating renin-angiotensin system (RAS plays an important role in the maintenance of blood pressure and fluid homeostasis. Recently, there has been a shift of emphasis from the circulating RAS to the local RAS in the regulation of individual tissue functions via a paracrine and/or autocrine mechanism. In fact, a local RAS has been proposed to be present in an array of tissues including the brain, heart, kidney and gonads. Our previous studies have provided solid evidence that several key elements of the RAS, notably angiotensinogen and renin, are present in the rat pancreas. The data support the existence of an intrinsic RAS in the pancreas and this local RAS may be important for the exocrine/endocrine functions of the pancreas. Interestingly, such a pancreatic RAS has been demonstrated to be markedly activated by experimental rat models of chronic hypoxia and acute pancreatitis. The activation of the pancreatic RAS by chronic hypoxia and experimental pancreatitis could play a role in the physiology and pathophysiology of the pancreas. The significant changes of pancreatic RAS may have clinical relevance to acute pancreatitis and hypoxia-induced injury in the pancreas.

  11. 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

    Brain-derived natriuretic peptide (BNP) is a cardioprotective peptide released, together with the inactive NH2-terminal part of its prohormone (NT-pro-BNP), in response to different kinds of myocardial stress. Hypoglycemia and hypoxemia are conditions that threaten cellular function and hence...... potentially stimulate BNP release. BNP interacts with the renin-angiotensin system (RAS). The aim of this study was, therefore, to explore if basal RAS activity has an impact on NT-pro-BNP concentrations during myocardial stress induced by hypoglycemia and hypoxemia. From a cohort of 303 healthy young men, 10...... (mean nadir Po-2 5.8 +/- 0.5 kPa), and 3) normoglycemic normoxia (control). NT-pro-BNP was measured at baseline, during the stimuli, and in the recovery phase. Hypoxemia was associated with a 9% increase in NT-pro-BNP from 2.2 +/- 1.5 pmol/l at baseline to 2.4 +/- 1.5 pmol/l during hypoxemia (P

  12. 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.

  13. High Order Gene-Gene Interactions in Eight Single Nucleotide Polymorphisms of Renin-Angiotensin System Genes for Hypertension Association Study

    Directory of Open Access Journals (Sweden)

    Cheng-Hong Yang

    2015-01-01

    Full Text Available Several single nucleotide polymorphisms (SNPs of renin-angiotensin system (RAS genes are associated with hypertension (HT but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR for multiloci genotypes to detect high order gene-gene (SNP-SNP interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen, AGT; angiotensin-converting enzyme, ACE; angiotensin II type 1 receptor, AT1R in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs of AGT and ACE genes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI 1.26~6.21; P<0.005. In 7- and 8-locus model, SNP A1166C of AT1R gene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29; P<1.63E−08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models. AGT, ACE, and AT1R genes have overall effects with susceptibility to hypertension, where the SNPs of ACE have a mainly hypertension-associated effect and show an interacting effect to SNPs of AGT and AT1R genes.

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

    OpenAIRE

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

    2015-01-01

    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. Re...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-01-01

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

  16. In vitro angiotensin I converting enzyme inhibition by a peptide isolated from Chiropsalmus quadrigatus Haeckel (box jellyfish) venom hydrolysate.

    Science.gov (United States)

    So, Pamela Berilyn T; Rubio, Peter; Lirio, Stephen; Macabeo, Allan Patrick; Huang, Hsi-Ya; Corpuz, Mary Jho-Anne T; Villaflores, Oliver B

    2016-09-01

    The anti-angiotensin I converting enzyme activity of box jellyfish, Chiropsalmus quadrigatus Haeckel venom hydrolysate was studied. The venom extract was obtained by centrifugation and ultrasonication. Protein concentration of 12.99 μg/mL was determined using Bradford assay. The pepsin and papain hydrolysate was tested for its toxicity by Limit test following the OECD Guideline 425 using 5 female Sprague-Dawley rats. Results showed that the hydrolysate is nontoxic with an LD50 above 2000 mg/kg. In vitro angiotensin I converting enzyme (ACE) inhibitory activity was determined using ACE kit-WST. Isolation of ACE inhibitory peptides using column chromatography with SP-Sephadex G-25 yielded 8 pooled fractions with fraction 3 (86.5%) exhibiting the highest activity. This was followed by reverse phase - high performance liquid chromatography (RP-HPLC) with an octadecyl silica column (Inertsil ODS-3) using methanol:water 15:85 at a flow rate of 1.0 mL/min. Among the 13 fractions separated with the RP-HPLC, fraction 3.5 exhibited the highest ACE inhibitory activity (84.1%). The peptide sequence ACPGPNPGRP (IC50 2.03 μM) from fraction 3.5 was identified using Matrix-assisted laser desorption/ionization with time-of-flight tandem mass spectroscopy analysis (MALDI-TOF/MS). PMID:27163886

  17. Angiotensin processing activities in the venom of Thalassophryne nattereri.

    Science.gov (United States)

    Tenório, Humberto de Araújo; Marques, Maria Elizabeth da Costa; Machado, Sonia Salgueiro; Pereira, Hugo Juarez Vieira

    2015-05-01

    The venom of marine animals is a rich source of compounds with remarkable functional specificity and diversity. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. This venom presents characterized components such as proteases (Natterins 1-4) and a lectin (Nattectin) with complex effects on the human organism. A specific inhibitor of tissue kallikrein (TKI) reduces the nociception and the edema caused by the venom in mice. Our study sought to investigate the proteolytic activities against vasopeptides Angiotensin I, Angiotensin II, Angiotensin 1-9 and Bradykinin. The venom indicated angiotensin conversion against angiotensin I, as well as kininase against bradykinin. Captopril conducted the total inhibition of the converting activity, featuring the first report of ACE activity in fish venoms. PMID:25702959

  18. Uptake and metabolism of the novel peptide angiotensin-(1-12 by neonatal cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Sarfaraz Ahmad

    Full Text Available BACKGROUND: Angiotensin-(1-12 [Ang-(1-12] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7 by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12 is incorporated by neonatal cardiac myocytes and the enzymatic pathways of ¹²⁵I-Ang-(1-12 metabolism in the cardiac myocyte medium from WKY and SHR rats. METHODOLOGY/PRINCIPAL FINDINGS: The degradation of ¹²⁵I-Ang-(1-12 (1 nmol/L in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of ¹²⁵I-Ang-(1-12 by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12 was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS enzymes inhibitors the hydrolysis of labeled Ang-(1-12 and the subsequent generation of smaller Ang peptides from Ang-(1-12 was significantly greater in SHR compared to WKY controls. ¹²⁵I-Ang-(1-12 degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12 in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR. CONCLUSIONS/SIGNIFICANCE: These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12 and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides.

  19. The predictability of renin-angiotensin-aldosterone system factors for clinical outcome in patients with acute decompensated heart failure.

    Science.gov (United States)

    Nakada, Yasuki; Takahama, Hiroyuki; Kanzaki, Hideaki; Sugano, Yasuo; Hasegawa, Takuya; Ohara, Takahiro; Amaki, Makoto; Funada, Akira; Yoshida, Akemi; Yasuda, Satoshi; Ogawa, Hisao; Anzai, Toshihisa

    2016-06-01

    Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events. PMID:25964073

  20. Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

    International Nuclear Information System (INIS)

    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

  1. 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.

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

    DEFF Research Database (Denmark)

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel;

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R......) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even....... Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual...

  3. Renin-angiotensin system and diabetic encephalopathy%肾素-血管紧张素系统与糖尿病脑病

    Institute of Scientific and Technical Information of China (English)

    张栋珉; 肖谦

    2008-01-01

    Renin-angiotensin system(RAS) is an important endocrine system in the body.Classical,well-defined actions of RAS in the body is the regulation of blood pressure and the balance of water aml electrolyte.However, RAS has additionally been implicated in some cognitive functions, such as Learning and memory.Furthermore, RAS plays an important role in the pathogenesis of diabetic eneephalupathy.For exampie, Ang Ⅱ inhibits acetylcholine release and long-term potentiation(LTP), impairs insulin signaLing,activates oxidative stress and reduces cerebral blood flow; Ang Ⅳ can enhance LTP and acetylcholine release;Ang-(1-7) enhances LTP and increases the blood flow of brain.These findings bring us new hope for the prevention and treatment of diabetic encephalopalhy.%肾素-血管紧张素系统是体内重要的内分泌系统之一,通常认为其功能主要是调节血压和保持水电解质平衡.但近年的研究证实该系统还参与学习、记忆等认知功能的调节,并在糖尿病脑病的发病过程中发挥重要作用.例如:血管紧张素(Ang)Ⅱ可以抑制乙酰胆碱的释放、抑制长时程增强(LTP)的诱导、干扰胰岛素的信号转导、激活体内的氧化应激以及减少中枢的血供;AngⅣ可以促进乙酰胆碱的释放,易化LTP;Ang-(1-7)可以易化LTP,还能改善中枢血流.这些发现为糖尿病脑病的防治提供了新思路.

  4. 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; Parving, H-H; Remuzzi, G; Dwyer, J; Vemer, P; de Zeeuw, D; Lambers Heerspink, H J

    2016-01-01

    the BENEDICT, IRMA-2, RENAAL and IDNT trials that assessed effects of RAS intervention in patients with type 2 diabetes. We built a model with discrete disease stages based on albuminuria and estimated glomerular filtration rate (eGFR). Using survival analyses, we assessed the effect of RAS......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...

  5. Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.

    Science.gov (United States)

    Weir, Matthew R; Bakris, George L; Gross, Coleman; Mayo, Martha R; Garza, Dahlia; Stasiv, Yuri; Yuan, Jinwei; Berman, Lance; Williams, Gordon H

    2016-09-01

    Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1-6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (-1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (-5.64 ± 1.04 mm Hg/-3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (-203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (-0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (-6.70 ± 1.59/-2.15 ± 1.06 mm Hg), whereas those on placebo did not (-1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (-3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors. PMID:27350174

  6. Angiotensin II type 1 receptors and systemic hemodynamic and renal responses to stress and altered blood volume in conscious rabbits

    Directory of Open Access Journals (Sweden)

    RogerGeorgeEvans

    2011-07-01

    Full Text Available We examined how systemic blockade of type 1 angiotensin (AT1- receptors affects reflex control of the circulation and the kidney. In conscious rabbits, the effects of candesartan on responses of systemic and renal hemodynamics and renal excretory function to acute hypoxia, mild hemorrhage and plasma volume expansion were tested. Candesartan reduced resting mean arterial pressure (MAP, -8 ± 2% without significantly altering cardiac output (CO, increased renal blood flow (RBF, +38 ± 9% and reduced renal vascular resistance (RVR, -32 ± 6%. Glomerular filtration rate (GFR was not significantly altered but sodium excretion (UNa+V increased four-fold. After vehicle treatment, hypoxia (10% inspired O2 for 30 min did not significantly alter MAP or CO, but reduced HR (-17 ± 6%, increased RVR (+33 ± 16% and reduced GFR (-46 ± 16% and UNa+V (-41 ± 17%. Candesartan did not significantly alter these responses. After vehicle treatment, plasma volume expansion increased CO (+35 ± 7%, reduced total peripheral resistance (TPR, -26 ± 5%, increased RBF (+62 ± 23% and reduced RVR (-32 ± 9%, but did not significantly alter MAP or HR. It also increased UNa+V (803 ± 184% yet reduced GFR (-47 ± 9%. Candesartan did not significantly alter these responses. After vehicle treatment, mild hemorrhage did not significantly alter MAP but increased HR (+16 ± 3%, reduced CO (-16 ± 4% and RBF (-18 ± 6%, increased TPR (+18 ± 4% and tended to increase RVR (+18 ± 9%, P = 0.1, but had little effect on GFR or UNa+V. But after candesartan treatment MAP fell during hemorrhage (-19 ± 1%, while neither TPR nor RVR increased, and GFR (-64 ± 18% and UNa+V (-83 ± 10% fell. AT1-receptor activation supports MAP and GFR during hypovolemia. But AT1-receptors appear to play little role in the renal vasoconstriction, hypofiltration and antinatriuresis accompanying hypoxia, or the systemic and renal vasodilatation and natriuresis accompanying plasma volume expansion.

  7. Angiotensin II receptor alterations during pregnancy in rabbits

    International Nuclear Information System (INIS)

    Despite activation of the renin-angiotensin system during pregnancy, renal and peripheral vascular blood flows increase, and the systemic blood pressure and the pressor response to exogenous angiotensin II (Ang II) fall. Gestational alterations in Ang II receptors could contribute to these changes. Ang II binding parameters were determining utilizing 125I-Ang II in vascular (glomeruli and mesenteric arteries) and nonvascular (adrenal glomerulosa) tissues from 24- to 28-day pregnant rabbits. Comparisons were made utilizing tissues from nonpregnant rabbits. Binding site concentrations (N) and dissociation constants (K/sub d/) were obtained by Scatchard analyses of binding inhibition data. Meclofenamate (M) inhibits prostaglandin synthesis, reduces plasma renin activity, and enhances the pressor response to infused Ang II in pregnant rabbits. Administration of M to pregnant rabbits increased N in glomerular and in mesenteric artery membranes. These data demonstrate that Ang II receptors in glomeruli and mesenteric arteries are down regulated during gestation in rabbits. Elevated endogenous Ang II during pregnancy in rabbits may contribute to the down regulation of vascular Ang II receptors

  8. 苹果多酚提取物对血管紧张素转化酶活性的抑制%Inhibition of Angiotensin Converting Enzyme Activity by Apple Polyphenols

    Institute of Scientific and Technical Information of China (English)

    王艺璇; 王世平; 马丽艳

    2012-01-01

    In order to research the effect of apple polyphenols of different variety and maturity on angiotensin converting enzyme activity, HPLC method was established for the analysis of ACE inhibitory activity by apple polyphenols. Effect of variety ('Fuji' and 'Rails') and maturity on the inhibition of ACE activity was studied in this research. The results showed that, when the concentration of apple polyphenols were at the range of 1-250 μg/mL, the inhibition of ACE activity by four groups of unripe 'Fuji', ripe 'Fuji', unripe 'Rails', ripe 'Rails' were more and more stronger. And IG50 value of unripe 'Fuji' apple polyphenols and ripe 'Rails' apple polyphenols were 16.9, 80.8 μg/mL, respectively. We could get the conclusion that unripe apple polyphenols had the best effect on the inhibition of ACE activity, and could be used as nature sources of ACE inhibitors.%为研究不同品种、成熟度的苹果多酚对血管紧张素转化酶(angiotensin converting enzyme,ACE)活性的影响,确立高效液相色谱法(HPLC)测定苹果多酚对血管紧张素转化酶(ACE)活性抑制的检测方法.选取‘富士’、‘国光’2个品种、2个成熟度的苹果多酚提取物作为实验材料,研究其对ACE活性的抑制.实验结果表明,多酚浓度在1~250 μg/mL范围时,未成熟‘富士’、成熟‘富士’、未成熟‘国光’、成熟‘国光’的苹果多酚对ACE活性的抑制逐渐增强,其中未成熟‘富士’多酚提取物的半抑制率浓度IC50值最低,成熟‘国光’的IC50值最高,分别为16.9、80.8 μg/mL.由以上结果得出,未成熟‘富士’的苹果多酚对ACE活性的抑制作用最强,可以作为天然优良的ACE活性抑制剂.

  9. Upregulation of the Renin-Angiotensin-Aldosterone-Ouabain System in the Brain Is the Core Mechanism in the Genesis of All Types of Hypertension

    Directory of Open Access Journals (Sweden)

    Hakuo Takahashi

    2012-01-01

    Full Text Available Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease blood pressure in resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered. These findings promoted the concept that the central nervous system may actually be involved in the pathogenesis of essential hypertension, which is closely associated with excess sodium intake. We have demonstrated that endogenous digitalis plays a key role in hypertension associated with excess sodium intake via sympathetic activation in rats. Increased sodium concentration inside the brain activates epithelial sodium channels and the renin-angiotensin-aldosterone system in the brain. Aldosterone releases ouabain from neurons in the paraventricular nucleus in the hypothalamus. Angiotensin II and aldosterone of peripheral origin reach the brain to augment sympathetic outflow. Collectively essential hypertension associated with excess sodium intake and obesity, renovascular hypertension, and primary aldosteronism and pseudoaldosteronism all seem to have a common cause originating from the central nervous system.

  10. Medullary Endocannabinoids Contribute to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression

    Science.gov (United States)

    Schaich, Chris L.; Grabenauer, Megan; Thomas, Brian F.; Shaltout, Hossam A.; Gallagher, Patricia E.; Howlett, Allyn C.; Diz, Debra I.

    2016-01-01

    CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS. PMID:27375489

  11. Medullary Endocannabinoids Contribute to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression.

    Science.gov (United States)

    Schaich, Chris L; Grabenauer, Megan; Thomas, Brian F; Shaltout, Hossam A; Gallagher, Patricia E; Howlett, Allyn C; Diz, Debra I

    2016-01-01

    CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS. PMID:27375489

  12. 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...

  13. Gene Expression Profiling Following Maternal Deprivation: Involvement of the Brain Renin-Angiotensin System

    OpenAIRE

    Liebl, Claudia; Panhuysen, Markus; Pütz, Benno; Trümbach, Dietrich; Wurst, Wolfgang; Deussing, Jan M.; Müller, Marianne B.; Schmidt, Mathias V.

    2009-01-01

    The postnatal development of the mouse is characterized by a stress hypo-responsive 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 paraventricu...

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

    OpenAIRE

    Wolfgang Wurst; Deussing, Jan M.

    2009-01-01

    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 paraventricul...

  15. Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression

    DEFF Research Database (Denmark)

    Dhamrait, Sukhbir S; Maubaret, Cecilia; Pedersen-Bjergaard, Ulrik;

    2016-01-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial...

  16. Effect of Beta Blockers and Renin-Angiotensin System Inhibitors on Survival in Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

    Science.gov (United States)

    Lee, Pil Hyung; Park, Gyung-Min; Kim, Young-Hak; Yun, Sung-Cheol; Chang, Mineok; Roh, Jae-Hyung; Yoon, Sung-Han; Ahn, Jung-Min; Park, Duk-Woo; Kang, Soo-Jin; Lee, Seung-Whan; Lee, Cheol Whan; Park, Seong-Wook; Park, Seung-Jung

    2016-03-01

    Because it remains uncertain whether β-blockers (BBs) and/or renin-angiotensin system inhibitors benefit a broad population of acute myocardial infarction (AMI) patients, we sought to evaluate the effectiveness of these drugs in improving survival for post-AMI patients who underwent a percutaneous coronary intervention (PCI).From the nationwide data of the South Korea National Health Insurance, 33,390 patients with a diagnosis of AMI who underwent a PCI between 2009 and 2013 and survived at least 30 days were included in this study. We evaluated the risk of all-cause death for patients treated with both BB and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor antagonist (ARB) (n = 16,280), only BB (n = 3683), and only ACEI/ARB (n = 9849), with the drug-untreated patients (n = 3578) as the reference.Over a median follow-up of 2.4 years, although treated patients displayed a trend toward improved survival, there were no significant differences in the adjusted risk of all-cause death when patients were treated with both drugs (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.70-1.06, P = 0.154), BB (HR 0.88, 95% CI 0.68-1.14, P = 0.325), or ACEI/ARB (HR 0.84, 95% CI 0.68-1.04, P = 0.111). No additional benefit was found for the combination therapy compared with either isolated BB (HR 0.98, 95% CI 0.80-1.21, P = 0.856) or ACEI/ARB (HR 1.03, 95% CI 0.89-1.19, P = 0.727) therapy.Treatment with BB and/or ACEI/ARB has limited effect on survival in unselected nonfatal AMI patients who undergo PCI. PMID:26962802

  17. Angiotensin system inhibitors and survival in patients with metastatic renal cell carcinoma treated with VEGF-targeted therapy: A pooled secondary analysis of clinical trials.

    Science.gov (United States)

    Sorich, Michael J; Kichenadasse, Ganessan; Rowland, Andrew; Woodman, Richard J; Mangoni, Arduino A

    2016-05-01

    Use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) has been reported to be associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with vascular endothelial growth factor-targeted therapies. This study was a secondary pooled analysis of two Phase III randomized controlled trials (RCTs) of patients with mRCC: NCT00334282 comparing pazopanib to placebo and NCT00720941 comparing pazopanib to sunitinib. ASI users were defined as patients using an ASI at baseline. Association with overall survival (OS; primary outcome) and progression-free survival (PFS) was evaluated using Cox proportional hazards regression. The association was adjusted in multivariable analysis for baseline systolic blood pressure (SBP), use of other antihypertensive drugs and prognostic factors comprising the Heng risk criteria for mRCC. Of 1,545 patients pooled from the two RCTs, 649 (42%) were using one or more antihypertensive drugs at baseline, 385 (59%) of which were using an ASI. In the multivariable analysis of patients using pazopanib or sunitinib, no significant association was observed between baseline ASI use and OS (hazard ratio [HR] 0.97 [95% confidence interval (CI) 0.80-1.18], p = 0.80) or PFS (HR 0.88 [95% CI 0.73-1.06], p = 0.17). Exploratory subgroup analysis of NCT00720941 highlighted that the effect of baseline ASI use on OS may differ between patients treated with sunitinib and pazopanib. In conclusion, use of ASIs at baseline was not a significant independent prognostic factor for improved survival in a pooled analysis of mRCC patients treated with pazopanib or sunitinib. PMID:26685869

  18. 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.

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-11

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

  1. Prospects for angiotensin receptor blockers in diabetic retinopathy

    DEFF Research Database (Denmark)

    Sjølie, Anne Katrin

    2007-01-01

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

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  3. Effects of steroids and angiotensin converting enzyme inhibition on circumferential strain in boys with Duchenne muscular dystrophy: a cross-sectional and longitudinal study utilizing cardiovascular magnetic resonance

    Directory of Open Access Journals (Sweden)

    Kinnett Kathi J

    2011-10-01

    Full Text Available Abstract Background Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI or angiotension receptor blocker (ARB on cardiovascular magnetic resonance (CMR derived circumferential strain (εcc. Methods We used CMR to assess effects of corticosteroids alone (Group A or in combination with ACEI or ARB (Group B on heart rate (HR, left ventricular ejection fraction (LVEF, mass (LVM, end diastolic volume (LVEDV and circumferential strain (εcc in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results. Results Patients in Group A (114 studies were younger than those in Group B (92 studies(10 ± 2.4 vs. 12.4 ± 3.2 years, p cc magnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004, age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, εcc worsened regardless of treatment group. Conclusions These results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.

  4. 20-Hydroxyeicosatetraenoic acid contributes to the inhibition of K+ channel activity and vasoconstrictor response to angiotensin II in rat renal microvessels.

    Directory of Open Access Journals (Sweden)

    Fan Fan

    Full Text Available The present study examined whether 20-hydroxyeicosatetraenoic acid (HETE contributes to the vasoconstrictor effect of angiotensin II (ANG II in renal microvessels by preventing activation of the large conductance Ca(2+-activated K(+ channel (KCa in vascular smooth muscle (VSM cells. ANG II increased the production of 20-HETE in rat renal microvessels. This response was attenuated by the 20-HETE synthesis inhibitors, 17-ODYA and HET0016, a phospholipase A2 inhibitor AACOF3, and the AT1 receptor blocker, Losartan, but not by the AT2 receptor blocker, PD123319. ANG II (10(-11 to 10(-6 M dose-dependently decreased the diameter of renal microvessels by 41 ± 5%. This effect was blocked by 17-ODYA. ANG II (10(-7 M did not alter KCa channel activity recorded from cell-attached patches on renal VSM cells under control conditions. However, it did reduce the NPo of the KCa channel by 93.4 ± 3.1% after the channels were activated by increasing intracellular calcium levels with ionomycin. The inhibitory effect of ANG II on KCa channel activity in the presence of ionomycin was attenuated by 17-ODYA, AACOF3, and the phospholipase C (PLC inhibitor U-73122. ANG II induced a peak followed by a steady-state increase in intracellular calcium concentration in renal VSM cells. 17-ODYA (10(-5 M had no effect on the peak response, but it blocked the steady-state increase. These results indicate that ANG II stimulates the formation of 20-HETE in rat renal microvessels via the AT1 receptor activation and that 20-HETE contributes to the vasoconstrictor response to ANG II by blocking activation of KCa channel and facilitating calcium entry.

  5. Controlled release and angiotensin-converting enzyme inhibition properties of an antihypertensive drug based on a perindopril erbumine-layered double hydroxide nanocomposite

    Directory of Open Access Journals (Sweden)

    Hussein Al Ali SH

    2012-04-01

    Full Text Available Samer Hasan Hussein Al Ali1, Mothanna Al-Qubaisi2, Mohd Zobir Hussein1,3, Maznah Ismail2,4, Zulkarnain Zainal1, Muhammad Nazrul Hakim51Department of Chemistry, Faculty of Science, 2Laboratory of Molecular Biomedicine, Institute of Bioscience, 3Advanced Materials and Nanotechnology Laboratory, Institute of Advanced Technology, 4Department of Nutrition and Dietetics, Faculty of Medicine and Health Science, 5Department of Biomedical Science, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor, MalaysiaBackground: The intercalation of perindopril erbumine into Zn/Al-NO3-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation.Results: Perindopril was intercalated into the interlayers and formed a well ordered, layered organic-inorganic nanocomposite. The basal spacing of the products was expanded to 21.7 Å and 19.9 Å by the ion-exchange and coprecipitation methods, respectively, in a bilayer and a monolayer arrangement, respectively. The release of perindopril from the nanocomposite synthesized by the coprecipitation method was slower than that of its counterpart synthesized by the ion-exchange method. The rate of release was governed by pseudo-second order kinetics. An in vitro antihypertensive assay showed that the intercalation process results in effectiveness similar to that of the antihypertensive properties of perindopril.Conclusion: Intercalated perindopril showed better thermal stability than its free counterpart. The resulting material showed sustained-release properties and can therefore be used as a controlled-release formulation.Keywords: perindopril erbumine, layered double hydroxides, ion-exchange, coprecipitation, sustained release, angiotensin-converting enzyme

  6. Angiotensin II during experimentally simulated central hypovolemia

    Directory of Open Access Journals (Sweden)

    Theo Walther Jensen

    2016-03-01

    Full Text Available Abstract:Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, like the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia.To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin-angiotensin system or its effect during simulated hypovolemia. 12 articles, using one of the three models, were included and showed a possible organ protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue.

  7. Angiotensin antagonists in the dog with chronic pericardial tamponade

    International Nuclear Information System (INIS)

    Assessing the role played by angiotensin in the pathogenesis and maintenance of the renal function and perfusion abnormalities dogs with chronic pericardial tamponade were used in the experiment as a stable model of chronic low output heart failure. The heptapeptide and octapeptide antagonist were used. The results of the experiments suggest that there is a role for angiotensin in the pathologenesis of congestive heart failure. The renin-angiotensin system was activated in the model. Plasma renin activity was elevated and increased further in response to angiotensin blockade. Under the experiment condition there was no evidence for a role for angiotensin in the maintenance of arterial blood pressure. But there was angiotensin-mediated renal vasoconstriction and a reduction in renal blood flow. Both analogues of angiotensin were able to antagonize this effect in similar fashion. Failure to achieve a natriuresis in response to angiotensin blockade may reflect the redistribution of blood flow that occured and suggests that additional factors are operative in this model. (APR)

  8. Angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Sørensen, P G; Rømer, F K; Cortes, D

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or...

  9. Responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system.

    Directory of Open Access Journals (Sweden)

    Mahmoud Alhaj Ali

    Full Text Available Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

  10. Effect of angiotensin Ⅱ receptor 1 antisense oligodoexynucleotides on physiological and pathophysiological growth of cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    Ying WANG; Jin-ming WANG; Shu-xun Yan; Ming-jiang LI; Jian-jun LI

    2004-01-01

    AIM: To evaluate the role of angiotensin Ⅱ receptor 1 antisense oligodexynucleotides (AT1R-AS-ODNs) on physiological and pathophysiological growth of cardiomyocytes from normotensive rats. METHODS: Cardiomyocytes were transfected with AT1R-AS-ODNs (200 nmol/L) followed by treatment with or without angiotensin Ⅱ (1 μmol/L).In situ hybridization and Western blot were used for AT1R mRNA and protein detection, respectively. c-Jun Nterminal protein kinase (JNK) activity was characterized by immune complex kinase assay. c-Jun protein expression was examined by immunocytochemistry. DNA content was detected by flow cytometric assay. Atrial natriuretic factor (ANF) expression was identified by radioimmunoassay. RESULTS: Treatment with AT1R-AS-ODNs for 24 h resulted in 51.2 % decrease in AT1R mRNA and 60.7 % in protein (P<0.05 vs control). However, the basal level of JNK activity, c-Jun protein expression, and DNA content were not altered by AT1R-AS treatment in absence of overactive hormonal system. After treatment with angiotensin Ⅱ for 30 min, both p46JNK and p54JNK were robustly activated. By 2 h, c-Jun protein expression was increased. By 24 h, angiotensin Ⅱ caused a marked increase both in G0/G1 and G2/M DNA content, and increased ANF expression by 1.8-fold. All these were inhibited by AT1R-AS-ODNs pretreatment. In contrast, sense sequence was ineffective. CONCLUSION: Decrease of AT1R expression by AS-ODNs did not interfere with normal growth, but protected cardiomyocytes from angiotensin Ⅱ-dependent pathophysiological growth.

  11. Cardiac remodelling and RAS inhibition.

    Science.gov (United States)

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  12. Assay of angiotensin I-converting enzyme-inhibiting activity based on the detection of 3-hydroxybutyrate with water-soluble tetrazolium salt.

    Science.gov (United States)

    Lam, Le Hoang; Shimamura, Tomoko; Manabe, Sachiyo; Ishiyama, Munetaka; Ukeda, Hiroyuki

    2008-08-01

    A newly synthesized substrate, 3-hydroxybutyrylglycyl-glycyl-glycine (3HB-GGG), was applied to the assay of ACE-inhibiting activity to overcome the smaller selectivity and sensitivity of the conventional method. In this study, an ACE-inhibiting assay was improved by the use of a water-soluble tetrazolium salt, 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt (WST-1), for the detection of 3-hydroxybutyrate, derived from 3HB-GGG. The optimized conditions were as follows: 0.333 mM NAD(+), 0.333 mM WST-1, 0.1 mM EDTA, 0.633 U ml(-1) diaphorase, and 0.700 U ml(-1) 3-hydroxybutyrate dehydrogenase. The developed assay was efficiently applicable to evaluate the ACE-inhibiting activity of practical ACE inhibitors. PMID:18689950

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

  14. Progress on relationship between renin-angiotensin system and skeletal muscle insulin resistance%肾素血管紧张素系统与骨骼肌胰岛素抵抗的关系

    Institute of Scientific and Technical Information of China (English)

    黄祺; 吴文君; 卜瑞芳

    2016-01-01

    Skeletal muscle is essential for the glucose disposal in organism, which is one of the major sites of insulin resistance.The over-activity of classical renin-angiotensin system ( RAS) induces the oxidative stress, leads to the impairment of insulin signaling and glucose transport, resulting in insulin resistance of skeleton muscle.The activation of non-classical RAS by inhibiting classical RAS activity, can ameliorate insulin resistance in skeletal muscle tissue.%骨骼肌是体内处理葡萄糖的重要组织,也是产生胰岛素抵抗的主要部位之一。经典的肾素血管紧张素系统( RAS)的过度激活会诱导氧化应激,导致骨骼肌胰岛素信号及葡萄糖转运活性受损,从而促进骨骼肌胰岛素抵抗的产生。通过抑制经典的RAS、激活非经典RAS,可以改善骨骼肌胰岛素抵抗。

  15. Renal effects of angiotensin II in the newborn period: role of type 1 and type 2 receptors

    OpenAIRE

    Vinturache, Angela E.; Francine G. Smith

    2016-01-01

    Background Evidence suggests a critical role for the renin-angiotensin system in regulating renal function during postnatal development. However, the physiological relevance of a highly elevated renin-angiotensin system early in life is not well understood, nor which angiotensin receptors might be involved. This study was designed to investigate the roles of angiotensin receptors type 1 (AT1R) and type 2 (AT2R) in regulating glomerular and tubular function during postnatal development. Method...

  16. 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

    potentials and hypoglycaemic symptoms were recorded. RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to......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 patients...... with low RAS activity. MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked...

  17. The Effect of Renin-Angiotensin-Aldosterone System Blockade Medications on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Zhijun Wu

    Full Text Available Contrast-induced nephropathy (CIN is the main complication of contrast media administration (CM in patients undergoing coronary angiography (CAG and percutaneous coronary intervention (PCI. There are inconsistent results in the literature regarding the effect of renin-angiotensin-aldosterone system (RAAS blockers (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs] on CIN. We evaluated the association between the administration of ACEI/ARBs and CIN, as well as the effect of ACEI/ARBs on post-procedural changes in renal function index, in patients undergoing CAG.We searched Pubmed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for relevant studies. The primary search generated 893 potentially relevant articles. A total of 879 studies were excluded because they did not meet the selection criteria. Finally, 14 studies were eligible for inclusion. There were 7,288 patients that received ACEI/ARBs and 8,159 patients that received placebo or naive to ACEI/ARBs in the study. A random or a fixed effect model was used to calculate the pooled odd ratios (ORs.The risk of CIN was significantly increased in the ACEI/ARBs group compared to the control group (OR= 1.50, 95%CI: 1.03-2.18, P =0.03. The magnitude of association was significantly reinforced in the observational studies (OR=1.84, 95%CI 1.19-2.85, P=0.006 but not in the randomized controlled trials (OR=0.88, 95%CI 0.41-1.90 P=0.74. The summary adjusted OR of 4 observational studies was 1.56 (95%CI 1.25-1.94, P<0.0001 and was weaker than the unadjusted OR.Although there is some evidence to suggest that the administration of RAAS blockers was associated with the increased risk of CIN in patients undergoing CAG, the robustness of our study remains weak. The results are based on small observational studies and need further validation.

  18. Antihypertensive effects of angiotensin-(1-7

    Directory of Open Access Journals (Sweden)

    M.C. Chappell

    1998-09-01

    Full Text Available Accumulating evidence suggests that angiotensin-(1-7 (Ang-(1-7 is an important component of the renin-angiotensin system and that the actions of the peptide may either contribute to or oppose those of Ang II. Ang-(1-7 can be converted directly from Ang I bypassing prerequisite formation of Ang II. Formation of Ang-(1-7 is under the control of at least three endopeptidases depending on the tissue compartment and include neprilysin, thimet oligopeptidase and prolyl oligopeptidase. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7 is an endogenous substrate for angiotensin converting enzyme. These enzymatic pathways may contribute to a complex relationship between the hypertensive actions of Ang II and various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. Ang-(1-7 is devoid of the vasoconstrictor, central pressor, or thirst-stimulating actions associated with Ang II. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, Ang-(1-7 may oppose the actions of Ang II directly or as a result of increasing prostaglandins or nitric oxide. In this review, we examine the mechanisms by which Ang-(1-7 may contribute to cardiovascular regulation.

  19. 12-Lipoxygenase Inhibition on Microalbuminuria in Type-1 and Type-2 Diabetes Is Associated with Changes of Glomerular Angiotensin II Type 1 Receptor Related to Insulin Resistance

    OpenAIRE

    Hong-Zhao Xu; Yan-Li Cheng; Wan-Ning Wang; Hao Wu; Yuan-Yuan Zhang; Chong-Sen Zang; Zhong-Gao Xu

    2016-01-01

    (1) Background: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) Methods: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription...

  20. Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    International Nuclear Information System (INIS)

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

  1. 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)

    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)

  2. Effect of exercise training on the renin-angiotensin-aldosterone system in healthy individuals: a systematic review and meta-analysis.

    Science.gov (United States)

    Goessler, Karla; Polito, Marcos; Cornelissen, Véronique Ann

    2016-03-01

    The aim of this systematic review and meta-analysis was to evaluate the effect of exercise training on parameters of the renin-angiotensin-aldosterone system (RAAS) in healthy adults, and to investigate the relation with training induced changes in blood pressure. A systematic search was conducted and we included randomized controlled trials lasting ⩾4 weeks investigating the effects of exercise on parameters of the RAAS in healthy adults (age ⩾18 years) and published in a peer-reviewed journal up to December 2013. Fixed effects models were used and data are reported as weighted means and 95% confidence limits (CL). Eleven randomized controlled trials with a total of 375 individuals were included. Plasma renin activity was reduced after exercise training (n= 7 trials, standardized mean difference -0.25 (95% CL -0.5 to -0.001), P=0.049), whereas no effect was observed on serum aldosterone ((n= 3 trials; standardized mean difference -0.79 (-1.97 to +0.39)) or angiotensin II (n=3 trials; standardized mean difference -0.16 (-0.61 to +0.30). Significant reductions in systolic blood pressure -5.65 mm Hg (-8.12 to -3.17) and diastolic blood pressure -3.64 mm Hg (-5.4 to -1.91) following exercise training were observed. No relation was found between net changes in plasma renin activity and net changes in blood pressure (P>0.05). To conclude, although we observed a significant reduction in plasma renin activity following exercise training this was not related to the observed blood pressure reduction. Given the small number of studies and small sample sizes, larger well-controlled randomized studies are required to confirm our results and to investigate the potential role of the RAAS in the observed improvements in blood pressure following exercise training. PMID:26399454

  3. The Angiotensin AT2 Receptor

    DEFF Research Database (Denmark)

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

    2015-01-01

    Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin......-angiotensin system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological...

  4. Angiotensin II Differentially Induces Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Production and Disturbs MMP/TIMP Balance

    OpenAIRE

    Yaghooti, Hamid; Firoozrai, Mohsen; Fallah, Soudabeh; Khorramizadeh, Mohammad Reza

    2010-01-01

    Angiotensin II, the main component of the renin-angiotensin system, is associated with cardiovascular diseases such as hypertension, vascular remodeling and inflammation. Remodeling process results from dysregulation of Matrix Metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). MMPs are considered as important target genes for angiotensin II. The aim of this study was to determine the effects of angiotensin II on MMP-9 and TIMP-1 production and MMP/TIMP balance in a monocytic cell ...

  5. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    Directory of Open Access Journals (Sweden)

    MacLean Charles D

    2008-12-01

    Full Text Available Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE. ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social (age, sex, alcohol drinking, cigarette smoking and clinical factors (systolic blood pressure, body mass index (BMI, glycosolated hemoglobin (A1C, number of comorbid conditions, and number of prescription medications. Results ACE users reported a history of any cancer (except the non-life-threatening skin cancers less frequently than non-users (10% vs. 15%; odd ratio = 0.59; 95% confidence interval [0.39, 0.89]; P = 0.01; and a history of stomach ulcers or peptic ulcer disease less frequently than non-users (12% vs. 16%, odd ratio = 0.70, [0.49, 1.01], P = 0.06. After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer (odds ratio = 0.59, [0.39, 0.89]; P = 0.01 and peptic ulcer disease (odd ratio = 0.68, [0.46, 1.00], P = 0.05. Conclusion ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid

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

    Science.gov (United States)

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

    2016-03-01

    Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses. PMID:25427952

  7. Role of the renin-angiotensin system in the regulation of intestinal blood flow and sympathetic neurotransmission

    International Nuclear Information System (INIS)

    The aims of the present studies were (1) to determine if endogenous angiotensin II (Ang II) plays a role in the local control of mesenteric blood flow (MBF) following volume depletion in anesthetized dogs, and (2) to investigate the mechanism(s) of actions of Ang II on the facilitation of sympathetic neurotransmission in the rate jejunum. To investigate the role of endogenous Ang II in the control of MBF, a dose of an antagonist of Ang II, saralasin, that has effects mainly localized to the mesenteric circulation was determined. The data demonstrated that blockage of actions of Ang II in the mesenteric circulation resulted in a decrease in intestinal vasoconstriction which occurred following acute hypotensive hemorrhage. The effect of Ang II on the uptake and release of norepinephrine from sympathetic nerve endings in the rat jejunum was investigated. The uptake of norepinephrine in rat jejunum was determined by incubating jejunal slices in Krebs buffer containing 0.01 μM 3H-norepinephrine. The accumulation of label in the tissue after 10 min incubation was determined by liquid scintillation spectrometry. Intracellular uptake of 3H-norepinephrine was calculated and shown to be an active process

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

    Science.gov (United States)

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

    2016-07-15

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

  9. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2008-01-01

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

  10. Angiotensin-converting enzymes modulate aphid–plant interactions

    OpenAIRE

    Wei Wang; Lan Luo; Hong Lu; Shaoliang Chen; Le Kang; Feng Cui

    2015-01-01

    Angiotensin-converting enzymes (ACEs) are key components of the renin–angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect–plant interaction. In this study, we showed that ACE modulates aphid–plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pis...

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

    DEFF Research Database (Denmark)

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

    1980-01-01

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

  12. Effects of angiotensin blockade on the splanchnic circulation in normotensive humans

    DEFF Research Database (Denmark)

    Stadeager, C; Hesse, B; Henriksen, O; Christensen, N J; Bonde-Petersen, F; Mehlsen, J; Giese, Jacob

    1989-01-01

    The effects of angiotensin-converting enzyme inhibition (ACE-I) by enalapril on splanchnic (n = 10) and central hemodynamics (n = 9) were examined in moderately salt-depleted healthy volunteers, at rest and during 15-20 min of lower body negative pressure (LBNP), reducing mean arterial pressure by...... levels during ACE-I. We conclude that, in normal sodium-depleted humans, acute ACE-I decreases splanchnic vascular resistance at rest and abolishes splanchnic vasoconstriction during LBNP. Furthermore, it may interfere with autonomic nervous system control of the circulation....

  13. Vasopressin and sympathetic system mediate the cardiovascular effects of the angiotensin II in the bed nucleus of the stria terminalis in rat.

    Science.gov (United States)

    Nasimi, Ali; Kafami, Marzieh

    2016-07-01

    The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. PMID:26820216

  14. Nonspecific Inhibition of the Motor System during Response Preparation

    OpenAIRE

    Greenhouse, Ian; Sias, Ana; Labruna, Ludovica; Ivry, Richard B

    2015-01-01

    Motor system excitability is transiently inhibited during the preparation of responses. Previous studies have attributed this inhibition to the operation of two mechanisms, one hypothesized to help resolve competition between alternative response options, and the other to prevent premature response initiation. By this view, inhibition should be restricted to task-relevant muscles. Although this prediction is supported in one previous study (Duque et al., 2010), studies of stopping ongoing act...

  15. Dietary t10,c12-CLA but not c9,t11 CLA Reduces Adipocyte Size in the Absence of Changes in the Adipose Renin–Angiotensin System in fa/fa Zucker Rats

    OpenAIRE

    DeClercq, Vanessa; Zahradka, Peter; Taylor, Carla G.

    2010-01-01

    In obesity, increased activity of the local renin–angiotensin system (RAS) and enlarged adipocytes with altered adipokine production are linked to the development of obesity-related health problems and cardiovascular disease. Mixtures of conjugated linoleic acid (CLA) isomers have been shown to reduce adipocyte size and alter the production of adipokines. The objective of this study was to investigate the effects of feeding individual CLA isomers on adipocyte size and adipokines associated wi...

  16. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study

    DEFF Research Database (Denmark)

    Krum, Henry; Massie, Barry; Abraham, William T;

    2011-01-01

    AIMS: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs......) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing Outcome...... plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril...

  17. 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.

  18. 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...

  19. Response Prediction and Influence of Tolvaptan in Chronic Heart Failure Patients Considering the Interaction of the Renin-Angiotensin-Aldosterone System and Arginine Vasopressin.

    Science.gov (United States)

    Kadota, Muneyuki; Ise, Takayuki; Yagi, Shusuke; Iwase, Takashi; Akaike, Masashi; Ueno, Rie; Kawabata, Yutaka; Hara, Tomoya; Ogasawara, Kozue; Bando, Mika; Bando, Sachiko; Matsuura, Tomomi; Yamaguchi, Koji; Yamada, Hirotsugu; Soeki, Takeshi; Wakatsuki, Tetsuzo; Sata, Masataka

    2016-07-27

    The renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP) regulate body fluids. Although conventional diuretics have been used for treating heart failure, they activate RAAS and exacerbate renal function. Tolvaptan, a newly developed vasopressin-2 receptor antagonist, elicits aquaresis and improves volume overload in heart failure patients, however, the predictors of tolvaptan effectiveness and the influence on the RAAS and renal function according to tolvaptan therapy are not established. We evaluated 26 chronic heart failure patients receiving therapy with 15 mg/day tolvaptan and examined their laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a body weight decrease by more than 2 kg in a week and a urine volume increase by 500 mL/ day compared with that before tolvaptan administration. Body weight, urine volume, and brain natriuretic peptide levels significantly improved (P < 0.05), without any worsening of renal function represented by serum creatinine, sodium, and potassium. Moreover, no significant changes were observed in the plasma renin activity and plasma aldosterone concentration (PAC). In the responder group, urine osmolality before tolvaptan administration was significantly higher (P < 0.05) but declined significantly after tolvaptan administration (P < 0.05). The AVP/PAC ratio before administration was positively correlated with the efficacy of tolvaptan. Tolvaptan treatment could prevent RAAS activation in chronic heart failure patients. Moreover, monitoring the AVP/PAC ratio may be useful in predicting the tolvaptan response. PMID:27357439

  20. MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS AS SIGNALLING MOLECULES OF INTRACELLULAR PATHWAYS TRIGGERED BY THE CARDIAC RENIN-ANGIOTENSIN II-ALDOSTERONE SYSTEM (RAAS.

    Directory of Open Access Journals (Sweden)

    Verónica Celeste De Giusti

    2013-05-01

    Full Text Available Mitochondria represent major sources of basal reactive oxygen species (ROS production of the cardiomyocyte. The role of ROS as signalling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1 and sodium/bicarbonate cotransporter (NBC via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

  1. Cardiovascular actions of angiotensin-(1-7

    Directory of Open Access Journals (Sweden)

    Ferreira A.J.

    2005-01-01

    Full Text Available Angiotensin-(1-7 (Ang-(1-7 is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7 are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Chronic administration of angiotensin-converting enzyme inhibitors (ACEI increases 10- to 25-fold the plasma levels of this peptide, suggesting that part of the beneficial effects of ACEI could be mediated by Ang-(1-7. Ang-(1-7 can be formed from Ang II or directly from Ang I. Other enzymatic pathways for Ang-(1-7 generation have been recently described involving the novel ACE homologue ACE2. This enzyme can form Ang-(1-7 from Ang II or less efficiently by the hydrolysis of Ang I to Ang-(1-9 with subsequent Ang-(1-7 formation. The biological relevance of Ang-(1-7 has been recently reinforced by the identification of its receptor, the G-protein-coupled receptor Mas. Heart and blood vessels are important targets for the formation and actions of Ang-(1-7. In this review we will discuss recent findings concerning the biological role of Ang-(1-7 in the heart and blood vessels, taking into account aspects related to its formation and effects on these tissues. In addition, we will discuss the potential of Ang-(1-7 and its receptor as a target for the development of new cardiovascular drugs.

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Rene Barro-Soria

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

  4. Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension

    Czech Academy of Sciences Publication Activity Database

    Neckář, Jan; Kopkan, L.; Husková, Z.; Kolář, František; Papoušek, František; Kramer, H. J.; Hwang, S.H.; Hammock, B.D.; Imig, J. D.; Malý, J.; Netuka, I.; Ošťádal, Bohuslav; Červenka, L.

    2012-01-01

    Roč. 122, č. 11 (2012), s. 513-525. ISSN 0143-5221 R&D Projects: GA AV ČR(CZ) IAAX01110901; GA AV ČR(CZ) KAN200520703; GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : hypertension * angiotensin II * kidney * epoxyeicosatrienoic acids * soluble epoxide hydrolase inhibitor * myocardial ischemia/reperfusion injury Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.859, year: 2012

  5. Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction

    DEFF Research Database (Denmark)

    Cechova, Sylvia; Zeng, Qing; Billaud, Marie;

    2013-01-01

    Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid...

  6. Human in vivo study of the renin-angiotensin-aldosterone system and the sympathetic activity after 8 weeks daily intake of fermented milk

    DEFF Research Database (Denmark)

    Usinger, Lotte; Ibsen, Hans; Linneberg, Allan;

    2010-01-01

    Milk fermented by lactic acid bacteria is suggested to have antihypertensive effect in humans. In vitro and animal studies have established an angiotensin-converting enzyme (ACE) inhibitor effect of peptides in fermented milk. However, other modes of action must be considered, because until today...

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

    DEFF Research Database (Denmark)

    Füchtbauer, L; Groth-Rasmussen, Maria; Holm, Thomas Hellesøe; Løbner, M; Toft-Hansen, Henrik; Khorooshi, Reza M. H.; Owens, T

    2011-01-01

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

  8. 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

  9. SARTANS AND ANGIOTENSIN CONVERTING ENZYME INHIBITORS: A DUEL BETWEEN TWO LEADERS OF PHARMACOTHERAPY OF CARDIOVASCULAR DISEASES

    OpenAIRE

    K. A. Gyamdzhyan; M. L. Maksimov

    2015-01-01

    Topical issues of cardiovascular disease pharmacotherapy influencing function of the renin-angiotensin-aldosterone system are discussed. Efficacy and safety of two major cardiovascular drug classes, angiotensin converting enzyme inhibitors and sartans, are compared. Data from evidence base of the both drug classes are presented.

  10. SARTANS AND ANGIOTENSIN CONVERTING ENZYME INHIBITORS: A DUEL BETWEEN TWO LEADERS OF PHARMACOTHERAPY OF CARDIOVASCULAR DISEASES

    Directory of Open Access Journals (Sweden)

    K. A. Gyamdzhyan

    2015-12-01

    Full Text Available Topical issues of cardiovascular disease pharmacotherapy influencing function of the renin-angiotensin-aldosterone system are discussed. Efficacy and safety of two major cardiovascular drug classes, angiotensin converting enzyme inhibitors and sartans, are compared. Data from evidence base of the both drug classes are presented.

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

    DEFF Research Database (Denmark)

    Hilliard, Lucinda M; Chow, Charis L E; Mirabito, Katrina M; Steckelings, Ulrike Muscha; Unger, Thomas; Widdop, Robert E; Denton, Kate M

    2014-01-01

    Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R stimul...

  12. Comparative Effects of Statin Therapy versus Renin-Angiotensin System Blocking Therapy in Patients with Ischemic Heart Failure Who Underwent Percutaneous Coronary Intervention

    Science.gov (United States)

    Won, Jumin; Jeong, Myung Ho; Park, Hyuk Jin; Kim, Min Chul; Kim, Woo Jin; Kim, Hyun Kuk; Sim, Doo Sun; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun

    2016-01-01

    Statins and renin-angiotensin system (RAS) blockers are key drugs for treating patients with an acute myocardial infarction (AMI). This study was designed to show the association between treatment with statins or RAS blockers and clinical outcomes and the efficacy of two drug combination therapies in patients with ischemic heart failure (IHF) who underwent revascularization for an AMI. A total of 804 AMI patients with a left ventricular ejection fraction <40% who undertook percutaneous coronary interventions (PCI) were analyzed using the Korea Acute Myocardial Infarction Registry (KAMIR). They were divided into four groups according to the use of medications [Group I: combination of statin and RAS blocker (n=611), Group II: statin alone (n=112), Group III: RAS blocker alone (n=53), Group IV: neither treatment (n=28)]. The cumulative incidence of major adverse cardiac and cerebrovascular events (MACCEs) and independent predictors of MACCEs were investigated. Over a median follow-up study of nearly 1 year, MACCEs had occurred in 48 patients (7.9%) in Group I, 16 patients (14.3%) in Group II, 3 patients (5.7%) in Group III, 7 patients (21.4%) in Group IV (p=0.013). Groups using RAS blocker (Group I and III) showed better clinical outcomes compared with the other groups. By multivariate analysis, use of RAS blockers was the most powerful independent predictor of MACCEs in patients with IHF who underwent PCI (odds ratio 0.469, 95% confidence interval 0.285-0.772; p=0.003), but statin therapy was not found to be an independent predictor. The use of RAS blockers, but not statins, was associated with better clinical outcomes in patients with IHF who underwent PCI. PMID:27231678

  13. Inhibition of Streptococcus mutans by the lactoperoxidase antimicrobial system.

    OpenAIRE

    Thomas, E L; Pera, K A; Smith, K W; Chwang, A K

    1983-01-01

    Inhibition of bacterial metabolism by the lactoperoxidase (LP)-hydrogen peroxide (H2O2)-thiocyanate system was studied with representatives of serotypes a through g of Streptococcus mutans. The aims were to determine whether the amount of H2O2 released from these catalase-negative bacteria is sufficient to activate the LP system and whether these oral bacteria are resistant to inhibition by the LP system, which is active in human saliva. When the washed, stationary-phase cells were incubated ...

  14. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

    Directory of Open Access Journals (Sweden)

    Shu Li

    2012-01-01

    Full Text Available The renin-angiotensin system (RAS plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B, one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN- induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I and α-smooth muscle actin (α-SMA production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β, and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.

  15. Fluoride inhibits the antimicrobial peroxidase systems in human whole saliva.

    Science.gov (United States)

    Hannuksela, S; Tenovuo, J; Roger, V; Lenander-Lumikari, M; Ekstrand, J

    1994-01-01

    Fluoride (F-) ions at concentrations present in vivo at the plaque/enamel interface (0.05-10 mM) inhibited the activities of lactoperoxidase (LP), myeloperoxidase (MP) and total salivary peroxidase (TSP) in a pH- and dose-dependent way. The inhibition was observed only at pH or = 0.1 mM. At pH 5.5 LP activity was inhibited by 85% and MP by 34% with 10 mM F-. TSP activity was also inhibited only at low pH (5.5) by approximately 25%. Furthermore, the generation of the actual antimicrobial agent in vivo, hypothiocyanite (HOSCN/OSCN-), of the oral peroxidase systems was inhibited by F-, again at low pH (5.0-5.5) both in buffer (by 45%) and in saliva (by 15%). This inhibition was observed only with the highest F- concentrations studied (5-10 mM). Fluoridated toothpaste (with 0.10 or 0.14% F) mixed with saliva did not inhibit TSP or HOSCN/OSCN- generation. This may have been due to the 'buffering' effect of toothpaste which did not allow salivary pH to drop below 5.9. We conclude that the F- ions in acidic fluoride products, e.g. in gels or varnishes (but not in toothpastes), may have the potential to locally inhibit the generation of a nonimmune host defense factor, HOSCN/OSCN/SCN-, produced by oral peroxidase systems. The possible clinical significance of this finding remains to be shown. PMID:7850846

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-02-10

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

  17. How should renin-angiotensin system blockade be applied in chronic kidney disease for optimal renal protection?

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xun; HOU Fan-fan

    2007-01-01

    @@ Chronic kidney disease (CKD) is a significant interactive disease in patients with diabetes,hypertension, and cardiovascular disease with major morbidity and mortality consequences and high costs to the healthcare system.1 CKD is characterized by a gradual loss of renal function.

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

    OpenAIRE

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

    2000-01-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT1 receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left...

  19. 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.

  20. Direct proof for local generation and release of angiotensin II in peripheral human vascular tissue.

    Science.gov (United States)

    Mizuno, K; Niimura, S; Tani, M; Haga, H; Inagami, T; Fukuchii, S

    1991-01-01

    Previously we reported that immunoreactive angiotensin II (Ang II) release from isolated perfused human umbilical veins was inhibited by the angiotensin-converting enzyme inhibitor captopril. To further investigate the mechanism by which Ang II is generated in the blood vessels of humans, we examined the effects of various inhibitors of the renin-angiotensin system (captopril, delapril, N-acetyl-pepstatin, and human renin inhibitor KRI-1314) on Ang II release from perfused human umbilical cord veins in vitro. Isolated human umbilical veins were perfused with Krebs-Ringer solution, and immunoreactive Ang II released into the perfusate was measured directly by using a Sep-Pak C18 cartridge connected to the perfusion system. Both captopril and delapril diacid (10(-9) to 5 x 10(-6) mol/L), an active metabolite of delapril hydrochloride, suppressed the Ang II release in a dose-dependent fashion; the maximal percent suppression of Ang II release evoked by these inhibitors (5 x 10(-6) mol/L) was 56% and 64%, respectively, for captopril and delapril. Both N-acetyl-pepstatin (10(-9) to 10(-5) mol/L) and KRI-1314 (10(-9) to 10(-6) mol/L) suppressed Ang II release in a dose-related manner. At a 10(-6) mol/L concentration, KRI-1314 produced a 74% reduction in the basal rate of Ang II release, and a reduction threefold greater than the maximal reduction in basal Ang II release produced by N-acetyl-pepstatin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2009152

  1. VDR Attenuates Acute Lung Injury by Blocking Ang-2-Tie-2 Pathway and Renin-Angiotensin System

    OpenAIRE

    Kong, Juan; Zhu, Xiangdong; Shi, Yongyan; Liu, Tianjing; Chen, Yunzi; Bhan, Ishir; Zhao, Qun; Thadhani, Ravi; Li, Yan Chun

    2013-01-01

    Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pul...

  2. Complex pathologies of angiotensin Ⅱ-induced abdominal aortic aneurysms

    Institute of Scientific and Technical Information of China (English)

    Alan DAUGHERTY; Lisa A. CASSIS; Hong LU

    2011-01-01

    Angiotensin Ⅱ (Angll) is the primary bioactive peptide of the renin angiotensin system that plays a critical role in many cardiovascular diseases.Subcutaneous infusion of Angll into mice induces the development of abdominal aortic aneurysms (AAAs).Like human AAAs,Angll-induced AAA tissues exhibit progressive changes and considerable heterogeneity.This complex pathology provides an impediment to the quantification of aneurysmal tissue composition by biochemical and immunostaining techniques.Therefore,while the mouse model of Angll-induced AAAs provides a salutary approach to studying the mechanisms of the evolution of AAAs in humans,meaningful interpretation of mechanisms requires consideration of the heterogeneous nature of the diseased tissue.

  3. Mechanism of renin-angiotensin-aldosterone system inhibitors%肾素-血管紧张素-醛固酮系统抑制剂的作用机制

    Institute of Scientific and Technical Information of China (English)

    朱凌倜; 周京敏

    2013-01-01

    Renin-angiotensin-aldosterone system (RAAS) is a complex network system in regulating cardiovascular and renal function. RAAS activation plays an extremely important role in the development and prognosis of hypertension, myocardial remodeling after acute myocardial infarction, acute and chronic heart failure and renal insufifciency. The symptoms and prognosis of patients with above-mentioned diseases can be signiifcantly improved by blocking different levels of RAAS. This article reviews the mechanism of several RAAS inhibitors which are commonly used in clinic.%肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)是一种调控心血管和肾功能的复杂的网络系统。RAAS的激活在高血压、急性心肌梗死后的心肌重塑、急性和慢性心力衰竭以及肾功能不全等多种疾病的进展中起着重要的作用,而RAAS抑制剂能够显著延缓上述疾病的进展和改善患者的预后。本文就目前临床常用的几类RAAS抑制剂的作用机制作一概述。

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

    OpenAIRE

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

    2013-01-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor tr...

  5. Angiotensin II and angiotensin-(1-7 decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study

    Directory of Open Access Journals (Sweden)

    Moorefield Cheryl

    2010-11-01

    Full Text Available Abstract Background During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF, placental growth factor (PLGF, soluble VEGF receptor 1 (sFlt1, and soluble endoglin (sEng are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy. Methods We evaluated the effects of angiotensin II (Ang II and angiotensin-(1-7 [Ang-(1-7] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV. CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM or Ang-(1-7 (1 nM and 1 microM. The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH, and human placenta lactogen (HPL was measured by ELISA. Results The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM and Ang-(1-7 (1 nM and 1 microM. There was a time-dependent increase in HPL indicating that the CV were functioning normally. Conclusions Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.

  6. 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 Henrik

    2006-01-01

    dysfunction and splanchnic and systemic haemodynamics (r = - 0.56-0.55), but only weakly with CBV (r = - 0.25, p < 0.02). In a multivariate regression analysis, plasma renin was determined by serum sodium, alkaline phosphatases and systolic blood pressure (p < 0.04 to p < 0.001). CONCLUSIONS: CBV correlates...... RAAS, including the CBV. Circulating plasma renin concentrations were measured using an immunoradiometric assay. RESULTS: Arterial renin concentrations were significantly higher in the patients than in the controls (p < 0.003). Plasma renin correlated significantly with several indicators of liver...

  7. Effects of angiotensin converting enzyme inhibitor: ramipril on different biochemical parameters in essential hypertensive patients

    Directory of Open Access Journals (Sweden)

    Pratibha S. Salve

    2016-06-01

    Conclusions: Ramipril has beneficial effects on RAS (Renin angiotensin system and kinin system or both may contribute to the improvement in different biochemical parameters by ramipril. [Int J Res Med Sci 2016; 4(6.000: 2288-2291

  8. Inverting Notions of the Biological Role of the Renin → Angiotensin-II → Aldosterone System and the Function of Arterial Pressure as a Metabolism Regulator

    Directory of Open Access Journals (Sweden)

    Vladimir N. Titov

    2014-09-01

    Full Text Available The phylogenetic theory of general pathology postulates that notions of the biological role of arterial pressure (AP in physiology and pathology have been subjected to inversion. The nephron’s activation of the synthesis of the components renin → angiotensin-II (A-II and the augmentation of aldosterone secretion are directed not at an increase in AP but at preserving the volume of the piece of the third world ocean, privatized by each species, - the pool of the intercellular milieu in which, just like millions of years before, there continue to live all cells. Phylogenetically earlier organs cannot regulate the action of a later one in AP phylogenesis – a physical factor in metabolism regulation. It is not the kidneys that increase AP but the vasomotor center, which, increasing AP in the proximal segment and further hydrodynamic pressure in the distal segment of the arterial bed, seeks to reanimate the function of nephrons, the biological function of endoecology and the biological reaction of excretion. In addition to playing a major role in the biological function of locomotion, AP is a physical factor in compensating for impairments in the biological functions of homeostasis, trophology, endoecology, and adaptation. There have formed sequentially three levels of metabolic regulation in phylogenesis. At an autocrine level, there occurs a specific regulation of biochemical reactions. Within paracrinally regulated communities of cells, in the distal segment of the arterial bed, metabolism is regulated by millions of local peristaltic pumps through compensating for the biological reaction of endothelium-dependent vasodilation, microcirculation, and the action of humoral mediators and hormonal principles. In vivo from the level of the vasomotor center metabolism is non-specifically, systemically regulated by the physical factor – AP – through sympathetic activation of the heart; in the proximal segment of the arterial bed and the distal

  9. Effect of angiotensin Ⅱ and angiotensin Ⅱ type 1 receptor antagonist on the proliferation,contraction and collagen synthesis in rat hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    LIU Jun; GONG Hao; ZHANG Zhong-tao; WANG Yu

    2008-01-01

    Background Angiotensin Ⅱ(Ang Ⅱ)is a very important vasoactive peptide that acts upon hepatic stellate cells(HSCs),which are major effector cells in hepatic cirrhosis and portal hypertension.The present study was aimed to investigate the effects of Ang Ⅱ and angiotensin Ⅱ type 1 receptor antagonist(AT1RA)on the proliferation,contraction and collagen synthesis in HSCs.Methods HSC-T6 rat hepatic stellate cell Iine was studied.The proliferation of the HSC cells was evaluated by MTT colorimetric assay while HSC DNA synthesis was measured by3 H-thymidine incorporation.The effects of angiotensin Ⅱ and AT1 RA on HSCs contraction were studied by analVSIs of the contraction of the collagen Iattice.CelI culture media were analyzed by RT-PCR to detect secretion of collagen Ⅰ(Col Ⅰ),collagen Ⅲ(Col Ⅲ)and transforming growth factor β1 (TGF-β1)by enzyme Iinked Immunosorbent assay.HSC was harvested to measure collagen Ⅰ,collagen Ⅲ and tissue inhibitor of metalloproteinase-1(TIMP-1)mRNA expression.Results Ang Ⅱ((1 x10-10-1×10-4)mol/L)stimulated DNA synthesis and proliferation in HSCs compared with untreated control cells.AT1 RA inhibited angiotensin Ⅱ induced proliferation of HSCs.A Iinear increase in the contractive area of collagen lattice correlated with the concentration of angiotensin Ⅱ(1×10-9-1×10-5mol/L)and with time over 48 hours.ATlRA blocks angiotensin Ⅱ induced contraction of collagen Iattice.Coll,Col Ⅲ and TGF-β1 levels of the Ang Ⅱ group were higher than those of control group and this increase was downregulated by AT1RA.The mRNA expressions of ColⅠ,CoI Ⅲ and TIMP-1 were higher in HSCs from the Ang Ⅱ group than the control group and downregulated by AT1RA.Conclusions Angiotensin Ⅱ increased DNA synthesis and proliferation of HSCs in a dose-dependent manner,stimulated the contraction of HSCs dose-and time-dependently.Angiotensin also promoted excretion of Col Ⅰ,ColⅢand TGF-β1 Ievels and stimulated Col Ⅰ,Col Ⅲ and

  10. Primary melanoma tumor inhibits metastasis through alterations in systemic hemostasis.

    Science.gov (United States)

    Kirstein, Jennifer M; Hague, M Nicole; McGowan, Patricia M; Tuck, Alan B; Chambers, Ann F

    2016-08-01

    Progression from a primary tumor to distant metastases requires extensive interactions between tumor cells and their microenvironment. The primary tumor is not only the source of metastatic cells but also can also modulate host responses to these cells, leading to an enhancement or inhibition of metastasis. Tumor-mediated stimulation of bone marrow can result in pre-metastatic niche formation and increased metastasis. However, a primary tumor can also inhibit metastasis through concomitant tumor resistance-inhibition of metastatic growth by existing tumor mass. Here, we report that the presence of a B16F10 primary tumor significantly restricted numbers and sizes of experimental lung metastases through reduction of circulating platelets and reduced formation of metastatic tumor cell-associated thrombi. Tumor-bearing mice displayed splenomegaly, correlated with primary tumor size and platelet count. Reduction in platelet numbers in tumor-bearing animals was responsible for metastatic inhibition, as restoration of platelet numbers using isolated platelets re-established both tumor cell-associated thrombus formation and experimental metastasis. Consumption of platelets due to a B16F10 primary tumor is a form of concomitant tumor resistance and demonstrates the systemic impact of a growing tumor. Understanding the interplay between primary tumors and metastases is essential, as clarification of concomitant tumor resistance mechanisms may allow inhibition of metastatic growth following tumor resection. Key messages Mice with a primary B16F10 tumor had reduced metastasis vs. mice without a primary tumor. Tumor-bearing mice had splenomegaly and fewer platelets and tumor-associated thrombi. Restoring platelets restored tumor-associated thrombi and increased metastasis. This work shows the impact that a primary tumor can have on systemic metastasis. Understanding these interactions may lead to improved ways to inhibit metastasis. PMID:27048169

  11. Statin therapy inhibits remyelination in the central nervous system

    DEFF Research Database (Denmark)

    Miron, Veronique E; Zehntner, Simone P; Kuhlmann, Tanja;

    2009-01-01

    Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood...... OPCs were maintained in an immature state (Olig2(strong)/Nkx2.2(weak)). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating the...... need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes....

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

    Science.gov (United States)

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

    2013-10-01

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

  13. Angiotensin I-Converting Enzyme Inhibitory Peptides of Chia (Salvia hispanica Produced by Enzymatic Hydrolysis

    Directory of Open Access Journals (Sweden)

    Maira Rubi Segura Campos

    2013-01-01

    Full Text Available Synthetic angiotensin I-converting enzyme (ACE-I inhibitors can have undesirable side effects, while natural inhibitors have no side effects and are potential nutraceuticals. A protein-rich fraction from chia (Salvia hispanica L. seed was hydrolyzed with an Alcalase-Flavourzyme sequential system and the hydrolysate ultrafiltered through four molecular weight cut-off membranes (1 kDa, 3 kDa, 5 kDa, and 10 kDa. ACE-I inhibitory activity was quantified in the hydrolysate and ultrafiltered fractions. The hydrolysate was extensive (DH = 51.64% and had 58.46% ACE-inhibitory activity. Inhibition ranged from 53.84% to 69.31% in the five ultrafiltered fractions and was highest in the <1 kDa fraction (69.31%. This fraction’s amino acid composition was identified and then it was purified by gel filtration chromatography and ACE-I inhibition measured in the purified fractions. Amino acid composition suggested that hydrophobic residues contributed substantially to chia peptide ACE-I inhibitory strength, probably by blocking angiotensin II production. Inhibitory activity ranged from 48.41% to 62.58% in the purified fractions, but fraction F1 (1.5–2.5 kDa exhibited the highest inhibition (IC50 = 3.97 μg/mL; 427–455 mL elution volume. The results point out the possibility of obtaining bioactive peptides from chia proteins by means of a controlled protein hydrolysis using Alcalase-Flavourzyme sequentional system.

  14. Intrarenal Distributions and Changes of Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 in Feline and Canine Chronic Kidney Disease

    OpenAIRE

    MITANI, Sawane; Yabuki, Akira; Sawa, Mariko; Chang, Hye-Sook; YAMATO, Osamu

    2013-01-01

    ABSTRACT Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system (RAS). ACE2 is a newly identified member of the RAS. The present immunohistochemical study focused on changes in intrarenal ACE and ACE2 immunoreactivity in feline and canine chronic kidney disease (CKD). ACE immunoreactivity was predominantly observed in the brush border of the proximal tubules in dogs and cats. ACE immunoreactivity was lower in CKD kidneys than in normal kidneys, and quantitative an...

  15. SUPPRESSION OF RENIN-ANGIOTENSIN SYSTEM TO PREVENT COMPLICATIONS OF CARDIOVASCULAR DISEASES: CURRENT "ROLES" DISTRIBUTION FROM CLINICAL PHARMACOLOGIST’S POINT OF VIEW

    Directory of Open Access Journals (Sweden)

    S. R. Gilyarevskiy

    2016-01-01

    Full Text Available A role of angiotensin-converting enzyme (ACE inhibitors in cardiovascular diseases treatment and prevention is discussed. Some large randomized clinical trials are analyzed. Physical and chemical properties of drugs and its evidence base are considered among possible factors of ACE inhibitors choice. A problem of ACE inhibitor choice is also discussed in context of secondary prevention of cardiovascular complications in arterial hypertension and after myocardial infarction. It is concluded that the choice of any drug for cardiovascular disease treatment is mainly determined by its evidence base.

  16. Long-term use of drugs affecting the renin-angiotensin system and the risk of cancer. A population-based case-control study

    DEFF Research Database (Denmark)

    Hallas, Jesper; Depont Christensen, Rene; Andersen, Morten; Friis, Søren; Bjerrum, Lars

    2012-01-01

    Aims: A recent meta-analysis of clinical trials has demonstrated a small excess of cancers in persons that had been allocated to angiotensin-receptor blockers (ARBs). We undertook this observational study to look at dose-response and dose-duration effects and look for specificity with respect to...... for each case by a risk-set sampling. Data on medication was retrieved from the Danish National Prescription Registry. We defined long-term exposure as at least 1000 defined daily doses redeemed within the past five years. Confounders were controlled by conditional logistic regression. Results: The...

  17. SUPPRESSION OF RENIN-ANGIOTENSIN SYSTEM TO PREVENT COMPLICATIONS OF CARDIOVASCULAR DISEASES: CURRENT "ROLES" DISTRIBUTION FROM CLINICAL PHARMACOLOGIST’S POINT OF VIEW

    Directory of Open Access Journals (Sweden)

    S. R. Gilyarevskiy

    2011-01-01

    Full Text Available A role of angiotensin-converting enzyme (ACE inhibitors in cardiovascular diseases treatment and prevention is discussed. Some large randomized clinical trials are analyzed. Physical and chemical properties of drugs and its evidence base are considered among possible factors of ACE inhibitors choice. A problem of ACE inhibitor choice is also discussed in context of secondary prevention of cardiovascular complications in arterial hypertension and after myocardial infarction. It is concluded that the choice of any drug for cardiovascular disease treatment is mainly determined by its evidence base.

  18. Corrosion inhibition approach of oil production systems in offshore oilfields

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, L.; Tan, X. [School of Environmental Science and Engineering, Tianjin University, Tianjin 300072 (China); Teng, H.K. [Tianjin Institute of Chemical Engineering, Tianjin 300076 (China); Yang, Y.S. [School of Civil Engineering, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG (United Kingdom)

    2004-09-01

    Synthesis and modification of imidazoline were carried out based on review of the corrosion inhibitor development and application for oilfields. A series of imidazoline compounds were synthesised through the solvent dewatering and vacuum dewatering methods. After reaction of imidazoline with ethane oxide, the produced compound was used to react with halogen hydrocarbon and polyphosphoric acid respectively. Finally an agent with performance of corrosion-inhibition, sterilisation and anti-scaling was obtained. The structures of the compounds were characterised by the Fourier transformation infrared spectrum. The relationships between corrosion inhibition effectiveness of the compounds and their structures were investigated so as to determine the structure of a novel corrosion inhibitor. The selected corrosion inhibitor was evaluated by a series of experiments to understand the characteristics of imidazoline derivative and some major factors associated with oil production in the oilfields of China. The experimental results showed that this corrosion inhibitor has outstanding performance of corrosion inhibition and sterilization, and is suitable for corrosion inhibition of the oil abstraction systems with high water-content in the offshore oilfields. (Abstract Copyright [2004], Wiley Periodicals, Inc.)

  19. Does angiotensin-1 converting enzyme genotype influence motor or cognitive development after pre-term birth?

    Directory of Open Access Journals (Sweden)

    Whitelaw Andrew

    2005-02-01

    Full Text Available Abstract Background Raised activity of the renin-angiotensin system (RAS may both amplify inflammatory and free radical responses and decrease tissue metabolic efficiency and thus enhance cerebral injury in the preterm infant. The angiotensin-converting enzyme (ACE DD genotype is associated with raised ACE and RAS activity as well as potentially adverse stimuli such as inflammation. The DD genotype has been associated with neurological impairments in the elderly, and thus may be also associated with poorer motor or cognitive development amongst children born preterm prematurely. Methods The association of DD genotype with developmental progress amongst 176 Caucasian children born at less than 33 weeks gestation (median birthweight 1475 g, range 645–2480 g; gestation 30 weeks, range 22–32; 108 male was examined at 2 and 5 1/2 years of age. Measured neuro-cognitive outcomes were cranial ultrasound abnormalities, cerebral palsy, disability, Griffiths Developmental Quotient [DQ] at 2 yrs, and General Cognitive Ability [British Ability Scales-11] and motor performance [ABC Movement], both performed at 5 1/2 yrs. All outcomes were correlated with ACE genotype. Results The DD genotype was not associated with lower developmental quotients even after accounting for important social variables. Conclusion These data do not support either a role for ACE in the development of cognitive or motor function in surviving infants born preterm or inhibition of ACE as a neuroprotective therapy.

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

    International Nuclear Information System (INIS)

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

  1. Estimation of the number of angiotensin II AT1 receptors in rat kidney afferent and efferent arterioles

    DEFF Research Database (Denmark)

    Razga, Zsolt; Nyengaard, Jens Randel

    2007-01-01

    OBJECTIVE: To examine the effects of the renin-angiotensin system (RAS) on renal arterioles to determine the association between the distribution of angiotensin II AT1 receptors and the morphologic and physiologic heterogeneity of renal arterioles. STUDY DESIGN: To estimate the number of angioten...

  2. Angiotensin converting enzyme (ACE) inhibitors and renal function. A review of the current status

    DEFF Research Database (Denmark)

    Kamper, A L

    1991-01-01

    Angiotensin converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and cardiac failure. Experimental studies in rats have suggested that these agents may protect renal function in chronic nephropathy by a mechanism other than simply lowering the systemic blood...... pressure. In human studies of incipient diabetic nephropathy, worsening of microalbuminuria was prevented during 3 years of ACE inhibition. ACE inhibitors reduce arterial blood pressure in chronic nephropathy, and may cause a fall in glomerular filtration rate. In diabetic nephropathy, proteinuria...... was reduced by 2 months' treatment with enalapril to less than half of the values obtained in a control group treated with metoprolol. Nonrandomised trials have suggested that ACE inhibitors may slow the deterioration of renal function, but no comparisons with other antihypertensive agents in prospective...

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

    Science.gov (United States)

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

    2016-11-01

    1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low. PMID:26931777

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

    Science.gov (United States)

    Cheng, Jiamei; Li, Huiyu; Jie, Shenghua

    2016-01-01

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

  5. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) IV: Circulating ACE2 as a Biomarker of Systolic Dysfunction in Human Hypertension and Heart Failure

    Science.gov (United States)

    Úri, Katalin; Fagyas, Miklós; Mányiné Siket, Ivetta; Kertész, Attila; Csanádi, Zoltán; Sándorfi, Gábor; Clemens, Marcell; Fedor, Roland; Papp, Zoltán; Édes, István; Tóth, Attila; Lizanecz, Erzsébet

    2014-01-01

    Background Growing evidence exists for soluble Angiotensin Converting Enzyme-2 (sACE2) as a biomarker in definitive heart failure (HF), but there is little information about changes in sACE2 activity in hypertension with imminent heart failure and in reverse remodeling. Methods, Findings Patients with systolic HF (NYHAII-IV, enrolled for cardiac resynchronisation therapy, CRT, n = 100) were compared to hypertensive patients (n = 239) and to a healthy cohort (n = 45) with preserved ejection fraction (EF>50%) in a single center prospective clinical study. The status of the heart failure patients were checked before and after CRT. Biochemical (ACE and sACE2 activity, ACE concentration) and echocardiographic parameters (EF, left ventricular end-diastolic (EDD) and end-systolic diameter (ESD) and dP/dt) were measured. sACE2 activity negatively correlated with EF and positively with ESD and EDD in all patient's populations, while it was independent in the healthy cohort. sACE2 activity was already increased in the hypertensive group, where signs for imminent heart failure (slightly decreased EF and barely increased NT-proBNP levels) were detected. sACE2 activities further increased in patients with definitive heart failure (EF<50%), while sACE2 activities decreased with the improvement of the heart failure after CRT (reverse remodeling). Serum angiotensin converting enzyme (ACE) concentrations were lower in the diseased populations, but did not show a strong correlation with the echocardiographic parameters. Conclusions Soluble ACE2 activity appears to be biomarker in heart failure, and in hypertension, where heart failure may be imminent. Our data suggest that sACE2 is involved in the pathomechanism of hypertension and HF. PMID:24691269

  6. The effect of angiotensin II on endogenous noradrenaline release in man.

    OpenAIRE

    Seidelin, P H; Coutie, W J; Struthers, A.D.

    1987-01-01

    1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and fo...

  7. Charakterisierung der Wirkung von Angiotensin II auf die elektrophysiologischen Eigenschaften reninsezernierenden Zellen der Rattenniere

    OpenAIRE

    Stehle, Alexander

    2006-01-01

    Das Renin-Angiotensin-Aldosteron System (RAAS) ist ein rückgekoppeltes Hormonsystem zur Aufrechterhaltung und Regulation von Plasmavolumen, Plasmaosmolarität und Blutdruck. Die Aspartylprotease Renin wird aus reninsezernierenden Zellen (RSZ) der Vasa afferentia der Nieren freigesetzt. Die Sekretion wird gesteuert durch den Sympathikus, den Blutdruck in den Vasa afferentia, die NaCl-Konzentration an der Macula densa und zirkulierende Hormone, insbesondere Angiotensin II (ANGII). Diese Faktoren...

  8. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil

    OpenAIRE

    Carlos Ferrario

    2009-01-01

    Carlos FerrarioHypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USAAbstract: Endothelial dysfunction is the common link between cardiovascular disease risk factors and the earliest event in the cascade of incidents that results in target organ damage. Angiotensin II, the terminal pressor effector arm of the renin-angiotensin-aldosterone system, increases blood pressure (BP) by vasoconstriction and sodium and fluid retention, and has a pro...

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

    Science.gov (United States)

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

    2011-05-01

    Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein-mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and β-arrestin-dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [(32)P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the β-arrestin-biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a β-arrestin-uncoupled receptor retained these properties. We also found angiotensin II-mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or β-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor. PMID:21383310

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

    International Nuclear Information System (INIS)

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT1 receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT1-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT1 receptor activation. ► Translocation of p47

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-11-01

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

  12. Local generation and action of angiotensin II in dog iris sphincter muscle.

    Science.gov (United States)

    Okamura, T; Wang, Y; Toda, N

    1992-10-01

    Existence of the renin-angiotensin system was pharmacologically investigated in the dog isolated iris sphincter muscle. The sphincter muscle contracted in response to tetradecapeptide, a synthetic renin substrate, angiotensin (ANG) I and ANG II dose-dependently. The contractions induced by these peptides were suppressed by treatment with saralasin, indomethacin and aspirin. Contractile responses to tetradecapeptide and ANG I were also reduced by KRI-1314, a renin inhibitor, and captopril, respectively. ANG II stimulated the release of prostaglandin (PG) F2 alpha from the sphincter muscle. Angiotensin-converting enzyme activity was measurable in the sphincter muscle. Miosis was observed by intracameral injection of ANG I and ANG II into the anterior chamber. These results strongly suggest that angiotensin generating enzymes function in the sphincter muscle and ANG II produced by these enzymes contracts the sphincter muscle via the formation of PG (s), possibly PG F2 alpha. PMID:1336465

  13. Reduced Expression of the Extracellular Calcium-Sensing Receptor (CaSR) Is Associated with Activation of the Renin-Angiotensin System (RAS) to Promote Vascular Remodeling in the Pathogenesis of Essential Hypertension

    Science.gov (United States)

    Wang, La-mei; Tang, Na; Zhong, Hua; Liu, Yong-min; Li, Zhen; Feng, Qian; He, Fang

    2016-01-01

    The proliferation of vascular smooth muscle cells (VSMCs), remodeling of the vasculature, and the renin-angiotensin system (RAS) play important roles in the development of essential hypertension (EH), which is defined as high blood pressure (BP) in which secondary causes, such as renovascular disease, are absent. The calcium-sensing receptor (CaSR) is involved in the regulation of BP. However, the underlying mechanisms by which the CaSR regulates BP are poorly understood. In the present study, the role of the CaSR in EH was investigated using male spontaneously hypertensive rats (SHRs) and rat and human plasma samples. The percentages of medial wall thickness to external diameter (WT%), total vessel wall cross-sectional area to the total area (WA%) of thoracic arteries, as well as the percentage of wall area occupied by collagen to total vessel wall area (CA%) were determined. Tissue protein expression and plasma concentrations of the CaSR, cyclic adenosine monophosphate (cAMP), renin, and angiotensin II (Ang II) were additionally assessed. WT%, WA%, and CA% were found to increase with increasing BP, whereas the plasma concentration of CaSR was found to decrease. With increasing BP, the levels of smooth muscle actin and calponin decreased, whereas those of osteopontin and proliferating cell nuclear antigen increased. The CaSR level negatively correlated with the levels of cAMP and Ang II, but positively correlated with those of renin. Our data suggest that reduced expression of the CaSR is correlated with activation of the RAS, which induces increased vascular remodeling and VSMC proliferation, and thereby associated with EH in the SHR model and in the Han Chinese population. Our findings provide new insights into the pathogenesis of EH. PMID:27391973

  14. Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results

    OpenAIRE

    Baltatzi, M; Savopoulos, Ch; Hatzitolios, A

    2011-01-01

    Chronic kidney disease (CKD) is a global health problem associated with considerable morbidity and mortality and despite advances in the treatment of end stage renal disease (ESRD) mechanisms to prevent and delay its progression are still being sought. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in many of the pathophysiologic changes that lead to progression of renal disease. Traditionally RAAS was considered as an endocrine system and its principal role was to maint...

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

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Suo, Yu-Ping [Department of Obstetrics and Gynecology, Shanxi Provincial People' s Hospital, Taiyuan 030012 (China); Yue, Li-Ying [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China)

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

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

    International Nuclear Information System (INIS)

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  17. Angiotensin converting enzyme and memory: preclinical and clinical data.

    Science.gov (United States)

    Sudilovsky, A; Turnbull, B; Croog, S H; Crook, T

    effects, and these are prevented if captopril is administered previously (Koller et al, 1979). Also, chronic oral treatment with captopril produces changes of brain renin angiotensin system parameters which suggest inhibition of AII biosyntheses in the brain (Scholkens et al, 1983). It is conceivable therefore, that our findings with prolonged administration of captopril are exerted through reduced formation of AII. Other possible mechanisms through which captopril may affect cognition include peptide-protein systems (Ganten et al, 1982, Sudilovsky et al, 1988) or the modulation of cerebral blood flow autoregulation mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2856549

  18. Hyperinsulinemic rats are normotensive but sensitized to angiotensin II

    DEFF Research Database (Denmark)

    Johansson, Maria E; Andersson, Irene J; Alexanderson, Camilla; Skøtt, Ole; Holmang, Agneta; Bergstrom, Goran

    2008-01-01

    rats received insulin (2 IU/day, INS, n=12) or insulin combined with losartan (30 mg/kg/day, INS-LOS, n=10), the angiotensin II receptor antagonist, for six weeks. Losartan-treated (LOS, n=10) and untreated rats served as controls (C, n=11). We used telemetry to measure BP and heart rate (HR), and......The effect of insulin on blood pressure is debated and an involvement of an activated renin-angiotensin aldosterone system (RAAS) has been suggested. We studied the effect of chronic insulin infusion on telemetry BP and assessed sympathetic activity and dependence of the RAAS. Female Sprague Dawley...... acute ganglion blockade and air-jet stress to investigate possible control of BP by the sympathetic nervous system. In addition, we used myograph technique to study vascular function ex vivo. INS and INS-LOS developed euglycemic hyperinsulinemia. Insulin did not affect BP but increased HR (27 beats...

  19. Angiotensin-I-Converting Enzyme (ACE Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Isuru Wijesekara

    2010-03-01

    Full Text Available Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.

  20. Silica Exposure and Serum Angiotensin Converting Enzyme Activity

    OpenAIRE

    YK Sharma; AB Karnik; RR Tiwari

    2010-01-01

    Background: Silicosis is known in industrial workers for centuries. Till recently, the mainstay of its diagnosis and progress was clinical examination of the respiratory system, pulmonary function test and chest radiography. Several biomarkers such as serum angiotensin converting enzyme (ACE) activity have been examined to determine the extent of silicosis. Objective: To elucidate the effect of age, gender, duration of exposure to silica dust, smoking habit, and pulmonary function status on t...

  1. Estimation of urinary angiotensin II by radioimmunoassay

    International Nuclear Information System (INIS)

    Urine samples were collected from fasting subjects after maintaining posture for 2 hr in early morning. Urinary angiotensin II was extracted with SE-Sephadex. The extracts, after being dissolved in phosphate buffer, pH 7.5, were measured by radioimmunoassay. Recovery, sensitivity and accuracy were found to be satisfactory. The normal values obtained from 6 subjects were 52-280 pg/2 hr. The values were almost normal in essential hypertension and in chronic glomerulonephritis. They were high in 3 out of 6 cases with renovascular hypertension and subsequently dropped after surgery. In 6 cases with primary aldosteronism, very low levels were found. These increased after the removal of adrenal adenomas. No positive correlation between simultaneous plasma and urinary angiotensin samples was apparent. Also no positive correlation between urinary angiotensin and urine volume was found. In renovascular hypertention, during glucose infusion, lower values in urine volume and angiotensin excretion were observed on the stenotic side as compared to the intact side. Thus, the angiotensin excretion rate does not appear to be regulated by arterial angiotensin concentration, but rather by the angiotensin perfusion rate. (author)

  2. Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade

    NARCIS (Netherlands)

    van den Heuvel, AFM; Dunselman, PHJM; Kingma, T; Verhorst, P; Boomsma, F; van Gilst, WH; van Veldhuisen, DJ

    2001-01-01

    OBJECTIVES We sought to study the effect of angiotensin-converting enzyme inhibition on exercise-induced myocardial ischemia. BACKGROUND Although angiotensin-converting enzyme inhibitors have been shown to reduce ischemic events after myocardial infarction, few data are available regarding their dir

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

    Science.gov (United States)

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

    2010-06-01

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

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

    Science.gov (United States)

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

    2016-08-01

    It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound 21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure. PMID:27267713

  5. Angiotensin II and Renal Tubular Ion Transport

    Directory of Open Access Journals (Sweden)

    Patricia Valles

    2005-01-01

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

  6. Angiotensin II Type 1 Receptor Signaling Regulates Feeding Behavior through Anorexigenic Corticotropin-releasing Hormone in Hypothalamus*

    OpenAIRE

    Yamamoto, Rie; Akazawa, Hiroshi; Fujihara, Hiroaki; Ozasa, Yukako; Yasuda, Noritaka; Ito, Kaoru; Kudo, Yoko; Qin, Yingjie; Ueta, Yoichi; Komuro, Issei

    2011-01-01

    The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT1) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a+/+ mice, AT1 receptor knock-out (Agtr1a−/−) mice were hyperphagic and obese with ...

  7. 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

  8. 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)

    S A Savelyeva

    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

  9. Ordering kinetics in model systems with inhibited interfacial adsorption

    DEFF Research Database (Denmark)

    Willart, J.-F.; Mouritsen, Ole G.; Naudts, J.; Descamps, M.

    1992-01-01

    The ordering kinetics in two-dimensional Ising-like spin moels with inhibited interfacial adsorption are studied by computer-simulation calculations. The inhibited interfacial adsorption is modeled by a particular interfacial adsorption condition on the structure of the domain wall between...

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

    Science.gov (United States)

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

    2009-01-01

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

  11. Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Griendling, K.K.; Rittenhouse, S.E.; Brock, T.A.; Ekstein, L.S.; Gimbrone, M.A. Jr.; Alexander, R.W.

    1986-05-05

    Angiotensin II acts on cultured rat aortic vascular smooth muscle cells to stimulate phospholipase C-mediated hydrolysis of membrane phosphoinositides and subsequent formation of diacylglycerol and inositol phosphates. In intact cells, angiotensin II induces a dose-dependent increase in diglyceride which is detectable after 5 s and sustained for at least 20 min. Angiotensin II (100 nM)-stimulated diglyceride formation is biphasic, peaking at 15 s (227 +/- 19% control) and at 5 min (303 +/- 23% control). Simultaneous analysis of labeled inositol phospholipids shows that at 15 s phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP) decline to 52 +/- 6% control and 63 +/- 5% control, respectively, while phosphatidylinositol (PI) remains unchanged. In contrast, at 5 min, PIP2 and PIP have returned toward control levels (92 +/- 2 and 82 +/- 4% control, respectively), while PI has decreased substantially (81 +/- 2% control). The calcium ionophore ionomycin (15 microM) stimulates diglyceride accumulation but does not cause PI hydrolysis. 4 beta-Phorbol 12-myristate 13-acetate, an activator of protein kinase C, inhibits early PIP and PIP2 breakdown and diglyceride formation, without inhibiting late-phase diglyceride accumulation. Thus, angiotensin II induces rapid transient breakdown of PIP and PIP2 and delayed hydrolysis of PI. The rapid attenuation of polyphosphoinositide breakdown is likely caused by a protein kinase C-mediated inhibition of PIP and PIP2 hydrolysis. While in vascular smooth muscle stimulated with angiotensin II inositol 1,4,5-trisphosphate formation is transient, diglyceride production is biphasic, suggesting that initial and sustained diglyceride formation from the phosphoinositides results from different biochemical and/or cellular processes.

  12. Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

    OpenAIRE

    Lubel, J. S.; Herath, C. B.; Velkoska, E.; Casley, D. J.; Burrell, L. M.; Angus, P. W.

    2008-01-01

    Cell culture experiments often employ the use of culture media that contain fetal calf serum (FCS). The angiotensin peptides angiotensin II and angiotensin 1–7 have opposing effects with angiotensin converting enzyme 2 (ACE2) being the enzyme predominantly responsible for generating angiotensin 1–7 from angiotensin II. The effect of FCS on angiotensin peptides has not previously been described. We have shown that FCS has ACE2 enzyme activity capable of degrading angiotensin II and generating ...

  13. NEW INSIGHTS INTO THE GENERATION OF THE ANGIOTENSIN PEPTIDES

    Directory of Open Access Journals (Sweden)

    Ion Raducu Popescu

    2012-06-01

    Full Text Available The classical concept of Ang II as main pressor angiotensin peptide has undergone experiencedsubstantial changes in the past few years. Many experimental research have revealed novel aspects of the circulating andtissue RAS. After a brief introduction concerning the two distinct forms of the angiotensin converting enzyme andproangiotensin – 12 as a new potential precursor for the formation of bioactive angiotensin peptides, the generation andactions of the main bioactive fragments of Ang II are also presented. Among them are mentioned the pathways offormation and biological effects of Ang (1-7, Ang III, Ang IV and Ang V involved in the modulation of the Ang II, themost active multifunctional hormone of RAS. The inhibitory properties of the ACE2–Ang (1-7–Mas axis are interpretedas a counterbalancing mechanism against the eventual deleterious actions of Ang II. As described here, these counter-regulatory properties provide the self-regulation of RAS, as a unitary and integrated hormone system.

  14. Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

    Directory of Open Access Journals (Sweden)

    Weiyong Shen

    Full Text Available OBJECTIVE: Royal College of Surgeons (RCS rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO on retinopathy in RCS rats. METHODS: Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR, pro-neurotrophin 3 (pro-NT3, tumour necrosis factor-α (TNFα, pigment epithelium derived factor (PEDF and vascular endothelial growth factor-A (VEGF-A, the production of CD34(+ cells and mobilization of CD34(+/VEGF-R2(+ cells as well as recruitment of CD34(+ cells into the retina were examined after EPO treatment. RESULTS: RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+ cells along with effective mobilization of CD34(+/VEGF-R2(+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. CONCLUSIONS: Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple

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

    International Nuclear Information System (INIS)

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

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

    LENUS (Irish Health Repository)

    Wan Md Adnan, Wan A H

    2011-03-01

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

  17. 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

  18. Expression and transport of Angiotensin II AT1 receptors in spinal cord, dorsal root ganglia and sciatic nerve of the rat

    OpenAIRE

    Pavel, Jaroslav; Tang, Hui; Brimijoin, Stephen; Moughamian, Armen; Nishioku, Tsuyoshi; Benicky, Julius; Saavedra, Juan M.

    2008-01-01

    To clarify the role of Angiotensin II in the regulation of peripheral sensory and motor systems, we initiated a study of the expression, localization and transport of Angiotensin II receptor types in the rat sciatic nerve pathway, including L4–L5 spinal cord segments, the corresponding dorsal root ganglia (DRGs) and the sciatic nerve.

  19. New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.

    Science.gov (United States)

    Zannad, Faiez; Rossignol, Patrick; Stough, Wendy Gattis; Epstein, Murray; Alonso Garcia, Maria de Los Angeles; Bakris, George L; Butler, Javed; Kosiborod, Mikhail; Berman, Lance; Mebazaa, Alexandre; Rasmussen, Henrik S; Ruilope, Luis M; Stockbridge, Norman; Thompson, Aliza; Wittes, Janet; Pitt, Bertram

    2016-08-01

    Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. PMID:27140336

  20. Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes.

    Science.gov (United States)

    Williams, Sarah M; Golden-Mason, Lucy; Ferguson, Bradley S; Schuetze, Katherine B; Cavasin, Maria A; Demos-Davies, Kim; Yeager, Michael E; Stenmark, Kurt R; McKinsey, Timothy A

    2014-02-01

    Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors block cardiac fibrosis in pre-clinical models of heart failure. However, which HDAC isoforms govern cardiac fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses angiotensin II (Ang II)-mediated cardiac fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and kidney failure, our results suggest broad utility for isoform-selective HDAC inhibitors as anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells. PMID:24374140

  1. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need...... inhibition in chronic kidney disease by reporting of the studies published so far as well as perspective on the future possibilites....... was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin...

  2. Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

    NARCIS (Netherlands)

    Krikken, Jan A.; Dallinga-Thie, Geesje M.; Navis, Gerjan; Dullaart, Robin P. F.

    2008-01-01

    Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the pla

  3. Novel roles of nuclear angiotensin receptors and signaling mechanisms.

    Science.gov (United States)

    Gwathmey, TanYa M; Alzayadneh, Ebaa M; Pendergrass, Karl D; Chappell, Mark C

    2012-03-01

    The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT2R) and ANG-(1-7) (AT7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. PMID:22170620

  4. Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation

    OpenAIRE

    Ferrari, Markus; Mudra, Harald; Grip, Lars; Voudris, Vassilis; Schächinger, Volker; de Jaegere, Peter; Rieber, Johannes; Hausmann, Dirk; Rothman, Martin; Koschyk, Dietmar H.; Figulla, Hans R

    2002-01-01

    Background. Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relation...

  5. Angiotensin Receptor Blockade Increases Pancreatic Insulin Secretion and Decreases Glucose Intolerance during Glucose Supplementation in a Model of Metabolic Syndrome

    OpenAIRE

    Rodriguez, Ruben; Viscarra, Jose A.; Minas, Jacqueline N.; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M.

    2012-01-01

    Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT1) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test ...

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

    Science.gov (United States)

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

    1975-01-01

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

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

    OpenAIRE

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

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT1R) and Ang II suppresses megalin expression in proximal tubule cells in vi...

  8. Effect of Jatropha curcas Peptide Fractions on the Angiotensin I-Converting Enzyme Inhibitory Activity

    OpenAIRE

    Segura-Campos, Maira R.; Fanny Peralta-González; Arturo Castellanos-Ruelas; Chel-Guerrero, Luis A.; David A. Betancur-Ancona

    2013-01-01

    Hypertension is one of the most common worldwide diseases in humans. Angiotensin I-converting enzyme (ACE) plays an important role in regulating blood pressure and hypertension. An evaluation was done on the effect of Alcalase hydrolysis of defatted Jatropha curcas kernel meal on ACE inhibitory activity in the resulting hydrolysate and its purified fractions. Alcalase exhibited broad specificity and produced a protein hydrolysate with a 21.35% degree of hydrolysis and 34.87% ACE inhibition. U...

  9. A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

    OpenAIRE

    Cressman, Alex M; Macdonald, Erin M.; Fernandes, Kimberly A.; Gomes, Tara; Paterson, J. Michael; Muhammad M Mamdani; Juurlink, David N.; ,

    2015-01-01

    Aims Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. Methods We conducted a nes...

  10. Plant Flavonoids as Angiotensin Converting Enzyme Inhibitors in Regulation of Hypertension

    Directory of Open Access Journals (Sweden)

    H.P. Vasantha Rupasinghe

    2011-05-01

    Full Text Available Background: Angiotensin converting enzyme (ACE is a key component in the renin angiotensin aldosterone system (RAAS which regulates blood pressure. As the over expression of RAAS is associated with vascular hypertension, ACE inhibition has become a major target control for hypertension. The research on potential ACE inhibitors is expanding broadly and most are focused on natural product derivatives such as peptides, polyphenolics, and terpenes. Plant polyphenolics are antioxidant molecules with various beneficial pharmacological properties. The current study is focused on investigating and reviewing the ACE inhibitory property of fruit flavonoids. An apple skin extract (ASE rich in flavonoids, the major constituents of the extract and their selected metabolites were assessed for the ACE inhibitory property in vitro. It is important to investigate the metabolites along with the flavonoids as they are the constituents active inside the human body.Objective: To investigate whether flavonoids, flavonoid rich apple extracts and their metabolites could inhibit ACE in vitro.Method: The samples were incubated with sodium borate buffer (30 μL, pH 8.3, 150 μL of substrate (Hip-His-Liu and ACE (30 μL at 37 oC for 1 h. The reaction was stopped by addition of 150 μL of 0.3M NaOH. The enzyme cleaved substrate was detected by making a fluorimetricadduct by adding 100 μL of o-phthaladehyde for 10 min at room temperature. Reaction wasstopped by adding 50 μL of 3M HCl. Fluorescence was measured by using a FluoStar Optimaplate reader at excitation of 350 nm and emission of 500 nm.Results: The extract and the compounds showed a concentration dependant enzyme inhibition.Increasing concentrations from 0.001 ppm to 100 ppm of ASE showed an increment of 29% to64% ACE inhibition. The IC50 (concentration of test compound which gives 50% enzymeinhibition values of ASE, quercetin, quercetin-3-glucoside, quercetin-3-galactoside, cyanidin-3-galactoside were 49

  11. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

    Science.gov (United States)

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-02-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  12. Angiotensin Converting Enzyme (ACE Inhibitor Extends Caenorhabditis elegans Life Span.

    Directory of Open Access Journals (Sweden)

    Sandeep Kumar

    2016-02-01

    Full Text Available Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms

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

    Directory of Open Access Journals (Sweden)

    James Phie

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

  14. Development of polyclonal antibodies against angiotensin type 2 receptors

    OpenAIRE

    1994-01-01

    Murine neuroblastoma N1E-115 cells are a useful system in which to study neuronal angiotensin II (AngII) receptors. N1E-115 cells possess both type 1 (AT1) and type 2 (AT2) AngII receptor subtypes, as does mammalian brain. AT2 receptors in brain or N1E-115 cells can be solubilized in 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. In the present study, heparin-Sepharose chromatography was used to partially purify solubilized N1E-115 membranes to produce an enriched population of AT...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    patients in a double-blind randomized placebo-controlled 1-year intervention trial using a predefined systolic blood pressure target of 140 mm Hg (SAFIR study). Each group of 41 patients did not differ in terms of age, blood pressure, comorbidity, antihypertensive treatment, dialysis parameters, and......Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis...

  16. Different modulatory effects of ammonium ions on angiotensin vascular actions in isolated rat aortic and renal arteries

    Directory of Open Access Journals (Sweden)

    Popescu Raducu I.

    2012-01-01

    Full Text Available In the present study, we were interested in the vascular effects of angiotensin II on perfused rings of the rat thoracic aorta and renal artery. Our results demonstrated different modulator alterations of these preparations induced by ammonium ions. Unlike the aortic rings, which exhibited only a reduction of angiotensin-induced contractility by NH4Cl, the renal artery preparations showed both activation of vasoconstriction and inhibition of vasorelaxation in the ring precontracted with phenylephrine or noradrenalin. These results are interpreted as a modulation by the ammonium ions of vascular reactions induced by the stimulation of the vasoconstrictor AT1 receptor on the one side and AT2 vasodilator receptors on the other. The potentiation of renal vasoconstriction accompanied by the reduction of angiotensin vasodilation by NH4Cl suggests the possibility of involvement from the blood flow and renal vascular tonus disturbances induced by ammonium ions during hyperammonemia of various causes.

  17. Mirtazapine inhibits tumor growth via immune response and serotonergic system.

    Directory of Open Access Journals (Sweden)

    Chun-Kai Fang

    Full Text Available To study the tumor inhibition effect of mirtazapine, a drug for patients with depression, CT26/luc colon carcinoma-bearing animal model was used. BALB/c mice were randomly divided into six groups: two groups without tumors, i.e. wild-type (no drug and drug (mirtazapine, and four groups with tumors, i.e. never (no drug, always (pre-drug, i.e. drug treatment before tumor inoculation and throughout the experiment, concurrent (simultaneously tumor inoculation and drug treatment throughout the experiment, and after (post-drug, i.e. drug treatment after tumor inoculation and throughout the experiment. The "psychiatric" conditions of mice were observed from the immobility time with tail suspension and spontaneous motor activity post tumor inoculation. Significant increase of serum interleukin-12 (sIL-12 and the inhibition of tumor growth were found in mirtazapine-treated mice (always, concurrent, and after as compared with that of never. In addition, interferon-γ level and immunocompetent infiltrating CD4+/CD8+ T cells in the tumors of mirtazapine-treated, tumor-bearing mice were significantly higher as compared with that of never. Tumor necrosis factor-α (TNF-α expressions, on the contrary, are decreased in the mirtazapine-treated, tumor-bearing mice as compared with that of never. Ex vivo autoradiography with [(123I]ADAM, a radiopharmaceutical for serotonin transporter, also confirms the similar results. Notably, better survival rates and intervals were also found in mirtazapine-treated mice. These findings, however, were not observed in the immunodeficient mice. Our results suggest that tumor growth inhibition by mirtazapine in CT26/luc colon carcinoma-bearing mice may be due to the alteration of the tumor microenvironment, which involves the activation of the immune response and the recovery of serotonin level.

  18. Pneumonia Risk and Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

    OpenAIRE

    Liu, Chia-Lin; Shau, Wen-Yi; Chang, Chia-Hsuin; Wu, Chi-Shin; Lai, Mei-Shu

    2013-01-01

    Background Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. Methods We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 199...

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

    Science.gov (United States)

    Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

    2016-06-15

    Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. PMID:27063446

  20. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis

    OpenAIRE

    Dutta., D; Fischler, M; McClung, A

    2001-01-01

    Secondary hyperkalaemic paralysis is a rare condition often mimicking the Guillain-Barré syndrome. There have been a few case reports of hyperkalaemia caused by renal failure, trauma, and drugs where the presentation has been with muscle weakness. A case of hyperkalaemic paralysis caused by an angiotensin converting enzyme inhibitor is reported.


Keywords: hyperkalaemia; paralysis; ACE inhibitors

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

    International Nuclear Information System (INIS)

    Highlights: ► Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. ► Angiotensin II may enhance the DNA synthesis via induction of superoxide. ► Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. ► Angiotensin II enhanced differentiation into mesodermal progenitor cells. ► Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT1R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression. Treatment with Ang II enhanced the phosphorylation of p38 MAPK in Col IV- exposed iPS cells. These results suggest that the stimulation of

  2. Selection of a high-affinity and in vivo bioactive ssDNA aptamer against angiotensin II peptide.

    Science.gov (United States)

    Heiat, Mohammad; Ranjbar, Reza; Latifi, Ali Mohammad; Rasaee, Mohammad Javad

    2016-08-01

    Unique features of aptamers have attracted interests for a broad range of applications. Aptamers are able to specifically bind to targets and inhibit their functions. This study, aimed to isolate the high affinity ssDNA aptamers against bio-regulator peptide angiotensin II (Ang II) and investigate their bioactivity in cellular and animal models. To isolate ssDNA aptamers, 12 rounds of affinity chromatography SELEX (Systematic Evolution of Ligands by EXponential enrichment) procedure were carried out. The SPR (surface plasmon resonance) and ELONA (enzyme linked oligonucleotide assay) analysis were used to determine the affinity and specificity of aptamers. The ability of selected aptamers to inhibit the proliferative effect of Ang II on human aortic vascular smooth muscle cells (HA-VSMCs) and their performance on Wistar rat urinary system and serum electrolyte levels were investigated. Two full-length aptamers (FLC112 and FLC125) with high affinity of respectively 7.52±2.44E-10 and 5.87±1.3E-9M were isolated against Ang II. The core regions of these aptamers (CRC112 and CRC125) also showed affinity of 5.33±1.15E-9 and 4.11±1.09E-9M. In vitro analysis revealed that FLC112 and FLC125 can inhibit the proliferative effect of Ang II on HA-VSMCs (Psodium level and increased the urine volume (Pbioactive aptamers may lead to excellent results in blocking Ang II activity. PMID:27298205

  3. Hypertensive retinopathy in a transgenic angiotensin-based model.

    Science.gov (United States)

    Reichhart, Nadine; Haase, Nadine; Crespo-Garcia, Sergio; Skosyrski, Sergej; Herrspiegel, Christina; Kociok, Norbert; Fuchshofer, Rudolf; Dillinger, Andrea; Poglitsch, Marco; Müller, Dominik N; Joussen, Antonia M; Luft, Friedrich C; Dechend, Ralf; Strauß, Olaf

    2016-07-01

    Severe hypertension destroys eyesight. The RAS (renin-angiotensin system) may contribute to this. This study relied on an established angiotensin, AngII (angiotensin II)-elevated dTGR (double-transgenic rat) model and same-background SD (Sprague-Dawley) rat controls. In dTGRs, plasma levels of AngII were increased. We determined the general retinal phenotype and observed degeneration of ganglion cells that we defined as vascular degeneration. We also inspected relevant gene expression and lastly observed alterations in the outer blood-retinal barrier. We found that both scotopic a-wave and b-wave as well as oscillatory potential amplitude were significantly decreased in dTGRs, compared with SD rat controls. However, the b/a-wave ratio remained unchanged. Fluorescence angiography of the peripheral retina indicated that exudates, or fluorescein leakage, from peripheral vessels were increased in dTGRs compared with controls. Immunohistological analysis of blood vessels in retina whole-mount preparations showed structural alterations in the retina of dTGRs. We then determined the general retinal phenotype. We observed the degeneration of ganglion cells, defined vascular degenerations and finally found differential expression of RAS-related genes and angiogenic genes. We found the expression of both human angiotensinogen and human renin in the hypertensive retina. Although the renin gene expression was not altered, the AngII levels in the retina were increased 4-fold in the dTGR retina compared with that in SD rats, a finding with mechanistic implications. We suggest that alterations in the outer blood-retinal barrier could foster an area of visual-related research based on our findings. Finally, we introduce the dTGR model of retinal disease. PMID:27026533

  4. Mechanism of arsenate inhibition of the glucose active transport system in Neurospora crassa

    International Nuclear Information System (INIS)

    The mechanism of arsenate inhibition of the glucose active transport system in wild-type cells of Neurospora crassa has been examined. Arsenate treatment results in approximately 65% inhibition of the glucose active transport system with only a small depression of cellular ATP levels. The transport system is not inhibited in cells treated with sodium arsenate in the presence of sodium azide. The transport inhibition is suppressed when orthophosphate is present during arsenate treatment, but is not reversed by orthophosphate when added after the arsenate treatment. The transport inhibition is completely reversed by treatment of the cells with mercaptoethanol. Gel chromatography of sonicates of intact cells which had been treated with [74As]arsenate reveals three radioactive peaks, one with the elution volume of arsenate, one with the elution volume of arsenite, and in high molecular-weight radioactive fraction. Treatment of the high molecular-weight radioactive fraction with mercaptoethanol results in the production of radioactive arsenite. In view of these findings, it is proposed that arsenate inhibition of the glucose active transport system in Neurospora involves transport of arsenate into the cells, probably via the orthophosphate transport system, reduction of the transported arsenate to arsenite, and interaction of arsenite with some component of the glucose active transport system, presumably via covalent binding with vicinal thiol groups. 15 references, 4 figures, 2 tables

  5. 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

    The role of the [alpha]-adrenergic system in the control of cardiac preload (central venous blood pressure; Pven) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was invest...

  6. Clinical Implication of the Renin-angiotensin-aldosterone Blockers in Chronic Kidney Disease Undergoing Hemodialysis

    OpenAIRE

    Morishita, Yoshiyuki; Kusano, Eiji; Nagata, Daisuke

    2014-01-01

    The renin-angiotensin-aldosterone system (RAAS) blockers have been widely used in chronic kidney disease patients undergoing hemodialysis; however, whether RAAS blockers have beneficial effects for cardiovascular disease in those patients has not been fully defined. This review focuses on the effects of RAAS blockers in chronic kidney disease undergoing hemodialysis for cardiovascular disease.

  7. 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.

  8. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease.

    Science.gov (United States)

    Lin, Mei; Gao, Ping; Zhao, Tianya; He, Lei; Li, Mengshi; Li, Yaoyao; Shui, Hua; Wu, Xiaoyan

    2016-05-01

    To investigate the effects of calcitriol on angiotensin-converting enzyme (ACE) and ACE2 in diabetic nephropathy. Streptozotocin (STZ) induced diabetic rats were treated with calcitriol for 16 weeks. ACE/ACE2 and mitogen activated protein kinase (MAPK) enzymes were measured in the kidneys of diabetic rats and rat renal tubular epithelial cells exposed to high glucose. Calcitriol reduced proteinuria in diabetic rats without affecting calcium-phosphorus metabolism. ACE and ACE2 levels were significantly elevated in diabetic rats compared to those in control rats. The increase in ACE levels was greater than that of ACE2, leading to an elevated ACE/ACE2 ratio. Calcitriol reduced ACE levels and ACE/ACE2 ratio and increased ACE2 levels in diabetic rats. Similarly, high glucose up-regulated ACE expression in NRK-52E cells, which was blocked by the p38 MAPK inhibitor SB203580, but not the extracellular signal-regulated kinase (ERK) inhibitor FR180204 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. High glucose down-regulated ACE2 expression, which was blocked by FR180204, but not SB203580 or SP600125. Incubation of cells with calcitriol significantly inhibited p38 MAPK and ERK phosphorylation, but not JNK phosphorylation, and effectively attenuated ACE up-regulation and ACE2 down-regulation in high glucose conditions. The renoprotective effects of calcitriol in diabetic nephropathy were related to the regulation of tubular levels of ACE and ACE2, possibly by p38 MAPK or ERK, but not JNK pathways. PMID:26968558

  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

    systemic resistance (Rsys) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after [alpha]-adrenoceptor blockade......The role of the [alpha]-adrenergic system in the control of cardiac preload (central venous blood pressure; Pven) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was...... responses were in fact due to activation of the RAS, because resting Pda and Rsys were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the [alpha]-adrenergic system normally plays an important role in the control of venous function during...

  10. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis.

    Science.gov (United States)

    Cao, Xi; Yang, Fangyuan; Shi, Tingting; Yuan, Mingxia; Xin, Zhong; Xie, Rongrong; Li, Sen; Li, Hongbing; Yang, Jin-Kui

    2016-01-01

    The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2(-/y)) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2(-/y) mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1-7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what's more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1-7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1-7)/Mas axis in prevention and treatment of hepatic lipid metabolism. PMID:26883384

  11. Crystallization inhibition of an amorphous sucrose system using raffinose

    Institute of Scientific and Technical Information of China (English)

    LEINEN K.M.; LABUZA T.P.

    2006-01-01

    The shelf life of pure amorphous sucrose systems, such as cotton candy, can be very short. Previous studies have shown that amorphous sucrose systems held above the glass transition temperature will collapse and crystallize. One study,however, showed that adding a small percent of another type of sugar, such as trehalose, to sucrose can extend the shelf life of the amorphous system by slowing crystallization. This study explores the hypothesis that raffinose increases the stability of an amorphous sucrose system. Cotton candy at 5 wt% raffinose and 95 wt% sucrose was made and stored at room temperature and three different relative humidities (%RH) 11%RH, 33%RH, and 43%RH. XRD patterns, and glass transition temperatures were obtained to determine the stability as a function of %RH. The data collected showed that raffinose slows sucrose crystallization in a low moisture amorphous state above the glass transition temperature and therefore improves the stability of amorphous sucrose systems.

  12. Designed Trpzip-3 β-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems.

    Science.gov (United States)

    Hopping, Gene; Kellock, Jackson; Caughey, Byron; Daggett, Valerie

    2013-09-12

    The trpzip peptides are small, monomeric, and extremely stable β-hairpins that have become valuable tools for studying protein folding. Here, we show that trpzip-3 inhibits aggregation in two very different amyloid systems: transthyretin and Aβ(1-42). Interestingly, Trp → Leu mutations renders the peptide ineffective against transthyretin, but Aβ inhibition remains. Computational docking was used to predict the interactions between trpzip-3 and transthyretin, suggesting that inhibition occurs via binding to the outer region of the thyroxine-binding site, which is supported by dye displacement experiments. PMID:24900756

  13. Research Advances in the Inhibition of Long Chain Fatty Acid to Methanogenic Activity in Anaeroic Digestion System

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    This article reviewed the inhibition mechanism of long chain fatty acid on the formation of anaerobic system, then thoroughly analyzed the inhibition factors of long chain fatty acid, and summarized the remission method to its inhibition, finally proposed some suggestions to further study on the influence of long chain fatty acid on anaerobic digestion system.

  14. Lipid Peroxidation Inhibitation Activity of Maillard Reaction Products Derived from Sugar-amino Acid Model Systems

    Directory of Open Access Journals (Sweden)

    Nanjing Zhong

    2015-08-01

    Full Text Available The present study aimed to evaluate the lipid peroxidation inhibitation activity of Maillard Reaction Products (MRPs derived from sugar (glucose, fructose, lactose and maltose and 18 amino acid model systems in soybean oil. MRPs were produced by heating at 130°C for 2 h. Of the 18 amino acids-fructose model systems studied, MRPs derived from fructose-leucine, fructose-methionine, fructose-phenylalanine and fructose-isoleucine model sytems showed high lipid peroxidation inhibitation activity and best performance was observed from fructose-phenylalanine MRPs. Interestingly, glucose-phenylalanine MRPs also exhibited high inhibitation activity and inhibitation activity of both glucose-phenylalanine and fructose-phenylalanine MRPs exceeded 87% even with concentration at 1.1 wt % after 8 days storage.

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

    Czech Academy of Sciences Publication Activity Database

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

    2012-01-01

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

  16. Upregulation of the Renin-Angiotensin-Aldosterone-Ouabain System in the Brain Is the Core Mechanism in the Genesis of All Types of Hypertension

    OpenAIRE

    Hakuo Takahashi

    2012-01-01

    Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease blood pressure in resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered....

  17. Effects of hydrolysis and digestion in vitro on the activity of bovine plasma hydrolysates as inhibitors of the angiotensin I converting enzyme

    OpenAIRE

    Leidy Johanna Gómez Sampedro; José Edgar Zapata Montoya

    2014-01-01

    The angiotensin I-converting enzyme (ACE) inhibiting activity of bovine plasma hydrolyzates obtained by Alcalase 2.4 L at different degrees of hydrolysis (DH) was evaluated. For the evaluation of ACE inhibition (ACEI), Hippuryl-His-Leu was used as substrate and the amount of hippuric acid liberated by non-inhibiting ACE was determined by spectrophotometry at 228 nm. The results showed that the enzymatic hydrolysis increased the ACEI activity as compared with the un-hydrolyzed plasma. The high...

  18. Changes of Plasma Angiotensin-Converting Enzyme Activity during Hemodialysis *

    OpenAIRE

    Koo, Wan Suh; Lee, Yong Joon; Kim, Hye Su; Kim, Suk Young; Choi, Euy Jin; Chang, Yoon Sik; Yoon, Young Suk; Bang, Byung Kee

    1987-01-01

    Plasma angiotensin-converting enzyme activity was measured by spectrophotometer in normal subjects and in patients with end stage renal failure, serially during a routine hemodialysis. Patients on maintenance hemodialysis tended to be associated with elevated plasma angiotensin-converting enzyme activity versus normal subjects. Plasma angiotensin-converting enzyme activity was significantly elevated in patients with chronic renal failure after 5 hours of hemodialysis(p

  19. Documentation of angiotensin II receptors in glomerular epithelial cells

    Science.gov (United States)

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

    1998-01-01

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

  20. The pressor effect of angiotensin-(1-7 in the rat rostral ventrolateral medulla involves multiple peripheral mechanisms

    Directory of Open Access Journals (Sweden)

    Rita C. Oliveira

    2013-01-01

    Full Text Available OBJECTIVE: In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7 in the rostral ventrolateral medulla was investigated. METHOD: Angiotensin-(1-7 (25 pmol was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium or a vasopressin V1 receptor antagonist [d(CH25 -Tyr(Me-AVP] given alone or in combination. RESULTS: Unexpectedly, the pressor response produced by angiotensin-(1-7 (16 ± 2 mmHg, n = 12, which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7 at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7 at the rostral ventrolateral medulla. CONCLUSION: These results indicate that angiotensin-(1-7 triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

  1. Angiotensin Receptors, Autoimmunity, and Preeclampsia1

    OpenAIRE

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

    2007-01-01

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

  2. Serum angiotensin converting enzyme in pneumonias.

    OpenAIRE

    Kerttula, Y; Weber, T H

    1986-01-01

    Serum concentrations of angiotensin converting enzyme (ACE) were studied in pneumonias caused by different pathogens and in cases in which the aetiology could not be defined. In all aetiological groups, except in viral pneumonia, there was a significant increase in ACE during recovery (p less than 0.001). In several patients the lowest values during the acute phase of disease and the highest values during recovery were outside the reference limits. In cases with known aetiology the highest AC...

  3. Inhibitor and substrate binding by angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Wang, Xuemei; Wu, Shanshan; Xu, Dingguo;

    2011-01-01

    . In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular......Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood...... computational protocol. Implications to ACE catalysis are discussed....

  4. 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.

  5. 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

    Science.gov (United States)

    Montes-Cobos, Elena; Li, Xiao; Fischer, Henrike J.; Sasse, André; Kügler, Sebastian; Didié, Michael; Toischer, Karl; Fassnacht, Martin; Dressel, Ralf; Reichardt, Holger M.

    2015-01-01

    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. PMID:26605921

  6. The Functional Angiotensin Converting Enzyme Gene I/D Polymorphism Does not Alter Susceptibility to Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Whitcomb DC

    2004-11-01

    Full Text Available CONTEXT: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. The angiotensin converting enzyme is a key enzyme in the renin-angiotensin system. A deletion polymorphism of a 287-bp fragment of intron 16 of the angiotensin converting enzyme gene allele results in higher levels of circulating enzyme. ACE deletion genotype has been linked to heart diseases, sarcoidosis and liver fibrosis. The pancreatic renin-angiotensin system plays a role in the development of pancreatic fibrosis and ACE inhibitors decrease pancreatic fibrosis in experimental models. OBJECTIVES: We investigated the frequency of the ACE gene insertion/deletion polymorphism in chronic pancreatitis patients and controls. PATIENTS: Subjects with familial pancreatitis (n=51, sporadic chronic pancreatitis (n=104, and healthy controls (n=163 were evaluated. MAIN OUTCOME MEASURE: The presence of ACE insertion/deletion polymorphism. RESULTS: The frequency of the ACE gene deletion allele was similar in familial pancreatitis (49.0% sporadic pancreatitis (51.0% and controls (55.8%. Furthermore, there was no significant difference in clinical features between patients with ACE-insertion or insertion/deletion genotypes vs. patients with ACE-deletion genotype. CONCLUSION: We conclude that the ACE deletion genotype does not make a significant contribution to the pathogenesis and the progression of chronic pancreatitis.

  7. Inhibition of angiogenesis by platelets in systemic sclerosis patients

    OpenAIRE

    Hirigoyen, Daniela; Burgos, Paula I.; Mezzano, Veronica; Duran, Josefina; Barrientos, Magaly; Saez, Claudia G.; Panes, Olga; Mezzano, Diego; Iruretagoyena, Mirentxu

    2015-01-01

    Introduction Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angi...

  8. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil

    Directory of Open Access Journals (Sweden)

    Carlos Ferrario

    2009-03-01

    Full Text Available Carlos FerrarioHypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USAAbstract: Endothelial dysfunction is the common link between cardiovascular disease risk factors and the earliest event in the cascade of incidents that results in target organ damage. Angiotensin II, the terminal pressor effector arm of the renin-angiotensin-aldosterone system, increases blood pressure (BP by vasoconstriction and sodium and fluid retention, and has a pro-oxidative action that induces endothelial dysfunction and contributes to vascular remodeling. Angiotensin receptor blockers (ARBs reduce BP and morbidity and mortality in patients with hypertension, ventricular hypertrophy, diabetes mellitus, and renal disease. Olmesartan medoxomil is a long-acting, well-tolerated, effective ARB that prevents or reverses endothelial dysfunction in animal models of atherosclerosis, hypertension, diabetes, nephropathy, and retinopathy. Olmesartan medoxomil, a prodrug of olmesartan approved for the treatment of hypertension, has been shown to ameliorate endothelial dysfunction in patients with hypertension or diabetes. In randomized studies, the drug reduces vascular inflammation and the volume of large atherosclerotic plaques, increases the number of regenerative endothelial progenitor cells in the peripheral circulation, improves endothelium-dependent relaxation, and restores the normal resistance vessel morphology. Importantly, the impact of olmesartan medoxomil on endothelial dysfunction is thought to be independent of BP lowering.Keywords: endothelial dysfunction, angiotensin receptor blocker, olmesartan medoxomil, hypertension, atherosclerosis 

  9. Formation and Inhibition of Nε-(Carboxymethyllysine in Saccharide-Lysine Model Systems during Microwave Heating

    Directory of Open Access Journals (Sweden)

    Bing Li

    2012-10-01

    Full Text Available  Nε-(carboxymethyl lysine (CML is the most abundant advanced glycation end product (AGE, and frequently selected as an AGEs marker in laboratory studies. In this paper, the formation and inhibition of Nε-(carboxymethyllysine in saccharide-lysine model systems during microwave heating have been studied. The microwave heating treatment significantly promoted the formation of CML during Maillard reactions, which was related to the reaction temperature, time and type of saccharide. The order of CML formation for different saccharides was lactose > glucose > sucrose. Then, the inhibition effect on CML by five inhibitors was further examined. According to the results, ascorbic acid and tocopherol did not affect inhibition of CML, in contrast, thiamin, rutin and quercetin inhibited CML formation, and the inhibitory effects were concentration dependent.

  10. Quantum Chemistry Calculation of Angiotensin Converting Enzyme Inhibitors

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Angiotensin Converting-Enzyme (ACE) inhibitors are potential drugs for hypertension.There are three requirements to be necessary for successful inhibition of ACE:1) a functional group capable of binding to zine in the active site (i.e.carboxylate,phosphonate,or sulfhydryl);2) a carbonyl oxygen capable of accepting a hydryogen bond from some donor residue functional groups and 3) an ionizable C-terminal carboxylate moiety which interacts with positively charged residue〔1〕. We reported active conformers of some ACE inhibitor molecules,which were derived by Distance Comparison〔2〕.In this paper,the electronic structure of the lowest energy conformers and active conformers of the ACE inhibitor molecules (Figure 1) were calculated through ab initio calculation by using Gaussian94 package.The Density Functional Theory (DFT) method and 6-31G** basis set were used 〔3〕.The calculation results were listed in Table 1.The total energies、HOMO energies and the charges of the marked atoms of all active conformers were higher than that of the correspondent lowest energy conformers.They were useful clues for designing novel analogs to inhibit the activity of ACE.

  11. Natural products inhibitors of the angiotensin converting enzyme (ACE: a review between 1980 - 2000 Produtos naturais inibidores da enzima conversora de angiotensina (ECA: uma revisão entre 1980 - 2000

    Directory of Open Access Journals (Sweden)

    José M. Barbosa-Filho

    2006-09-01

    Full Text Available Inhibition of Angiotensin Converting Enzyme (ACE is a modern therapeutic target in the treatment of hypertension. Within the enzyme cascade of the renin-angiotensin system, ACE removes histidyl-leucine from angiotensin I to form the physiologically active octapeptide angiotensin II, one of the most potent known vasoconstrictors. Therefore, a rationale for treating hypertension would be to administer drugs or natural compounds which selectively inhibit ACE. The present work constitutes a review of the literature of plants and chemically defined molecules from natural sources with in vitro anti-hypertensive potential based on the inhibition of ACE. The review refers to 321 plants, the parts utilized, type of extract and whether they are active or not. It includes also the names of 158 compounds isolated from higher plants, marine sponges and algae, fungi and snake venom. Some aspects of recent research with natural products directed to produce anti-hypertensive drugs are discussed. In this review, 148 references were cited.A inibição da Enzima Conversora da Angiotensina (ECA é um alvo terapêutico moderno e eficaz no tratamento da hipertensão arterial. Na cascata enzimática que envolve o sistema renina-angiotensina, a ECA promove a remoção dos aminoácidos histidil-leucina da angiotensina I para formar o octapeptídio angiotensina II, a qual é fisiologicamente ativa em diversos sistemas, e considerado como um dos mais potentes vasoconstrictores endógenos conhecido. Portanto, uma racionalidade no tratamento da hipertensão seria administrar drogas ou compostos de origem natural que inibam seletivamente a ECA. O presente estudo constitui uma revisão da literatura sobre plantas e moléculas de origem natural com potencial anti-hipertensivo, baseado na inibição in vitro da ECA. A revisão referencia 321 plantas, partes usadas, tipo de extrato e se é ativo ou não. Inclui ainda o nome de 158 compostos isolados de plantas superiores

  12. Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease

    Science.gov (United States)

    Zhang, Yanling; Thai, Kerri; Kepecs, David M.; Gilbert, Richard E.

    2016-01-01

    Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD. PMID:26741142

  13. Inhibition of the classical pathway of the complement system by saliva of Amblyomma cajennense (Acari: Ixodidae).

    Science.gov (United States)

    Franco, Paula F; Silva, Naylene C S; Fazito do Vale, Vladimir; Abreu, Jéssica F; Santos, Vânia C; Gontijo, Nelder F; Valenzuela, Jesus G; Pereira, Marcos H; Sant'Anna, Mauricio R V; Gomes, Alessandra P S; Araujo, Ricardo N

    2016-05-01

    Inhibition of the complement system during and after haematophagy is of utmost importance for tick success in feeding and tick development. The role of such inhibition is to minimise damage to the intestinal epithelium as well as avoiding inflammation and opsonisation of salivary molecules at the bite site. Despite its importance, the salivary anti-complement activity has been characterised only in species belonging to the Ixodes ricinus complex which saliva is able to inhibit the alternative and lectin pathways. Little is known about this activity in other species of the Ixodidae family. Thus, the aim of this study was to describe the inhibition of the classical pathway of the complement system by the saliva of Amblyomma cajennense at different stages of the haematophagy. The A. cajennense saliva and salivary gland extract (SGE) were able to inhibit the complement classical pathway through haemolytic assays with higher activity observed when saliva was used. The anti-complement activity is present in the salivary glands of starving females and also in females throughout the whole feeding process, with significant higher activity soon after tick detachment. The SGE activity from both females fed on mice or horses had no significant correlation (p > 0.05) with tick body weight. The pH found in the intestinal lumen of A. cajennense was 8.04 ± 0.08 and haemolytic assays performed at pH 8.0 showed activation of the classical pathway similarly to what occurs at pH 7.4. Consequently, inhibition could be necessary to protect the tick enterocytes. Indeed, the inhibition observed by SGE was higher in pH 8.0 in comparison to pH 7.4 reinforcing the role of saliva in protecting the intestinal cells. Further studies should be carried out in order to identify the inhibitor molecule and characterise its inhibition mechanism. PMID:26948715

  14. AT2R autoantibodies block angiotensin II and AT1R autoantibody-induced vasoconstriction.

    Science.gov (United States)

    Liles, Campbell; Li, Hongliang; Veitla, Vineet; Liles, Jonathan T; Murphy, Taylor A; Cunningham, Madeleine W; Yu, Xichun; Kem, David C

    2015-10-01

    Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with angiotensin II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on angiotensin II-induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental angiotensin II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared with normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for the study of their roles in blood pressure regulation and possible therapeutic intervention. PMID:26259590

  15. BRAF inhibition improves tumor recognition by the immune system

    DEFF Research Database (Denmark)

    Donia, Marco; Fagone, Paolo; Nicoletti, Ferdinando;

    2012-01-01

    be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T......-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade...... expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to...

  16. Inhibition of Endosome-Lysosome System Acidification Enhances Porcine Circovirus 2 Infection of Porcine Epithelial Cells▿

    OpenAIRE

    Misinzo, Gerald; Delputte, Peter; Nauwynck, Hans

    2007-01-01

    Recently, Misinzo et al. (G. Misinzo, P. Meerts, M. Bublot, J. Mast, H. M. Weingartl, and H. J. Nauwynck, J. Gen. Virol. 86:2057-2068, 2005) reported that inhibiting endosome-lysosome system acidification reduced porcine circovirus 2 (PCV2) infection of monocytic 3D4/31 cells. The present study examined the effect of inhibiting endosome-lysosome system acidification in epithelial cells, since epithelial cells support PCV2 infection in vivo and are used in culturing PCV2 in vitro. Ammonium chl...

  17. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chatsudthipong, V.; Chan, Y.L.

    1986-03-01

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

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

    International Nuclear Information System (INIS)

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

  20. The role of renin-angiotensin-aldosterone system in salty taste and sodium intake regulation%肾素-血管紧张素-醛固酮系统在咸味觉功能及摄钠调控中的作用

    Institute of Scientific and Technical Information of China (English)

    吕波; 闫剑群

    2011-01-01

    咸味觉感受功能对摄钠行为的引导和调控至关重要,体钠平衡失调将引起一系列神经内分泌变化以产生钠欲,并伴有咸味觉感受功能的变化.肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system,RAAS)的多个成分在体钠平衡失调对咸味觉功能的调控中扮演重要角色.外周及脑源性血管紧张素II(angiotensin II,ANG II)和醛固酮(aldosterone,ALD)可协同作用于中枢相应敏感神经元,调控动物咸味觉喜好及敏感性,进而调控摄钠行为,并帮助机体维持体钠平衡.

  1. Measures of Behavioral Inhibition and Activation System Sensitivity as Predictors of Big Five Personality Traits

    OpenAIRE

    Valerija Križanić; Zrinka Greblo; Zvonimir Knezović

    2015-01-01

    In the Reinforcement Sensitivity Theory, Gray (1987) described three hypothetical biological brain systems, assumed to represent underpinnings of the stable patterns of experience and behaviour. Most research has been devoted to studying behavioural inhibition system (BIS) and behavioural activation system (BAS), which have shown relatively stable associations with neuroticism and extroversion, respectively. BIS/BAS scale (Carver & White, 1994) is one of the most frequently used instrumen...

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

    OpenAIRE

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

    2012-01-01

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

  3. Genetic silencing of Nox2 and Nox4 reveals differential roles of these NADPH oxidase homologues in the vasopressor and dipsogenic effects of brain angiotensin-II

    OpenAIRE

    Peterson, Jeffrey R.; Burmeister, Melissa A.; TIAN, XIN; Zhou, Yi; Guruju, Mallikarjuna R.; Stupinski, John A.; Sharma, Ram V.; Davisson, Robin L.

    2009-01-01

    The renin angiotensin system (RAS) exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of the RAS, acts in the CNS to regulate neurohumoral outflow and thirst. Dysregulation of Ang-II signaling in the CNS is implicated in cardiovascular diseases, however the mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)-derived superoxide acting in the forebrain subfornical organ (SFO) is critical in the ...

  4. Nitric oxide impacts on angiotensin AT2 receptor modulation of high-pressure baroreflex control of renal sympathetic nerve activity in anaesthetized rats

    OpenAIRE

    Abdulla, M H; Johns, E. J.

    2013-01-01

    Aim Nitric oxide (NO) interacts with the local brain renin-angiotensin system to modulate sympathetic outflow and cardiovascular homoeostasis. This study investigated whether NO influenced the ability of angiotensin AT2 receptor activation to modify the high-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR). Methods Anaesthetized (chloralose/urethane) rats were prepared to allow generation of baroreflex gain curves for RSNA or HR following intrace...

  5. High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

    OpenAIRE

    Samuel, Preethi; Ali, Quaisar; Sabuhi, Rifat; Wu, Yonnie; Hussain, Tahir

    2012-01-01

    High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II recept...

  6. Identification of Angiotensin I-Converting Enzyme Inhibitory Peptides Derived from Enzymatic Hydrolysates of Razor Clam Sinonovacula constricta

    OpenAIRE

    Yun Li; Sadiq, Faizan A.; Li Fu; Hui Zhu; Minghua Zhong; Muhammad Sohail

    2016-01-01

    Angiotensin I-converting enzyme (ACE) inhibitory activity of razor clam hydrolysates produced using five proteases, namely, pepsin, trypsin, alcalase, flavourzyme and proteases from Actinomucor elegans T3 was investigated. Flavourzyme hydrolysate showed the highest level of degree of hydrolysis (DH) (45.87%) followed by A. elegans T3 proteases hydrolysate (37.84%) and alcalase (30.55%). The A. elegans T3 proteases was observed to be more effective in generating small peptides with ACE-inhibit...

  7. Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay

    OpenAIRE

    Sharifi, Niusha; Souri, Effat; Ziai, Seyed Ali; Amin, Gholamreza; Amanlou, Massoud

    2013-01-01

    Background and purpose of the study Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension. The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay. Methods The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC). Total phenolic content and antioxi...

  8. Angiotensin II-Induced Production of Mitochondrial Reactive Oxygen Species: Potential Mechanisms and Relevance for Cardiovascular Disease

    OpenAIRE

    Dikalov, Sergey I.; Nazarewicz, Rafal R.

    2013-01-01

    Significance: The role of reactive oxygen species (ROS) in angiotensin II (AngII) induced endothelial dysfunction, cardiovascular and renal remodeling, inflammation, and fibrosis has been well documented. The molecular mechanisms of AngII pathophysiological activity involve the stimulation of NADPH oxidases, which produce superoxide and hydrogen peroxide. AngII also increases the production of mitochondrial ROS, while the inhibition of AngII improves mitochondrial function; however, the speci...

  9. Development of a Spectrophotometric Method for Monitoring Angiotensin-Converting Enzyme in Dairy Products

    Directory of Open Access Journals (Sweden)

    Julijana Tomovska*, S. Presilski, N. Gjorgievski, N. Tomovska1, M. S. Qureshi2 and N. P. Bozinovska3

    2013-01-01

    Full Text Available The angiotensin-converting enzyme (ACE regulates the levels of blood pressure through generation of angiotensin-II from angiotensin-I. It is of great importance to have a reliable and yet simple method for a quantitative determination ACE inhibitory peptides in whey of milk products. A rapid, simple, sensitive and accurate spectrophotometric kinetic method has been developed for determination of ACE inhibitory peptides, using competitive inhibition. Samples of dairy product from the market were used for the determination of ACE inhibitory peptides in whey. Holmquist’s kinetic method was used for determining ACE inhibitory activity in blood serum and Ronca-Testoni method was used for the determination of ACE inhibitory activity in whey. Enzymatic inhibition activity was determined using 0.8 mmol/L FAPGG (N-[3-(Furyl –Acryloyl]-L-Phenylalanyl Glycyl Glycyne as the substrate in 50 mmol/L Tris buffer at pH 8.2 at 37°C and a standard serum containing ACE. First, a solution of whey was mixed in a 1 to 10 ratio with serum (elevation containing high ACE activity. The enzymatic activity was determined by monitoring the decrease in absorbance at 340 nm as result of hydrolysis of the substrate. The concentration of ACE inhibitory peptides was determined from a standard curve of inhibitor concentration versus percent of ACE inhibition. The study suggests that the method possesses good reproducibility and accuracy. The linear range enabled determination of high enzymatic activity of ACE and all ACE inhibitory peptides from dairy products act as competitive inhibitors.

  10. Inhibition Effect of Mace Extract Microemulsion on Vitamin C Photooxidation in Aqueous Systems

    Directory of Open Access Journals (Sweden)

    Hasbullah Hasbullah

    2014-01-01

    Full Text Available Photooxidation in food systems cause nutritional losses and produces undesirable flavor, toxic and color compounds, which make foods less acceptable or unacceptable to consumers. The objective of this research was to know the effectiveness of mace extract microemulsion to inhibit vitamin C photooxidation in aqueous systems. Aqueous food systems used are both beverage model system and apple juice beverage, where in each system enriched by 100 ppm vitamin C as substrate and 20 ppm erytrosin as photosensitiser. It is about one percent and two percent of microemulsion that contain mace extract of 0, 500 and 750 ppm were added into each of aqueous food system. Inhibition effect of mace extract microemulsion toward vitamin C photooxidation based on the rate of vitamin C degradation in aqueous food systems that illuminated by fluorescent light with 2000 lux intensity within eight hours. The result indicated the mace extract microemulsion has anti-photooxidation activity and ability to inhibit vitamin C photooxidation in aqueous systems.

  11. Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1.

    Science.gov (United States)

    Abd Allah, Eman S H; Gomaa, Asmaa M S

    2015-10-01

    Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy. PMID:26398443

  12. 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.

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

    Science.gov (United States)

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

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. PMID:26612192

  14. Isolation of an angiotensin converting enzyme (ACE) inhibitor from Olea europea and Olea lancea

    DEFF Research Database (Denmark)

    Hansen, K; Adsersen, A.; Brøgger Christensen, S.;

    1996-01-01

    The aqueous extract of the leaves of Olea europea and Olea lancea both inhibited Angiotensin Converting Enzyme (ACE) in vitro. A bioassay-directed fractionation resulted in the isolation of a strong ACE-inhibitor namely the secoiridoid 2-(3,4-dihydroxyphenyl)ethyl 4-formyl-3-(2-oxoethyl)-4E...... have not been described previously in the literature as inhibitors of ACE. Oleacin showed a low toxicity in the brine shrimp (Artemia salina) lethality test (LC50(24 h) = 969 ppm).......-hexenoate (oleacin)(IC50 = 26 myM). Five secoiridoid glucosides (oleuropein, ligstroside, excelsioside, oleoside 11-methyl ester, oleoside) isolated from Oleaceous plants showed no significant ACE-inhibition whereas, after enzymatic hydrolysis, the ACE-inhibition at 0.33 mg/ml was between 64% to 95%. Secoiridoids...

  15. Transcellular transport of angiotensin II through a cultured arterial endothelial monolayer

    International Nuclear Information System (INIS)

    We have studied the mechanisms of angiotensin II (A-II) transport through a cultured arterial endothelial cell monolayer. The transport of 125I-labeled A-II was inhibited by excess unlabeled A-II (50 microM) and [Sar1, Ile8]-A-II (50 microM), but was not inhibited by bradykinin (50 microM). The transport process was shown to be temperature dependent and was inhibited by 10 mM NaN3 plus 50 mM 2-deoxyglucose. Monensin (50 microM), an inhibitor of endocytotic trafficking, reduced the rate of transport of 125I-A-II. It is also shown that the specific pathway for A-II transport was unidirectional from the apical to the basolateral surface of the endothelial cell monolayer

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

    International Nuclear Information System (INIS)

    Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22phox, p47phox, p67phox, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H2O2. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac fibroblast growth and collagen formation

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-15

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

  18. Inhibition of corrosion of carbon steel by heptane sulphonic acid – Zn2+ system

    Directory of Open Access Journals (Sweden)

    C. MARY ANBARAS

    2012-03-01

    Full Text Available Corrosion inhibition of carbon steel in dam water by sodium heptane sulphonate (SHS and zinc ion system was investigated using weight loss and potentiodynamic polarization methods. Results of weight loss method indicated that inhibition efficiency (IE increased as the inhibitor concentration increased. A synergistic effect existed between SHS and Zn2+. The influence of sodium potassium tartrate (SPT on the IE of the SHS-Zn2+ system was evaluated. As the immersion period increased, the IE decreased. Polarization study revealed that SHS-Zn2+ system functioned as a cathodic inhibitor. AC impedance spectra revealed that a protective film was formed on the metal surface. The nature of the metal surface was analyzed by FTIR spectra, SEM and AFM analyses.

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Update on the role of regional renin-angiotensin system in cutaneous wound repair and regeneration%局部组织肾素-血管紧张素系统在皮肤损伤修复和再生中的作用

    Institute of Scientific and Technical Information of China (English)

    刘宏伟; 程飚; 付小兵

    2011-01-01

    @@ 随着对皮肤生物学功能认识的深入,人们发现皮肤是一个内分泌器官和激素、神经递质敏感性器官.皮肤的神经-内分泌系统包括局部产生神经-内分泌介导子(neuro-endocrine mediators),与相应的特异性受体通过旁分泌和自分泌产生作用,在组织修复与再生过程中扮演重要角色[1].%Accumulating evidence has indicated that the skin can serve as a peripheral neuroendocrine organ,and is also a target organ of hormones and neurotransmitters.The cutaneous neuroendocrine system plays a critical role in tissue repair and regeneration through their special receptors in the paracrine or autocrine manner.Renin - angiotensin system( RAS )is one of the several important hormonal systems, which regulates global and local homeostasis.During the last decade, completely new aspects have emerged in the field of RAS research.It is clear that angiotensin Ⅱ ( Ang Ⅱ ) , a key peptide of RAS, plays a role not only in regulation of blood pressure and body fluids but also in cell proliferation and differentiation.Ang Ⅱ has been showed to be involved in cutaneous self - turnover, embryonic development as well as repair and remodeling.This review mainly presents the evidence that skin is a source and target organ of RAS, and RAS plays roles in cutaneous wound repair and regeneration.