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Sample records for angiotensin system inhibition

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

    Science.gov (United States)

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

    2011-08-01

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

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

    Science.gov (United States)

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

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

  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. Renin–angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis

    DEFF Research Database (Denmark)

    Bang, Casper N; Greve, Anders M; Køber, Lars

    2014-01-01

    BACKGROUND: Renin-angiotensin system inhibition (RASI) is frequently avoided in aortic stenosis (AS) patients because of fear of hypotension. We evaluated if RASI with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) increased mortality in patients with mild...

  5. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV Mcmurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved. There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  6. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV McMurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses.The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved.There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  7. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system

    NARCIS (Netherlands)

    Roks, AJM; van Geel, PP; Pinto, YM; Buikema, H; Henning, RH; de Zeeuw, D; van Gilst, WH

    The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to

  8. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system

    NARCIS (Netherlands)

    Roks, A. J.; van Geel, P. P.; Pinto, Y. M.; Buikema, H.; Henning, R. H.; de Zeeuw, D.; van Gilst, W. H.

    1999-01-01

    The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to

  9. 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

  10. Persistent phenotypic shift in cardiac fibroblasts: impact of transient renin angiotensin system inhibition.

    Science.gov (United States)

    Hale, Taben M

    2016-04-01

    Fibrotic cardiac remodeling ultimately leads to heart failure - a debilitating and costly condition. Select antihypertensive agents have been effective in reducing or slowing the development of cardiac fibrosis. Moreover, some experimental studies have shown that the reduction in fibrosis induced by these agents persists long after stopping treatment. What has not been as well investigated is whether this transient treatment results in a protection against future fibrotic cardiac remodeling. In the present review, previously published studies are re-examined to assess whether the relative percent increase in collagen deposition over an off-treatment period is attenuated, relative to control, following transient antihypertensive treatment in young or adult rats. Present findings suggest that transient inhibition of the renin angiotensin system (RAS) not only produces a sustained reduction in cardiac fibrosis, but also results in a degree of protection against future collagen deposition. In addition, prior transient RAS inhibition appears to alter the cardiac fibroblast phenotype such that these cells show a muted response to myocardial injury - namely reduced proliferation, chemokine release, and collagen deposition. This review puts forth several potential mechanisms underlying this long-term cardiac protection that is afforded by transient RAS inhibition. Specifically, fibroblast phenotypic change, cardiac fibroblast apoptosis, sustained suppression of the RAS, persistent reduction in left ventricular hypertrophy, and persistent reduction in arterial pressure are each discussed. Identifying the mechanisms ultimately responsible for this change in cardiac fibroblast response to injury, hypertension, and aging may reveal novel targets for therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

    Su, Qing; Qin, Da-Nian; Wang, Fu-Xin; Ren, Jun; Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie; Zhu, Zhiming; Zhu, Guo-Qing; Kang, Yu-Ming

    2014-01-01

    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 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 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

  12. 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.

  13. Daily sesame oil supplementation attenuates local renin-angiotensin system via inhibiting MAPK activation and oxidative stress in cardiac hypertrophy.

    Science.gov (United States)

    Liu, Chuan-Teng; Liu, Ming-Yie

    2017-04-01

    The renin-angiotensin system (RAS) is involved in the development of left ventricular hypertrophy (LVH) by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a potent antioxidant, attenuates hypertension-dependent LVH. We examined the protective role of sesame oil on RAS-mediated MAPK activation and oxidative stress in rats. We induced LVH using a hypertensive model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Cardiac histopathology, RAS parameters, expression of MAPKs, reactive oxygen species and lipid peroxidation were assessed 24 h after the last dose of sesame oil. Sesame oil significantly decreased the size of cardiomyocytes and the levels of cardiac renin, angiotensin-converting enzyme and angiotensin II. In addition, sesame oil down-regulated the expression of angiotensin type 1 receptor, JNK and p38 MAPK and apoptosis signal regulating kinase 1, c-Fos and c-Jun in rats receiving DOCA/salt. Furthermore, the induction of nicotinamide adenine dinucleotide phosphate oxidase, superoxide anion and hydroxyl radical and lipid peroxidation by DOCA/salt were inhibited by sesame oil. Sesame oil modulates cardiac RAS to ameliorate LVH by inhibiting MAPK activation and lowering oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture.

    Science.gov (United States)

    Gao, Xiao-Ming; Tsai, Alan; Al-Sharea, Annas; Su, Yidan; Moore, Shirley; Han, Li-Ping; Kiriazis, Helen; Dart, Anthony M; Murphy, Andrew J; Du, Xiao-Jun

    2017-04-01

    Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI. Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P infarct tissue were attenuated by losartan and/or perindopril treatment (all P acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    G. Albertoni

    2015-01-01

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

  17. 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.

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

    DEFF Research Database (Denmark)

    Lindhardt, Morten; Persson, Frederik; Currie, Gemma

    2016-01-01

    INTRODUCTION: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment...

  19. Sodium status and angiotensin-converting enzyme inhibition : effects on plasma angiotensin-(1-7) in healthy man

    NARCIS (Netherlands)

    Kocks, MJA; Lely, AT; Boomsma, F; de Jong, PE; Navis, G

    Objective Angiotensin-converting enzyme (ACE) inhibitors provide effective intervention for cardiovascular and renal disease. Changes in angiotensin-(1-7) have been proposed to be involved in the mechanism of action of ACE inhibition (ACEi). In particular, an altered balance between angiotensin II

  20. Response to angiotensin-converting enzyme inhibition is selectively blunted by high sodium in angiotensin-converting enzyme DD genotype : Evidence for gene-environment interaction in healthy volunteers

    NARCIS (Netherlands)

    Lely, A. Titia; Lambers Heerspink, Hiddo J.; Zuurman, Mike; Visser, Folkert W.; Kocks, Menno J. A.; Boomsma, Frans; Navis, Gerjan

    2010-01-01

    Background Renin-angiotensin-aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the

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

    NARCIS (Netherlands)

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

    1997-01-01

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

  2. Local renin-angiotensin systems

    NARCIS (Netherlands)

    A.H.J. Danser (Jan)

    1992-01-01

    textabstractThe aim of this thesis was twofold. First, the regional metabolism and production of angiotensin I and angiotensin U were quantified in vivo in man and in anesthetized pigs. This was done by giving constant infusions of radiolabelect J25J-angiotensin I into either a peripheral vein

  3. Angiotensin-converting enzyme inhibition in diabetic nephropathy

    DEFF Research Database (Denmark)

    Parving, H H; Rossing, P; Hommel, E

    1995-01-01

    The aim of our prospective study was to evaluate putative progression promoters, kidney function, and prognosis during long-term treatment with angiotensin-converting enzyme inhibition in insulin-dependent diabetes mellitus patients suffering from diabetic nephropathy. Eighteen consecutive......, albuminuria (geometric mean +/- antilog SE) 982 +/- 1.2 micrograms/min, and GFR 98 +/- 5 mL/min/1.73 m2. Angiotensin-converting enzyme inhibition induced a significant reduction during the whole treatment period of blood pressure (137/85 +/- 3/1 mm Hg; P

  4. Individual variability in response to renin angiotensin aldosterone system inhibition predicts cardiovascular outcome in patients with type 2 diabetes: A primary care cohort study.

    Science.gov (United States)

    Apperloo, Ellen M; Pena, Michelle J; de Zeeuw, Dick; Denig, Petra; Heerspink, Hiddo J L

    2018-01-18

    To assess variability in systolic blood pressure (SBP) and albuminuria (urinary albumin creatinine ratio [UACR]) responses in patients with type 2 diabetes mellitus initiating renin angiotensin aldosterone system (RAAS) inhibition, and to assess the association of response variability with cardiovascular outcomes. We performed an observational cohort study in patients with type 2 diabetes who started RAAS inhibition between 2007 and 2013 (n = 1600). Patients were identified from general practices in the Netherlands. Individual response in SBP and UACR was assessed during 15 months' follow-up. Patients were categorized as: good responders (∆SBP 0% or ∆SBP >0 mm Hg and ∆UACR 0 mm Hg and ∆UACR >0%). Multivariable Cox regression was performed to test the association between initial RAAS inhibition response and subsequent cardiovascular outcomes. After starting RAAS inhibition, the mean SBP change was -13.2 mm Hg and the median UACR was -36.6%, with large between-individual variability, both in SBP [5th to 95th percentile: 48.5-20] and UACR [5th to 95th percentile: -87.6 to 171.4]. In all, 812 patients (51%) were good responders, 353 (22%) had a good SBP but poor UACR response, 268 (17%) had a good UACR but poor SBP response, and 167 patients (10%) were poor responders. Good responders had a lower risk of cardiovascular events than poor responders (hazard ratio 0.51, 95% confidence interval 0.30-0.86; P = .012). SBP and UACR response after RAAS inhibition initiation varied between and within individual patients with type 2 diabetes treated in primary care. Poor responders had the highest risk of cardiovascular events, therefore, more efforts are needed to develop personalized treatment plans for these patients. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  5. Clinical impacts of inhibition of renin-angiotensin system in patients with acute ST-segment elevation myocardial infarction who underwent successful late percutaneous coronary intervention.

    Science.gov (United States)

    Park, Hyukjin; Kim, Hyun Kuk; Jeong, Myung Ho; Cho, Jae Yeong; Lee, Ki Hong; Sim, Doo Sun; Yoon, Nam Sik; Yoon, Hyun Ju; Hong, Young Joon; Kim, Kye Hun; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jim

    2017-01-01

    Successful percutaneous coronary intervention (PCI) of the occluded infarct-related artery (IRA) in latecomers may improve long-term survival mainly by reducing left ventricular remodeling. It is not clear whether inhibition of renin-angiotensin system (RAS) brings additional better clinical outcomes in this specific population subset. Between January 2008 and June 2013, 669 latecomer patients with acute ST-segment elevation myocardial infarction (STEMI) (66.2±12.1 years, 71.0% males) in Korea Acute Myocardial Infarction Registry (KAMIR) who underwent a successful PCI were enrolled. The study population underwent a successful PCI for a totally occluded IRA. They were divided into two groups according to whether they were prescribed RAS inhibitors at the time of discharge: group I (RAS inhibition, n=556), and group II (no RAS inhibition, n=113). During the one-year follow-up, major adverse cardiac events (MACE), which consist of cardiac death and myocardial infarction, occurred in 71 patients (10.6%). There were significantly reduced incidences of MACE in the group I (hazard ratio=0.34, 95% confidence interval 0.199-0.588, p=0.001). In subgroup analyses, RAS inhibition was beneficial in patients with male gender, history of hypertension or diabetes mellitus, and even in patients with left ventricular ejection fraction (LVEF) ≥40%. In the baseline and follow-up echocardiographic data, benefit in changes of LVEF and left ventricular end-systolic volume was noted in group I. In latecomers with STEMI, RAS inhibition improved long-term clinical outcomes after a successful PCI, even in patients with low risk who had relatively preserved LVEF. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

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

    1990-01-01

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

  7. The Renal Renin-Angiotensin System

    Science.gov (United States)

    Harrison-Bernard, Lisa M.

    2009-01-01

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

  8. Angiotensin-converting enzyme inhibition by Brazilian plants.

    Science.gov (United States)

    Braga, Fernão C; Serra, Carla P; Viana, Nilton S; Oliveira, Alaíde B; Côrtes, Steyner F; Lombardi, Júlio A

    2007-07-01

    The potential antihypertensive activity of Brazilian plants was evaluated in vitro by its ability to inhibit the angiotensin-converting enzyme (ACE). Forty-four plants belonging to 30 families were investigated. Plants were selected based on their popular use as antihypertensive and/or diuretics. The following plants presented significant ACE inhibition rates: Calophyllum brasiliense, Combretum fruticosum, Leea rubra, Phoenix roebelinii and Terminalia catappa.

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2018-04-03

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Angiotensin(Ang)-(1-7) is now recognized as a biologically active component of renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. ...

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  13. Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of renin-angiotensin system: a prospective observational study

    Directory of Open Access Journals (Sweden)

    De Nicola Luca

    2012-11-01

    Full Text Available Abstract Background Whether paricalcitol (PCT reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects. Methods Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day and three months after drug withdrawal. Results Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m2, diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline, proteinuria was 2.44 (95% CI 1.80-3.04 g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2–3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51. Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93, with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R2 = 0.459, P  Conclusions In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake.

  14. Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of renin-angiotensin system: a prospective observational study.

    Science.gov (United States)

    De Nicola, Luca; Conte, Giuseppe; Russo, Domenico; Gorini, Antonio; Minutolo, Roberto

    2012-11-20

    Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects. Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal. Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m(2), diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2-3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R(2) = 0.459, P proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake.

  15. The Effect of Angiotensin-Converting Enzyme Inhibition Using Captopril on Energy Balance and Glucose Homeostasis

    Science.gov (United States)

    de Kloet, Annette D.; Krause, Eric G.; Kim, Dong-Hoon; Sakai, Randall R.; Seeley, Randy J.; Woods, Stephen C.

    2009-01-01

    Increasing evidence suggests that the renin-angiotensin-system contributes to the etiology of obesity. To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril (∼40 mg/kg · d). Rats given captopril weighed less than controls when fed a high-fat diet (369.3 ± 8.0 vs. 441.7 ± 8.5 g after 35 d; P captopril ate significantly less [3110.3 ± 57.8 vs. 3592.4 ± 88.8 kcal (cumulative 35 d high fat diet intake); P captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for 2 d. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that angiotensin-converting enzyme inhibition protects against the development of diet-induced obesity and glucose intolerance. PMID:19497971

  16. Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography

    International Nuclear Information System (INIS)

    Sakaguchi, K.; Chai, S.Y.; Jackson, B.; Johnston, C.I.; Mendelsohn, F.A.

    1988-01-01

    Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [ 125 I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors

  17. Relationship Between Aldosterone and Parathyroid Hormone, and the Effect of Angiotensin and Aldosterone Inhibition on Bone Health

    DEFF Research Database (Denmark)

    L.S., Bislev; T., Sikjaer; L., Rolighed

    2015-01-01

    Emerging evidence suggests a stimulating effect of parathyroid hormone (PTH) on the reninnullangiotensinnullaldosterone system (RAAS). In primary hyperparathyroidism, chronic-elevated PTH levels seem to stimulate the RAAS which may explain the increased risk of cardiovascular disease (CVD......). In addition to increased PTH levels, low vitamin D levels may also directly increase risk of CVD, as vitamin D, itself, has been shown to inhibit the RAAS. Angiotensin II, aldosterone and cortisol all negatively impact bone health. Hyperaldosteronism is associated with a reversible secondary...... hyperparathyroidism due to increased renal calcium excretion. Moreover, the angiotensin II receptor is expressed by human parathyroid tissue, and angiotensin may therefore directly stimulates PTH secretion. An increased bone loss is found in patients with hyperaldosteronism. The angiotensin II receptor seems main...

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

    DEFF Research Database (Denmark)

    will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...... understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor...... research; Dr. Ulrike M. Steckelings, who contributed significantly to first preclinical studies with a novel specific AT2-agonist, and Dr. Robson Santos who pioneered research on angiotensin-(1-7) and its receptor Mas. Shows that the protective RAS axes are able to ameliorate the course of several...

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

    NARCIS (Netherlands)

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

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

  20. Classical Renin-Angiotensin system in kidney physiology.

    Science.gov (United States)

    Sparks, Matthew A; Crowley, Steven D; Gurley, Susan B; Mirotsou, Maria; Coffman, Thomas M

    2014-07-01

    The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardiovascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the "classical" renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the "classical" renin-angiotensin system, with an emphasis on new developments and modern concepts. © 2014 American Physiological Society.

  1. AVE 0991-angiotensin-(1-7) receptor agonist, inhibits atherogenesis in apoE-knockout mice.

    Science.gov (United States)

    Toton-Zuranska, J; Gajda, M; Pyka-Fosciak, G; Kus, K; Pawlowska, M; Niepsuj, A; Wolkow, P; Olszanecki, R; Jawien, J; Korbut, R

    2010-04-01

    Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.

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

    Science.gov (United States)

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

    2017-04-01

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

  3. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction

    Directory of Open Access Journals (Sweden)

    Paolo Verdecchia

    2008-10-01

    Full Text Available Paolo Verdecchia1, Fabio Angeli1, Giovanni Mazzotta1, Giorgio Gentile2, Gianpaolo Reboldi21Department of Cardiology, Clinical Research Unit ‘Preventive Cardiology’, Hospital ‘Santa Maria della Misericordia’, and Fondazione Umbra Cuore e Ipertensione – AUCI Onlus, Perugia, Italy; 2Department of Internal Medicine University of Perugia, ItalyAbstract: An association has been shown between plasma renin activity (PRA and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS can be inhibited through inhibition of angiotensin I (Ang I generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a lowmolecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.Keywords: plasma renin activity, renin angiotensin system, aliskiren, angiotensinogen, renin, hypertension, heart failure, diabetes

  4. Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis

    NARCIS (Netherlands)

    Wapstra, FH; vanGoor, H; Navis, G; deJong, PE; deZeeuw, D

    1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate, Inhibition of proteinuria might play a role, If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal

  5. 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 angiotensin...

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

    NARCIS (Netherlands)

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

    2001-01-01

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

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

    Science.gov (United States)

    Azevedo, Eduardo R; Mak, Susanna; Floras, John S; Parker, John D

    2017-10-01

    The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF. Copyright © 2017 the American Physiological Society.

  8. Regulation of the renin–angiotensin system in coronary atherosclerosis: A review of the literature

    Directory of Open Access Journals (Sweden)

    Ramadan A Hammoud

    2008-01-01

    Full Text Available Ramadan A Hammoud, Christopher S Vaccari, Sameer H Nagamia, Bobby V KhanEmory University School of Medicine, Division of Cardiology, Grady Memorial Hospital Vascular Research Laboratory, Atlanta, Georgia, USAAbstract: Activation of the renin–angiotensin system (RAS is significant in the pathogenesis of cardiovascular disease and specifically coronary atherosclerosis. There is strong evidence that the RAS has effects on the mechanisms of action of atherosclerosis, including fibrinolytic balance, endothelial function, and plaque stability. Pharmacological inhibition of the renin angiotensin system includes angiotensin converting enzyme (ACE inhibitors, angiotensin receptor blockers (ARBs, and renin inhibitors. These agents have clinical benefits in reducing morbidity and mortality in the management of hypertension. In addition, ACE inhibitors and ARBs have shown to be effective in the management of congestive heart failure and acute myocardial infarction. This review article discusses the biochemical and molecular mechanisms involving the RAS in coronary atherosclerosis as well as the effects of RAS inhibition in clinical studies involving coronary atherosclerosis.Keywords: angiotensin II, atherosclerosis, endothelium, inflammation, vasculature

  9. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) : Essential study design and rationale of a randomised clinical multicentre trial

    NARCIS (Netherlands)

    Lindhardt, Morten; Persson, Frederik; Currie, Gemma; Pontillo, Claudia; Beige, Joachim; Delles, Christian; von der Leyen, Heiko; Mischak, Harald; Navis, Gerjan; Noutsou, Marina; Ortiz, Alberto; Ruggenenti, Piero Luigi; Rychlik, Ivan; Spasovski, Goce; Rossing, Peter

    2016-01-01

    Introduction Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in

  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. Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension

    NARCIS (Netherlands)

    Rasoul, S; Carretero, OA; Peng, HM; Cavasin, MA; Zhuo, JL; Sanchez-Mendoza, A; Brigstock, DR; Rhaleb, NE

    Objective N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen

  12. The renin-angiotensin system: a possible new target for depression.

    Science.gov (United States)

    Vian, João; Pereira, Círia; Chavarria, Victor; Köhler, Cristiano; Stubbs, Brendon; Quevedo, João; Kim, Sung-Wan; Carvalho, André F; Berk, Michael; Fernandes, Brisa S

    2017-08-01

    Depression remains a debilitating condition with an uncertain aetiology. Recently, attention has been given to the renin-angiotensin system. In the central nervous system, angiotensin II may be important in multiple pathways related to neurodevelopment and regulation of the stress response. Studies of drugs targeting the renin-angiotensin system have yielded promising results. Here, we review the potential beneficial effects of angiotensin blockers in depression and their mechanisms of action. Drugs blocking the angiotensin system have efficacy in several animal models of depression. While no randomised clinical trials were found, case reports and observational studies showed that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had positive effects on depression, whereas other antihypertensive agents did not. Drugs targeting the renin-angiotensin system act on inflammatory pathways implicated in depression. Both preclinical and clinical data suggest that these drugs possess antidepressant properties. In light of these results, angiotensin system-blocking agents offer new horizons in mood disorder treatment.

  13. 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.)

  14. The renin-angiotensin system in kidney development

    DEFF Research Database (Denmark)

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

    2004-01-01

    Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the develo......Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data...... on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay...

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

    African Journals Online (AJOL)

    Original Research Article. Effect of Dual Blockade of Renin-Angiotensin Aldosterone. System on Proteinuria in Patients with Diabetic. Nephropathy and Advanced Azotemia. Hatice Odabas1, İlyas Capoglu2, Ramazan Cetinkaya3, Ali Riza Odabas3,. Abdullah Uyanik3 and Mustafa Keles3*. 1Department of Internal Medicine, ...

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

    Science.gov (United States)

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

    2015-05-01

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

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

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2008-01-01

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

  18. 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.

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

    OpenAIRE

    Yoon, Hye Eun; Choi, Bum Soon

    2014-01-01

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

  20. Purification and characterization of angiotensin I converting enzyme inhibition peptides from sandworm Sipunculus nudus

    Science.gov (United States)

    Sun, Xueping; Wang, Man; Liu, Buming; Sun, Zhenliang

    2017-10-01

    Three angiotensin I converting enzyme (ACE) inhibition peptides were isolated from sandworm Sipunculus nudus protein hydrolysate prepared using protamex. Consecutive purification methods, including size exclusion chromatography and reverse-phase high performance liquid chromatography (RP-HPLC), were used to isolate the ACE inhibition peptides. The amino acid sequences of the peptides were identified as Ile-Asn-Asp, Val-Glu-Pro-Gly and Leu-Ala-Asp-Glu-Phe. The IC50 values of the purified peptides for ACE inhibition activity were 34.72 μmol L-1, 20.55 μmol L-1 and 22.77 μmol L-1, respectively. These results suggested that S. nudus proteins contain specific peptides that can be released by enzymatic hydrolysis. This study may provide an experimental basis for further systematic research, rational development and clinical utilization of sandworm resources.

  1. Inhibition of angiotensin converting enzyme with enalapril maleate in infants with congestive heart failure.

    Science.gov (United States)

    Dutertre, J P; Billaud, E M; Autret, E; Chantepie, A; Oliver, I; Laugier, J

    1993-05-01

    We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg-1 enalapril maleate once a day. Baseline ACE activities were compared between these infants and control children without CHF or ACE inhibitor. Except for one infant who vomited, inhibition of ACE activity was 75.5 +/- 12.2%, 75.5 +/- 10.5% and 51.7 +/- 12.2%, at 4, 12 and 24 h after drug intake respectively. There was no correlation between postnatal age and inhibition of ACE activity. In infants with CHF, mean baseline ACE activity was significantly higher than in control infants (36.4 +/- 7.2 mu ml-1 vs 26.9 +/- 6.9 mu ml-1, P < 0.05). These results were very similar to those seen in adults.

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

    Directory of Open Access Journals (Sweden)

    C. Becari

    2011-09-01

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

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

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2004-01-01

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

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

    Science.gov (United States)

    Haber, E.

    1975-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2004-03-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2017-12-27

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  9. Cholera toxin but not pertussis toxin inhibits angiotensin II-enhanced contractions in the rat portal vein

    NARCIS (Netherlands)

    Zhang, J.; van Meel, J. C.; Pfaffendorf, M.; van Zwieten, P. A.

    1993-01-01

    Angiotensin II (Ang II)-enhanced phasic contractions in the rat portal vein were concentration dependently inhibited by cholera toxin (0.1-10 micrograms/ml) and dibutyryl cyclic AMP (0.1-1 mM), but not by pertussis toxin (1 micrograms/ml), which suggests that Gi is not involved in the Ang II signal

  10. 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

    and ACE inhibition, indicating that peptide measurement constitutes a convenient selection method. The effect of active fermentates on in vivo ACE activity was demonstrated in normotensive rats. The pressor effect of angiotensin I (0.3 μg/kg) upon intravenous injection was significantly lower when rats...

  11. 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

  12. 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.

  13. 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.

  14. Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition.

    Science.gov (United States)

    Bhat, Shahnawaz Ali; Goel, Ruby; Shukla, Rakesh; Hanif, Kashif

    2016-12-01

    Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 μg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 μM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling.

  15. 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.

  16. Renin-angiotensin system gene expression and neurodegenerative diseases.

    Science.gov (United States)

    Goldstein, Benjamin; Speth, Robert C; Trivedi, Malav

    2016-07-01

    Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases. Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease. A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis. No single nucleotide polymorphisms in any of the 14 RAS-related protein genes were significantly associated with the five neurodegenerative diseases investigated. There was an inverse association between expression of ATP6AP2, which encodes the (pro)renin receptor, and multiple sclerosis, Alzheimer's disease and Parkinson's disease. An association of AGTR, which encodes the AT1 angiotensin II receptor, and Parkinson's disease and Alzheimer's disease was also observed. To date, no single nucleotide polymorphisms in components of the RAS can be definitively linked to the neurodegenerative diseases evaluated in this study. However, altered gene expression of several components of the RAS is associated with several neurodegenerative diseases, which may indicate that the RAS contributes to the pathology of these diseases. © The Author(s) 2016.

  17. Renal oxygen content is increased in healthy subjects after angiotensin-converting enzyme inhibition

    Directory of Open Access Journals (Sweden)

    Anna Stein

    2012-07-01

    Full Text Available OBJECTIVE: The association between renal hypoxia and the development of renal injury is well established. However, no adequate method currently exists to non-invasively measure functional changes in renal oxygenation in normal and injured patients. METHOD: R2* quantification was performed using renal blood oxygen level-dependent properties. Five healthy normotensive women (50±5.3 years underwent magnetic resonance imaging in a 1.5T Signa Excite HDx scanner (GE Healthcare, Waukesha, WI. A multiple fast gradient-echo sequence was used to acquire R2*/T2* images (sixteen echoes from 2.1 ms/slice to 49.6 ms/slice in a single breath hold per location. The images were post-processed to generate R2* maps for quantification. Data were recorded before and at 30 minutes after the oral administration of an angiotensin II-converting enzyme inhibitor (captopril, 25 mg. The results were compared using an ANOVA for repeated measurements (mean + standard deviation followed by the Tukey test. ClinicalTrials.gov: NCT01545479. RESULTS: A significant difference (p<0.001 in renal oxygenation (R2* was observed in the cortex and medulla before and after captopril administration: right kidney, cortex = 11.08 ± 0.56ms, medulla = 17.21 ± 1.47ms and cortex = 10.30 ± 0.44ms, medulla = 16.06 ± 1.74ms, respectively; and left kidney, cortex= 11.79 ± 1.85ms, medulla = 17.03 ± 0.88ms and cortex = 10.89 ± 0.91ms, medulla = 16.43 ± 1.49ms, respectively. CONCLUSIONS: This result suggests that the technique efficiently measured alterations in renal blood oxygenation after angiotensin II-converting enzyme inhibition and that it may provide a new strategy for identifying the early stages of renal disease and perhaps new therapeutic targets.

  18. 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.

  19. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy.

    Science.gov (United States)

    Forbes, Josephine M; Thorpe, Suzanne R; Thallas-Bonke, Vicki; Pete, Josefa; Thomas, Merlin C; Deemer, Elizabeth R; Bassal, Sahar; El-Osta, Assam; Long, David M; Panagiotopoulos, Sianna; Jerums, George; Osicka, Tanya M; Cooper, Mark E

    2005-08-01

    Recent studies have identified that first-line renoprotective agents that interrupt the renin-angiotensin system not only reduce BP but also can attenuate advanced glycation end product (AGE) accumulation. This study used in vitro, preclinical, and human approaches to explore the potential effects of these agents on the modulation of the receptor for AGE (RAGE). Bovine aortic endothelial cells that were exposed to the angiotensin-converting enzyme inhibitor (ACEi) ramiprilat in the presence of high glucose demonstrated a significant increase in soluble RAGE (sRAGE) secreted into the medium. In streptozotocin-induced diabetic rats, ramipril treatment (ACEi) at 3 mg/L for 24 wk reduced the accumulation of skin collagen-linked carboxymethyllysine and pentosidine, as well as circulating and renal AGE. Renal gene upregulation of total RAGE (all three splice variants) was observed in ACEi-treated animals. There was a specific increase in the gene expression of the splice variant C-truncated RAGE (sRAGE). There were also increases in sRAGE protein identified within renal cells with ACEi treatment, which showed AGE-binding ability. This was associated with decreases in renal full-length RAGE protein from ACEi-treated rats. Decreases in plasma soluble RAGE that were significantly increased by ACEi treatment were also identified in diabetic rats. Similarly, there was a significant increase in plasma sRAGE in patients who had type 1 diabetes and were treated with the ACEi perindopril. Complexes between sRAGE and carboxymethyllysine were identified in human and rodent diabetic plasma. It is postulated that ACE inhibition reduces the accumulation of AGE in diabetes partly by increasing the production and secretion of sRAGE into plasma.

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

    Science.gov (United States)

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

    2009-04-01

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

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

    Science.gov (United States)

    Yoon, Hye Eun; Choi, Bum Soon

    2014-05-01

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

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

    Science.gov (United States)

    Luo, Jinghong; Chen, Xuanlan; Luo, Chufan; Lu, Guihua; Peng, Longyun; Gao, Xiuren; Zuo, Zhiyi

    2017-04-01

    Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects. © 2016 John Wiley & Sons Ltd.

  3. Involvement of Renin-Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice.

    Science.gov (United States)

    Liu, Jin-Xin; Wang, Liang; Zhang, Yan

    2015-01-01

    This study was performed to investigate the effect of angiotensin-converting enzyme inhibitor, captopril, on bone metabolism and histology, and the action of captopril on the components of the skeletal renin-angiotensin system (RAS) and bradykinin receptor in normal male mice. The mice were orally administered captopril (10 mg/kg) for 4 weeks with vehicle-treated mice as normal control. The histology of trabecular bone at the distal femoral end was determined by hematoxylin & eosin, Safranin O and Masson-Trichrome staining. The captopril-treated mice showed a decreased level of testosterone (pCaptopril has detrimental effects on trabecular bone as demonstrated by the loss of cancellous bone mass and network connections as well as changes to the chondrocytes zone. The expression of angiotensin-converting enzyme (pcaptopril treatment. Thus, the potential underlying mechanism of the damage of captopril on bone can be attributed the increased activity of local bone RAS and the activation of bradykinin receptor.

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  5. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension

    Science.gov (United States)

    De Man, Frances; Tu, Ly; Handoko, Louis; Rain, Silvia; Ruiter, Gerrina; François, Charlène; Schalij, Ingrid; Dorfmüller, Peter; Simonneau, Gérald; Fadel, Elie; Perros, Frederic; Boonstra, Anco; Postmus, Piet; Van Der Velden, Jolanda; Vonk-Noordegraaf, Anton; Humbert, Marc; Eddahibi, Saadia; Guignabert, Christophe

    2012-01-01

    Rationale Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems like renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system are upregulated but this may have long-term negative effects on the progression of iPAH. Objectives Assess systemic and pulmonary RAAS-activity in iPAH-patients and determine the efficacy of chronic RAAS-inhibition in experimental PAH. Measurements and Main Results We collected 79 blood samples from 58 iPAH-patients in the VU University Medical Center Amsterdam (between 2004–2010), to determine systemic RAAS-activity. We observed increased levels of renin, angiotensin (Ang) I and AngII, which was associated with disease progression (p<0.05) and mortality (p<0.05). To determine pulmonary RAAS-activity, lung specimens were obtained from iPAH-patients (during lung transplantation, n=13) and controls (during lobectomy or pneumonectomy for cancer, n=14). Local RAAS-activity in pulmonary arteries of iPAH-patients was increased, demonstrated by elevated ACE-activity in pulmonary endothelial cells and increased AngII type 1 (AT1) receptor expression and signaling. In addition, local RAAS- upregulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT1-receptor signaling in iPAH-patients compared to controls. Finally, to determine the therapeutic potential of RAAS-activity, we assessed the chronic effects of an AT1-receptor antagonist (losartan) in the monocrotaline PAH-rat model (60 mg/kg). Losartan delayed disease progression, decreased RV afterload and pulmonary vascular remodeling and restored right ventricular-arterial coupling in PAH-rats. Conclusions Systemic and pulmonary RAAS-activities are increased in iPAH-patients and associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH. PMID:22859525

  6. Angiotensin-converting Enzyme Inhibition Improves the Effectiveness of Transcutaneous Carbon Dioxide Treatment.

    Science.gov (United States)

    Nemeth, Balazs; Kiss, Istvan; Jencsik, Timea; Peter, Ivan; Kreska, Zita; Koszegi, Tamas; Miseta, Attila; Kustan, Peter; Boncz, Imre; Laczo, Andrea; Ajtay, Zeno

    2017-01-01

    To study the effect of carbon dioxide (CO 2 ) therapy on the nitric oxide (NO) pathway by monitoring plasma asymmetric dimethylarginine (ADMA) concentrations. Forty-seven hypertensive patients who underwent transcutaneous CO 2 therapy were enrolled. Thirty healthy individuals were recruited for the control group. Blood samples were taken one hour before, as well as one hour, 24 hours and 3 weeks after the first CO 2 treatment. Controls did not undergo CO 2 treatment. Plasma ADMA levels were measured by ELISA. ADMA levels decreased significantly one hour after the first CO2 treatment compared to the baseline concentrations (p=0.003). Significantly greater reduction was found among patients in whom angiotensin converting enzyme inhibitors (ACEIs) were administered (p=0.019). The short- and long-term decrease of ADMA levels suggests that CO 2 is not only a vasodilator, but also has a beneficial effect on the NO pathway. ACE inhibition seems to enhance the effect of CO 2 treatment. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis.

    Science.gov (United States)

    Bruce, E; Shenoy, V; Rathinasabapathy, A; Espejo, A; Horowitz, A; Oswalt, A; Francis, J; Nair, A; Unger, T; Raizada, M K; Steckelings, U M; Sumners, C; Katovich, M J

    2015-05-01

    Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH. © 2014 The British Pharmacological Society.

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

    Science.gov (United States)

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

    2015-06-11

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

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

    African Journals Online (AJOL)

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

  10. 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

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

    OpenAIRE

    Zhang, Zhen-Ye; Qian, Ling-Ling; Wang, Ru-Xing

    2017-01-01

    Large-conductance calcium-activated potassium channels (BK channels) belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone...

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

    Directory of Open Access Journals (Sweden)

    Aline Cristina Piratello

    2010-01-01

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

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    BACKGROUND AND OBJECTIVES: In the treatment of CKD, individual patients show a wide variation in their response to many drugs, including renin-angiotensin-aldosterone system inhibitors (RAASi). To investigate whether therapy resistance to RAASi can be overcome by uptitrating the dose of drug......, changing the mode of intervention (with drugs from similar or different classes), or lowering dietary sodium intake, we meta-analyzed individual responses to different modes of interventions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Randomized crossover trials were analyzed to assess correlation...... of individual responses to RAASi and nonsteroidal anti-inflammatory drugs (NSAIDs; n=395 patients). Included studies compared the antialbuminuric effect of uptitrating the dose of RAASi (n=10 studies) and NSAIDs (n=1), changing within the same class of RAASi (e.g., angiotensin-converting enzyme inhibition...

  14. A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia.

    Science.gov (United States)

    Liao, Zhaohui; Chakrabarty, Anuradha; Mu, Ying; Bhattacherjee, Aritra; Goestch, Martha; Leclair, Catherine M; Smith, Peter G

    2017-05-01

    Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on angiotensin II receptor type 2 (AT2) receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients' nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages, and B-cells, whereas mast cells were unchanged. RAS proteins were increased because of greater numbers of T cells and B cells expressing angiotensinogen, and increased renin-expressing T cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, whereas those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechanonociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain

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

    Directory of Open Access Journals (Sweden)

    Monika Chaszczewska-Markowska

    2016-09-01

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

  16. Effects of truncated angiotensins in humans after double blockade of the renin system

    DEFF Research Database (Denmark)

    Plovsing, Ronni R; Wamberg, Christian; Sandgaard, Niels C F

    2003-01-01

    -sodium diet (30 mmol/day). The subjects were acutely pretreated with canrenoate and captopril to inhibit aldosterone actions and ANG II synthesis, respectively. ANG II infusion increased plasma angiotensin immunoreactivity to 53 +/- 6 pg/ml (+490%), plasma aldosterone to 342 +/- 38 pg/ml (+109%), and blood...

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

    Directory of Open Access Journals (Sweden)

    Celeste Trejo-Moreno

    2018-02-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2018-02-01

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2017-01-01

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

  3. Outcome of Angiotensin II Inhibition in Pregnant Irradiated Rats and their Embryos

    International Nuclear Information System (INIS)

    Ramadan, F. L.; Ashry, Kh. M.

    2010-01-01

    The study aims to evaluate the synergism of losartan and or irradiation stress on the female rat mothers and their developing embryos as judged by the maternal biochemical pathways during gestation and teratogenic effects on the embryos. Losartan is an angiotensin II AT1-receptor antagonist used to regulate blood pressure. Losartan (5 mg/kg b.wt day) was daily orally administrated to pregnant rats from the 6 th to 18 th gestational days during which they were subjected to intermittent radiation dose levels of 0.5 Gy/4 times at the 9 th, 10 th, 11 th and 12 th days of gestation whereas investigation has been carried out one day prior to parturition. Dual treatment of losartan and radiation resulted in increased maternal serum levels of creatinine and bilirubin.The developing embryos in the uteri due to their high sensitivity showed various teratological, skeletal and histological impairment. Losartan and/or radiation induced effects were detected as growth retardation, malformations expressed as anopthalmia, kypophysis, subcutaneous haemorrhage and microtia as well as elevated intrauterium death and embryonic resorption. Moreover, the examination of endo skeletal system of fetuses showed retardation in the ossification of the skull bones and lack of ossification at the vertebrae and edges. Also, maternal and embryonic histological examination revealed that losartan and gamma radiation induced injury to kidney tissue manifested in rupture and shrinkage of renal corpuscle, infiltration, disappearance of glomularies, while the kidney of fetuses showed loss of renal pattern. Results point out that losartan should be used with caution in women at the reproductive age and those occupationally exposed to irradiation

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

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

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

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  6. Electrochemically reduced graphene and iridium oxide nanoparticles for inhibition-based angiotensin-converting enzyme inhibitor detection.

    Science.gov (United States)

    Kurbanoglu, Sevinc; Rivas, Lourdes; Ozkan, Sibel A; Merkoçi, Arben

    2017-02-15

    In this work, a novel biosensor based on electrochemically reduced graphene oxide and iridium oxide nanoparticles for the detection of angiotensin-converting enzyme inhibitor drug, captopril, is presented. For the preparation of the biosensor, tyrosinase is immobilized onto screen printed electrode by using 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-Hydroxysuccinimide coupling reagents, in electrochemically reduced graphene oxide and iridium oxide nanoparticles matrix. Biosensor response is characterized towards catechol, in terms of graphene oxide concentration, number of cycles to reduce graphene oxide, volume of iridium oxide nanoparticles and tyrosinase solution. The designed biosensor is used to inhibit tyrosinase activity by Captopril, which is generally used to treat congestive heart failure. It is an angiotensin-converting enzyme inhibitor that operates via chelating copper at the active site of tyrosinase and thioquinone formation. The captopril detections using both inhibition ways are very sensitive with low limits of detection: 0.019µM and 0.008µM for chelating copper at the active site of tyrosinase and thioquinone formation, respectively. The proposed methods have been successfully applied in captopril determination in spiked human serum and pharmaceutical dosage forms with acceptable recovery values. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system.

    Science.gov (United States)

    Ocaranza, Maria Paz; Michea, Luis; Chiong, Mario; Lagos, Carlos F; Lavandero, Sergio; Jalil, Jorge E

    2014-11-01

    Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT1R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by the AT2R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.

  8. 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.

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

    Science.gov (United States)

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

    2017-06-01

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

  10. 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

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

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Dhamrait, Sukhbir S.; Sethi, Amar A

    2008-01-01

    BACKGROUND: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are sim...

  12. Identification, In Vitro Testing and Molecular Docking Studies of Microginins’ Mechanism of Angiotensin-Converting Enzyme Inhibition

    Directory of Open Access Journals (Sweden)

    Fernanda C. R. Paiva

    2017-12-01

    Full Text Available Cyanobacteria are able to produce a wide range of secondary metabolites, including toxins and protease inhibitors, with diverse biological activities. Microginins are small linear peptides biosynthesized by cyanobacteria species that act against proteases. The aim of this study was to isolate and identify microginins produced by the LTPNA08 strain of Microcystis aeruginosa, as well as to verify their potential to inhibit angiotensin-converting enzyme (ACE; EC. 3.4.15.1 using in vitro and in silico methods. The fractionation of cyanobacterial extracts was performed by liquid chromatography and the presence of microginins was monitored by both LC-MS and an ACE inhibition assay. Enzyme inhibition was assayed by ACE with hippuryl-histidyl-leucine as the substrate; monitoring of hippuric acid was performed by HPLC-DAD. Isolated microginins were confirmed by mass spectrometry and were used to carry out the enzymatic assay. Molecular docking was used to evaluate microginin 770 (MG 770 and captopril (positive control, in order to predict similar binding interactions and determine the inhibitory action of ACE. The enzyme assay confirmed that MG 770 can efficiently inhibit ACE, with an IC50 equivalent to other microginins. MG 770 presented with comparable interactions with ACE, having features in common with commercial inhibitors such as captopril and enalaprilate, which are frequently used in the treatment of hypertension in humans.

  13. 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 Test...

  14. The Renin-Angiotensin system in Hypertension and Diabetes: from man to rodent and back

    NARCIS (Netherlands)

    L.C.W. Roksnoer (Lodi)

    2016-01-01

    markdownabstractAbstract In addition to the systemic (endocrine) RAS, it is generally believed that the kidney has its own (paracrine) RAS, since it is capable of local angiotensin II synthesis, and all RAS components are expressed locally. Another source of RAS components in the kidney may be

  15. 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...

  16. 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

    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...

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

    NARCIS (Netherlands)

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

    1997-01-01

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

  18. Flavonoids-Rich Orthosiphon stamineus Extract as New Candidate for Angiotensin I-Converting Enzyme Inhibition: A Molecular Docking Study.

    Science.gov (United States)

    Shafaei, Armaghan; Sultan Khan, Md Shamsuddin; F A Aisha, Abdalrahim; Abdul Majid, Amin Malik Shah; Hamdan, Mohammad Razak; Mordi, Mohd Nizam; Ismail, Zhari

    2016-11-09

    This study aims to evaluate the in vitro angiotensin-converting enzyme (ACE) inhibition activity of different extracts of Orthosiphon stamineus (OS) leaves and their main flavonoids, namely rosmarinic acid (RA), sinensetin (SIN), eupatorin (EUP) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Furthermore, to identify possible mechanisms of action based on structure-activity relationships and molecular docking. The in vitro ACE inhibition activity relied on determining hippuric acid (HA) formation from ACE-specific substrate (hippuryl-histidyl-leucine (HHL)) by the action of ACE enzyme. A High Performance Liquid Chromatography method combined with UV detection was developed and validated for measurement the concentration of produced HA. The chelation ability of OS extract and its reference compounds was evaluated by tetramethylmurexide reagent. Furthermore, molecular docking study was performed by LeadIT-FlexX : BioSolveIT's LeadIT program. OS ethanolic extract (OS-E) exhibited highest inhibition and lowest IC 50 value (45.77 ± 1.17 µg/mL) against ACE compared to the other extracts. Among the tested reference compounds, EUP with IC 50 15.35 ± 4.49 µg/mL had highest inhibition against ACE and binding ability with Zn (II) (56.03% ± 1.26%) compared to RA, TMF and SIN. Molecular docking studies also confirmed that flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. In this study, we have demonstrated that changes in flavonoids active core affect their capacity to inhibit ACE. Moreover, we showed that ACE inhibition activity of flavonoids compounds is directly related to their ability to bind with zinc ion in the active site of ACE enzyme. It was also revealed that OS extract contained high amount of flavonoids other than RA, TMF, SIN and EUP. As such, application of OS extract is useful as inhibitors of ACE.

  19. 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

  20. Furosemide- sup 131 I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Erbsloeh-Moeller, B.Du.; Dumas, A.; Roth, D.; Sfakianakis, G.N.; Bourgoignie, J.J. (Univ. of Miami/Jackson Memorial Medical Center, FL (USA))

    1991-01-01

    We have previously demonstrated the greater sensitivity of 131I-hippuran renography than 99mTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-131I-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. All patients were investigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function and 22 had renal insufficiency. Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 micrograms/kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 131I-hippuran. The residual cortical activity (RCA) of 131I-hippuran was measured at 20 minutes. RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely, RVH was present when 131I-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and 100%, RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition, RVH was likely; whereas, intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20).

  1. Furosemide-131I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension

    International Nuclear Information System (INIS)

    Erbsloeh-Moeller, B.Du.; Dumas, A.; Roth, D.; Sfakianakis, G.N.; Bourgoignie, J.J.

    1991-01-01

    We have previously demonstrated the greater sensitivity of 131I-hippuran renography than 99mTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-131I-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. All patients were investigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function and 22 had renal insufficiency. Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 micrograms/kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 131I-hippuran. The residual cortical activity (RCA) of 131I-hippuran was measured at 20 minutes. RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely, RVH was present when 131I-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and 100%, RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition, RVH was likely; whereas, intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20)

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

    Science.gov (United States)

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

    2015-01-15

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

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

    Science.gov (United States)

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

    2010-12-01

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

  4. Cerebrovascular effects of angiotensin converting enzyme inhibition involve large artery dilatation in rats

    DEFF Research Database (Denmark)

    Postiglione, A; Bobkiewicz, T; Vinholdt-Pedersen, E

    1991-01-01

    The aim of the study was to selectively examine the effects of converting enzyme inhibition on the large brain arteries by using concomitant inhibition of carbonic anhydrase to cause severe dilatation of mainly parenchymal resistance vessels....

  5. 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.

  6. Antioxidant activity and angiotensin I-converting enzyme inhibition by enzymatic hydrolysates from bee bread.

    Science.gov (United States)

    Nagai, Takeshi; Nagashima, Toshio; Suzuki, Nobutaka; Inoue, Reiji

    2005-01-01

    Enzymatic hydrolysates were prepared from bee bread using three proteases. The antioxidant properties of these hydrolysates were measured using four different methods. These had remarkable antioxidant activity similar or superior to that of 1 mM alpha-tocopherol. They also had high scavenging activities against active oxygen species as the superoxide anion radical and hydroxyl radicals. Moreover, they showed angiotensin I-converting enzyme inhibitory activities and the activities were similar to those from various fermented foods such as fish sauce, sake, vinegar, cheese, miso, and natto. The present studies reveal that enzymatic hydrolysates from bee bread are of benefit not only for the materials of health food diets, but also for in patients undergoing various diseases such as cancer, cardiovascular diseases, diabetes, and hypertension.

  7. Effects of warming yang and invigorating qi prescription on renin-angiotensin-aldosterone system in rats with heart failure after myocardial infarction

    Directory of Open Access Journals (Sweden)

    Lihua HAN

    Full Text Available Abstract This study investigated the effects of warming yang and invigorating qi prescription on renin-angiotensin-aldosterone system (RAAS in rats with heart failure after myocardial infarction. 126 rats were randomly divided into model group, sham operation, warming yang, invigorating qi, warming yang+invigorating qi, digoxin and captopril group for respective treatment. After intervention for 6, 8 and 10 weeks, the left ventricular ejection fraction (LVEF was calculated, and the plasma renin, angiotensin II and aldosterone levels were measured. Results showed that, after 6, 8 and 10 weeks, LVEF in warming yang, invigorating qi, warming yang+invigorating qi and captopril group was significantly higher than model group (P < 0.05, and the plasma renin, angiotensin II and aldosterone levels in warming yang, invigorating qi, warming yang+invigorating qi and captopril groups were significantly lower than model group (P < 0.05. Renin angiotensin II and aldosterone levels in invigorating qi, warming yang+invigorating qi and captopril groups after 10 weeks was significantly lower than after 6 weeks (P < 0.05; aldosterone level in captopril groups after 10 weeks was significantly lower than after 6 weeks (P < 0.05. Warming yang and invigorating qi prescription can improve LVEF in rats with heart failure after myocardial infarction, which may be related with the inhibition of RAAS activation.

  8. Characterization of the cardiac renin angiotensin system in oophorectomized and estrogen-replete mRen2.Lewis rats.

    Directory of Open Access Journals (Sweden)

    Hao Wang

    Full Text Available The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17 or sham-operation (Sham; n = 13 was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 β-estradiol (E2, 36 µg/pellet, 60-day release, n = 8 or vehicle (OVX-V, n = 9 for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7 content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE, and Ang II type 1 receptor (AT1R. E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7 mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.

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

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

  11. Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa.

    Science.gov (United States)

    Ojeda, Deyanira; Jiménez-Ferrer, Enrique; Zamilpa, Alejandro; Herrera-Arellano, Armando; Tortoriello, Jaime; Alvarez, Laura

    2010-01-08

    The beverages of Hibiscus sabdariffa calyces are widely used in Mexico as diuretic, for treating gastrointestinal disorders, liver diseases, fever, hypercholesterolemia and hypertension. Different works have demonstrated that Hibiscus sabdariffa extracts reduce blood pressure in humans, and recently, we demonstrated that this effect is due to angiotensin converting enzyme (ACE) inhibitor activity. The aim of the current study was to isolate and characterizer the constituents responsible of the ACE activity of the aqueous extract of Hibiscus sabdariffa. Bioassay-guided fractionation of the aqueous extract of dried calyces of Hibiscus sabdariffa using preparative reversed-phase HPLC, and the in vitro ACE Inhibition assay, as biological monitor model, were used for the isolation. The isolated compounds were characterized by spectroscopic methods. The anthocyanins delphinidin-3-O-sambubioside (1) and cyanidin-3-O-sambubioside (2) were isolated by bioassay-guided purification. These compounds showed IC(50) values (84.5 and 68.4 microg/mL, respectively), which are similar to those obtained by related flavonoid glycosides. Kinetic determinations suggested that these compounds inhibit the enzyme activity by competing with the substrate for the active site. The competitive ACE inhibitor activity of the anthocyanins 1 and 2 is reported for the first time. This activity is in good agreement with the folk medicinal use of Hibiscus sabdariffa calyces as antihypertensive. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  12. Hypocholesterolemic properties of grapefruit (Citrus paradisii and shaddock (Citrus maxima juices and inhibition of angiotensin-1-converting enzyme activity

    Directory of Open Access Journals (Sweden)

    Ganiyu Oboh

    2014-12-01

    Full Text Available Grapefruit (Citrus paradisii and shaddock (Citrus maxima juices are used in folk medicine for the management of hypertension and other cardiovascular diseases, but the mechanism of action by which they exert their therapeutic action is unclear. The aim of this study was to investigate the effect of grapefruit and shaddock juices on angiotensin-1-converting enzyme (ACE activity in vitro and the hypocholesterolemic properties of the juices in rats fed a high-cholesterol diet. Grapefruit juice had higher total phenol and flavonoid contents than shaddock juice, while both juices inhibited ACE activity in a dose-dependent manner. Furthermore, administration of the juices to rats fed a high-cholesterol diet caused a significant reduction in plasma total cholesterol, triglyceride, and low-density lipoprotein–cholesterol levels and an increase in high-density lipoprotein–cholesterol levels. The inhibition of ACE activity in vitro and in vivo hypocholesterolemic effect of the juices could explain the use of the juices in the management of cardiovascular diseases.

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

  15. 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.

  16. Flavonoids-Rich Orthosiphon stamineus Extract as New Candidate for Angiotensin I-Converting Enzyme Inhibition: A Molecular Docking Study

    Directory of Open Access Journals (Sweden)

    Armaghan Shafaei

    2016-11-01

    Full Text Available This study aims to evaluate the in vitro angiotensin-converting enzyme (ACE inhibition activity of different extracts of Orthosiphon stamineus (OS leaves and their main flavonoids, namely rosmarinic acid (RA, sinensetin (SIN, eupatorin (EUP and 3′-hydroxy-5,6,7,4′-tetramethoxyflavone (TMF. Furthermore, to identify possible mechanisms of action based on structure–activity relationships and molecular docking. The in vitro ACE inhibition activity relied on determining hippuric acid (HA formation from ACE-specific substrate (hippuryl-histidyl-leucine (HHL by the action of ACE enzyme. A High Performance Liquid Chromatography method combined with UV detection was developed and validated for measurement the concentration of produced HA. The chelation ability of OS extract and its reference compounds was evaluated by tetramethylmurexide reagent. Furthermore, molecular docking study was performed by LeadIT-FlexX: BioSolveIT’s LeadIT program. OS ethanolic extract (OS-E exhibited highest inhibition and lowest IC50 value (45.77 ± 1.17 µg/mL against ACE compared to the other extracts. Among the tested reference compounds, EUP with IC50 15.35 ± 4.49 µg/mL had highest inhibition against ACE and binding ability with Zn (II (56.03% ± 1.26% compared to RA, TMF and SIN. Molecular docking studies also confirmed that flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. In this study, we have demonstrated that changes in flavonoids active core affect their capacity to inhibit ACE. Moreover, we showed that ACE inhibition activity of flavonoids compounds is directly related to their ability to bind with zinc ion in the active site of ACE enzyme. It was also revealed that OS extract contained high amount of flavonoids other than RA, TMF, SIN and EUP. As such, application of OS extract is useful as inhibitors of ACE.

  17. 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

  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

    2010-01-01

    OBJECTIVE: 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. MATERIALS AND METHODS: We undertook a double-blinded randomized placebo-controlled study including 94 borderline-hypertensive persons to study the effect on human physiology of Lactobacillus...... helveticus fermented milk. The subjects were randomized into three groups: Cardi04-300 ml, Cardi04-150 ml or placebo. All components of the renin-angiotensin-aldosterone system were measured several times. Sympathetic activity was estimated by plasma noradrenaline and cardiovascular response to head-up tilt...

  19. 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.

  20. MATHEMATICAL MODEL FOR THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN PATIENTS

    OpenAIRE

    Dr. T. Geetha; K. Balamurugan

    2016-01-01

    In this paper we use mathematical model for the application of The Renin-Angiotensin-Aldosterone system the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression. The huge increase in aldosterone in depressed subjects compared to controls and the unchanged cross correlation between the time course of noc...

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

    Directory of Open Access Journals (Sweden)

    Masaya Koshizaka

    2012-01-01

    Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Birger; Meyer, Christian; Hove, Jens D.; Holm, Soeren; Kofoed, Klaus F. [Department of Clinical Physiology and Nuclear Medicine, KF 4011, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen (Denmark); Nielsen, Flemming S.; Sato, Asako; Parving, Hans-Henrik [Steno Diabetes Center, Gentofte (Denmark); Bang, Lia E.; Svendsen, Tage L. [Department of Internal Medicine, Naestved County Hospital (Denmark); Opie, Lionel H. [Department of Medicine, Cape Heart Center, University of Cape Town (South Africa)

    2004-03-01

    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{sup -1} g{sup -1}; P<0.05), and perfusion reserve was also lower, at borderline significance (2.7{+-}1.0 vs 3.6{+-}1.3; P=0.059). During perindoprilat infusion, myocardial perfusion reserve in patients increased to 3.9{+-}0.9 (P<0.001) due to normalisation of maximal perfusion (2.3{+-}0.5 ml min{sup -1} g{sup -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.)

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

    Directory of Open Access Journals (Sweden)

    Alfredo Csibi

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

  4. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Andersen, S; Tarnow, L; Rossing, P

    2000-01-01

    BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hem...... inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy....... and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM...

  5. Inflammatory Renin-Angiotensin System Disruption Attenuates Sensory Hyperinnervation and Mechanical Hypersensitivity in a Rat Model of Provoked Vestibulodynia.

    Science.gov (United States)

    Chakrabarty, Anuradha; Liao, Zhaohui; Mu, Ying; Smith, Peter G

    2018-03-01

    Vestibulodynia is characterized by perivaginal mechanical hypersensitivity, hyperinnervation, and abundant inflammatory cells expressing renin-angiotensin system proteins. We developed a tractable rat model of vestibulodynia to further assess the contributions of the renin-angiotensin system. Complete Freund's adjuvant injected into the posterior vestibule induced marked vestibular hypersensitivity throughout a 7-day test period. Numbers of axons immunoreactive for PGP9.5, calcitonin gene-related peptide, and GFRα2 were increased. Numbers of macrophages and T cells were also increased whereas B cells were not. Renin-angiotensin-associated proteins were abundant, with T cells as well as macrophages contributing to increased renin and angiotensinogen. Media conditioned with inflamed vestibular tissue promoted neurite sprouting by rat dorsal root ganglion neurons in vitro, and this was blocked by the angiotensin II receptor type 2 receptor antagonist PD123319 or by an angiotensin II function blocking antibody. Sensory axon sprouting induced by inflamed tissue was dependent on activity of angiotensin-converting enzyme or chymase, but not cathepsin G. Thus, vestibular Complete Freund's adjuvant injection substantially recapitulates changes seen in patients with provoked vestibulodynia, and shows that manipulation of the local inflammatory renin-angiotensin system may be a useful therapeutic strategy. This study provides evidence that inflammation of the rat vestibule induces a phenotype recapitulating behavioral and cytological features of human vestibulodynia. The model confirms a crucial role of the local inflammatory renin-angiotensin system in hypersensitivity and hyperinnervation. Targeting this system holds promise for developing new nonopioid analgesic treatment strategies. Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

  6. Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage.

    Science.gov (United States)

    Griessenauer, Christoph J; Tubbs, R Shane; Foreman, Paul M; Chua, Michelle H; Vyas, Nilesh A; Lipsky, Robert H; Lin, Mingkuan; Iyer, Ramaswamy; Haridas, Rishikesh; Walters, Beverly C; Chaudry, Salman; Malieva, Aisana; Wilkins, Samantha; Harrigan, Mark R; Fisher, Winfield S; Shoja, Mohammadali M

    2017-05-01

    OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin Angiotensin System (CARAS) study prospectively evaluated associations of common RAS polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5'exonuclease genotyping assays and pyrosequencing. Analysis of associations of RAS polymorphisms and clinical course after aSAH were performed. RESULTS A total of 166 patients were screened, and 149 aSAH patients were included for analysis. A recessive effect of allele I (insertion) of the ACE I/D (insertion/deletion) polymorphism was identified for Hunt and Hess grade in all patients (OR 2.76, 95% CI 1.17-6.50; p = 0.0206) with subsequent poor functional outcome. There was a similar effect on delayed cerebral ischemia (DCI) in patients 55 years or younger (OR 3.63, 95% CI 1.04-12.7; p = 0.0439). In patients older than 55 years, there was a recessive effect of allele A of the angiotensin II receptor Type 2 (AT2) A/C single nucleotide polymorphism (SNP) on DCI (OR 4.70, 95% CI 1.43-15.4; p = 0.0111). CONCLUSIONS Both the ACE I/D polymorphism and the AT2 A/C single nucleotide polymorphism were associated with an age-dependent risk of delayed cerebral ischemia, whereas only the ACE I/D polymorphism was associated with poor clinical grade at presentation. Further studies are required to elucidate the relevant pathophysiology and its potential implication in the treatment of patients with aSAH.

  7. Empirical and bioinformatic characterization of buffalo (Bubalus bubalis) colostrum whey peptides & their angiotensin I-converting enzyme inhibition.

    Science.gov (United States)

    Ashok, N R; Aparna, H S

    2017-08-01

    Whey based peptides are well known for their nutritional and multifunctional properties. In this context, whey proteins from buffalo colostrum & milk were digested by in vitro simulation digestion and analyzed by nano-LC-MS/MS. Functional protein association networks, gene annotations and localization of identified proteins were carried out. An ACE inhibitory peptide sorted from the library was custom synthesized and an in vitro ACE assay was performed. The study led to the identification of 74 small peptides which were clustered into 5 gene functional groups and majority of them were secretory proteins. Among the identified peptides, majority of them were found identical to angiotensin I-converting enzyme (ACE) inhibitors, antioxidant, antimicrobial, immunomodulatory and opioidal peptides. An octapeptide (m/z - 902.51, IQKVAGTW) synthesized was found to inhibit ACE with an IC 50 of 300±2µM. The present investigation thus establishes newer vista for food derived peptides having ACE inhibitory potential for nutraceutical or therapeutic applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Central metabolism of angiotensins

    International Nuclear Information System (INIS)

    Camara, C.G.

    1984-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Madhu Nath

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report...... 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....

  12. Angiotensin-converting enzyme inhibition after myocardial infarction: the Trandolapril Cardiac Evaluation Study

    DEFF Research Database (Denmark)

    Torp-Pedersen, C; Køber, L; Carlsen, J

    1996-01-01

    % of patients in both treatment groups reached the target dose of 4 mg trandolapril or placebo at the end of dose titration. Nearly half of the patients in both treatment groups discontinued taking study medication before death or trial closure. The need for open-label ACE inhibition was the reason...... for discontinuation for 48 and 75 patients in the trandolapril and placebo groups, respectively. In conclusion, long-term treatment with trandolapril in patients with reduced left ventricular function shortly after myocardial infarction significantly reduced mortality and morbidity. Most patients received the target...... dose of 4 mg trandolapril daily. The benefit observed is likely to reflect the benefit in clinical practice because the majority of eligible patients were randomized and the difference in patients leaving the trial to receive open-label ACE inhibition was moderate....

  13. Circadian Differences in the Contribution of the Brain Renin-Angiotensin System in Genetically Hypertensive Mice

    Directory of Open Access Journals (Sweden)

    Kristy L. Jackson

    2018-03-01

    Full Text Available Objective: Genetically hypertensive BPH/2J mice are recognized as a neurogenic model of hypertension, primarily based on sympathetic overactivity and greater neuronal activity in cardiovascular regulatory brain regions. Greater activity of the central renin angiotensin system (RAS and reactive oxygen species (ROS reportedly contribute to other models of hypertension. Importantly the peripheral RAS contributes to the hypertension in BPH/2J mice, predominantly during the dark period of the 24 h light cycle. The aim of the present study was to determine whether central AT1 receptor stimulation and the associated ROS signaling contribute to hypertension in BPH/2J mice in a circadian dependent manner.Methods: Blood pressure (BP was measured in BPH/2J and normotensive BPN/3J mice (n = 7–8 via pre-implanted telemetry devices. Acute intracerebroventricular (ICV microinjections of AT1 receptor antagonist, candesartan, and the superoxide dismutase (SOD mimetic, tempol, were administered during the dark and light period of the 24 h light cycle via a pre-implanted ICV guide cannula. In separate mice, the BP effect of ICV infusion of the AT1 receptor antagonist losartan for 7 days was compared with subcutaneous infusion to determine the contribution of the central RAS to hypertension in BPH/2J mice.Results: Candesartan administered ICV during the dark period induced depressor responses which were 40% smaller in BPH/2J than BPN/3J mice (Pstrain < 0.05, suggesting AT1 receptor stimulation may contribute less to BP maintenance in BPH/2J mice. During the light period candesartan had minimal effect on BP in either strain. ICV tempol had comparable effects on BP between strains during the light and dark period (Pstrain > 0.08, suggesting ROS signaling is also not contributing to the hypertension in BPH/2J mice. Chronic ICV administration of losartan (22 nmol/h had minimal effect on BPN/3J mice. By contrast in BPH/2J mice, both ICV and subcutaneously administered

  14. LmrBPP9: A synthetic bradykinin-potentiating peptide from Lachesis muta rhombeata venom that inhibits the angiotensin-converting enzyme activity in vitro and reduces the blood pressure of hypertensive rats.

    Science.gov (United States)

    Pinheiro-Júnior, Ernesto Lopes; Boldrini-França, Johara; de Campos Araújo, Luciana Mattoso Pires; Santos-Filho, Norival Alves; Bendhack, Lusiane Maria; Cilli, Eduardo Maffud; Arantes, Eliane Candiani

    2018-04-01

    Bradykinin-potentiating peptides (BPPs) are an important group of toxins present in Lachesis muta rhombeata venom. They act directly at renin-angiotensin-aldosterone system, through the inhibition of angiotensin-converting enzyme (ACE). This action may contribute to the hypotensive shock observed during the envenoming by this species. Thus, the main goal of this study was the solid-phase synthesis of a BPP found in L. m. rhombeata venom and its in vitro and in vivo characterization in relation to ACE inhibition and hypotensive activity, respectively. The LmrBPP9 peptide was synthesized using an automated solid-phase peptide synthesizer and purified by reversed-phase fast protein liquid chromatography (FPLC). The in vitro IC50 of the synthetic peptide is 4.25 ± 0.10 μM, showing a great capacity of ACE inhibition. The in vivo studies showed that LmrBPP9 induces blood pressure reduction, both in normotensive and hypertensive rats, being more pronounced in the last ones. These results agree with the in vitro results, showing that the synthetic peptide LmrBPP9 is a potential molecule to the development of a new antihypertensive drug. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. [The in vitro cross-effects of inhibitors of renin-angiotensin and fibrinolytic systems on the key enzymes of these systems].

    Science.gov (United States)

    Mukhametova, L I; Gulin, D A; Binevskiĭ, P V; Aĭsina, R B; Kost, O A; Nikol'skaia, I I

    2008-01-01

    The effects of hypotensive agents (captopril, enalaprilate, and lisinopril) on the activities of components of the fibrinolytic system (FS) and the effects of antifibrinolytic agents (6-aminohexanoic acid (6-AHA) and tranexamic acid (t-AMCHA)) on the activities of angiotensin converting enzyme (ACE) were studied in vitro. Enalaprilate did not affect the FS activity. Captopril considerably inhibited the amidase activities of urokinase (u-PA), plasminogen tissue activator (t-PA), and plasmin ([I]50 (2.0-2.6) +/- 0.1 mM), and the activation of Glu-plasminogen affected by t-PA and u-PA ([I]50 (1.50-1.80) +/- 0.06 mM), which may be due to the presence of a mercapto group in the inhibitor molecule. Lisinopril did not affect the amidase activities of FS enzymes, but stimulated Glu-plasminogen and u-PA activation and inhibited activation of t-PA-fibrin-bound Glu-plasminogen ([I]50 (12.0 +/- 0.5) mM). Presumably, these effects can be explained by the presence in lisinopril of a Lys side residue, whose binding to lysine-binding Glu-plasminogen centers resulted, on the one hand, in the transformation of its closed conformation to a semi-open one and, on the other hand, in its desorption from fibrin. Unspecific inhibition of the activity of ACE, a key enzyme of the renin-angiotensin system, in the presence of 6-AHA and t-AMCHA ([I]50 10.0 +/- 0.5 and 7.5 +/- 0.4 mM, respectively) was found. A decrease in the ACE activity along with the growth of the fibrin monomer concentration was revealed. The data demonstrate that, along with endogenous mediated interactions, relations based on the direct interactions of exogenous inhibitors of one system affecting the activities of components of another system can take place.

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

    Science.gov (United States)

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

    2003-04-01

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

  17. 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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Guoxing Wang

    2015-11-01

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

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

    Science.gov (United States)

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

    2010-03-01

    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. We undertook a double-blinded randomized placebo-controlled study including 94 borderline-hypertensive persons to study the effect on human physiology of Lactobacillus helveticus fermented milk. The subjects were randomized into three groups: Cardi04-300 ml, Cardi04-150 ml or placebo. All components of the renin-angiotensin-aldosterone system were measured several times. Sympathetic activity was estimated by plasma noradrenaline and cardiovascular response to head-up tilt at baseline and after 8 weeks of intervention. No ACE inhibition of the fermented milk was demonstrated, as none of the components of the renin-angiotensin-aldosteron system changed. Plasma noradrenaline response to tilt test after intervention stayed unchanged between groups (P = 0.38), but declined in the group Cardi04-300 from 2.01 +/- 0.93 nmol l(-1) at baseline to 1.49 +/- 0.74 nmol l(-1) after 8 weeks (P = 0.002). There was no change in 24-h ambulatory blood pressure or heart rate between groups. Despite a known ACE inhibitory effect in vitro and in animals, milk fermented with Lb. helveticus did not inhibit ACE in humans. Our results suggest that the intake of fermented milk decreases sympathetic activity, although not to an extent mediating reductions of blood pressure and heart rate in borderline-hypertensive subjects.

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

    African Journals Online (AJOL)

    Chibuike

    derived BAPs can promote their use as safe antihypertensive agents. Moreover, future studies are needed to elucidate the long-term systemic molecular interactions of antihypertensive BAPs with the human genome, proteome and other cellular ...

  2. The angiotensin-converting enzyme inhibitor captopril inhibits poly(ADP-ribose)polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury

    Science.gov (United States)

    Asmussen, Sven; Bartha, Eva; Olah, Gabor; Sbrana, Elena; Rehberg, Sebastian W.; Yamamoto, Yusuke; Enkhbaatar, Perenlei; Hawkins, Hal K.; Ito, Hiroshi; Cox, Robert A.; Traber, Lillian D.; Traber, Daniel L.; Szabo, Csaba

    2011-01-01

    We investigated the effect of the angiotensin converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress, activation of poly(ADP-ribose) polymerase in the lung and in circulating leukocytes. Female, adult sheep (28–40 kg) were divided into 3 groups. After tracheostomy and under deep anesthesia both vehicle-control (n=5) and captopril (20 mg/kg/d, iv., starting 0.5 hour before the injury) treated (n=5) groups were subjected to 2×20%, third degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n=5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of TGF-β in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of ROS-induced PARP over-activation. ACE inhibition may also exert additional beneficial effects by inhibiting the expression of the pro-fibrotic mediator TGF-β. PMID:21701415

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

    Science.gov (United States)

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

    2006-09-01

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

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    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 high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring...

  5. Increased Dietary Salt Changes Baroreceptor Sensitivity and Intrarenal Renin-Angiotensin System in Goldblatt Hypertension.

    Science.gov (United States)

    Shimoura, Caroline G; Lincevicius, Gisele S; Nishi, Erika E; Girardi, Adriana C C; Simon, Karin A; Bergamaschi, Cassia T; Campos, Ruy R

    2017-01-01

    Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance. The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system. After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated. High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys. Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please

  6. 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...... on mechanisms of postnatal development the renal medulla and putting medullary developmental lesions into perspective with regard to the programming effect. Moreover, the renin-angiotensin system is critically involved in mammalian kidney development and signaling disorders give rise to developmental renal...

  7. Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet.

    Science.gov (United States)

    Cao, Gabriel; Della Penna, Silvana Lorena; Kouyoumdzian, Nicolás Martín; Choi, Marcelo Roberto; Gorzalczany, Susana; Fernández, Belisario Enrique; Toblli, Jorge Eduardo; Rosón, María Inés

    2017-01-06

    To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system. Sprague-Dawley rats were fed with 8% NaCl high-salt (HS) or 0.4% NaCl (normal-salt, NS) diet for 3 wk, with or without tempol (T) (1 mmol/L, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa) were measured. We evaluated angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), mas receptor (MasR), angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) in renal tissues by immunohistochemistry. The intake of high sodium produced a slight but significant increase in MAP and differentially regulated components of the renal renin-angiotensin system (RAS). This included an increase in Ang II and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang II and AT1R, as increase in AT2, ACE2, Ang (1-7) and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang (1-7) and MasR. These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang II. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS.

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

    Science.gov (United States)

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

    2010-03-01

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

  9. The association of renin–angiotensin system blockades and pneumonia requiring admission in patients with COPD

    Directory of Open Access Journals (Sweden)

    Kim J

    2016-09-01

    Full Text Available Junghyun Kim,1 Jung-Kyu Lee,2 Eun Young Heo,2 Hee Soon Chung,2 Deog Kyeom Kim2 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea Background: The hallmark of COPD is chronic airway inflammation, which may be mediated by renin–angiotensin system. The renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEi and angiotensin II receptor blockers (ARBs have exhibited anti-inflammatory and immunomodulatory effects in patients with various diseases. We explored the effects of ACEi and ARBs on the risk of pneumonia in patients with COPD.Methods: A nested case–control study was performed on COPD patients recruited from January 2010 to August 2013 in two referral hospitals in Korea. A total of 130 COPD patients admitted with pneumonia were included, and 245 COPD patients without pneumonia were selected as controls from a total of 1,646 such patients. Controls were matched with test patients by age, sex, and severity of airflow limitation. The effects of ACEi/ARBs use on the odds ratio (OR for the development of pneumonia were tested through conditional logistic regression.Results: Elderly patients (over 70 years of age constituted ~30% of each group; most of the patients were male (85%. Of the COPD patients with pneumonia, 21.5% had taken ACEi/ARBs for a mean of 9.8 months (standard deviation ±3.5 months. The proportions of ACEi/ARBs users and the mean duration of such use did not differ when compared to those of the control patients (26.9%, P=0.25; 9.6±3.6 months, P=0.83. Univariate analyses indicated that the use of ACEi/ARBs was not associated with a decreased risk of pneumonia (OR =0.70, 95% confidence interval 0.41–1.23, P=0.21, whereas both a history of pulmonary

  10. 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.

  11. Effects of enalapril maleate on blood pressure, renin-angiotensin-aldosterone system, and peripheral sympathetic activity in essential hypertension.

    Science.gov (United States)

    Cerasola, G; Cottone, S; D'Ignoto, G; Grasso, L; Carone, M B; Carapelle, E; Contorno, A

    1987-01-01

    Recent experimental studies showed that inhibition of angiotensin II synthesis may reduce sympathetic activity as evaluated by plasma catecholamine assay, sharing in the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. Fifteen patients with essential hypertension were studied. Blood pressure and heart rate were evaluated both at rest and after stressor laboratory tests, before and four hours after administration of 20 mg of enalapril maleate and on the 14th and 120th days of continued administration. At the same time, blood samples were drawn for determinations of plasma renin activity, ACE, angiotensin II, plasma aldosterone concentration, and plasma norepinephrine levels. Enalapril in a dosage of 20 mg/day significantly and progressively lowered systolic and diastolic blood pressure at rest, with maximal decreases observed on the 120th day of the study period (P less than 0.001). Heart rate at rest and after exercise showed no significant differences throughout the study period. Good blood pressure control was observed during stressor laboratory tests. The greatest impact of blood pressure was observed on the 120th day during dynamic exercise (mean blood pressure from 139 +/- 3.9 to 111.5 +/- 6.3 mmHg; P less than 0.01) and on the 14th day during the cold pressure test (mean blood pressure from 133.3 +/- 3.9 to 111.2 +/- 4.7 mmHg; P less than 0.005). A marked and persistent ACE inhibition and a gradual and progressive decrease of angiotensin II (from 12.42 +/- 2.15 to 5.45 +/- 1.68 pg/ml; P less than 0.005) characterized the humoral activity of enalapril maleate. Moreover, a significant decrease of plasma norepinephrine levels was observed during the follow-up period with maximal reduction on the 120th day (from 311 +/- 34 to 197 +/- 33 pg/ml; P less than 0.01). It has been demonstrated that the pressor effect of angiotensin II was blunted during exercise. Our hemodynamic and humoral results appear to confirm the hypothesis that

  12. Dual renin-angiotensin system blockade at optimal doses for proteinuria.

    Science.gov (United States)

    Laverman, Gozewijn D; Navis, Gerjan; Henning, Robert H; de Jong, Paul E; de Zeeuw, Dick

    2002-09-01

    The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy. To this purpose, lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% CI, 3.5, 6.4), creatinine clearance of 80 mL/min (95% CI, 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95% CI, 93, 112). First, in two protocols with six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50, 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs. The antiproteinuric response by losartan was optimal at 100 mg (-46%; 95% CI, -60, -24%), being larger than at the 50 mg dose (-27%; 95% CI, -42, -4%, P 150 mg dose (-46%; 95% CI, -58; -20%). Proteinuria decreased further at each up-titration step of lisinopril to -75% (95% CI, -85, -43%) at the 40 mg dose. Combination therapy reduced proteinuria more effectively (-85%; 95% CI, -96, -58) than monotherapy with losartan, and to a lesser extent than with lisinopril. Optimal blood pressure responses were obtained at similar doses. Dose-titration with a renin-angiotensin system blocker, followed by add-on therapy is highly effective in order to reduce proteinuria. The safety of this regimen needs to be addressed in future studies.

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

    Science.gov (United States)

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

    2018-04-01

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

  14. 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.

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

    Science.gov (United States)

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

    2017-02-01

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

  16. The placental renin-angiotensin system and oxidative stress in pre-eclampsia.

    Science.gov (United States)

    Mistry, H D; Kurlak, L O; Broughton Pipkin, F

    2013-02-01

    There is an inverse correlation between human birthweight and umbilical venous angiotensin II (AngII) concentrations. Oxidative stress and increased pro-renin receptor (PRR) both enhance the cleavage of angiotensin I from angiotensinogen (AGT). Pre-eclampsia, a hypertensive disorder of pregnancy, manifests as high blood pressure and proteinuria, and is a state of increased oxidative stress. Pre-eclampsia will be associated with increased placental expression of components of the renin-angiotensin system, which could result in reduced infant birthweight. Biopsies were taken 1 cm from the placental edge from 27 normotensive controls and 23 pre-eclamptic White European women. Immunohistochemistry was performed for AGT, PRR, glutathione peroxidase 3 (GPx3) and the AT1R and AT2R AngII receptors. Protein expression was semi-quantitatively assessed (H-score). AT1R expression was significantly increased in pre-eclamptic placentae, and negatively correlated with birthweight (r = -0.529, P = 0.009). AT1R expression was also negatively correlated with GPx3 expression overall (r = -0.647; P = 0.005). AT2R expression positively correlated with AGT (r = 0.615, P = 0.002) in the pre-eclamptic placentae only. The raised AT1R expression in pre-eclampsia, together with inadequate antioxidant protection, possibly through lower GPx activity, might enhance the vasoconstrictor effect of locally-generated AngII, contributing to the restricted fetal growth characteristic of pre-eclampsia. Conversely, the AT2R:AGT association within the pre-eclamptic placenta may provide a compensatory mechanism. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Dysregulation of the renin-angiotensin system during lung ischemia-reperfusion injury.

    Science.gov (United States)

    Kehoe, K; Gielis, J F; Vliegen, G; Van Elzen, R; Verkerk, R; Driessens, E; Domen, A; Lambeir, A M; Maes, L; Cos, P; De Meester, I; Van Schil, P E Y

    2016-08-01

    Aim/Purpose of the Study: Activation of the renin-angiotensin system leading to increased angiotensin-(1-7) (Ang-(1-7)) and decreased angiotensin 2 (Ang 2) levels may be a new therapeutic approach to reduce acute lung injury. Prolylcarboxypeptidase (PRCP) and prolyloligopeptidase (PREP) are capable of hydrolyzing Ang 2 into Ang-(1-7). However, their relation with circulating Ang 2 levels after lung ischemia-reperfusion injury (LIRI) has never been explored. This study determines whether the activity and expression of PRCP and PREP in plasma and lung tissue is related to circulating Ang 2 levels in a murine model of LIRI. LIRI in Swiss mice (6 animals per group) was induced by temporary left lung hilar clamping (1 h) followed by 0, 1 or 24 h of reperfusion. Animals in the sham group received thoracotomy only. PRCP activity was measured via RP-HPLC, PREP activity using a fluorogenic substrate and plasma Ang 2 levels via ELISA. Western blotting was used to determine the PRCP and PREP protein expression profiles in left lung tissue. Plasma Ang 2 levels significantly rise after lung ischemia and remain increased after 1 h and 24 h of reperfusion compared to the sham group. While a significant decrease in plasma PREP activity was found after 24 h of reperfusion, a transient increase in plasma PRCP activity was observed after ischemia. However, no correlation with plasma Ang 2 levels could be demonstrated. The activity profiles of PRCP and PREP and the protein expression of PRCP in the lung tissues remained unchanged after LIRI. LIRI causes a dysregulation of circulating Ang 2 levels and plasma PREP activity, although no direct link between both phenomena could be shown. The activity profile of pulmonary PRCP and PREP was not significantly changed after LIRI, which implies a minor role for local PRCP and PREP in the ischemic lung itself.

  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

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

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

    International Nuclear Information System (INIS)

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

    1976-01-01

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

  20. Involvement of renin-angiotensin system in hypertensive effect of cadmium in rats.

    Science.gov (United States)

    Lall, S B; Peshin, S S; Gulati, K; Khattar, S; Das, N; Seth, S D

    1997-04-01

    Role of renin-angiotensin system in hypertension induced by cadmium chloride (CdCl2) in rats has been investigated. Intravenous administration of CdCl (1 mg/kg) produced a biphasic response i.e. a transient fall followed by a marked and consistent rise in blood pressure. The peak hypertensive effect was accompanied by raised PRA levels. Pretreatment with captopril (1 mg/kg, i.v.) losartan (1 mg/kg, i.v.) or captopril + losartan attenuated the pressor response to Cd by 62%, 42% and 100% respectively in separate groups. Central administration of Cd (10 micrograms/rat, i.c.v.) showed a biphasic response similar to that observed after i.v. route. However, it was not accompanied by raised PRA levels. Prior treatment with losartan (10 micrograms/rat, i.c.v.) completely abolished the pressor response to Cd (i.c.v.) whereas it was not affected significantly by captopril (10 micrograms/rat, i.c.v.). On the other hand, centrally administered losartan only partially reduced the pressor response to i.v. Cd. The results are discussed in light of a differential involvement of central vs peripheral renin-angiotensin system in the hypertensive effect of Cd.

  1. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)

    NARCIS (Netherlands)

    McMurray, J.J.; Packer, M.; Desai, A.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.; Shi, V.C.; Solomon, S.D.; Swedberg, K.; Zile, M.R.; Bellersen, L.; et al.,

    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

  2. Gene-load score of the renin-angiotensin-aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia

    NARCIS (Netherlands)

    van der Net, Jeroen B.; van Etten, Jeroen; Yazdanpanah, Mojgan; Dallinga-Thie, Geesje M.; Kastelein, John J. P.; Defesche, Joep C.; Koopmans, Richard P.; Steyerberg, Ewout W.; Sijbrands, Eric J. G.

    2008-01-01

    AIMS: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin-angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of importance

  3. Independent regulation of renin-angiotensin-aldosterone system in the kidney.

    Science.gov (United States)

    Nishiyama, Akira; Kobori, Hiroyuki

    2018-03-29

    Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and renal disease. In the kidney, angiotensin II (Ang II) production is controlled by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid with much higher concentrations than those existing in the circulation. Inappropriate activation of the intrarenal RAAS is an important contributor to the pathogenesis of hypertension and renal injury. It has been revealed that intrarenal Ang II levels are predominantly regulated by angiotensinogen and therefore, urinary angiotensinogen could be a biomarker for intrarenal Ang II generation. In addition, recent studies have demonstrated that aldosterone contributes to the progression of renal injury via direct actions on glomerular podocytes, mesangial cells, proximal tubular cells and tubulo-interstitial fibroblasts through the activation of locally expressed mineralocorticoid receptor. Thus, it now appears that intrarenal RAAS is independently regulated and its inappropriate activation contributes to the pathogenesis of the development of hypertension and renal disease. This short review article will focus on the independent regulation of the intrarenal RAAS with an emphasis on the specific role of angiotensinogen.

  4. 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

    1990-01-01

    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...

  5. 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

    BACKGROUND: In patients with severe aortic stenosis (AS), treatment with angiotensin-converting enzyme inhibitors has previously been considered contraindicated. However, there is a lack of clinical evidence to confirm these potential hemodynamic risks and benefits. METHODS: Forty-four patients...... hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with left ventricular unloading....

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

    Science.gov (United States)

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

    2017-04-01

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

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

    NARCIS (Netherlands)

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

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Morduchowicz, G.A.; Sheikh-Hamad, D.; Dwyer, B.E.; Stern, N.; Jo, O.D.; Yanagawa, N. (Sepulveda Veterans Administration, CA (USA))

    1991-05-01

    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.

  9. 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

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

    NARCIS (Netherlands)

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

    2007-01-01

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

  11. 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

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

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Gerjan; 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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral...

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

    Science.gov (United States)

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

    2018-03-01

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

  15. Dual renin-angiotensin system blockade at optimal doses for proteinuria

    NARCIS (Netherlands)

    Laverman, GD; Navis, G; Henning, RH; de Jong, PE; dE Zeeuw, D

    Background. The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy. Methods. To this purpose, lisinopril and losartan were

  16. Therapeutic Approaches in Lowering Albuminuria : Travels Along the Renin-Angiotensin-Aldosterone-System Pathway

    NARCIS (Netherlands)

    Lambers Heerspink, Hiddo J.

    Achieving optimal blood pressure and albuminuria control is a major therapeutic treatment goal in patients with renal insufficiency. Angiotensin-converting enzyme-inhibitors (ACEIs) and angiotensin-receptor blockers (ARB) are the mainstay of therapy in these patients. However, despite these

  17. Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study.

    Science.gov (United States)

    Ando, Katsuyuki; Nitta, Kosaku; Rakugi, Hiromi; Nishizawa, Yoshiki; Yokoyama, Hitoshi; Nakanishi, Takeshi; Kashihara, Naoki; Tomita, Kimio; Nangaku, Masaomi; Takahashi, Katsutoshi; Isshiki, Masashi; Shimosawa, Tatsuo; Fujita, Toshiro

    2014-01-01

    This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

  18. 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.

  19. Role of the inhibitors of angiotensin renin system on the DNA integrity of irradiated spermatozoids

    International Nuclear Information System (INIS)

    Spadella, Maria A.; Mansano, Naira S.; Schwarz, Franciele C.; Viani, Gustavo A.; Chies, Agnaldo B.

    2016-01-01

    Radiation action in the testes can significantly affect the reproductive capacity due to oxidative stress generated; phenomenon in which there is evidence of involvement of the Renin Angiotensin System (RAS). This study evaluated the role of AT1 receptor inhibitors, in mitigating the radioinduced DNA damage sperm from semen samples left vas deferens. Male Wistar rats were divided into six experimental groups: Control, 5Gy, Telmisartan (12mg/kg/day) and Losartan (34mg/kg/2x/day), 5 Gy + Telmisartan and 5 Gy + Losartan. The results showed increase in the percentage of sperm with fragmented DNA in irradiated groups when compared to controls, which was not reversed in the irradiated and treated groups. The radiation of 5Gy (single dose) affected the DNA-protein complex of the sperm and the treatments did not influence in reversing this damage, considering the experimental protocol used. (author)

  20. 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.

  1. The renin-angiotensin system in conscious newborn sheep: metabolic clearance rate and activity.

    Science.gov (United States)

    Velaphi, Sithembiso C; Despain, Kevin; Roy, Timothy; Rosenfeld, Charles R

    2007-06-01

    The role of the renin-angiotensin system (RAS) in regulating newborn mean arterial blood pressure (MAP) and tissue blood flow remains unclear. Although postnatal MAP increases, vascular responsiveness to infused angiotensin II (ANG II) is unchanged, possibly reflecting increased metabolic clearance rate of ANG II (MCR(ANG II)). To address this, we examined MAP, heart rate, plasma ANG II and renin activity (PRA), and MCR(ANG II) in conscious postnatal sheep (n = 9, 5-35 d old) before and during continuous systemic ANG II infusions to measure MCR (ANG II). Postnatal MAP increased (p < 0.02), whereas plasma ANG II decreased from 942 +/- 230 (SEM) to 471 +/- 152 and 240 +/- 70 pg/mL at <10 d, 10-20 d, and 21-35 d postnatally (p = 0.05), respectively. Despite high plasma ANG II, PRA remained elevated, averaging 6.70 +/- 1.1 ng/mL.h throughout the postnatal period, but decreased 35% (p = 0.01) during ANG II infusions. MCR(ANG II) decreased approximately sixfold after birth and averaged 115 mL/min.kg during the first month. Circulating ANG II is markedly increased after birth, reflecting placental removal, high fetal MCR(ANG II), and enhanced RAS activity. Although circulating ANG II decreases as MAP increases, MCR(ANG II) is unchanged, suggesting decreased ANG II production. Persistent vascular smooth muscle (VSM) AT2 receptor subtype (AT2R) expression after birth may modify the hypertensive effects of ANG II postnatally.

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

    Directory of Open Access Journals (Sweden)

    Ronaldo Altenburg Gismondi

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-10-02

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

  7. Regression of cardiac hypertrophy in the SHR by combined renin-angiotensin system blockade and dietary sodium restriction

    Directory of Open Access Journals (Sweden)

    Emad Abro

    2001-03-01

    Full Text Available Altered operation of the renin-angiotensin-aldosterone system (RAAS and dietary sodium intake have been identified as independent risk factors for cardiac hypertrophy. The way in which sodium intake and the operation of the renin-angiotensin-aldosterone system interact in the pathogenesis of cardiac hypertrophy is poorly understood. The aims of this study were to investigate the cardiac effects of the renin-angiotensin system (RAS blockade in the spontaneously hypertensive rat (SHR, using co-treatment with an angiotensin II receptor blocker (ARB and an angiotensin-converting enzyme (ACE inhibitor with different sodium intakes. Our experiments with SHR show that, at high levels of sodium intake (4.0%, aggressive RAS blockade treatment with candesartan (3 mg/kg and perindopril (6 mg/kg does not result in regression of cardiac hypertrophy. In contrast, RAS blockade coupled with reduced sodium diet (0.2% significantly regresses cardiac hypertrophy, impairs animal growth and is associated with elevated plasma renin and dramatically suppressed plasma angiotensinogen levels. Histological analyses indicate that the differential effect of reduced sodium on heart growth during RAS blockade is not associated with any change in myocardial interstitial collagen, but reflects modification of cellular geometry. Dimensional measurements of enzymatically-isolated ventricular myocytes show that, in the RAS blocked, reduced sodium group, myocyte length and width were decreased by about 16—19% compared with myocytes from the high sodium treatment group. Our findings highlight the importance of `titrating' sodium intake with combined RAS blockade in the clinical setting to optimise therapeutic benefit.

  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. 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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

    Dahlöf, B

    1995-11-01

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

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

    Science.gov (United States)

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

    2016-10-01

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

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

    International Nuclear Information System (INIS)

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

    1987-01-01

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

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

    NARCIS (Netherlands)

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

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sharifi A M

    2003-08-01

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

  16. Angiotensin-(1?7) inhibits inflammation and oxidative stress to relieve lung injury induced by chronic intermittent hypoxia in rats

    OpenAIRE

    Lu, W.; Kang, J.; Hu, K.; Tang, S.; Zhou, X.; Yu, S.; Li, Y.; Xu, L.

    2016-01-01

    Obstructive sleep apnea is associated with inflammation and oxidative stress in lung tissues and can lead to metabolic abnormalities. We investigated the effects of angiotensin1–7 [Ang-(1–7)] on lung injury in rats induced by chronic intermittent hypoxia (CIH). We randomly assigned 32 male Sprague-Dawley rats (180–200 g) to normoxia control (NC), CIH-untreated (uCIH), Ang-(1–7)-treated normoxia control (N-A), and Ang-(1–7)-treated CIH (CIH-A) groups. Oxidative stress biomarkers were measured ...

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

    International Nuclear Information System (INIS)

    Kamper, A.L.; Thomsen, H.S.; Nielsen, S.L.; Strandgaard, S.; Herlev Hospital

    1990-01-01

    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 function. Scintigrams of the kidneys showed an unaltered distribution of DMSA during treatment. GFR estimated by 51 Cr-EDTA plasma clearance fell by 14% (P 99m Tc-DMSA increased by 10% (P<0.01). It is concluded that DMSA in chronic renal failure is mainly taken up by the tubular cells from the peritubular capillaries since the uptake was unaffected by the acute decrease in GFR. (orig.)

  18. Effect of L-5-Hydroxytryptophan on drinking behavior in Coturnix japonica (Temminck and Schlegel, 1849 (Galliformes: Aves: involvement of renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    PL Cedraz-Mercez

    Full Text Available The purpose of this study was to explore the role of L-5-hydroxytryptophan (L-HTP and its relationship with the renin-angiotensin system (RAS on the drinking behavior in Japanese quails. Normally-hydrated quails that received injections of L-HTP (12.5; 25 and 50 mg.kg-1 by the intracoelomic route (ic expressed an increase in water intake, which was inhibited by captopril, an angiotensin converting enzyme (ACE inhibitor. In addition, captopril also induced such a response in birds under previous fluid deprivation. High doses of captopril (35-70 mg.kg-1, sc in normally-hydrated quails decreased the spontaneous water intake while low doses of captopril (2-5 mg.kg-1, sc did not prompt water intake after L-HTP administration. Losartan, an AT1 receptor antagonist in mammals, did not change the water intake levels in normally-hydrated or water-deprivated birds. Serotonin (5-HT injections did not provoke its known dipsogenic response.

  19. Structural characteristics and antihypertensive effects of angiotensin ...

    African Journals Online (AJOL)

    Structural characteristics and antihypertensive effects of angiotensin-iconverting enzyme inhibitory peptides in the renin-angiotensin and kallikrein kinin systems. ... Background: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven ...

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

    International Nuclear Information System (INIS)

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

    1986-01-01

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

  1. 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.

  2. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS

    DEFF Research Database (Denmark)

    Leonhardt, Julia; Villela, Daniel C.; Teichmann, Anke

    2017-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may......, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked...

  3. RETRACTED: Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy.

    Science.gov (United States)

    Zhou, Tian-Biao; Li, Hong-Yan; Jiang, Zong-Pei; Zhou, Jia-Fan; Huang, Miao-Fang; Zhou, Zhi-Yang

    2015-12-01

    The following article has been included in a multiple retraction: Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System ( JRAAS) 1470320314563424, first published 18 December 2014. DOI: 10.1177/1470320314563424 . This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the JRAAS (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer-review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online-first articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy JRAAS 1470320314563426, first published 18 December 2014. DOI: 10.1177/1470320314563426 . Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy JRAAS 1470320314563424, first published 18 December 2014. DOI: 10.1177/1470320314563424 . Weiqiang Zhong, Zongpei Jiang and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population JRAAS1470320314566019, first published 26 January 2015. DOI: 10.1177/1470320314566019 . Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into

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

    DEFF Research Database (Denmark)

    Persson, Frederik; Lindhardt, Morten; Rossing, Peter

    2016-01-01

    Hypothesis/objectives: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can p......-cause mortality(p=0.07). Conclusions: We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria.......Hypothesis/objectives: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can...

  5. 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

    2015-09-09

    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.

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

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Marcussen, Niels; Pedersen, Michael

    2010-01-01

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

  7. Characterization of angiotensin-I converting enzyme inhibiting peptide from Venerupis philippinarum with nano-liquid chromatography in combination with orbitrap mass spectrum detection and molecular docking

    Science.gov (United States)

    Shi, Lei; Wu, Tizhi; Sheng, Naijuan; Yang, Li; Wang, Qian; Liu, Rui; Wu, Hao

    2017-06-01

    The complexity and diversity of peptide mixture from protein hydrolysates make their characterization difficult. In this study, a method combining nano LC-MS/MS with molecular docking was applied to identifying and characterizing a peptide with angiotensin-I converting enzyme (ACE-I) inhibiting activity from Venerupis philippinarum hydrolysate. Firstly, ethanol supernatant of V. philippinarum hydrolysate was separated into active fractions with chromatographic methods such as ion-exchange chromatography and high performance liquid chromatography in combination. Then seven peptides from active fraction were identified according to the searching result of the MS/MS spectra against protein databases. Peptides were synthesized and subjected to ACE-I-inhibition assay. The peptide NTLTLIDTGIGMTK showed the highest potency with an IC50 of 5.75 μmol L-1. The molecular docking analysis showed that the ACE-I inhibiting peptide NTLTLIDTGIGMTK bond with residues Glu123, Glu403, Arg522, Glu376, Gln281 and Asn285 of ACE-I. Therefore, active peptides could be identified with the present method rather than the traditional purification and identification strategies. It may also be feasible to identify other food-derived peptides which target other enzymes and receptors with the method developed in this study.

  8. 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

    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....

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

    Science.gov (United States)

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

    2016-01-01

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

  10. 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...... no human studies have confirmed an ACE inhibition in relation to the intake of fermented milk....

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    N. F. Renna

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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

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

    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...

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

    DEFF Research Database (Denmark)

    Stadeager, C; Hesse, B; Henriksen, O

    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....... It is concluded that, in the human forearm, angiotensin II is not necessary for sympathetic vasoconstrictor reflexes but may, through a central effect, have some influence on arteriolar tone at rest....

  16. 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...

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

    Directory of Open Access Journals (Sweden)

    Therese Featherston

    2016-09-01

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

  18. Angioedema Triggered by Medication Blocking the Renin/Angiotensin System: Retrospective Study Using the French National Pharmacovigilance Database.

    Science.gov (United States)

    Faisant, Charles; Armengol, Guillaume; Bouillet, Laurence; Boccon-Gibod, Isabelle; Villier, Céline; Lévesque, Hervé; Cottin, Judith; Massy, Nathalie; Benhamou, Ygal

    2016-01-01

    Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. The national MedDRA database was searched using the term "angioedema". Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21% of cases (24 patients), or an ACEi in 77% of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90% of cases (tongue: 48.2%, larynx: 23.2%). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug.

  19. Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

    Science.gov (United States)

    Kikuchi, Kiyoshi; Tancharoen, Salunya; Ito, Takashi; Morimoto-Yamashita, Yoko; Miura, Naoki; Kawahara, Ko-ichi; Maruyama, Ikuro; Murai, Yoshinaka; Tanaka, Eiichiro

    2013-01-01

    Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. PMID:24065095

  20. Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo.

    Science.gov (United States)

    Mao, Yingying; Pei, Nana; Chen, Xinglu; Chen, Huiying; Yan, Renhe; Bai, Na; Li, Andrew; Li, Jinlong; Zhang, Yanling; Du, Hongyan; Chen, Baihong; Sumners, Colin; Wang, Xuejun; Wang, Shengqi; Li, Hongwei

    2018-01-01

    Background: Angiotensin-(1-7) [Ang-(1-7)] has been identified to inhibit the growth of many types of tumor cells both in vitro and in vivo . However, the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Adeno-associated virus (AAV) serotype-8 is a remarkable vector for long-term in vivo gene delivery. Method: This study was designed to investigate the effects of AAV-mediated Ang-(1-7) overexpression on hepatocellular carcinoma. We first generated three different tyrosine (Y) to phenylalanine (F) mutants of AAV8 (Y447F, Y703F, Y708F) and evaluated their in vivo transduction efficiencies. Results: The data indicated that the Y703F mutant elicited a significant enhancement of liver gene delivery when compared with wild-type AAV8 (wtAAV8). The anti-tumor effect of Ang-(1-7) mediated by this optimized vector was evaluated in H22 hepatoma-bearing mice. Our results demonstrated that AAV-Ang-(1-7) persistently inhibited the growth of hepatocellular carcinoma by significantly downregulating angiogenesis. This was confirmed by observed decreases in the levels of the proangiogenic factors VEGF and PIGF. Conclusion: Collectively, these data suggest that Ang-(1-7) overexpression mediated by the optimized vector may be an effective alternative for hepatocellular carcinoma therapy due to its long-term and significant anti-tumor activity.

  1. Renin-angiotensin system-related highlights from the High Blood Pressure Research Conference annual meeting.

    Science.gov (United States)

    Luft, Friedrich C

    2008-12-01

    The High Blood Pressure Research Conference of the American Heart Association is a theoretical meeting for hypertension researchers who direct their attention to hypertension-related basic disease mechanisms. The items that I have selected for this brief review are molecular intracellular receptor function, novel angiotensin (Ang)-related pathways, including Ang-(1-7), the Mas receptor, and angiotensin-converting enzyme 2, oxidative stress, immunity, the (pro)renin receptor, and until now unappreciated signalling pathways, such as the tonicity element binding protein.

  2. Antioxidation, angiotensin converting enzyme inhibition activity, nattokinase, and antihypertension of Bacillus subtilis (natto-fermented pigeon pea

    Directory of Open Access Journals (Sweden)

    Bao-Hong Lee

    2015-12-01

    Full Text Available Because of the high incidence of cardiovascular diseases in Asian countries, traditional fermented foods from Asia have been increasingly investigated for antiatherosclerotic effects. This study investigated the production of nattokinase, a serine fibrinolytic enzyme, in pigeon pea by Bacillus subtilis fermentation. B. subtilis 14714, B. subtilis 14715, B. subtilis 14716, and B. subtilis 14718 were employed to produce nattokinase. The highest nattokinase activity in pigeon pea was obtained using B. subtilis 14715 fermentation for 32 hours. In addition, the levels of antioxidants (phenolics and flavonoids and angiotensin converting enzyme inhibitory activity were increased in B. subtilis 14715-fermented pigeon pea, compared with those in nonfermented pigeon pea. In an animal model, we found that both water extracts of pigeon pea (100 mg/kg body weight and water extracts of B. subtilis-fermented pigeon pea (100 mg/kg body weight significantly improved systolic blood pressure (21 mmHg and diastolic blood pressure (30 mmHg in spontaneously hypertensive rats. These results suggest that Bacillus-fermented pigeon pea has benefits for cardiovascular health and can be developed as a new dietary supplement or functional food that prevents hypertension.

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

    African Journals Online (AJOL)

    Ehab

    2012-06-18

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

  4. Method for the optimum formation of angiotensin I from angiotensinogen and radioimmunoassay for angiotensin I

    International Nuclear Information System (INIS)

    Pagnucco, R.G.; Murty, D.R.; Muse, R.J.

    1978-01-01

    The invention deals with a method to optimize the formation of angiotensin I from angiotensinogens by optimizing the temperature, pH value and buffer system. Furthermore, the invention concerns a radioimmunoassay method to determine angiotensin I. Iodine 125 labelled angiotensin I is preferably used as tracer. (VJ) [de

  5. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Kristensen, Karl Emil; Torp-Pedersen, Christian; Gislason, Gunnar Hilmar

    2015-01-01

    OBJECTIVE: The renin-angiotensin system is thought to play a pivotal role in the pathogenesis of abdominal aortic aneurysms (AAAs). However, effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) on human AAAs remain unclear. We therefore ex...

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    The role for ANG II in renal blood flow (RBF) autoregulation is unsettled. The present study was designed to test the effect of clamping plasma ANG II concentrations ([ANG II]) by simultaneous infusion of the angiotensin-converting enzyme inhibitor captopril and ANG II on RBF autoregulation...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2011-05-15

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

  9. [Elevated serum aldosterone levels in dialysis patients: Are we underusing renin-angiotensin-aldosterone system blockers?

    Science.gov (United States)

    Fernández-Reyes, M J; Velasco, S; Gutierrez, C; Gonzalez Villalba, M J; Heras, M; Molina, A; Callejas, R; Rodríguez, A; Calle, L; Lopes, V

    Serum aldosteronelevels (SA) are a marker of cardiovascular (CV) risk in the general population. To analyze SA levels in dialysis patients and its relationship with characteristics of dialysis; comorbidity; blood pressure and the use of blocking renin-angiotensin-aldosterone system agents (BSRAA). We determined SA in 102 patients: 81 on hemodialysis (HD) and 21 on peritoneal dialysis. Mean age 71.4±12 years; 54.9% male; 29.4% diabetics. Mean time on dialysis 59.3±67 months. In 44 HD patients plasma renin activity (PRA) was measured. Mean SA was 72.6±114.9ng/dl (normal range 1.17-23.6ng/dl). A total of 57.8% of patients had above normal levels which were not related to dialysis characteristics or comorbidity. Only 21% of patients with heart failure and 19.2% with ischemic heart disease used BSRAA. A number of 25 patients treated with BSRAA had significantly lower levels of SA. There was an inverse correlation between AS and systolic blood pressure (SBP), and direct with PRA. The logistic regression analysis conducted to find SA levels above the median associated factors showed that SBP was the only independent risk variable in the overall population (OR 0.97; P=.022); in the 44 patients in whom PRA was determined this was the only independent risk factor (OR 2.24; P=.012). A high percentage of dialysis patients have elevated levels of SA that are associated to diminished SBP and activated PRA and not to dialysis characteristics. In patients with a history of heart disease we underuse BSRAA. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Renin-angiotensin-aldosterone system in bodybuilders using supraphysiological doses of anabolic-androgenic steroids

    Directory of Open Access Journals (Sweden)

    K Chrostowski

    2011-03-01

    Full Text Available This study was carried out in 40 bodybuilders voluntarily taking supraphysiological doses of anabolic-androgenic steroids (AAS. Echocardiographic examination of the heart and blood analysis were performed, and concentration of AAS in urine was examined. The presence, or absence, of AAS in urine had no influence on the echocardiographic parameters of the heart, body mass, body mass index (BMI and aldosterone level in blood plasma. It seems, therefore, that the presence of AAS in urine may confirm heart hypertrophy and overuse of AAS, while the absence of AAS in urine does not exclude the cardiological changes occurring as a result of taking the drugs. Metabolites detected in urine showed that the intake of 17α-alkyl testosterone derivatives caused higher values of left ventricular mass and BMI. However, the level of HDL cholesterol was lower in bodybuilders using only 19-nor-testosterone. Elevated level of plasma aldosterone did not differ between the two groups. As could be expected, the highest level of AAS in urine was detected in bodybuilders currently self-administering the anabolic-androgenic steroids (on cycle. The level of AAS in the urine decreased after stopping taking the drugs (off cycle. Refraining from AAS abuse for a period of 1-2 years was associated with a significant decrease in aldosterone level in the plasma. The positive correlations found between the blood plasma aldosterone, left ventricular mass and BMI lead to the conclusion that large doses of AAS taken by bodybuilders would cause extra activation of the renin-angiotensin-aldosterone system.

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Science.gov (United States)

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

    2005-08-01

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

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

    Science.gov (United States)

    Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

    2014-01-01

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

  14. 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

  15. Protein kinase C epsilon mediates the inhibition of angiotensin II on the slowly activating delayed-rectifier potassium current through channel phosphorylation.

    Science.gov (United States)

    Gou, Xiangbo; Wang, Wenying; Zou, Sihao; Qi, Yajuan; Xu, Yanfang

    2018-03-01

    The slowly activating delayed rectifier K + current (I Ks ) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I Ks through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I Ks by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I Ks in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited I Ks in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1-2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human I Ks in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on I Ks and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-03-09

    Objective  To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. Design  Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics. Setting  UK primary care, 1997-2014. Participants  Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363). Main outcome measures  Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs. Results  Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using creatinine

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

    Science.gov (United States)

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

    2014-01-01

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

  19. Impact of angiotensin-converting enzyme inhibition on platelet tissue factor expression in stroke-prone rats.

    Science.gov (United States)

    Brambilla, Marta; Gelosa, Paolo; Rossetti, Laura; Castiglioni, Laura; Zara, Chiara; Canzano, Paola; Tremoli, Elena; Sironi, Luigi; Camera, Marina

    2018-03-06

    Hypertension is a well known risk factor for thrombotic events such as myocardial infarction and stroke. Platelets express tissue factor (TF), the key activator of blood coagulation and thrombus formation. The number of TF-positive platelets increases in pathological conditions characterized by thrombotic complications but whether this occurs in hypertension is unknown. Here we investigated whether platelet TF expression is increased in a hypertensive status through a mechanism acting on megakaryocytes; the phenomenon could be modulated by antihypertensive drug as captopril; angiotensin (AngII) influences platelet TF expression. Spontaneously hypertensive stroke prone (SHRSP) rats received standard diet (StD) or a Japanese high-salt permissive diet (JpD). After 3 weeks, JpD animals were randomized to receive captopril or vehicle. Normotensive Wistar Kyoto (WKY) rats were used as controls. Cell-associated TF expression and activity were analyzed by flow cytometry and calibrated automated thrombogram, respectively. Hypertensive StD-SHRSP showed an increased number of TF-positive platelets compared with normotensive WKY. After JpD administration, SHRSP developed severe hypertension and renal damage; the number of TF-positive megakaryocytes significantly increased compared with StD-SHRSP resulting in a higher number of TF-positive platelets with a faster kinetic of thrombin generation. These effects were reverted by captopril. Ex-vivo stimulation of platelets, isolated from normotensive WKY and from healthy individuals, with AngII induced a concentration-dependent increase of surface-associated TF expression. The current study shows for the first time that in hypertension the number of TF-positive megakaryocytes increases thus releasing in the circulation more platelets carrying a functionally active TF. AngII stimulates platelets to express TF.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives

  20. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

    2009-01-01

    PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive...... peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA. DESIGN: Experimental retrospective...... with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls. CONCLUSIONS: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA. FINANCIAL...

  1. Low birth weight activates the renin?angiotensin system, but limits cardiac angiogenesis in early postnatal life

    OpenAIRE

    Wang, Kimberley C W; Brooks, Doug A; Summers-Pearce, Brooke; Bobrovskaya, Larisa; Tosh, Darran N; Duffield, Jaime A; Botting, Kimberley J; Zhang, Song; Caroline McMillen, I; Morrison, Janna L

    2015-01-01

    Low birth weight (LBW) is associated with increased risk of adult cardiovascular disease and this association may be partly a consequence of early programming of the renin?angiotensin system (RAS). We investigated the effects of LBW on expression of molecules in the RAS and cardiac tissue remodeling. Left ventricular samples were collected from the hearts of 21?days old lambs that were born average birth weight (ABW) and LBW. Cardiac mRNA expression was quantified using real-time RT-PCR and p...

  2. Changes in angiotensin AT1 receptor mRNA levels in the rat brain after immobilization stress and inhibition of central nitric oxide synthase.

    Science.gov (United States)

    Kiss, A; Jurkovicova, D; Jezova, D; Krizanova, O

    2001-06-01

    To study functional interactions between angiotensin II AT1 receptors and nitric oxide (NO) activity in different brain areas in rats exposed to immobilization stress. Central inhibition of nitric oxide synthase (NOS) was provided by intracerebroventricular (i.c.v.) administration of (N-omega-nitro-L-arginine-methylester) L-NAME and analysis of AT1 receptor mRNA was performed using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) technique. The immobilization in prone position lasted 2 hrs and the rats were sacrificed 24 hr later. The hypothalamus, hippocampus, thalamus, and cortex were isolated from fresh brains. In the cortex, gene expression of AT1 receptors was unaffected either by L-NAME treatment, or by a single exposure to immobilization stress for 2 hours followed by 24 hours of rest. In the hippocampus, the repeated treatment with L-NAME increased mRNA levels of AT1 receptors approximately 9-times compared to those in the control (untreated) group. Immobilization also increased AT1 receptor mRNA levels in the hippocampus which was similar to that induced by the L-NAME. The increase of AT1 receptor mRNA levels in the hippocampus of immobilized rats was not further altered when the animals were pretreated with L-NAME. In control rats, exposure to immobilization resulted in a significant rise in mRNA levels coding for AT1 receptors in the hypothalamus, but not in the thalamus. L-NAME treatment showed a tendency of increase in AT1 receptor mRNA levels in the hypothalamus. Moreover, when animals treated with L-NAME were subjected to immobilization, a further increase in AT1 receptor mRNA levels was observed in the hypothalamus in comparison with corresponding controls. The present data indicate that a single immobilization stress results in increased gene expression of AT1 receptors in the hypothalamus and hippocampus. The rise in AT1 mRNA levels in the same brain structures after repeated treatment with L-NAME allow to suggest an

  3. Influence of Angiotensin-Aldosterone System on Ultrasound of Joints in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    O.B. Komarova

    2014-02-01

    Full Text Available In patients with rheumatoid arthritis and high level of angiotensin II in the blood at ultrasound of joints there are often being detected effusion in the joint cavity, hypervascularization of synovium with 2–3 points and tenosynovitis characterizing inflammatory exudative processes. In patients with high level of aldosterone, hyperplasia of synovium, presence of pannus and bone and cartilage erosions, indicating proliferative-destructive processes, were predominated. Identified correlations show that with increasing levels of angiotensin II in the blood increases the intensity of the vascularization of the synovial membrane, joint effusion, and an increase in the concentration of aldosterone in the blood affects the synovial thickness indicators, the presence of pannus and bone erosions amount.

  4. Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

    Science.gov (United States)

    Jellyman, Juanita K.; De Blasio, Miles J.; Johnson, Emma; Giussani, Dino A.; Broughton Pipkin, Fiona; Fowden, Abigail L.

    2015-01-01

    Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10–11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment. PMID:26039155

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

    Directory of Open Access Journals (Sweden)

    Linting Wei

    2017-12-01

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

  6. Different expression of renin-angiotensin system components in hearts of normotensive and hypertensive rats

    Czech Academy of Sciences Publication Activity Database

    Jurkovičová, D.; Dobešová, Zdenka; Kuneš, Jaroslav; Križanová, O.

    2001-01-01

    Roč. 50, č. 1 (2001), s. 35-42 ISSN 0862-8408 R&D Projects: GA AV ČR IAA7011805 Grant - others:VEGA(SK) 2/7158(OK) Institutional research plan: CEZ:AV0Z5011922 Keywords : renin- angiotensin systém * heart * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.027, year: 2001

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

    Directory of Open Access Journals (Sweden)

    Ming-Horng Tsai

    2017-08-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

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

    Czech Academy of Sciences Publication Activity Database

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

    2015-01-01

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

  10. Renin angiotensin system blockers-associated angioedema in the Thai population: analysis from Thai National Pharmacovigilance Database.

    Science.gov (United States)

    Win, Thet Su Zin; Chaiyakunapruk, Nathorn; Suwankesawong, Wimon; Dilokthornsakul, Piyameth; Nathisuwan, Surakit

    2015-09-01

    Renin-angiotensin-aldosterone system (RAS) blockers are commonly used for cardiovascular diseases. Currently, little information exists for the Asian population on angioedema, a rare yet serious adverse event. This study aimed to describe characteristics of RAS blockers-associated angioedema (RASBA) in Thai patients. A retrospective study using the national pharmacovigilance database of Thailand was undertaken. Cases indicating the presence of angioedema with RAS blockers uses from 1984-2011 were identified. Patient demographics, co-morbidities, concomitant drugs, information for the RAS blockers and angioedema were obtained as well as causality assessment and quality of reports. A total of 895 cases were identified. Mean age was 59.9+12.8 years and 66.5% being female. Most angioedema events (48.6%) occurred during the first week of treatment. Angiotensin converting enzyme inhibitors (87.7%) were the most commonly implicated agents followed by angiotensin receptor blockers (10.5%), aldosterone antagonist (2.1%) and direct renin inhibitor (0.2%). Out of the 895 cases incorporated in this study, 165 (18.4%) were classified as serious events and resulted in hospitalization. The overall case fatality rate was 0.4%. Respiratory disturbance occurred in 46 cases (5.1%). Patients with respiratory complications tended to be younger (53.4+13.9 vs 60.3+12.7 years old; p=0.002) and with higher frequency of allergy history (26.1% vs 14.7%; p=0.032) compared to those without respiratory complications. Based on multivariate logistic regression, the adjusted OR for history of allergy was 2.23 (95%CI: 1.04 - 4.78, p = 0.041). RASBA in Thai population occurred mostly in elderly female patients and often led to hospitalization. Since large number of patients is regularly exposed to RAS-blockers, a nationwide attempt to raise awareness of clinicians when prescribing RAS-blockers is prudent.

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

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    Ilić Vesna

    2014-01-01

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

  12. Renin-angiotensin system blockade reduces cardiovascular events in nonheart failure, stable patients with prior coronary intervention.

    Science.gov (United States)

    Choi, Young; Lim, Sungmin; Lee, Kwan Yong; Park, Ha-Wook; Byeon, Jaeho; Hwang, Byung-Hee; Kim, Jin Jin; Oh, Yong-Seog; Youn, Ho-Joong; Jung, Wook Sung; Seung, Ki-Bae; Chang, Kiyuk

    2018-02-27

    The effects of renin-angiotensin system (RAS) blockade on the clinical outcome in patients with stable coronary artery disease (SCAD) are conflicting. We evaluated the long-term effects of RAS blockers (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) on the clinical outcomes in patients with SCAD without heart failure (HF) who underwent percutaneous coronary intervention (PCI) with drug-eluting stent using a large-scale, multicenter, prospective cohort registry. A total of 5722 patients with SCAD were enrolled and divided into two groups according to the use of RAS blockers after PCI: RAS blocker group included 4070 patients and no RAS blocker group included 1652 patients. Exclusion criteria were left ventricular ejection fraction less than 50% and the history of HF or myocardial infarction. A major adverse cardiovascular event (MACE) was defined as a composite of cardiovascular death, nonfatal myocardial infarction, and stroke. During a median follow-up of 29.7 months, RAS blockers were associated with a significant reduction in the risk of MACE [adjusted hazard ratio (HR): 0.781; 95% confidence interval (CI): 0.626-0.975; P=0.015] and all-cause death (adjusted HR: 0.788; 95% CI: 0.627-0.990; P=0.041) but did not affect the risk of coronary revascularization. In the propensity score matched cohort, overall findings were consistent (MACE: adjusted HR: 0.679; 95% CI: 0.514-0.897; P=0.006; all-cause death: adjusted HR: 0.723; 95% CI: 0.548-0.954; P=0.022), and the benefit of RAS blockade was maintained in all predefined subgroups. This study demonstrated that RAS blockers were effective preventive therapies for reducing long-term cardiovascular events in patients with SCAD without HF who underwent PCI.

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

    Science.gov (United States)

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

    2015-08-01

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

  14. 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...

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

    Science.gov (United States)

    Ito, Takashi; Schaffer, Stephen; Azuma, Junichi

    2014-01-01

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

  16. Angiotensin AT1 - α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats.

    Science.gov (United States)

    Berg, Torill

    2013-01-01

    α2-Adrenoceptors lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR). Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R) precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake. Presynaptic control of vesicular release is therefore reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY) and SHR were pre-treated with (1) vehicle or α2AR-antagonist (L-659,066), followed by fadolmidine (α2C>B>A + α1AR-agonist), ST-91 (α2non-A-selective agonist), or m-nitrobiphenyline (α2CAR-agonist + α2A+B-antagonist), or (2) AT1R-antagonist losartan, losartan + L-659,066, or losartan + clonidine. In WKY, L-659,066 alone, L-659,066 + agonist or losartan + L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR). In SHR, L-659,066 + fadolmidine/ST-91/m-nitrobiphenyline and losartan + L-659,066 greatly increased, and losartan + clonidine reduced, catecholamine concentrations, and L-659,066 + ST-91, losartan + L-659,066 and losartan + clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of

  17. ANGIOTENSIN AT1 - α2C-ADRENOCEPTOR INTERACTION DISTURBS α2A-AUTO-INHIBITION OF CATECHOLAMINE RELEASEIN HYPERTENSIVE RATS

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2013-06-01

    Full Text Available α2-adrenoceptors (AR lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR. Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anaesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake, and presynaptic control of vesicular release is reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY and SHR were pre-treated with 1 vehicle or α2AR antagonist (L-659,066, followed by fadolmidine (α2C>B>A+α1AR agonist, ST-91 (α2non-A-selective agonist or m-nitrobiphenyline (α2CAR-agonist+α2A+B-antagonist, or 2 AT1R antagonist losartan, losartan+L-659,066 or losartan+clonidine. In WKY, L-659,066 alone, L-659,066+agonist or losartan+L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR. In SHR, L-659,066+fadolmidine/ST-91/m-nitrobiphenyline and losartan+L-659,066 greatly increased, and losartan+clonidine reduced, catecholamine concentrations, and L-659,066+ST-91, losartan+L-659,066 and losartan+clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of norepinephrine and epinephrine release and control of TPR in SHR.

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

    International Nuclear Information System (INIS)

    Eliahou, H.E.; Iaina, A.

    1980-01-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Manisha Nautiyal

    2013-01-01

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

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

    Science.gov (United States)

    Silva, Rondineli Mendes da; Chaves, Gabriela Costa; Chaves, Luisa Arueira; Campos, Mônica Rodrigues; Luiza, Vera Lucia; Bertoldi, Andréa Dâmaso; Ross-Degnan, Dennis; Emmerick, Isabel Cristina Martins

    2017-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Rondineli Mendes da Silva

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

  3. Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism*

    Science.gov (United States)

    Mateos, Laura; Ismail, Muhammad-Al-Mustafa; Gil-Bea, Francisco-Javier; Schüle, Rebecca; Schöls, Ludger; Heverin, Maura; Folkesson, Ronnie; Björkhem, Ingemar; Cedazo-Mínguez, Angel

    2011-01-01

    Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration. PMID:21628469

  4. Efficacy of renin-angiotensin system (RAS) blockers on cardiovascular and renal outcomes in patients with type 2 diabetes.

    Science.gov (United States)

    Cao, Zemin; Cooper, Mark E

    2012-08-01

    Cardiovascular disease is the predominant cause of morbidity in people with type 2 diabetes. Hypertension frequently coexists with diabetes and substantially increases the risk of developing end-organ damage. Controlling hypertension in patients with diabetes is therefore critical to reducing microvascular and macrovascular complications. Agents that block the renin-angiotensin system are increasingly used in patients with diabetes based on their cardiovascular and renoprotective effects, in addition to their direct effects on reducing blood pressure. Telmisartan, an angiotensin II receptor blocker (ARB), has a number of distinguishing pharmacological properties such as having the longest half-life and highest lipophilicity in its class. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET(®)) trial showed that telmisartan reduces cardiovascular morbidity (including myocardial infarction and stroke) in subjects with a broad spectrum of cardiovascular risk factors, including type 2 diabetes. Telmisartan is the only ARB indicated for the reduction of cardiovascular morbidity in patients with diabetes and end-organ damage, as well as in patients without diabetes but with a history of coronary artery disease, peripheral artery disease, or previous stroke. Trials of telmisartan in patients with diabetes and varying degrees of nephropathy also suggest that this drug can slow the progression of renal disease, an effect that appears to be at least partly independent of reduction in blood pressure. Telmisartan is therefore an important therapeutic option for optimizing cardiovascular and renal protection in the type 2 diabetic population.

  5. Family history and renin-angiotensin system gene polymorphisms in Chinese patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Pan, Yan-Hong; Huang, Yan-Mei; Qiao, Yong-Chao; Ling, Wei; Geng, Li-Jun; Xiao, Jian-Long; Zhang, Xiao-Xi; Zhao, Hai-Lu

    2017-12-01

    A positive family history is recognized as an important risk factor for type 2 diabetes mellitus (T2DM), but the association of family history with rennin-angiotensin system (RAS) gene polymorphisms has not been reported yet, thus we aim to investigate it.Family history records, clinical and biochemical data were obtained from 1239 T2DM patients. Polymerase chain reaction (PCR) was performed for angiotensin-converting enzyme (ACE) genotyping and PCR-restricted fragment length polymorphism was used for angiotensinogen (AGT) genotyping.Patients with a negative family history had higher level of triglyceride and blood pressure, whereas those with a positive family history showed younger onset age and lower body mass index value (All P history (All P history and those with a negative family history had comparable genotype and allele distribution of ACE gene insertion/deletion polymorphisms and AGT gene M/T polymorphisms.A positive family history of diabetes was not associated with the RAS gene polymorphisms. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

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

    Science.gov (United States)

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

    2015-05-20

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

  7. Drug-Induced Inhibition of Angiotensin Converting Enzyme and Dipeptidyl Peptidase 4 Results in Nearly Therapy Resistant Bradykinin Induced Angioedema: A Case Report.

    Science.gov (United States)

    Hahn, Janina; Trainotti, Susanne; Hoffmann, Thomas K; Greve, Jens

    2017-05-25

    BACKGROUND Bradykinin is an underestimated mediator of angioedema. One subgroup of bradykinin induced angioedema is angioedema triggered by treatment with angiotensin converting enzyme (ACE) inhibitors. Due to its localization in the head and neck region and its unpredictable course, it is a possibly life-threatening condition. There is not an officially approved treatment for ACE inhibitor induced angioedema. CASE REPORT We present a case of an 83-year-old woman, who presented to our ENT department because of acute swelling of the tongue. On admission, there was no pharyngeal or laryngeal edema and no dyspnea. Treatment with glucocorticoids and antihistamines had no response. The patient had ramipril as regular medication, so we assumed ACE inhibitor induced angioedema and treated consequently with C1-inhibitor (human) 1,500 IU. Nevertheless, swelling was progressive and required intubation. Even after the second specific treatment with icatibant, her angioedema subsided extremely slowly. The patient also had regular treatment with saxagliptin, a dipeptidyl peptidase 4 inhibitor, so we assumed that the simultaneous inhibition of two bradykinin degrading enzymes led to a treatment-refractory course of angioedema. CONCLUSIONS General awareness for bradykinin induced angioedema due to regular medication is limited. Our case demonstrated the importance of improving awareness and knowledge about this side effect. We need a better understanding of the pathomechanism to aid in more precise clinical diagnosis. Securing the patient's airway as well as administration of an officially approved therapy is of utmost importance. As the number of patients simultaneously treated with antihypertensive and antidiabetic drugs is likely to increase, the incidence of bradykinin mediated drug induced angioedema is likely to increase as well.

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

    Directory of Open Access Journals (Sweden)

    Diego Lopes Mendes Barretti

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

  9. Inhibition of RAS in diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yacoub R

    2015-04-01

    Full Text Available Rabi Yacoub, Kirk N Campbell Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Diabetic kidney disease (DKD is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII, the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. Keywords: renin–angiotensin system, diabetic kidney disease, angiotensin II, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

  10. In Vitro Regulation of Enzymes of the Renin-angiotensin-aldosterone System by Isoquercitrin, Phloridzin and their Long Chain Fatty Acid Derivatives

    Directory of Open Access Journals (Sweden)

    Khushwant S. Bhullar

    2014-05-01

    Full Text Available Background: Hypertension is a crucial risk factor for development of cardiovascular and neurological diseases. Flavonoids exhibit a wide range of biological effects and have had increased interest as a dietary approach for the prevention or possible treatment of hypertension. However, continuous efforts have been made to structurally modify natural flavonoids with the hope of improving their biological activities. One of the methods used for the possible enhancement of flavonoid efficacy is enzymatic esterification of flavonoids with fatty acids. Objective: The current study is designed to investigate the antihypertensive activity of isoquercitrin (quercetin-3-O-glucoside, Q3G and phloridzin (PZ in comparison to their twelve long chain fatty acid derivatives via enzymatic inhibition of renin angiotensin aldosterone system (RAAS enzymes. Methods: The novel flavonoid esters were synthesized by the acylation of isoquercitrin and phloridzin with long chain unsaturated and saturated fatty acids (C18–C22. These acylated products were then tested for their in vitro angiotensin converting enzyme (ACE, renin and aldosterone synthase activities. Results: The linoleic and α-linolenic acid esters of PZ were the strongest (IC50 69.9-70.9 µM while Q3G and PZ (IC50 >200 µM were the weakest renin inhibitors in vitro (p≤0.05. The eicosapentaenoic acid ester of PZ (IC50 16.0 µM was the strongest inhibitor of ACE, while PZ (IC50 124.0 µM was the weakest inhibitor (p≤0.05 among all tested compounds. However, all investigated compounds had low (5.0-11.9% or no effect on aldosterone synthase inhibition (p≤0.05. The parent compound Q3G and the eicosapentaenoic acid ester of PZ emerged as the strongest ACE inhibitors. Conclusions: The structural modification of Q3G and PZ significantly improved their antihypertensive activities. The potential use of PZ derivatives as natural health products to treat hypertension needs to be further evaluated

  11. Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualised with 1-[1-{sup 11}C]-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Kagaya, Yutaka; Chida, Masanobu; Namiuchi, Shigeto; Takeda, Morihiko; Yamane, Yuriko; Otani, Hiroki; Watanabe, Jun; Fukuchi, Mitsumasa; Shirato, Kunio [Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574 (Japan); Imahori, Yoshio [Department of Neurosurgery, Kyoto Prefectural University of Medicine, Kyoto (Japan); Fujii, Ryou [Cyclotron Unit, Nishijin Hospital, Kyoto (Japan); Tezuka, Fumiaki [Department of Pathology, National Sendai Hospital, Sendai (Japan); Ido, Tatsuo [Cyclotron and Radioisotope Center, Tohoku University, Sendai (Japan)

    2002-11-01

    We recently reported that myocardial phosphoinositide (PI) metabolism can be visualised by 1-[1-{sup 11}C]-butyryl-2-palmitoyl-rac-glycerol ({sup 11}C-DAG) in rats with myocardial infarction (MI). Angiotensin II, the receptors for which are expressed predominantly in infarcted areas with active fibrogenesis rather than in non-infarcted regions, is involved in the upstream signalling systems of PI metabolism and plays an important role in the process of left ventricular (LV) remodelling after MI. We therefore hypothesised that the distribution of {sup 11}C-DAG after MI may be affected by the inhibition of angiotensin converting enzyme, which is one of the most important factors in the development of LV remodelling after MI. Rats were injected with {sup 11}C-DAG after 3 or 10weeks of treatment with captopril or no treatment following coronary artery ligation, and quantitative autoradiography was performed. Cells occupying the infarcted region were identified by immunohistochemistry. Compared with untreated rats, treatment with captopril for 3 weeks after MI elicited a reduction in the {sup 11}C-DAG uptake in the infarcted region (P<0.05) but not in the non-infarcted region, and was associated with a 22% decrease in the heart weight/body weight ratio. The thallium-201 distribution in the infarcted area was similarly low in the rats with and rats without the 3-week captopril treatment after MI. Abundant macrophages and myofibroblasts occupied the infarcted area in both rats with and rats without the captopril treatment for 3 weeks after MI. The {sup 11}C-DAG radioactivity in the infarcted region in the untreated rats was lower 10 weeks after MI than 3 weeks after MI (P<0.01). This finding was in agreement with the results of immunohistochemistry demonstrating that the number and size of macrophages and myofibroblasts were remarkably reduced in rats 10 weeks after MI compared with 3 weeks after MI. Captopril treatment for 10 weeks after MI did not decrease the {sup 11}C

  12. Renal and cardio-protective effects of direct renin inhibition : a systematic literature review

    NARCIS (Netherlands)

    Lambers Heerspink, Hiddo J.; Perkovic, Vlado; de Zeeuw, Dick

    2009-01-01

    Background Blockade of the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step by means of renin inhibition has led to the development of direct renin inhibitors (DRIs). Given the renal and cardioprotective effects of RAAS blockade by angiotensin-converting enzyme inhibitors and

  13. Quantification of systemic renin-angiotensin system peptides of hypertensive black and white African men established from the RAS-Fingerprint®

    Directory of Open Access Journals (Sweden)

    JM van Rooyen

    2016-10-01

    Full Text Available Objective: The objective of this study was to make use of a quantitative and qualitative approach comparing the systemic renin-angiotensin system (RAS of hypertensive black and white African men by using RAS equilibrium analysis. Materials and methods: This sub-study involved 23 black (n = 15 and white (n = 8 hypertensive men aged 39.5–41 years, living in the North West Province of South Africa. The RAS-Fingerprinting was determined with LC-MS/MS quantification of angiotensin peptides. Blood pressure and other variables were determined with known methods. Results: The main finding of this study was the significant lower Ang I (<5.0 and 45.1 pg/ml; p = 0.005 and Ang II (15.6 and 123.9 pg/ml; p ⩽ 0.001 encountered in the hypertensive black African men compared to their white counterparts. Levels of Ang 1-5 (downstream metabolite of Ang 1-7 (1.8 and 3.0 pg/ml, were detected in black and white hypertensive men, respectively. Conclusions: The observed differences between circulating RAS components, which are reflected via equilibrium angiotensin levels, point to a distinctive molecular regulation of the RAAS in the two study cohorts. The increased peripheral resistance observed in hypertensive black individuals might take over a dominant role in control of blood pressure in this study population. A novel highly sensitive LC-MS/MS method resolved the issue of peptide recovery variations during sample preparation by using internal standards for each individual angiotensin metabolite.

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  18. 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

  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

    2016-02-15

    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.

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

    Science.gov (United States)

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

    2015-12-01

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

  1. Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

    Directory of Open Access Journals (Sweden)

    Jian-Dong Li

    2016-01-01

    Full Text Available Heart failure (HF is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS activity and elevated levels of proinflammatory cytokines (PICs. Renal denervation (RD has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO- induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD.

  2. Myeloperoxidase, asymmetric dimethyl-arginine and the renin-angiotensin-aldosterone-system in cardiovascular risk patients: Cross-sectional findings from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

    Science.gov (United States)

    Zelzer, Sieglinde; Enko, Dietmar; Pilz, Stefan; Tomaschitz, Andreas; März, Winfried; Meinitzer, Andreas

    2017-09-01

    The leukocyte-derived myeloperoxidase (MPO), the nitric oxidase synthase (NOS) inhibitor asymmetrical dimethyl-arginine (ADMA) and the renin-angiotensin-aldosterone-system (RAAS) are associated with cardiovascular diseases (CVD). This study aimed to investigate potential interactions between the RAAS, ADMA and MPO in cardiovascular risk patients. All in all, 1446 patients, who were referred to coronary angiography, were included in this prospective study. MPO, ADMA and circulating serum markers of the RAAS system were measured. Additionally, all-cause and CVD mortality, cardiovascular risk factors, inflammatory and endothelial markers, and medication use were investigated. MPO concentrations were significantly associated with ADMA (P=0.002), renin (P=0.001) and angiotensin II levels (P=0.015), whereas ADMA was in tendency associated with renin (P=0.059) and significantly with angiotensin II (P=0.001). Both, ADMA and MPO were inversely correlated with angiotensinogen, angiotensin I and the angiotensin I/angiotensin II ratio. ADMA and angiotensin II were found stronger independent risk factors for all-cause and CVD mortality compared to MPO. MPO concentrations were significantly associated with higher ADMA levels and an up-regulated circulating RAAS in patients with CVD. Moreover, serum levels of ADMA and angiotensin II were shown to be more predictive for all-cause and CVD mortality compared to MPO. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  3. Phenotype standardization of angioedema in the head and neck region caused by agents acting on the angiotensin system

    NARCIS (Netherlands)

    Wadelius, M.; Marshall, S. E.; Islander, G.; Nordang, L.; Karawajczyk, M.; Yue, Q.-Y.; Terreehorst, I.; Baranova, E. V.; Hugosson, S.; Sköldefors, K.; Pirmohamed, M.; Maitland-van der Zee, A.-H.; Alfirevic, A.; Hallberg, P.; Palmer, C. N. A.

    2014-01-01

    Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient

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

    Science.gov (United States)

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

    2014-07-01

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

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

    Science.gov (United States)

    Rebrov, B A

    1996-01-01

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

  6. Is there a difference between an angiotensin-converting enzyme ...

    African Journals Online (AJOL)

    Modulation of the RAS by the two most widely used inhibitors of the system, i.e. angiotensin-converting enzyme (ACE) inhibitors and angiotensin-specific receptor blockers (ARBs) plays a crucial role in the primary and secondary prevention of cardiovascular events. These drugs both target angiotensin II, but in different.

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

    Science.gov (United States)

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

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

  8. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

    Science.gov (United States)

    Mangiafico, Sarah; Costello-Boerrigter, Lisa C.; Andersen, Ingrid A.; Cataliotti, Alessandro; Burnett, John C.

    2013-01-01

    Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID:22942338

  9. 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.

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

    Science.gov (United States)

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

    2015-06-01

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

  11. Progression of chronic kidney disease : The role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition - A patient-level meta-analysis

    NARCIS (Netherlands)

    Jafar, TH; Stark, PC; Schmid, CH; Landa, M; Maschio, G; de Jong, PE; de Zeeuw, D; Shahinfar, S; Toto, R; Levey, AS

    2003-01-01

    Background: Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and urine protein excretion and slow the progression of chronic kidney disease. Purpose: To determine the levels of blood pressure and urine protein excretion associated with the lowest risk for progression of chronic

  12. 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.

  13. The Renin-Angiotensin-Aldosterone system in patients with depression compared to controls – a sleep endocrine study

    Directory of Open Access Journals (Sweden)

    Künzel Heike

    2003-10-01

    Full Text Available Abstract Background Hypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS as 1. adrenocorticotropic hormone (ACTH is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR agonists 3. angiotensin II (ATII releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM-nonREM cycle. Methods Here we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD 53.3 ± 14.4 yr. and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.. After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h were used for statistical analysis, with analysis of co variance being performed with age as a covariate. Results No differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p Conclusion Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.

  14. KCNQ1 A340E impairs electrolyte homeostasis independently of the renin-angiotensin-aldosterone system in mice.

    Science.gov (United States)

    Pan, Q; Sang, Y; Sun, C; Li, G; Wang, Y

    2016-07-25

    KCNQ1 (KvLQT1) is the pore-forming a-subunit of the potassium channel. To uncover its role in electrolyte metabolism, we investigated the effects of KCNQ1 A340E, a loss-of-function mutant, on J343 mice. Compared with the normal controls (C57BL/6J mice) bearing the wild-type KCNQ1 gene, J343 mice bearing KCNQ1 A340E demonstrated a much higher 24-h intake of electrolytes (potassium, sodium, and chloride). However, they suffered from significant electrolyte loss through both the feces and urine during a period of 24 h. Unbalance in electrolyte metabolism disrupted the electrolyte homeostasis in the J343 mice, which was characterized by the comparatively lower level of serum potassium (J343 vs C57BL/6J: 12.06 ± 1.47 vs 14.44 ± 3.58 mM, P = 0.01) and higher levels of serum sodium (J343 vs C57BL/6J: 148.05 ± 4.47 vs 115.15 ± 17.25 mM, P = 4.20 x 10(-4)) and chloride (J343 vs C57BL/6J: 118.0 ± 4.47 vs 85.21 ± 11.90 mM, P = 2.47 x 10(-5)). Between the J343 and C57BL/6J mice, there was no statistically significant difference in KCNQ1 expression in the gastrointestinal tract and kidney. Normal concentrations of plasma renin, angiotensin I, and aldosterone were also detected in both lines of mice. KCNQ1, therefore, is suggested to play a central role in electrolyte metabolism. KCNQ1 A340E, with the loss-of-function phenotype, may dysregulate electrolyte homeostasis in mice independently of the activity of the renin-angiotensin-aldosterone system.

  15. Low birth weight activates the renin–angiotensin system, but limits cardiac angiogenesis in early postnatal life

    Science.gov (United States)

    Wang, Kimberley C W; Brooks, Doug A; Summers-Pearce, Brooke; Bobrovskaya, Larisa; Tosh, Darran N; Duffield, Jaime A; Botting, Kimberley J; Zhang, Song; Caroline McMillen, I; Morrison, Janna L

    2015-01-01

    Low birth weight (LBW) is associated with increased risk of adult cardiovascular disease and this association may be partly a consequence of early programming of the renin–angiotensin system (RAS). We investigated the effects of LBW on expression of molecules in the RAS and cardiac tissue remodeling. Left ventricular samples were collected from the hearts of 21 days old lambs that were born average birth weight (ABW) and LBW. Cardiac mRNA expression was quantified using real-time RT-PCR and protein expression was quantified using Western blotting. DNA methylation and histone acetylation were assessed by combined bisulfite restriction analysis and chromatin immunoprecipitation, respectively. There were increased plasma renin activity, angiotensin I (ANGI), and ANGII concentrations in LBW compared to ABW lambs at day 20. In LBW lambs, there was increased expression of cardiac ACE2 mRNA, decreased ANGII receptor type 1 (AT1R) protein, and acetylation of histone H3K9 of the AT1R promoter but no changes in AT1R mRNA expression and AT1R promoter DNA methylation. There was no difference in the abundance of proteins involved in autophagy or fibrosis. BIRC5 and VEGF mRNA expression was increased; however, the total length of the capillaries was decreased in the hearts of LBW lambs. Activation of the circulating and local cardiac RAS in neonatal LBW lambs may be expected to increase cardiac fibrosis, autophagy, and capillary length. However, we observed only a decrease in total capillary length, suggesting a dysregulation of the RAS in the heart of LBW lambs and this may have significant implications for heart health in later life. PMID:25649246

  16. Low birth weight activates the renin-angiotensin system, but limits cardiac angiogenesis in early postnatal life.

    Science.gov (United States)

    Wang, Kimberley C W; Brooks, Doug A; Summers-Pearce, Brooke; Bobrovskaya, Larisa; Tosh, Darran N; Duffield, Jaime A; Botting, Kimberley J; Zhang, Song; Caroline McMillen, I; Morrison, Janna L

    2015-02-01

    Low birth weight (LBW) is associated with increased risk of adult cardiovascular disease and this association may be partly a consequence of early programming of the renin-angiotensin system (RAS). We investigated the effects of LBW on expression of molecules in the RAS and cardiac tissue remodeling. Left ventricular samples were collected from the hearts of 21 days old lambs that were born average birth weight (ABW) and LBW. Cardiac mRNA expression was quantified using real-time RT-PCR and protein expression was quantified using Western blotting. DNA methylation and histone acetylation were assessed by combined bisulfite restriction analysis and chromatin immunoprecipitation, respectively. There were increased plasma renin activity, angiotensin I (ANGI), and ANGII concentrations in LBW compared to ABW lambs at day 20. In LBW lambs, there was increased expression of cardiac ACE2 mRNA, decreased ANGII receptor type 1 (AT1R) protein, and acetylation of histone H3K9 of the AT1R promoter but no changes in AT1R mRNA expression and AT1R promoter DNA methylation. There was no difference in the abundance of proteins involved in autophagy or fibrosis. BIRC5 and VEGF mRNA expression was increased; however, the total length of the capillaries was decreased in the hearts of LBW lambs. Activation of the circulating and local cardiac RAS in neonatal LBW lambs may be expected to increase cardiac fibrosis, autophagy, and capillary length. However, we observed only a decrease in total capillary length, suggesting a dysregulation of the RAS in the heart of LBW lambs and this may have significant implications for heart health in later life. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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

    Science.gov (United States)

    Ishihata, Akira; Katano, Yumi

    2006-05-01

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

  18. [The renin-angiotensin system and the sympathetic nervous system in essential hypertension].

    Science.gov (United States)

    Vincent, M; Milon, H; Revol, T; Annat, G; Froment, A; Sassard, J; Cier, J F

    1982-06-01

    In 112 patients with essential hypertension (HTA), free of any therapeutic and receiving the standard ward, a significant inverse relationship was found between age and plasma renin activity (PRA) and plasma aldosterone (PA), measured in the supine and upright position. Urinary epinephrine and norepinephrine were not related with age. When dividing the patients in 4 different age groups, it appeared that those younger than 30 years exhibited a significantly higher PRA and PA values and a higher frequency of borderline hypertension (45 p. 100) than the older ones (12 p. 100). So as to determine the characteristics associated with borderline HTA, it was necessary to eliminate the influence of age. This was achieved by comparing two groups of carefully age-matched patients, one with borderline HTA and the other with stable HTA. The only significant difference found was a significantly more marked increase in PRA in response to orthostatism, in patients with borderline HTA. Since renin responses to an orthostatic stress are largely mediated by renal nerves, this result suggest that borderline HTA could be associated with an increased reactivity of the sympathetic nervous system.

  19. 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

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

    Science.gov (United States)

    Mirkovic, Katarina; Frenay, Anne-Roos S; van den Born, Jacob; van Goor, Harry; Navis, Gerjan; de Borst, Martin H

    2017-08-01

    Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake. Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment. Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes. The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.

  1. A method to evaluate the renin-angiotensin system in rat renal cortex using a microdialysis technique combined with HPLC-fluorescence detection.

    Science.gov (United States)

    Kajiro, Toshi; Nakajima, Yuki; Fukushima, Takeshi; Imai, Kazuhiro

    2002-09-01

    A microdialysis (MD) technique, combined with HPLC-fluorescence (FL) detection, was developed for the evaluation of the tissue-specific renin-angiotensin system (RAS) in the rat renal cortex. An MD probe constructed with a hydrophilic hollow fiber dialysis tubing, AN69, showed high recovery (more than 50%) in vitro for all four angiotensins: angiotensin I (Ang I), Ang II, Ang III, and Ang (1-7). Angiotensins, successfully derivatized with m-BS-ABD-F, a water-soluble fluorogenic reagent that has a 2,1,3-benzoxadiazole (benzofurazan) structure, could be simultaneously determined by coupled-column HPLC. The detection limit for Ang I, Ang II, Ang III, and Ang (1-7) were 94, 44, 47, and 83 fmol, respectively. All these peptides were determined with good linearity (0.0125-3.1 microM, equivalent to 0.25-62 pmol, correlation coefficient >0.99) and good precision (recovery >91%). In the MD studies, generation of Ang (1-7) and Ang II was observed when Ang I was perfused, and Ang (1-7) was the major biologically active angiotensin found in the dialysate samples. The concentration of Ang (1-7) and Ang II in the dialysate samples showed good correlation to that of Ang I in a MD perfusate (20-100 microM). Cleavage of Ang I to Ang (1-7) was drastically suppressed by the co-perfusion of phoshoramidon (0.5-5 mM), an inhibitor of neprilysin, which generates Ang (1-7) from Ang I. These results are consistent with the previously reported characteristics of tissue-specific renal RAS, suggesting that our MD/HPLC-FL system may have the potential to be employed to evaluate tissue-specific RAS in the rat renal cortex.

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

    DEFF Research Database (Denmark)

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R...... blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal...

  3. Angiotensin-I converting enzyme gene and I/D polymorphism ...

    Indian Academy of Sciences (India)

    Angiotensin-I converting enzyme (ACE) gene is one of the most intensely studied genes because of the key role it plays in the renin–angiotensin system (RAS). ACE catalyses the conversion of angiotensin I to angiotensin II, a vasoactive and aldosterone-stimulating peptide, and inactivates bradykinin. (Erdos and Skidgel ...

  4. 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...... (LVSD). METHODS: Systematic review of the literature and meta-analysis of eligible studies providing data on end-diastolic and end-systolic volumes and left ventricular ejection fraction (LVEF) were performed. RESULTS: Data from 16 eligible studies were meta-analysed. The results of studies including...... patients with MI and preserved LVEF (>45%) showed no significant benefit of ACE inhibition. Results of studies/subgroups with mean LVEF diastolic and systolic volumes of 3.0 (0.1, 6.0) ml and 2.25 (0.04, 4.4) ml in short-term (4-14 weeks) follow...

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

    Science.gov (United States)

    Khanmoradi, Mehrangiz; Nasimi, Ali

    2016-10-06

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

  6. Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System

    Science.gov (United States)

    Wadelius, M; Marshall, S E; Islander, G; Nordang, L; Karawajczyk, M; Yue, Q-Y; Terreehorst, I; Baranova, E V; Hugosson, S; Sköldefors, K; Pirmohamed, M; Maitland-van der Zee, A-H; Alfirevic, A; Hallberg, P; Palmer, C N A

    2014-01-01

    Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema. PMID:24960520

  7. 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

    vascular resistance (SVR). SVR was determined in supine and seated positions in 12 HF patients [NYHA class II-III; ejection fraction=0.29 +/- 0.03 (mean +/- SE)] and 9 control subjects. HF patients were investigated during high (n=11; withdrawal of ACE-I treatment for 24 h) and low (n=9; sustained ACE...

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

    Science.gov (United States)

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

    2017-05-08

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

  9. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension.

    Science.gov (United States)

    Muñoz-Durango, Natalia; Fuentes, Cristóbal A; Castillo, Andrés E; González-Gómez, Luis Martín; Vecchiola, Andrea; Fardella, Carlos E; Kalergis, Alexis M

    2016-06-23

    Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.

  10. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Natalia Muñoz-Durango

    2016-06-01

    Full Text Available Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.

  11. Differential clinical profile of candesartan compared to other angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    Zimlichman R

    2011-12-01

    Full Text Available Relu Cernes1,2, Margarita Mashavi1,3, Reuven Zimlichman1,31The Brunner Institute for Cardiovascular Research, Wolfson Medical Center and Tel Aviv University, Tel Aviv, Israel; 2Department of Nephrology, Wolfson Medical Center, Holon, Israel; 3Department of Medicine, Wolfson Medical Center, Holon, IsraelAbstract: The advantages of blood pressure (BP control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1] receptor antagonist (angiotensin receptor blocker [ARB] that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.Keywords: angiotensin receptor blockers, candesartan, candesartan cilexetil, clinical trials, efficacy studies, safety, blood pressure

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  14. Acute Total and Chronic Partial Sleep Deprivation: Effects on Neurobehavioral Functions, Waking EEG and Renin-Angiotensin System

    Science.gov (United States)

    Dijk, Derk-Jan

    1999-01-01

    protocol of the Quantitative EEG and Waking Neurobehavioral Function project. This will allow us to investigate two additional specific aims: 1) Test the hypothesis that chronic partial sleep deprivation during a 17 day bed rest experiment results in deterioration of neurobehavioral function during waking and increases in EEG power density in the theta frequencies, especially in frontal areas of the brain, as well as the nonREM- REM cycle dependent modulation of heart-rate variability. 2) Test the hypothesis that acute total sleep deprivation modifies the circadian rhythm of the renin-angiotensin system, changes the acute responsiveness of this system to posture beyond what a microgravity environment alone does and affects the nonREM-REM cycle dependent modulation of heart-rate variability.

  15. 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

  16. The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.

    Science.gov (United States)

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

    2017-04-01

    Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans. Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP. In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.

  17. Exercise attenuates dexamethasone-induced hypertension through an improvement of baroreflex activity independently of the renin-angiotensin system.

    Science.gov (United States)

    Constantino, Paula B; Dionísio, Thiago J; Duchatsch, Francine; Herrera, Naiara A; Duarte, Josiane O; Santos, Carlos F; Crestani, Carlos C; Amaral, Sandra L

    2017-12-01

    Dexamethasone-induced hypertension may be caused by baroreflex alterations or renin-angiotensin system (RAS) exacerbation. Aerobic training has been recommended for hypertension treatment, but the mechanisms responsible for reduction of arterial pressure (AP) in dexamethasone (DEX) treated rats are still inconclusive.This study evaluated whether mechanisms responsible for training-induced attenuation of hypertension involve changes in autonomic nervous system and in RAS components. Rats underwent aerobic training protocol on treadmill or were kept sedentary for 8 weeks. Additionally, animals were treated with DEX during the last 10 days of exercise. Body weight (BW), AP and baroreflex activity were analyzed. Tibialis anterior (TA), soleus (SOL) and left ventricle (LV) were collected for evaluation of RAS components gene expression and protein levels. Dexamethasone decreased BW (20%), caused TA atrophy (16%) and increased systolic AP (SAP, 16%) as well as decreased baroreflex activity. Training attenuated SAP increase and improved baroreflex activity, although it did not prevent DEX-induced BW reduction and muscle atrophy. Neither DEX nor training caused expressive changes in RAS components. In conclusion, exercise training was effective in attenuating hypertension induced by DEX and this response may be mediated by a better autonomic balance through an improvement of baroreflex activity rather than changes in RAS components. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

    Science.gov (United States)

    Wang, Wang; McKinnie, Shaun M K; Farhan, Maikel; Paul, Manish; McDonald, Tyler; McLean, Brent; Llorens-Cortes, Catherine; Hazra, Saugata; Murray, Allan G; Vederas, John C; Oudit, Gavin Y

    2016-08-01

    Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. © 2016 American Heart Association, Inc.

  19. Epistatic Effects of Polymorphisms in Genes from the Renin-Angiotensin, Bradykinin, and Fibrinolytic Systems on Plasma t-PA and PAI-1 Levels

    Science.gov (United States)

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

    2007-01-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2,527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (p=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (p=0.006). In both females as well as males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (p=0.026 and p=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology. PMID:17207964

  20. Angiotensin receptor blockers are associated with lower mortality than ACE inhibitors in predialytic stage 5 chronic kidney disease: A nationwide study of therapy with renin-angiotensin system blockade.

    Directory of Open Access Journals (Sweden)

    Chih-Ching Lin

    Full Text Available Dual renin angiotensin system (RAS blockade using angiotensin-receptor blockers (ARBs in combination with angiotensin converting enzyme inhibitors (ACEIs is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD. From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit <28% under the treatment with erythropoiesis stimulating agents and RAS blockade. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs against the commencement of long-term dialysis and all-cause mortality for ACEI/ARB users. Over a median follow-up of 7 months, 9,867 patients (69.9% required long-term dialysis and 2,805 (19.9% died before progression to end-stage renal disease requiring dialysis. In comparison with the ARB-only users, dual blockade with ACEIs and ARBs was associated with a significantly higher risk of (1 death in all CKD patients (HR = 1.49, [95%CI, 1.30-1.71]; P = 0.02 and in diabetic subgroup (HR = 1.58, [95%CI, 1.34-1.86]; P = 0.02; (2 composite endpoint of long-term dialysis or death in diabetic subgroup (HR = 1.10, [95%CI, 1.01-1.20]; P = 0.04; (3 hyperkalemia-associated hospitalization in non-diabetic subgroup (HR, 2.74, [95%CI, 1.05-7.15]; P = 0.04. However, ACEIs users were associated with higher mortality than ARBs users in all CKD patients (HR = 1.17, [95%CI, 1.07-1.27]; P = 0.03 and in diabetic subgroup (HR = 1.32, [95%CI, 1.18-1.48]; P = 0.03. Monotherapy of RAS blockade, especially ARB, is more effective and safer than dual RAS blockade in pre-dialytic stage 5 CKD patients.

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

    Science.gov (United States)

    Santollo, Jessica

    2017-11-01

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

  2. ROLE OF RENIN-ANGIOTENSIN SYSTEM AND OXIDATIVE STRESS AND INFLAMMATION TO THE BLOOD PRESSURE CONTROL IN YOUNG SUBJECTS

    Directory of Open Access Journals (Sweden)

    Emiko Sato

    2012-06-01

    Full Text Available Renin-Angiotensin System (RAS, oxidative stress and inflammation is involved in the pathogenesis of hypertension and salt sensitivity of hypertension. The present study was designed to evaluate the role of RAS, oxidative stress and inflammation to the regulation of blood pressure in young subjects. 111 young students (19.2±0.8 years old who have taken health checkup were randomly selected for the study. Urinary excretions of angiotensinogen (AGT, oxidative stress (TBARS, and inflammatory markers (MCP-1 were analyzed. Urinary excretions of these parameters were estimated by 24-hour urinary creatinine excretion, age, height and body weight. Subjects were divided to two groups based on the blood pressure: below 140/90 mmHg (Normal and over 140/90 mmHg (High. Blood pressure was significantly increased with increased BMI. Urinary AGT, TBARS, and MCP-1 of high blood pressure group were significantly (p<0.05 increased compared to those of normal blood pressure. Urinary AGT has significant positive correlation with urinary TBARS, though it did not have a significant correlation with MCP-1. Estimated 24-h urinary Na excretion was significantly increased with increased urinary MCP-1, and TBARS. These results indicate that increase in blood pressure is accompanied with RAS, oxidative stress, and inflammation in young subjects, which is associated with salt intake.

  3. 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.

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

    Science.gov (United States)

    Zou, Xia; Zhang, Xiao-xi; Liu, Xin-yu; Li, Rong; Wang, Min; Wu, Wei-jie; Sui, Yi; Zhao, Hai-lu

    2015-01-01

    Purpose. The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS) on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN). Methods. Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF-) β and α-smooth muscle action (SMA). Results. DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all P < 0.05). Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-β, and α-SMA. Conclusion. The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response. PMID:25918729

  5. [Cardiovascular risk study in patients with renin-angiotensin system blockade by means of the proteone of circulating extracellular vesicles].

    Science.gov (United States)

    de la Cuesta, F; Baldan-Martin, M; Mourino-Alvarez, L; Sastre-Oliva, T; Alvarez-Llamas, G; Gonzalez-Calero, L; Ruiz-Hurtado, G; Segura, J; Vivanco, F; Ruilope, L M; Barderas, M G

    2016-01-01

    Extracellular vesicles (EVs) are released to the bloodstream by certain cell types due to transport, activation and cell death processes. Blood count of EVs from platelet and endothelial origin has been proved to be a cardiovascular risk biomarker. Thus, EVs proteome might reflect the underlying cellular processes in hypertensive patients with albuminuria. Protein content of circulating EVs was analyzed by liquid chromatography coupled to mass spectrometry. EVs were isolated by an ultracentrifugation protocol optimized in order to avoid contamination by blood plasma proteins. Purity of the isolated fraction was verified by electronic and confocal microscopy, and by flow cytometry. We hereby show a method to isolate circulating EVs from hypertensive patients with/without albuminuria with high yield and purity. Besides, we provide a reference proteome of the EVs of these patients, composed of 2,463 proteins, and prove that the proteins carried by these vesicles are associated with crucial processes involved in the inherent cardiovascular risk. The proteome of circulating EVs is an interesting source of indicators in the evaluation of cardiovascular risk in hypertensive patients with renin-angiotensin system blockage. Copyright © 2015 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

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

    Science.gov (United States)

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

    2003-09-01

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

  7. Angiotensin II during Experimentally Simulated Central Hypovolemia

    DEFF Research Database (Denmark)

    Jensen, Theo Walther; Olsen, Niels Vidiendal

    2016-01-01

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

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

    DEFF Research Database (Denmark)

    de Kloet, Annette D; Wang, Lei; Ludin, Jacob A

    2016-01-01

    Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited...... ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent...

  9. Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers

    Directory of Open Access Journals (Sweden)

    Georg Nickenig

    2006-03-01

    Full Text Available Targeting the renin-angiotensin-aldosterone system (RAAS, specifically the effector peptide angiotensin II (Ang II, represents a major opportunity for slowing the progression of cardiovascular disease (CVD and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors P, (ACE-Is in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough. By blocking Ang II at the AT1 receptor level, Ang II receptor blockers (ARBs provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but may also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor. Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.

  10. Targeting of captopril to the kidney reduces renal angiotensin-converting enzyme activity without affecting systemic blood pressure

    NARCIS (Netherlands)

    Kok, RJ; Haverdings, Rene; Grijpstra, F; Koiter, J.; Moolenaar, F; De Zeeuw, D; Meijer, DKF

    We have synthesized a prodrug of the angiotensin-converting enzyme (ACE) inhibitor captopril by coupling this drug covalently to the low molecular weight protein (LMWP) lysozyme. Such drug-LMWP conjugates can be used for renal drug delivery, since LMWPs accumulate specifically in the proximal

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

    DEFF Research Database (Denmark)

    Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique

    2017-01-01

    was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P...... development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2-/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L...

  12. 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.

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

    Science.gov (United States)

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

    2016-04-01

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

  14. Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system.

    Science.gov (United States)

    Biollaz, J; Schelling, J L; Jacot Des Combes, B; Brunner, D B; Desponds, G; Brunner, H R; Ulm, E H; Hichens, M; Gomez, H J

    1982-09-01

    1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed ( r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).

  15. 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

    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....... Follow up time was 24-50 months (mean 26 months). RESULTS: Four hundred patients (23%) had a history of arterial hypertension. A total of 173 (43%) patients with a history of hypertension died during follow up versus 500 (37%) patients in the normotensive group. Treatment with trandolapril...... in the hypertensive individuals was associated with a reduction in the relative risk of death to 0.59 (95% confidence interval 0.44-0.80), versus 0.85 (0.72-1.02) in the normotensive individuals. The significant reduction in mortality in hypertensive individuals persisted after multivariate analysis controlling...

  16. Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration.

    Directory of Open Access Journals (Sweden)

    Erika Costa de Alvarenga

    Full Text Available The angiotensin-I converting enzyme (ACE plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II. More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet.Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration.We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC, and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5 showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein.ACE activation regulates melanoma cell proliferation and migration.

  17. [The effect of the I/D polymorphism of the angiotensin-converting enzyme gene on the cardiovascular risk and graft survival of kidney transplant patients].

    Science.gov (United States)

    Fedor, Roland; Kovács, Dávid Ágoston; Lőcsey, Lajos; Fagyas, Miklós; Asztalos, László; Tóth, Attila

    2016-06-12

    Renal transplantation provides longer life expectancy in patients with renal failure. Nonetheless, this improved life expectancy is still shorter than that for the general population. The main couse of death in renal transplant patients is cardiovascular disease, and chronic allograft nephropathy is the most significant cause of graft loss. Genetic polymorphisms of the renin angiotensin system have been implicated in both chronic allograft nephropathy and fatal cardiovascular diseases. The long term goal of the authors was to improve the survival of renal transplanted patients. The authors aimed to identify novel biomarkers which correlate with the survival of the transplant organ and the recipient with a special attention to elements of the renin-angiotensin system. A retrospective clinical trial was performed involving 72 renal transplanted patients. Angiotensin-converting enzyme I/D genotypes and activity, kidney function and morphological properties of the heart were determined. A significant positive correlation was found between the DD genotype of the angiotensin-converting enzíme gene, and the DD genotype predicted severe left ventricular hypertrophy. These findings suggest that the I/D genotypes of the angiotensin-converting enzyme gene predict not only the expected survival of the transplanted organ, but also that of the patient. Patients with the DD genotype are more susceptible for transplant failure. These patients should be identified and a special attention should be made on their pharmacological treatment (renin-angiotensin system inhibition), and their complience should also be maintained.

  18. Polyphenol-Rich Blackcurrant Juice Prevents Endothelial Dysfunction in the Mesenteric Artery of Cirrhotic Rats with Portal Hypertension: Role of Oxidative Stress and the Angiotensin System.

    Science.gov (United States)

    Rashid, Sherzad; Idris-Khodja, Noureddine; Auger, Cyril; Kevers, Claire; Pincemail, Joël; Alhosin, Mahmoud; Boehm, Nelly; Oswald-Mammosser, Monique; Schini-Kerth, Valérie B

    2018-04-01

    Chronic liver diseases with portal hypertension are characterized by a progressive vasodilatation, endothelial dysfunction, and NADPH oxidase-derived vascular oxidative stress, which have been suggested to involve the angiotensin system. This study evaluated the possibility that oral intake of polyphenol-rich blackcurrant juice (PRBJ), a rich natural source of antioxidants, prevents endothelial dysfunction in a rat model of cirrhosis induced by chronic bile duct ligation (CBDL), and, if so, determined the underlying mechanism. Male Wistar rats received either control drinking water or water containing 60 mg/kg gallic acid equivalents of PRBJ for 3 weeks before undergoing surgery with CBDL or sham surgery. After 4 weeks, vascular reactivity was assessed in mesenteric artery rings using organ chambers. Both the acetylcholine-induced nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations in mesenteric artery rings were significantly reduced in CBDL rats compared to sham rats. An increased level of oxidative stress and expression of NADPH oxidase subunits, COX-2, NOS, and of the vascular angiotensin system are observed in arterial sections in the CBDL group. Chronic intake of PRBJ prevented the CBDL-induced impaired EDH-mediated relaxation, oxidative stress, and expression of the different target proteins in the arterial wall. In addition, PRBJ prevented the CBDL-induced increase in the plasma level of proinflammatory cytokines (interleukin [IL]-1α, monocyte chemotactic protein 1, and tumor necrosis factor α) and the decrease of the anti-inflammatory cytokine, IL-4. Altogether, these observations indicate that regular ingestion of PRBJ prevents the CBDL-induced endothelial dysfunction in the mesenteric artery most likely by normalizing the level of vascular oxidative stress and the angiotensin system.

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

    Directory of Open Access Journals (Sweden)

    Sarfaraz Ahmad

    2011-01-01

    Full Text Available 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.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.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.

  20. Effect of angiotensin II type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Ik Soo Byon

    2017-06-01

    Full Text Available AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB and angiotensin converting enzyme inhibitor (ACEI on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS: Forty Sprague-Dawley rats were divided into 4 groups: control, diabetes mellitus (DM, candesartan-treated DM, and enalapril-treated DM (each group, n=10. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/(kg·d] and enalapril [ACEI, 10 mg/(kg·d] were administered to rats orally for 4wk. Vascular endothelial growth factor (VEGF and angiotensin II (Ang II concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor (AT1R levels were assessed at week 4 by Western blotting. RESULTS: Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control (P=0.04 and 0.005, respectively. Vitreous AT1R increased significantly in DM compared to the other three groups (P<0.007. Candesartan-treated DM rats showed higher vitreal AT1R concentration than the enalapril-treated DM group and control (P<0.001 and P=0.005, respectively. No difference in vitreous Ang II and AT1R concentration was found between the enalapril-treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION: Increased Ang II and AT1R in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

  1. 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.

  2. Angiotensin-converting enzyme insertion/deletion gene polymorphism in Egyptian children with systemic lupus erythematosus: a possible relation to proliferative nephritis.

    Science.gov (United States)

    Hammad, A; Yahia, S; Laimon, W; Hamed, S M; Shouma, A; Shalaby, N M; Abdel-Hady, D; Ghanem, R; El-Farahaty, R M; El-Bassiony, S R; Hammad, E M

    2017-06-01

    Introduction Angiotensin-converting enzyme (ACE) is crucial in the pathogenesis of systemic lupus erythematosus through angiotensin II which regulates vascular tone and endothelial functions. Objectives To study the frequency of ACE insertion/deletion (I/D) gene polymorphism in Egyptian children with systemic lupus erythematosus and its possible relation to the renal pathology in cases with lupus nephritis. Subjects and methods The frequency of ACE gene insertion/deletion polymorphism genotypes was determined in 78 Egyptian children with systemic lupus erythematosus and compared to a matched group of 140 healthy controls using polymerase chain reaction. Results The DD genotype of the ACE gene was higher in systemic lupus erythematosus patients when compared to controls ( Plupus erythematosus patients in comparison to controls ( P lupus nephritis group, the DD genotype was significantly higher in those with proliferative lupus nephritis when compared to those with non-proliferative lupus nephritis ( P = 0.02; OR = 1.45; 95% CI = 1.4-1.6). Also, patients with proliferative lupus nephritis showed a higher frequency of the D allele ( P lupus erythematosus and occurrence of proliferative nephritis in Egyptian children.

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

    DEFF Research Database (Denmark)

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

    2018-01-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance...... of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption...

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

    Czech Academy of Sciences Publication Activity Database

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Dysregulation of microRNAs and renin-angiotensin system in high salt diet-induced cardiac dysfunction in uninephrectomized rats.

    Science.gov (United States)

    Amara, Venkateswara Rao; Surapaneni, Sunil Kumar; Tikoo, Kulbhushan

    2017-01-01

    Uninephrectomy is not associated with major adverse events in cardiovascular and renal functions of live kidney donors. The effect of high salt diet on the quality of life of live kidney donors is largely unknown. Hence in this study, we aimed to determine the effect of high salt diet on the alterations of renin-angiotensin system and microRNAs leading to CV and renal dysfunction in uninephrectomized rats. In order to mimic clinical scenario, uninephrectomized male Sprague Dawley rats were fed initially with normal pellet diet for 12 weeks and then for 20 weeks with high salt (10% w/w NaCl) diet. At the end of the study, biochemical, functional, histological and molecular parameters were measured. High salt diet feeding resulted in renal dysfunction & fibrosis, decreased baroreflex sensitivity, increased in vivo cardiovascular reactivity to angiotensin II owing to upregulation of angiotensin II type 1 receptors and L-type calcium channels leading to cardiovascular dysfunction in uninephrectomized rats (UNX+HSD) worse than that of normal (binephric) rats fed with high salt diet (HSD). Protein expression of functional and hypertrophic protein markers revealed decreased SERCA, p-AMPK and increased p-AKT. Interestingly, levels of miR-25, miR-451 and miR-155 increased and miR-99 decreased in heart of uninephrectomized rats fed with high salt. However, circulating miR-25 and miR-451 levels decreased and miR-99b increased in these animals. Our study points out that since tissue and circulating levels of miRNAs are not similar, caution must be exercised during the usage of miRs as diagnostic or prognostic biomarkers. To our knowledge, we are the first to show that epigenetic alterations result in cardiac dysfunction in uninephrectomized rats fed with high salt diet.

  7. Evaluation of the Clinical Utility of Renin-Angiotensin System Inhibitors in Patients Undergoing Radical Surgery for Urothelial Carcinoma of the Upper Urinary Tract.

    Science.gov (United States)

    Yoshida, Takashi; Matsuzaki, Tomoaki; Murota, Takashi; Kawa, Gen; Matsuda, Tadashi; Kinoshita, Hidefumi

    2017-12-01

    Renin-angiotensin system (RAS) inhibitors are effective for treating patients with cancer. The present study evaluated the impact of RAS inhibitors, including angiotensin-2 converting enzyme inhibitors and angiotensin 2 receptor blockers, after patients underwent radical surgery for upper urinary tract urothelial carcinoma (UTUC). This retrospective study included 312 patients with nonmetastatic UTUC who underwent radical surgery. The oncological outcomes of patients treated or not treated with RAS inhibitors following surgery were evaluated. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using the Kaplan-Meier method and Cox regression analysis. The median follow-up duration after radical surgery was 44.7 months. The 5-year RFS, CSS, and OS rates of patients who did or did not receive RAS inhibitors were 82.3% versus 68.9% (P = .018), 88.9% versus 71.8% (P = .0044), and 68.7% versus 61.8% (P = .047), respectively. Multivariable analyses revealed that the use of RAS inhibitors was an independent prognostic factor for RFS, CSS, and OS (hazard ratio [HR] 0.48, P = .013; HR 0.31, P = .002; and HR 0.52, P = .01, respectively). Moreover, patients treated with RAS inhibitors versus untreated patients had better 5-year RFS compared with those in the pT2 and < pN1 subgroups (pT2: 100.0% vs. 62.2%, P = .014 and < pN1: 87.2% vs. 74.7%, P = .034). RAS inhibitors significantly improved RFS, CSS, and OS of patients with UTUC who underwent radical surgery. These agents may be particularly beneficial for patients with stage pT2 or < pN1 disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Renin-angiotensin-aldosterone system blockers for heart failure with reduced ejection fraction or left ventricular dysfunction: Network meta-analysis.

    Science.gov (United States)

    Xie, Wuxiang; Zheng, Fanfan; Song, Xiaoyu; Zhong, Baoliang; Yan, Li

    2016-02-15

    Renin-angiotensin-aldosterone system (RAAS) blockers are effective therapies for heart failure and reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVD). We aimed to assess the efficacy and safety of RAAS blockers in these patients. We searched MEDLINE, EMBASE, and Cochrane Library in May 2015. Twenty-one double-blind randomized controlled trials (RCTs) with 69,229 patients were included this network meta-analysis. Compared with placebo, an angiotensin receptor-neprilysin inhibitor (ARNI) had the highest probability of reducing all-cause mortality (odds ratio [OR]=0.67, 95% credible interval [CrI]: 0.48-0.86), followed by an aldosterone receptor antagonist (ARA, OR=0.74, 95% CrI: 0.62-0.88) and an angiotensin-converting enzyme inhibitor (ACEI, OR=0.80, 95% CrI: 0.71-0.89). The most efficacious therapy for preventing heart failure hospitalization was ARNI (OR=0.55, 95% CrI: 0.40-0.71), followed by combination therapy with an angiotensin II receptor blocker (ARB) plus an ACEI (OR=0.61, 95% CrI: 0.49-0.75), then an ACEI alone (OR=0.69, 95% CrI: 0.61-0.77). Sensitivity analysis restricted to nine RCTs with a high background use of ACEI and/or ARB (>80%) indicated that adding an ARA to current standard therapy significantly reduced mortality (OR=0.73, 95% CrI: 0.51-0.95) and hospitalization risk (OR=0.67, 95% CrI: 0.47-0.87), but did not significantly increase the discontinuation risk (OR=1.29, 95% CrI: 0.83-2.31). ARNI has the highest probability of being the most efficacious therapy for HFrEF in reducing death and hospitalization for heart failure. ARA has the most favorable benefit-risk profile as an adjunct to background ACEI and/or ARB therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators.

    Science.gov (United States)

    Baldan-Martin, Montserrat; Mourino-Alvarez, Laura; Gonzalez-Calero, Laura; Moreno-Luna, Rafael; Sastre-Oliva, Tamara; Ruiz-Hurtado, Gema; Segura, Julian; Lopez, Juan Antonio; Vazquez, Jesus; Vivanco, Fernando; Alvarez-Llamas, Gloria; Ruilope, Luis M; de la Cuesta, Fernando; Barderas, Maria G

    2016-07-01

    Albuminuria is a risk factor strongly associated with cardiovascular disease, the first cause of death in the general population. It is well established that renin-angiotensin system suppressors prevent the development of new-onset albuminuria in naïf hypertensive patients and diminish its excretion, but we cannot forget the percentage of hypertensive patients who develop de novo albuminuria. Here, we applied multiple proteomic strategy with the purpose to elucidate specific molecular pathways involved in the pathogenesis and provide predictors and chronic organ damage indicators. Briefly, 1143 patients were followed up for a minimum period of 3 years. One hundred and twenty-nine hypertensive patients chronically renin-angiotensin system suppressed were recruited, classified in 3 different groups depending on their albuminuria levels (normoalbuminuria, de novo albuminuria, and sustained albuminuria), and investigated by multiple proteomic strategies. Our strategy allowed us to perform one of the deepest plasma proteomic analysis to date, which has shown 2 proteomic signatures: (1) with predictive value of de novo albuminuria and (2) sustained albuminuria indicator proteins. These proteins are involved in inflammation, immune as well as in the proteasome activation occurring in situations of endoplasmic reticulum stress. Furthermore, these results open the possibility of a future strategy based on anti-immune therapy to treat hypertension which could help to prevent the development of albuminuria and, hence, the progression of kidney damage. © 2016 American Heart Association, Inc.

  10. The renin–angiotensin–aldosterone system blockade in patients with advanced diabetic kidney disease

    Directory of Open Access Journals (Sweden)

    Sheila Bermejo

    2018-03-01

    Full Text Available Background and objectives: Diabetic kidney disease is the leading cause of end-stage chronic kidney disease (CKD. The renin–angiotensin–aldosterone system (RAAS blockade has been shown to slow the progression of diabetic kidney disease. Our objectives were: to study the percentage of patients with diabetic kidney disease treated with RAAS blockade, to determine its renal function, safety profile and assess whether its administration is associated with increased progression of CKD after 3 years of follow-up. Materials and methods: Retrospective study. 197 diabetic kidney disease patients were included and divided into three groups according to the treatment: patients who had never received RAAS blockade (non-RAAS blockade, patients who at some point had received RAAS blockade (inconstant-RAAS blockade and patients who received RAAS blockade (constant-RAAS blockade. Clinical characteristics and analytical variables such as renal function, electrolytes, glycosylated hemoglobin and glomerular filtration rate according to CKD-EPI and MDRD formulas were assessed. We also studied their clinical course (baseline, 1 and 3 years follow-up in terms of treatment group, survival, risk factors and renal prognosis. Results: Non-RAAS blockade patients had worse renal function and older age (p < 0.05 at baseline compared to RAAS blockade patients. Patients who received RAAS blockade were not found to have greater toxicity or chronic kidney disease progression and no differences in renal prognosis were identified. Mortality was higher in non-RAAS blockade patients, older patients and patients with worse renal function (p < 0.05. In the multivariate analysis, older age and worse renal function were risk factors for mortality. Conclusions: Treatment with RAAS blockade is more common in diabetic kidney disease patients with eGFR ≥ 30 ml/min/1.73 m2. In our study, there were no differences in the evolution of renal function

  11. Direct renin inhibition — a new way of targeting the renin system

    Directory of Open Access Journals (Sweden)

    Morris J Brown

    2006-06-01

    Full Text Available The renin system plays a key role in the pathology of hypertension and is influenced, both directly and indirectly, by most antihypertensive agents. The system is the target of several established classes of antihypertensive agents including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers. Of currently available drugs, only the beta-blockers suppress renin secretion, but these also reduce heart rate and cardiac output. Calcium channel blockers and diuretics cause a modest activation of the renin system secondary to the fall in renal afferent arteriolar pressure and reduction in filtered sodium load. Aliskiren is the first orally available direct inhibitor that blocks the renin system at its rate limiting step and is shown to reduce angiotensin I and II and plasma renin activity.

  12. 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.

  13. Angiotensin-(1-7) : Pharmacological properties and pharmacotherapeutic perspectives

    NARCIS (Netherlands)

    Iusuf, Dilek; Henning, Robert H.; van Gilst, Wiek H.; Roks, Anton J. M.

    2008-01-01

    Therapeutic modulation of the renin-angiotensin system is not complete without taking into consideration the beneficial effects of angiotensin-(1-7) in cardiovascular pathology. Various pharmacological pathways are already exploited to involve this heptapeptide in therapy as both inhibitors of

  14. 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...

  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. The role of angiotensin(1-7) in renal vasculature of the rat

    NARCIS (Netherlands)

    van der Wouden, Els A.; Ochodnický, Peter; van Dokkum, Richard Pe; Roks, Anton Jm; Deelman, Leo E.; de Zeeuw, Dick; Henning, Robert H.

    2006-01-01

    Angiotensin(1-7) is an active component of the renin-angiotensin-aldosterone system. Its exact role in renal vascular function is unclear. We therefore studied the effects of angiotensin(1-7) on the renal vasculature in vitro and in vivo. Isolated small renal arteries were studied in an arteriograph

  17. The role of angiotensin(1-7) in renal vasculature of the rat

    NARCIS (Netherlands)

    van der Wouden, Els A.; Ochodnicky, Peter; van Dokkum, Richard P. E.; Roks, Anton J. M.; Deelman, Leo E.; de Zeeuw, Dick; Henning, Robert H.

    2006-01-01

    Objective Angiotensin(1-7) is an active component of the renin-angiotensin-aldosterone system. Its exact role in renal vascular function is unclear. We therefore studied the effects of angiotensin(1-7) on the renal vasculature in vitro and in vivo. Methods Isolated small renal arteries were studied

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

    NARCIS (Netherlands)

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

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

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

    Science.gov (United States)

    Beketov, A I; Korneliuk, I K

    1981-01-01

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

  20. 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...

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

    Science.gov (United States)

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

    2015-01-01

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

  2. Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation

    NARCIS (Netherlands)

    Groenewegen, Hendrik C.; van der Harst, Pim; Roks, Anton J. M.; Buikema, Hendrik; Zijlstra, Felix; van Gilst, Wiek H.; de Smet, Bart J. G. L.

    2008-01-01

    Background: To evaluate the effect of supraphysiological levels of angiotensin II and selective angiotensin II type 1 receptor ( AT1-receptor) blockade on neointimal formation and systemic endothelial function after stent implantation in the rat abdominal aorta. Methods: Male Wistar rats were

  3. Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Garrido-Gil Pablo

    2012-02-01

    Full Text Available Abstract Background Several recent studies have shown that angiotensin type 1 receptor (AT1 antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ. PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. Methods We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. Results We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co

  4. 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....

  5. 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.

  6. 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...... 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...

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  8. Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme.

    Science.gov (United States)

    Khan, Mahmud Tareq Hassan; Dedachi, Kenichi; Matsui, Toshiro; Kurita, Noriyuki; Borgatti, Monica; Gambari, Roberto; Sylte, Ingebrigt

    2012-01-01

    Thermolysin (TLN) and other thermolysin-like zinc metalloproteinases (TLPs),are important virulence factors for pathogenesis of bacterial infections by suppressing the innate immune system of the host. Therapeutic inhibition ofTLPs is believed to be a novel strategy inthe development of a new generation antibiotics.In the present study inhibition of TLN and angiotensin I-converting enzyme (ACE) by small peptides were studied by in vitro binding assays and theoretical calculations. The capacity of the peptides to inhibitTLN induced cleavage ofthe transcription factor nuclear factor kappa beta (NF-κB) was studied by electrophoretic mobility shift assays (EMSAs).Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) μM, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) μM. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupiedthe S1' and S2' subsites, while FW, WL and WV occupiedthe S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-κB. The studied peptides may form as a basis for the design of new compoundstargeting TLN with a potential in the treatment of bacterial infections.

  9. Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.

    Science.gov (United States)

    Hampl, V; Herget, J; Bíbová, J; Baňasová, A; Husková, Z; Vaňourková, Z; Jíchová, Š; Kujal, P; Vernerová, Z; Sadowski, J; Červenka, L

    2015-01-01

    The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT₁) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT₁receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT₁receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.

  10. 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...

  11. Is the use of renin-angiotensin system inhibitors in patients with aortic valve stenosis safe and of prognostic benefit?

    DEFF Research Database (Denmark)

    Andersson, Charlotte; Abdulla, Jawdat

    2017-01-01

    risk [576/3389 patients receiving RASi vs. 1118/4384 controls died; relative risk 0.93 (95% confidence interval 0.78-1.11), P = 0.44]. Use of RASi was also observed to lower the risk of aortic valve replacement (AVR) surgery [67/2913 patients with RASi vs. 154/3666 controls underwent AVR; relative risk......Aortic valve stenosis (AVS) is associated with significant morbidity and mortality, especially in the presence of symptoms and echocardiographic signs of left ventricular remodelling (i.e. increase in left ventricular mass, left ventricular dilation, and systolic dysfunction). Renin...... for inclusion (PubMed, EMBASE, and Cochrane library search criteria: aortic stenosis, aortic valve, angiotensin-converting enzyme inhibitor in different combinations, published in English at any time up to 1 April 2016). Our analyses suggested that use of RASi was safe, with no observed increase in mortality...

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-03-25

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

  14. Effect of angiotensin converting enzyme inhibition after acute myocardial infarction in patients with arterial hypertension. TRACE Study Group, Trandolapril Cardiac Event

    DEFF Research Database (Denmark)

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

    1997-01-01

    the Trandolapril Cardiac Event (TRACE) study. The TRACE study was a randomized, double-blind, placebo-controlled study in which patients with an enzyme-verified AMI and ejection fraction oral trandolapril or placebo 3-7 days after the infarction. Of 1749...... patients. In a multivariate analysis, treatment with trandolapril was associated with a reduction in mortality among patients with a history of hypertension (P = 0.03). CONCLUSION: In this retrospective analysis, ACE inhibition after AMI complicated with left ventricular dysfunction was of greater benefit...

  15. 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......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...

  16. Inhibitory activity of Plantago major L. on angiotensin I-converting enzyme.

    Science.gov (United States)

    Nhiem, Nguyen Xuan; Tai, Bui Huu; Van Kiem, Phan; Van Minh, Chau; Cuong, Nguyen Xuan; Tung, Nguyen Huu; Thu, Vu Kim; Trung, Trinh Nam; Anh, Hoang Le Tuan; Jo, Sung-Hoon; Jang, Hae-Dong; Kwon, Young-In; Kim, Young Ho

    2011-03-01

    Eight compounds were isolated from methanol extract of Plantago major L. leaves and investigated for their ability to inhibit angiotensin I-converting enzyme activity. Among them, compound 1 showed the most potent inhibition with rate of 28.06 ± 0.21% at a concentration of 100 μM. Compounds 2 and 8 exhibited weak activities. These results suggest that compound 1 might contribute to the ability of P. major to inhibit the activity of angiotensin I- converting enzyme.

  17. Kinetics and molecular docking studies of the inhibitions of angiotensin converting enzyme and renin activities by hemp seed (Cannabis sativa L.) peptides.

    Science.gov (United States)

    Girgih, Abraham T; He, Rong; Aluko, Rotimi E

    2014-05-07

    Four novel peptide sequences (WVYY, WYT, SVYT, and IPAGV) identified from an enzymatic digest of hemp seed proteins were used for enzyme inhibition kinetics and molecular docking studies. Results showed that WVYY (IC50 = 0.027 mM) was a more potent (p < 0.05) ACE-inhibitory peptide than WYT (IC50 = 0.574 mM). However, WYT (IC50 = 0.054 mM) and SVYT (IC50 = 0.063 mM) had similar renin-inhibitory activity, which was significantly better than that of IPAGV (IC50 = 0.093 mM). Kinetics studies showed that WVYY had a lower inhibition constant (Ki) of 0.06 mM and hence greater affinity for ACE when compared to the 1.83 mM obtained for WYT. SVYT had lowest Ki value of 0.89 mM against renin, when compared to the values obtained for WYT and IPAGV. Molecular docking results showed that the higher inhibitory activities of WVYY and SVYT were due to the greater degree of noncovalent bond-based interactions with the enzyme protein, especially formation of higher numbers of hydrogen bonds with active site residues.

  18. The impact of age and sex on the reporting of cough and angioedema with renin-angiotensin system inhibitors: a case/noncase study in VigiBase.

    Science.gov (United States)

    Alharbi, Fawaz F; Kholod, Anzhelika A V; Souverein, Patrick C; Meyboom, Ronald H; de Groot, Mark C H; de Boer, Anthonius; Klungel, Olaf H

    2017-12-01

    The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin-angiotensin system (RAS) inhibitors. A case/noncase study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema, and noncases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin-converting enzyme (ACE) inhibitors was significantly higher in women than in men [adjusted reporting odds ratio (ROR): 44.0, 95% CI (43.2-44.8) for women vs. 29.2, 95% CI (28.5-29.9) for men]. There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women, but for aliskiren, women had a significantly higher ROR than men [adjusted ROR: 5.20, 95% CI (4.18-6.46) for women vs. 3.04, 95% CI (2.30-4.02) for men]. The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40-59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60-79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different adverse drug reaction risks in subgroups or also can be explained by factors influencing reporting. © 2017 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.

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

    International Nuclear Information System (INIS)

    Nakagawa, Naoki; Yao, Naoyuki; Hirayama, Tomoya

    2011-01-01

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

  20. Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin-angiotensin-aldosterone system among patients with obesity and proteinuria.

    Science.gov (United States)

    Morales, Enrique; Gutiérrez, Eduardo; Caro, Jara; Sevillano, Angel; Rojas-Rivera, Jorge; Praga, Manuel

    2015-01-01

    Over the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin-angiotensin-aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. This study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI ≥30kg/m2) and a control group. Seventy-one patients were included in the study, with a mean age of 56.7±15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14-84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8±2.1 vs. 1.3±1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6±9 to 92.1±7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9±1.4 to 0.8±0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non

  1. [Association between visual improvement after photocoagulation and the use of angiotensin converting enzyme inhibitors in diabetic macular oedema].

    Science.gov (United States)

    Somilleda-Ventura, Selma Alin; García-Rubio, Yatzul Zuhaila; Razo Blanco-Hernández, Dulce Milagros; Lima-Gómez, Virgilio

    2016-01-01

    Angiotensin converting enzyme inhibitors are effective in delaying the progression of diabetic retinopathy. It is unknown if their use is associated with a better visual outcome in patients with diabetic macular oedema. A non-experimental, comparative, longitudinal and retrospective study was performed on patients with diabetic macular oedema treated by focal photocoagulation, and with systemic arterial hypertension treated with angiotensin converting enzyme inhibitors (Group 1), and without hypertension (Group 2). The dependent variable was the proportion with visual improvement, operatively defined as the gain of one or more lines of vision three weeks after photocoagulation. The independent variable was the use of angiotensin converting enzyme inhibitors. The proportion of eyes with visual improvement after treatment was compared between groups using the Chi squared (χ(2)) test. A total of 33 eyes (51.6%) were assigned to group 1, and 31 (48.2%), to group 2. The mean of visual acuity improved after three weeks, compared with baseline (p=0.002). The proportion of eyes with visual improvement did not differ between patients treated with angiotensin converting enzyme inhibitors (45.5%) and those that did not use them (51.6%, p=0.4). There was no statistical difference in the proportion of eyes with visual improvement between patients treated with angiotensin converting enzyme inhibitors and in those where they were not used. There is no support for the inhibition of angiotensin II in addition to photocoagulation for improving the outcome in patients with diabetic macular oedema. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    R. Leite

    1997-05-01

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

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

    Science.gov (United States)

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

    2015-03-25

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

  4. Effects of Renin-Angiotensin System Inhibitors on Renal Expression of Renalase in Sprague-Dawley Rats Fed With High Salt Diet.

    Science.gov (United States)

    Wang, Yang; Xie, Bing-Qing; Gao, Wei-Hua; Yan, Ding-Yi; Zheng, Wen-Ling; Lv, Yong-Bo; Cao, Yu-Meng; Hu, Jia-Wen; Yuan, Zu-Yi; Mu, Jian-Jun

    2015-01-01

    The aim of our study was to investigate the effect of high-salt diet on the renal expression of renalase and the potential role of the local renin-angiotensin system in this process. Sprague-Dawley (SD) rats were divided into groups according to salt content in diet and drug treatment as follows: normal-salt diet (NS), high-salt diet (HS), high-salt intake with hydralazine (HS+H), high-salt diet with enalapril (HS+E), and high-salt diet with valsartan (HS+V). The dietary intervention and drugs were given for four weeks. Renin activity and angiotensin II type 1 receptor (AT1R) levels were detected by real-time PCR. Renalase mRNA and protein were also measured. After four weeks, systolic blood pressure and proteinuria were significantly increased in the HS group with respect to the NS group. Dietary salt intake caused a dramatic decrease in renalase expression in the rat kidneys. Renal cortex renin and AT1R increased significantly in the HS and HS+H groups. Urinary protein was positively correlated with renal renin and AT1R levels. However, in the HS+E and HS+V groups, enalapril and valsartan failed to influence renal renalase expression but abolished the increase in proteinuria, renal cortex renin, and AT1R levels with respect to the HS group. This study indicates that high salt intake reduces renal expression, and renal RAS may be not involved in the regulation of renalase in SD rats fed with high-salt diet. © 2015 The Author(s) Published by S. Karger AG, Basel.

  5. 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.

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

    Science.gov (United States)

    Boshra, Vivian; Abbas, Amr M

    2017-07-26

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

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

    Science.gov (United States)

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

    1999-03-01

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

  8. 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.

  9. 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

  10. Urinary renin-angiotensin markers in polycystic kidney disease

    NARCIS (Netherlands)

    Salih, Mahdi; Bovee, Dominique M.; Roksnoer, Lodi C. W.; Casteleijn, Niek F.; Bakker, Stephan J. L.; Gansevoort, Ronald T.; Zietse, Robert; Danser, A. H. Jan; Hoorn, Ewout J.

    2017-01-01

    In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase

  11. Quantitative assessment of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and digestive system cancer risk.

    Science.gov (United States)

    Wang, J; Yang, S; Guo, F H; Mao, X; Zhou, H; Dong, Y Q; Wang, Z M; Luo, F

    2015-11-13

    The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been reported to be associated with digestive system cancer; however, the results from previous studies have been conflicting. The present study aimed to investigate the association between the ACE I/D polymorphism and the risk of digestive system cancer using a meta-analysis of previously published studies. Databases were systematically searched to identify relevant studies published prior to December 2014. We estimated the pooled OR with its 95%CI to assess the association. The meta-analysis consisted of thirteen case-control studies that included 2557 patients and 4356 healthy controls. Meta-analysis results based on all the studies showed no significant association between the ACE I/D polymorphism and the risk of digestive system cancer (DD vs II: OR = 0.85, 95%CI = 0.59-1.24; DI vs II: OR = 0.94, 95%CI = 0.78-1.15; dominant model: OR = 0.96, 95%CI = 0.81- 1.15; recessive model: OR = 1.06, 95%CI = 0.76-1.48). Subgroup analyses by race and cancer type did not detect an association between the ACE I/D polymorphism and digestive system cancer risk. However, when the analyses were restricted to smaller studies (N digestive system cancer. Further large and well-designed studies are needed to confirm these conclusions.

  12. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...... the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1...

  13. Angiotensin II disrupts inhibitory avoidance memory retrieval.

    Science.gov (United States)

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

    2006-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Yuki Hamano

    2011-09-01

    Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

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

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2001-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2001-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Luis Rodriguez-Padial

    2017-12-01

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

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

    NARCIS (Netherlands)

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

    1982-01-01

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

  19. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, L.

    2008-01-01

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

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

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    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.

  1. Interactive effects of apelin, renin-angiotensin system and nitric oxide in treatment of obesity-induced type 2 diabetes mellitus in male albino rats.

    Science.gov (United States)

    Sabry, Maha Mohamed; Mahmoud, Manal Moustafa; Shoukry, Heba Samy; Rashed, Laila; Kamar, Samaa Samir; Ahmed, Mona Mohamed

    2018-03-22

    Apelin and its receptor (APJ) are involved in the regulation of a variety of pathophysiological processes. We studied the effect of apelin treatment on obesity-induced type 2 diabetes mellitus (T2DM) and possible interaction between apelin/APJ system and renin-angiotensin system (RAS). Forty eight male albino rats were divided into two groups: control group and diabetic group. Diabetic group was subdivided into: control diabetic, apelin-treated, apelin + losartan-treated, apelin + l-NAME-treated and losartan-treated diabetic subgroup. Administration of apelin-13 yielded an improvement of IR, dyslipidaemia, inflammation, oxidative stress with significant decrease in AT1R gene expression and significant increase in ACE2 gene expression in adipose tissues. Losartan + apelin yielded a further significant decrease in ATR1 gene expression, glycaemic indices, serum TGs and TPA versus Apelin only. Adding l-NAME in subgroup (2D) reversed the effect of apelin. We suggested that the beneficial effect of Apelin is mainly mediated by NO-activated pathway and/or ACE2/Ang (1-7) dependent pathway.

  2. 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...

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

    DEFF Research Database (Denmark)

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

    1980-01-01

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

  4. Activity-guided discovery of (S)-malic acid 1'-O-β-gentiobioside as an angiotensin I-converting enzyme inhibitor in lettuce (Lactuca sativa).

    Science.gov (United States)

    Lagemann, Annika; Dunkel, Andreas; Hofmann, Thomas

    2012-07-25

    Angiotensin-converting enzyme (ACE), playing a crucial role in the renin angiotensin aldosterone system, is well-known to catalyze the conversion of the decapeptide angiotensin I into the physiologically active octapeptide angiotensin II, triggering blood pressure increasing mechanisms. To meet the demand for natural phytochemicals as antihypertensive agents in functional food development, extracts prepared from a series of vegetables were screened for their ACE-inhibitory activity by means of a LC-MS/MS-based in vitro assay. By far the highest ACE inhibition was found for a lettuce extract, in which the most active compound was located by means of activity-guided fractionation. LC-MS, NMR spectroscopy, and hydrolysis experiments followed by ion chromatography led to the unequivocal identification of the ACE inhibitor as the previously not reported (S)-malic acid 1'-O-β-gentiobioside. This glycoside represents a novel class of ACE-inhibiting phytochemicals with a low IC(50) value of 27.8 μM. First incubation experiments in saliva and aqueous hydrochloric acid demonstrated the stability of (S)-malic acid 1'-O-β-gentiobioside against salivary glycosidases and stomach acid.

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

    Science.gov (United States)

    Høi-Hansen, Thomas; Pedersen-Bjergaard, Ulrik; Andersen, Rikke Due; Kristensen, Peter Lommer; Thomsen, Carsten; Kjaer, Troels; Høgenhaven, Hans; Smed, Annelise; Holst, Jens Juul; Dela, Flemming; Boomsma, Frans; Thorsteinsson, Birger

    2009-12-01

    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. 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 potentials and hypoglycaemic symptoms were recorded. 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 cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

  6. 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.

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

    Science.gov (United States)

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

    2016-05-25

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

  8. Paradoxic activation of the renin-angiotensin system in twin-twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient.

    Science.gov (United States)

    Mahieu-Caputo, Dominique; Meulemans, Alain; Martinovic, Jelena; Gubler, Marie-Claire; Delezoide, Anne-Lise; Muller, Françoise; Madelenat, Patrick; Fisk, Nicholas M; Dommergues, Marc

    2005-10-01

    Despite advances in treatment, twin-to-twin transfusion syndrome (TTTS) still carries a high risk for perinatal mortality and morbidity. Simple blood transfer from the donor to the recipient twin cannot explain all of the features of this disease, in particular the recipient's hypertensive cardiomyopathy. We report a case in which TTTS resulted in preterm delivery with early neonatal death of both twins, allowing assessment of the renin angiotensin system (RAS) status of each fetus, both by cord blood renin and aldosterone assay and by renal immunohistochemistry. The donor had severe oliguria/oligohydramnios, whereas the recipient, in addition to severe polyuria/polyhydramnios, had cardiomyopathy, atrioventricular regurgitation, and ascites. Although immunohistochemistry demonstrated that renal secretion of renin was up-regulated in the donor and down-regulated in the recipient, cord blood levels of renin and aldosterone were similar, with high renin levels in both twins. This observation supports the hypothesis that despite renal RAS down-regulation, the recipient is exposed to RAS effectors elaborated in the donor and transferred via placental shunts. This may contribute to cardiomyopathy and hypertension in the recipient, which cannot be accounted for by hypervolemia alone. We thus hypothesized that in TTTS, the recipient's hypertensive cardiomyopathy could be due to a mechanism similar to the classical model of hypertension referred to as "2 kidneys-1 clip." Thus the hypovolemic donor twin, comparable to the clipped kidney, produces vasoactive hormones that compromise the recipient, comparable to the normal kidney, causing hypertension and cardiomyopathy.

  9. Association between renin-angiotensin-aldosterone system blockade and future osteoporotic fracture risk in hypertensive population: A population-based cohort study in Taiwan.

    Science.gov (United States)

    Chen, Chang-I; Yeh, Jong-Shiuan; Tsao, Nai-Wen; Lin, Fen-Yen; Shih, Chun-Ming; Chiang, Kuang-Hsing; Kao, Yung-Ta; Fang, Yu-Ann; Tsai, Lung-Wen; Liu, Wen-Chi; Nakagami, Hironori; Morishita, Ryuichi; Kuo, Yi-Jie; Huang, Chun-Yao

    2017-11-01

    Tissue renin-angiotensin-aldosterone system (RAAS) activation in sites of osteoporosis had been demonstrated in animal studies; however, the possibility of RAAS blockade to prevent future osteoporotic fracture had rarely been verified in clinical studies. We Used the Taiwan Longitudinal Health insurance database 2000 to 2008, the cohort study comprised patients age over 40 with a recorded new diagnosis of hypertension between January 1, 2000 to December 31, 2008, in addition, patients who had diagnosis of osteoporosis before the date of cohort enter were excluded. After the definite diagnosis of hypertension, each patient was followed until osteoporotic fracture happened or the end of 2008. The occurrence of osteoporotic fracture was evaluated in patients who either were or without taking RAAS blockade agents. Cox proportional hazard regressions were used to evaluate the osteoporotic fracture incidence after adjusting for known confounding factors. In total, 57,132 hypertensive patients comprised the study cohort. Our study results showed that the incidence of osteoporosis fracture in the whole cohort was significantly higher in the RAAS blockade non-user group than the user group. This phenomenon was observed in both sex and all age categories. Sensitivity analysis further showed the concordant lower osteoporosis fracture risk in patients with various RAAS blockers usage durations; the risk of osteoporosis fracture was the lowest in those drug use >365 days when compared with the non-user cohort. In conclusion, our study result demonstrated the lower future osteoporotic fracture risk in hypertensive subjects who received long term RAAS blocker treatment.

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

    DEFF Research Database (Denmark)

    Schievink, B; Kröpelin, T; Mulder, S

    2016-01-01

    AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from......, intermediate and advanced stage of disease, whose mean age was 60 years and who received placebo, the median time to ESRD was 21.4, 10.8 and 4.7 years, respectively. RAS intervention delayed the predicted time to ESRD by 4.2, 3.6 and 1.4 years, respectively. The benefit of early RAS intervention was more...... pronounced in younger patients; for example, for patients with a mean age of 45 years, RAS intervention at early, intermediate or advanced stage delayed ESRD by 5.9, 4.0 and 1.1 years versus placebo. CONCLUSIONS: RAS intervention early in the course of proteinuric DKD is more beneficial than late...

  11. The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

    Science.gov (United States)

    Kobayashi, Mamoru; Hirooka, Kazuyuki; Ono, Aoi; Nakano, Yuki; Nishiyama, Akira; Tsujikawa, Akitaka

    2017-03-01

    Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

  12. Orthostatic effects of midodrine versus L-NAME on cerebral blood flow and the renin-angiotensin-aldosterone system in tetraplegia.

    Science.gov (United States)

    Wecht, Jill M; Radulovic, Miroslav; Rosado-Rivera, Dwindally; Zhang, Run-Lin; LaFountaine, Michael F; Bauman, William A

    2011-11-01

    To compare responses to head-up tilt (HUT) in individuals with chronic tetraplegia after midodrine hydrochloride (10 mg) versus nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) administration. Prospective comparative drug trial. Veterans Affairs medical center. Participants (N=7) were studied during 3 laboratory visits: no drug, midodrine (administered orally 30 min before HUT), and L-NAME (infused over a 60-min period). Anti-hypotensive agents, midodrine, and L-NAME. Mean arterial pressure (MAP), cerebral blood flow (CBF), and markers of the renin-angiotensin-aldosterone system (RAAS, plasma renin and serum aldosterone) were measured in the supine position at baseline (BL) and during a 45° HUT maneuver. Data were compared between BL and the average of 3 assessments collected during HUT. Orthostatic MAP and CBF were increased with the midodrine and L-NAME groups compared with the no drug trial and the relationship between the change in MAP and CBF was significant (r=0.770; Pmidodrine appeared to suppress the post-HUT RAAS response compared with no drug. Increasing orthostatic blood pressure with L-NAME or midodrine appears to increase CBF and suppress the RAAS during HUT in persons with tetraplegia, although more data are needed to confirm these preliminary findings. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  13. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention.

    Science.gov (United States)

    Schirger, John A; Chen, Horng H; Jougasaki, Michihisa; Lisy, Ondrej; Boerrigter, Guido; Cataliotti, Alessandro; Burnett, John C

    2004-01-20

    While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms. In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade. Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.

  14. ANGIOTENSIN II AND MYOCARDIAL INFARCTION

    Directory of Open Access Journals (Sweden)

    O. P. Shevchenko

    2008-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    during low-salt diet in PE patients (n = 7), healthy pregnant women (n = 15), and nonpregnant women (n = 13). High-salt intake decreased renin and angiotensin II concentrations significantly in healthy pregnant women (P ... in aldosterone and increases in brain natriuretic peptid (BNP) were similar in the groups. In PE patients, uterine and umbilical artery indices were not adversely changed during low-salt diet. Creatinine clearance was significantly lower in PE with no change by salt intake. PE patients displayed alterations...... of plasma renin and angiotensin II in response to changes in dietary salt intake compatible with a primary increase in renal sodium reabsorption in hypertensive pregnancies....

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

    Science.gov (United States)

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

    2017-11-15

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

  17. Does ACE inhibition limit structural changes in the heart following myocardial infarction?

    NARCIS (Netherlands)

    Smits, J. F.; Passier, R. C.; Nelissen-Vrancken, H. J.; Cleutjens, J. P.; Kuizinga, M. C.; Daemen, M. J.

    1995-01-01

    A recent series of experiments in our laboratory were designed to elucidate the cellular changes that underlie the cardiac remodelling response following myocardial infarction (MI) in the rat as well as the potential role of the renin-angiotensin system (RAS) in this response. Inhibition of the RAS

  18. 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

  19. A Unique "Angiotensin-Sensitive" Neuronal Population Coordinates Neuroendocrine, Cardiovascular, and Behavioral Responses to Stress.

    Science.gov (United States)

    de Kloet, Annette D; Wang, Lei; Pitra, Soledad; Hiller, Helmut; Smith, Justin A; Tan, Yalun; Nguyen, Dani; Cahill, Karlena M; Sumners, Colin; Stern, Javier E; Krause, Eric G

    2017-03-29

    Stress elicits neuroendocrine, autonomic, and behavioral responses that mitigate homeostatic imbalance and ensure survival. However, chronic engagement of such responses promotes psychological, cardiovascular, and metabolic impairments. In recent years, the renin-angiotensin system has emerged as a key mediator of stress responding and its related pathologies, but the neuronal circuits that orchestrate these interactions are not known. These studies combine the use of the Cre-recombinase/loxP system in mice with optogenetics to structurally and functionally characterize angiotensin type-1a receptor-containing neurons of the paraventricular nucleus of the hypothalamus, the goal being to determine the extent of their involvement in the regulation of stress responses. Initial studies use neuroanatomical techniques to reveal that angiotensin type-1a receptors are localized predominantly to the parvocellular neurosecretory neurons of the paraventricular nucleus of the hypothalamus. These neurons are almost exclusively glutamatergic and send dense projections to the exterior portion of the median eminence. Furthermore, these neurons largely express corticotrophin-releasing hormone or thyrotropin-releasing hormone and do not express arginine vasopressin or oxytocin. Functionally, optogenetic stimulation of these neurons promotes the activation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as well as a rise in systolic blood pressure. When these neurons are optogenetically inhibited, the activity of these neuroendocrine axes are suppressed and anxiety-like behavior in the elevated plus maze is dampened. Collectively, these studies implicate this neuronal population in the integration and coordination of the physiological responses to stress and may therefore serve as a potential target for therapeutic intervention for stress-related pathology. SIGNIFICANCE STATEMENT Chronic stress leads to an array of physiological responses that ultimately

  20. Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats

    Science.gov (United States)

    Haverdings, R Folgert G; Haas, Marijke; Navis, Gerjan; van Loenen-Weemaes, Anne-miek; Meijer, Dirk K F; de Zeeuw, Dick; Moolenaar, Frits

    2002-01-01

    In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril–lysozyme also results in an enhanced effect on renal parameters, relative to the systemic effects. Renal effects: intravenous infusion of captopril–lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31±2% vs 17±4% at 0.5 mg kg−1 6h−1, Pcaptopril as a free drug. In correspondence with these findings, renal ACE inhibition was potentiated approximately 5 fold (−50±4% vs −22±3% at 1 mg kg−1 6 h−1, Pcaptopril did not affect blood pressure in dosages up to 5 mg kg−1 6 h−1. This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (−12±3% vs −66±5% at 1 mg kg−1 6 h−1, Pcaptopril. An experiment of continued intravenous administration of captopril–lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (−67±5% vs −15±7% at 4 mg kg−1 24 h−1, Pcaptopril–lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself. PMID:12163343

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

    Directory of Open Access Journals (Sweden)

    Ning-Ping Wang

    2017-05-01

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

  3. 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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2016-06-01

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

  6. Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression.

    Science.gov (United States)

    Gonzalez-Calero, Laura; Martin-Lorenzo, Marta; de la Cuesta, Fernando; Maroto, Aroa S; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Pulido-Olmo, Helena; Segura, Julian; Barderas, Maria G; Ruilope, Luis M; Vivanco, Fernando; Alvarez-Llamas, Gloria

    2016-01-16

    Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients. 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied. CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development. CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings

  7. Beta2-adrenergic receptor genotype affects the renin-angiotensin-aldosterone system response to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern.

    Science.gov (United States)

    Sun, Bei; Williams, Jonathan S; Svetkey, Laura P; Kolatkar, Nikheel S; Conlin, Paul R

    2010-08-01

    Beta(2)-adrenergic receptor (beta2-AR) is a susceptibility locus for hypertension, and polymorphisms at this site relate to salt sensitivity and low plasma renin activity (PRA). The Dietary Approaches to Stop Hypertension (DASH) dietary pattern lowers blood pressure and appears to interact with the renin-angiotensin-aldosterone system (RAAS). We hypothesized that the DASH diet associates with increased RAAS activity, and genotype status at beta2-AR G46A modifies this response. We genotyped participants in the DASH-Sodium study (n = 372) at beta2-AR G46A to determine the association with blood pressure, RAAS components, and consumption of the DASH diet. We used 2-way mixed linear regression and an additive model for all primary analyses. Mean (+/-SEM) PRA was significantly higher in participants in the DASH group than in participants in the control group (0.68 +/- 0.03 compared with 0.54 +/- 0.03 ng x mL(-1) x h(-1), P = 0.002). Serum aldosterone, urinary aldosterone, and urinary potassium concentrations were also significantly higher in the DASH group (P diet interactions for changes in systolic blood pressure (SBP) and concentrations of aldosterone and urinary potassium (P for interaction = 0.048, 0.017, and 0.001 for SBP and aldosterone and urinary potassium concentrations, respectively). There was an association between the A allele of beta2-AR G46A and greater blood pressure reduction and blunted aldosterone and PRA responses to the DASH diet. Our results indicate that the DASH diet lowers blood pressure and increases PRA and aldosterone concentrations. There is an association between the G46A polymorphism of beta2-AR and blood pressure and RAAS responses to the DASH diet, which suggests that beta2-AR may be a genetic modifier of DASH-diet responsiveness. This trial was registered at clinicaltrials.gov as NCT00000608.

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

    Science.gov (United States)

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

    2005-10-01

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

  9. 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...... that 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....

  10. 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.

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

    Herichová, Iveta

    2016-01-01

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

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

    African Journals Online (AJOL)

    Abstract. Background: Genetic variability in the genes of different components of renin-angiotensin system (RAS) is likely to contribute for its heterogenous association in renal diseased patients. Among the candidate genes of RAS, angiotensin II type 1 receptor gene polymorphism (AT1R A1166C) seems to be particularly ...

  14. 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.

  15. Reducing Disease Activity in Animal Models of MS by Activation of the Protective Arm of the Renin-Angiotensin System

    Science.gov (United States)

    2015-10-01

    in EAE is to skew expression of the RAS system in the brain to the anti- inflammatory, regulatory arm. In our proposal we hypothesized that if we were...followed by progressive accruing disability and paralysis with stabilization at a high level of disability. MOG-EAE is similar in many aspects to...progressive MS with extensive neuronal damage both in the brain and spinal cord, and once established treatment intervention can be very limited. Spinal

  16. Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitors in Patients With Left Ventricular Systolic Dysfunction and Hyponatremia

    DEFF Research Database (Denmark)

    Balling, Louise; Kober, Lars; Schou, Morten

    2013-01-01

    The presence of hyponatremia has been perceived to increase the risk of adverse events on initiation of treatment with angiotensin-converting enzyme inhibition in heart failure patients. The aim of this study was to investigate if baseline hyponatremia (plasma Na(+)......The presence of hyponatremia has been perceived to increase the risk of adverse events on initiation of treatment with angiotensin-converting enzyme inhibition in heart failure patients. The aim of this study was to investigate if baseline hyponatremia (plasma Na(+)...

  17. Ordering kinetics in model systems with inhibited interfacial adsorption

    DEFF Research Database (Denmark)

    Willart, J.-F.; Mouritsen, Ole G.; Naudts, J.

    1992-01-01

    . The results are related to experimental work on ordering processes in orientational glasses. It is suggested that the experimental observation of very slow ordering kinetics in, e.g., glassy crystals of cyanoadamantane may be a consequence of low-temperature activated processes which ultimately lead......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......, of the algebraic growth law, R(t)∼Atn, whereas the growth exponent, n, remains close to the value n=1/2 predicted by the classical Lifshitz-Allen-Cahn growth law for systems with nonconserved order parameter. At very low temperatures there is, however, an effective crossover to a much slower algebraic growth...

  18. Angioedema related to Angiotensin inhibitors.

    Science.gov (United States)

    Knecht, Stephanie E; Dunn, Steven P; Macaulay, Tracy E

    2014-10-01

    Angiotensin inhibitors have been extensively evaluated in clinical trials and have demonstrated significant reductions in morbidity and mortality following myocardial infarction and stroke, as well as in patients with heart failure or who are at risk of cardiovascular disease. Further, both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently prescribed for the treatment of hypertension and to preserve renal function in patients with diabetes mellitus and chronic kidney disease. Angioedema is a known, but rare, adverse effect of ACEIs and ARBs. Therefore, it is important for clinicians to have a thorough understanding of risks and benefits of prescribing these medications, particularly in patients with a history of angioedema. This review describes the literature evaluating the incidence and cross-reactivity of angioedema with ACEIs and ARBs in order to provide guidance for clinical decision making. © The Author(s) 2014.

  19. Distribution of Human Leukocyte Antigen alleles in Systemic Lupus Erythematosus patients with Angiotensin Converting Enzyme Insertion/Deletion Polymorphism

    Directory of Open Access Journals (Sweden)

    Nageen Hussain

    2013-02-01

    Full Text Available Systemic Lupus Erythematosus is one of the classic examples of autoimmune diseases among human beings and is a rare disease in Pakistani population. Clinically it is a quite diverse and complicated autoimmune disease in a sense that it involves multiple organs of the body and mimics with other diseases as well. This study focused on the distribution of HLA alleles in SLE patients with ACE I/D Polymorphism. A total of 122 individuals were enrolled in this study, 61 were the SLE patients who fulfilled revised ACR criteria and 61 were the healthy controls. Mean age of SLE patients at diagnosis was 30.35 ± 1.687 years (12-68 years. ACE gene I/D polymorphism was performed by nested PCR and DNA based HLA typing technique was used. ACE gene I/D polymorphism of Intron16 was studied and found to be involved in the activity of SLE. There is high frequency of HLA-A*01, HLA-B*40, HLA-DRB1*01 alleles in SLE patients with ACE DD genotype. The distribution of HLA-A, -B, -DRB1 alleles was analyzed in SLE patients with various disease phenotypes. HLA-A*01 and HLA-B*40 was the most common allele found in SLE patients with the involvement of skin. HLA-A*01, -A*03, HLA-B*13 and -B*46 were common in SLE patients with arthritis while HLA-A*26 and -A*69 were commonly found in Lupus nephritis cases. SLE patients involving both skin and kidney had an allele HLA-DRB1*01 common in them.

  20. 8C.03: A KEY ROLE FOR ENDOTHELIN-1 IN THE PATHOGENESIS OF PREECLAMPSIA AND THE ASSOCIATED SUPPRESSION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM.

    Science.gov (United States)

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

    2015-06-01

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

  1. ASSOCIATION OF GENE POLYMORPHISMS OF THE RENIN-ANGIOTENSIN SYSTEM AND ENDOTHELIAL DYSFUNCTION WITH DEVELOPMENT AND SEVERITY OF PORTAL HYPERTENSION IN PATIENTS WITH CHRONIC HEPATITIS C

    Directory of Open Access Journals (Sweden)

    O. V. Taratina

    2016-01-01

    Full Text Available Background: At present, much attention is paid to genetic factors explaining the clinical course of chronic hepatitis C. Aim: To evaluate an association of the gene polymorphisms involved in the formation of endothelial dysfunction (NOS3 894G/T, CYBA 242C/T, MTHFR 677C/T and encoding components of the renin-angiotensin system (ATR1 1166A/C, AGT (-6G/T and 235M/T with development and severity of portal hypertension syndrome in patients with chronic hepatitis C. Materials and methods: 162 patients with chronic hepatitis C and HCV-related cirrhosis (114 women and 48 men were divided into the following groups: no portal hypertension (n = 98, "compensated" (n = 19 and "decompensated" (n = 45 portal hypertension. The gene polymorphisms were assessed by molecular genetic methods. Results: TT genotype of CYBA was more common in patients with portal hypertension than in those without (odds ratio (OR for TT = 3.59, p = 0.031. This difference becomes larger when comparing the decompensated portal hypertension group with the no portal hypertension group (OR TT = 5.46, p = 0.009. Other gene polymorphisms were not associated with development or decompensation of portal hypertension. Multivariate analysis of the impact of genetic, clinical and demographic factors showed that portal hypertension was associated primarily with patients age at the time of the study (Wald's х2 = 14.99 and with their body mass index (Wald's х2 = 4.35. After exclusion of these population-wide risk factors from the model, the development of portal hypertension correlated with the carriage of 235TT genotype of CYBA (Wald's х2 = 6.07, OR = 4.29 and (-6AA genotype AGT (Wald's х2 = 4.73, OR = 4.13, as well as with the lack of protective 235TT genotype AGT (Wald's х2 = 4.06, OR = 0.33. The combined effects of the studied gene polymorphisms on decompensation of the portal hypertension in patients with chronic HCV infection were similar. Conclusion: The development and increase in

  2. Cardiovascular effects of the angiotensin type 2 receptor.

    Science.gov (United States)

    Faria-Costa, Gabriel; Leite-Moreira, Adelino; Henriques-Coelho, Tiago

    2014-01-01

    The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angiotensin type 1 receptor, AT1R. Although the quantities of the AT2R found in the adult are low, its expression rises in pathological situations. The AT2R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT2R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT1R inhibitor). After myocardial infarction, the AT2R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT2R promotes natriuresis. Until now, treatment directed at the renin-angiotensin-aldosterone system has been based on angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT2R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  3. Mixed inhibitors of angiotensin-converting enzyme and enkephalinase: Rational design, properties, and potential cardiovascular applications of glycopril and alatriopril

    Energy Technology Data Exchange (ETDEWEB)

    Gros, C.; Noel, N.; Souque, A.; Schwartz, J.C. (Inst. National de la Sante et de la Recherche Medicale, Paris (France)); Danvy, D.; Plaquevent, J.C.; Duhamel, L.; Duhamel, P. (Univ. de Rouen, Mont Saint Aignan (France)); Lecomte, J.M. (Lab. Bioprojet, Paris (France)); Bralet, J. (Lab. de Pharmacodynamie, Dijon (France))

    1991-05-15

    Angiotensin-converting enzyme (ACE) and enkephalinase, two cell surface metallopeptidases, are responsible for angiotensin II formation and atrial natriuretic factor (ANF) degradation, respectively, and thereby play a critical role in the metabolism of hormonal peptides exerting essentially opposite actions in cardiovascular regulations. To affect simultaneously both hormonal systems by a single molecular structure, the authors designed glycoprilat and alatrioprilat {l brace}(S)-N-(3-(3,4-methylenedioxyphenyl)-2-(mercaptomethyl)-1-oxopropyl)glycine and -alanine, respectively{r brace}. In vitro the two compounds inhibit both ACE and enkephalinase activities with similar, nanomolar potencies, and in vivo, glycopril and alatriopril, the corresponding diester prodrugs, occupy the two enzyme molecules in lung at similar low dosages. The high potency of these compounds is attributable to interaction of the methylenedioxy group with the S{sub 1} subsite of ACE and of the aromatic ring with the S{prime}{sub 1} subsite of enkephalinase. In rodents, low doses of these mixed inhibitors exert typical actions of ACE inhibitors--i.e., prevention of angiotensin I-induced hypertension-as well as of enkephalinase inhibitors--i.e., protection from {sup 125}I-ANF degradation or enhancement of diuresis and natriuresis following acute extracellular volume expansion. In view of the known counterbalanced physiological actions of the two hormonal peptides, whose metabolism is controlled by ACE and enkephalinase, mixed inhibitors of the two peptidases show promise for the treatment of various cardiovascular and salt-retention disorders.

  4. The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-07-15

    The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Effects of natural peptides from food proteins on angiotensin converting enzyme activity and hypertension.

    Science.gov (United States)

    Martin, Melanie; Deussen, Andreas

    2017-12-15

    Cardiovascular diseases are the leading cause of death. The underlying pathophysiology is largely contributed by an overactivation of the renin-angiotensin-aldosterone-system (RAAS). Herein, angiotensin II (AngII) is a key mediator not only in blood pressure control and vascular tone regulation, but also involved in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Since more than three decades suppression of AngII generation by inhibition of the angiotensin-converting enzyme (ACE) or blockade of the AngII-receptor has shown clinical benefit by reducing hypertension, atherosclerosis and other inflammation-associated cardiovascular diseases. Besides pharmaceutical ACE-inhibitors some natural peptides derived from food proteins reduce in vitro ACE activity. Several animal studies and a few human clinical trials have shown antihypertensive effects of such peptides, which might be attractive as food additives to prevent age-related RAAS activation. However, their inhibitory potency on in vitro ACE activity does not always correlate with an antihypertensive impact. While some peptides with high inhibitory activity on ACE-activity in vitro show no antihypertensive effect in vivo, other peptides with only a moderate ACE inhibitory activity in vitro cause such effects. The explanation for this conflicting phenomenon between inhibitory activity and antihypertensive effect remains unclear to date. This review shall critically address the effects of natural peptides derived from different food proteins on the cardiovascular system and the possible underlying mechanisms. A central aspect will be to point to conceptual gaps in the current understanding of the action of these peptides with respect to in vivo blood pressure lowering effects.

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

    OpenAIRE

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

    2017-01-01

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

  7. 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

    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...... 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 odds...

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

  9. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS.

    Science.gov (United States)

    Leonhardt, Julia; Villela, Daniel C; Teichmann, Anke; Münter, Lisa-Marie; Mayer, Magnus C; Mardahl, Maibritt; Kirsch, Sebastian; Namsolleck, Pawel; Lucht, Kristin; Benz, Verena; Alenina, Natalia; Daniell, Nicholas; Horiuchi, Masatsugu; Iwai, Masaru; Multhaup, Gerhard; Schülein, Ralf; Bader, Michael; Santos, Robson A; Unger, Thomas; Steckelings, Ulrike Muscha

    2017-06-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other. © 2017 American Heart Association, Inc.

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

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    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.

  11. Behavioral inhibition system (BIS), Behavioral activation system (BAS) and schizophrenia : Relationship with psychopathology and physiology

    NARCIS (Netherlands)

    Scholten, Marion R. M.; van Honk, Jack; Aleman, Andre; Kahn, Rene S.

    2006-01-01

    Objective: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been conceptualized as two neural motivational systems that regulate sensitivity to punishment (BIS) and reward (BAS). Imbalance in BIS and BAS levels has been reported to be related to various forms of

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

    Science.gov (United States)

    Tokuda, C; Kimura, K; Kamishima, Y

    1995-04-01

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

  13. PROSPECTIVE COMPARISON OF ARNI [ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR] WITH ACEI [ANGIOTENSIN CONVERTING-ENZYME INHIBITOR] TO DETERMINE IMPACT ON GLOBAL MORTALITY AND MORBIDITY IN HEART FAILURE TRIAL

    Directory of Open Access Journals (Sweden)

    2015-01-01

    Full Text Available Источник: McMurray J.J., Packer M., Desai A.S., et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N. Engl. J. Med. – 2014. – Vol. 371. – P. 993–1004.

  14. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome

    NARCIS (Netherlands)

    Wösten-van Asperen, Roelie M.; Bos, Albert P.; Bem, Reinout A.; Dierdorp, Barbara S.; Dekker, Tamara; van Goor, Harry; Kamilic, Jelena; van der Loos, Chris M.; van den Berg, Elske; Bruijn, Martijn; van Woensel, Job B.; Lutter, René

    2013-01-01

    Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin

  15. Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril

    Science.gov (United States)

    Akif, Mohd; Masuyer, Geoffrey; Schwager, Sylva L U; Bhuyan, Bhaskar J; Mugesh, Govindasamy; Isaac, R Elwyn; Sturrock, Edward D; Acharya, K Ravi

    2011-01-01

    Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin–angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356–1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein–selenolate interaction. These new structures of tACE–SeCap and AnCE–SeCap inhibitor complexes presented here pr