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Sample records for dual renin-angiotensin system

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

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

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

  2. 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

  3. Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension.

    Science.gov (United States)

    Moniwa, Norihito; Varagic, Jasmina; Ahmad, Sarfaraz; VonCannon, Jessica L; Simington, Stephen W; Wang, Hao; Groban, Leanne; Brosnihan, K Bridget; Nagata, Sayaka; Kato, Johji; Kitamura, Kazuo; Gomez, R Ariel; Lopez, Maria L Sequeira; Ferrario, Carlos M

    2013-02-01

    We examined the antihypertensive effects of valsartan, aliskiren, or both drugs combined on circulating, cardiac, and renal components of the renin-angiotensin system in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg per day; n=10), aliskiren (SC by osmotic mini-pumps, 50 mg/kg per day; n=10), or valsartan (30 mg/kg per day) combined with aliskiren (50 mg/kg per day; n=10). Arterial pressure and heart rate were measured by telemetry before and during 2 weeks of treatment; trunk blood, heart, urine, and kidneys were collected for measures of renin-angiotensin system components. Arterial pressure and left-ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren, and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma angiotensin (Ang) II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1-7) induced by aliskiren recovered in the combination group. Kidney Ang-(1-12) was increased by the combination therapy whereas the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate end points of blood pressure, ventricular mass, and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response attributable to loss of tubuloglomerular feedback by Ang II.

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

    OpenAIRE

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

    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 histop...

  5. Reproduction and the renin-angiotensin system.

    Science.gov (United States)

    Ganong, W F

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  6. Reproduction and the renin-angiotensin system

    Science.gov (United States)

    Ganong, W. F.

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  7. Reproduction and the renin-angiotensin system

    Science.gov (United States)

    Ganong, W. F.

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  8. Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin-angiotensin system

    NARCIS (Netherlands)

    Hoskova, Lenka; Malek, Ivan; Kautzner, Josef; Honsova, Eva; van Dokkum, Richard P. E.; Huskova, Zuzana; Vojtiskova, Alzbeta; Varcabova, Sarka; Cervenka, Ludek; Kopkan, Libor

    Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and

  9. Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin-angiotensin system

    NARCIS (Netherlands)

    Hoskova, Lenka; Malek, Ivan; Kautzner, Josef; Honsova, Eva; van Dokkum, Richard P. E.; Huskova, Zuzana; Vojtiskova, Alzbeta; Varcabova, Sarka; Cervenka, Ludek; Kopkan, Libor

    2014-01-01

    Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and ren

  10. 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…

  11. Blockade of the renin-angiotensin system

    OpenAIRE

    Cheung, BMY.

    2002-01-01

    The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors inhibit angiotensin-converting enzyme and have been shown to be effective in many cardiovascular diseases. They should be considered for the treatment of hypertension in patients with heart failure, previous myocardial infarction, diabetes, or proteinuria. There are a number of side-effects associated with angiotensin-converting enzyme inhibito...

  12. 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

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

    Directory of Open Access Journals (Sweden)

    Xia Zou

    2015-01-01

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

  14. Renin-angiotensin system in sepsis.

    Science.gov (United States)

    Hilgenfeldt, U; Kienapfel, G; Kellermann, W; Schott, R; Schmidt, M

    1987-01-01

    The time course of the components of the renin-angiotensin system was investigated in the plasma of three patients on the intensive care unit. Two of them, which were both polytraumatized, suffered from adult respiratory distress syndrome (ARDS). All patients had sepsis and impaired pulmonary and renal function. Plasma samples were investigated for up to two weeks, in which time all three patients showed a decrease in their angiotensin converting enzyme (ACE) plasma concentration. Two of the patients with deteriorating renal function had three to four times elevated angiotensinogen (Ao) plasma levels, which were measured by both the direct and indirect radioimmunoassay. The ratio of the mean values between both assays was 1:1 in two patients and shifted to higher values in the direct assay in the third patient. This suggests that higher amounts of des-AngI-angiotensinogen were present in the latter patient, because "inactive" Ao is also detected by the direct assay. The decrease in active Ao may be caused by an up to twenty times elevated plasma renin activity (PRA). The PRA was correlated with the angiotensin I (AngI) plasma levels. However, at PRA values higher than 200 pmol AngI/ml/h this correlation decreased because of the rapid substrate consumption. In addition there was a good correlation between AngI and AngII plasma levels in two patients which could not be observed in the patient with the highest PRA and AngII values. A relationship between plasma ACE concentration and AngII formation could not be observed. Thus in two of the three septic patients the components of the renin angiotensin system were extremely stimulated at very low blood pressure values. These data show, that it is reasonable to follow the time course of the components of the renin angiotensin system in single patients. In addition it is demonstrated that the direct measurement of Ao is a valid supplement in the diagnosis of the renin angiotensin system.

  15. Renin-angiotensin system blockade: Its contribution and controversy.

    Science.gov (United States)

    Miyajima, Akira; Kosaka, Takeo; Kikuchi, Eiji; Oya, Mototsugu

    2015-08-01

    Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin-angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin-angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time.

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

    DEFF Research Database (Denmark)

    The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...... 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...

  17. The Renin-Angiotensin System in the Endocrine Pancreas

    Directory of Open Access Journals (Sweden)

    Carlsson PO

    2001-01-01

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

  18. Molecular biology of the renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Dzau, V.J.; Burt, D.W.; Pratt, R.E. (Harvard Medical School, Boston, MA (USA))

    1988-10-01

    This paper reviews the molecular biology of the renin-angiotensin system. The renin gene structure is analyzed in detail, including an examination of the putative regulatory regions. The combined action of these regulatory sequences would result in the complex, tissue-specific expression and regulation observed in vivo. The expression of the tissue renin-angiotensin systems, which may have important physiological functions, is also described. In addition, the pathway of renin biosynthesis and secretion is reviewed. This includes speculation on the fate of circulating prorenin and the physiological role of multiple renin forms and secretory pathways. The molecular approaches described in this paper have greatly advanced our knowledge of the biology of the renin-angiotensin system. Future studies using these and other approaches should provide further insight into this complex system.

  19. The renin-angiotensin system and its blockers

    Directory of Open Access Journals (Sweden)

    Igić Rajko

    2014-01-01

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

  20. Activated tissue renin-angiotensin systems add to the progression of heart failure

    NARCIS (Netherlands)

    Pinto, YM; Buikema, H; vanGilst, WH; Lie, KI

    1996-01-01

    In this paper, we review the hypothesis that activated tissue renin-angiotensin systems play a detrimental role in heart failure. The main arguments for this idea are discussed: a) tissue renin-angiotensin systems behave functionally distinct from the circulating renin-angiotensin system; b) tissue

  1. Some Comparative Aspects of the Renin-Angiotensin System.

    Science.gov (United States)

    Malvin, Richard L.

    1984-01-01

    The renin-angiotensin system (RAS) maintains salt and water balance. Discusses functions of the RAS as defined in mammalian species, considering how the system arose and what its original function was. Also discusses where some of the changes occurred in the system (and why) as well as other topics. (JN)

  2. Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond

    NARCIS (Netherlands)

    K. Verdonk (Koen)

    2015-01-01

    markdownabstract__Abstract__ The renin-angiotensin-aldosterone system (RAAS) plays an essential role in the regulation of blood pressure and body fluid homeostasis, but also contributes importantly to the pathophysiology of hypertension, renal disease and heart failure. Clinically, the RAAS is of g

  3. The Renin-Angiotensin System and the Exocrine Pancreas

    Directory of Open Access Journals (Sweden)

    Chappell MC

    2001-01-01

    Full Text Available An accumulating body of evidence strongly indicates a local tissue renin-angiotensin system in the pancreas of a various species. In contrast to the majority of tissues that primarily express the angiotensin type 1 (AT1 receptor, the pancreas is one of the few tissues that contain a significant proportion of the AT2 subtype. Moreover, our findings indicate a greater distribution angiotensin II binding sites in the exocrine pancreas. Although the physiological aspects of a local pancreatic renin-angiotensin system remain largely unexplored, recent studies in our laboratory utilizing an acinar cell model demonstrate both functional AT1 and AT2 receptors. Indeed, we show that the AR42J cell line expresses all components of an angiotensin system including the mRNA for renin, angiotensinogen, angiotensin converting enzyme (ACE, AT1a, AT1b and AT2 receptors. Thus, these cells may be of particular value to study the interplay of the AT1 and AT2 receptors to regulate cell growth and potentially exocrine function.

  4. African Americans,hypertension and the renin angiotensin system

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  5. Cardiovascular Risk Reduction with Renin-Angiotensin Aldosterone System Blockade

    Directory of Open Access Journals (Sweden)

    Nancy Houston Miller

    2010-01-01

    Full Text Available This paper examines the evidence supporting treatments within the renin-angiotensin aldosterone system (RAS, the role cardioprotection plays within the management of hypertension, considerations around medication adherence, and the role of the nurse or nurse practitioner in guiding patients to achieve higher hypertension control rates. A large body of data now exists to support the use of angiotensin receptor blockers (ARBs and angiotensin-converting enzyme inhibitors (ACEIs which act on RAS, in the management of hypertension and their effect on cardiovascular risk reduction. Current evidence suggests that inhibition of the RAS is an important target for cardioprotection. RAS inhibition controls blood pressure and also reduces target-organ damage. This is especially important in populations at high-risk for damage including patients with diabetes and those with chronic kidney disease. Both ARBs and ACEIs target the RAS offering important reductions in both BP and target organ damage.

  6. Engagement of renin-angiotensin system in prostate cancer.

    Science.gov (United States)

    Uemura, Hiroji; Hoshino, Koji; Kubota, Yoshinobu

    2011-05-01

    Angiotensin II (Ang-II) plays a role not only as a vasoconstrictor in controlling blood pressure and electrolyte and fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1 (AT1) receptor in cardiovascular cells. Since a low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors has been reported, the molecular mechanisms of the renin-angiotensin system (RAS) in cancer cells have been elucidated. Interestingly, there is increasing evidence that the RAS is implicated in the development of prostate cancer. As previously reported, AT1 receptor blockers (ARBs), a class of antihypertensive agent, have the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor. This review highlights that the RAS plays a potential role in various aspects of prostate cancer, and ARBs could be useful for treatment of prostate cancer or its chemoprevention.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  8. 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.

  9. Macrophages in neuroinflammation: role of the renin-angiotensin-system.

    Science.gov (United States)

    Hammer, Anna; Stegbauer, Johannes; Linker, Ralf A

    2017-04-01

    Macrophages are essential players of the innate immune system which are involved in the initiation and progression of various inflammatory and autoimmune diseases including neuroinflammation. In the past few years, it has become increasingly clear that the regulation of macrophage responses by the local tissue milieu is also influenced by mediators which were first discovered as regulators in the nervous or also cardiovascular system. Here, the renin-angiotensin system (RAS) is a major focus of current research. Besides its classical role in blood pressure control, body fluid, and electrolyte homeostasis, the RAS may influence (auto)immune responses, modulate T cells, and particularly act on macrophages via different signaling pathways. Activation of classical RAS pathways including angiotensin (Ang) II and AngII type 1 (AT1R) receptors may drive pro-inflammatory macrophage responses in neuroinflammation via regulation of chemokines. More recently, alternative RAS pathways were described, such as binding of Ang-(1-7) to its receptor Mas. Signaling via Mas pathways may counteract some of the AngII/AT1R-mediated effects. In macrophages, the Ang-(1-7)/Mas exerts beneficial effects on neuroinflammation via modulating macrophage polarization, migration, and T cell activation in vitro and in vivo. These data delineate a pivotal role of the RAS in inflammation of the nervous system and identify RAS modulation as a potential new target for immunotherapy with a special focus on macrophages.

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

    Directory of Open Access Journals (Sweden)

    Suyeon Kim

    2006-01-01

    Full Text Available Background. The adipose tissue renin-angiotensin system (RAS contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO, mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO, and mice overexpressing Agt in adipose tissue (aP2-Agt was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  11. The renin-angiotensin system and the central nervous system.

    Science.gov (United States)

    Ganong, W F

    1977-04-01

    One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons

  12. Renin-angiotensin system in the pathogenesis of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Regina Maria Pereira; Robson Augusto Souza dos Santos; Filipi Leles da Costa Dias; Mauro Martins Teixeira; Ana Cristina Sim(o)es e Silva

    2009-01-01

    Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system (RAS) have progressively assumed an important role. Angiotensin (Ang) Ⅱ acts as a profibrotic mediator and Ang-(1-7), the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis,focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.

  13. Brain renin angiotensin system in cardiac hypertrophy and failure

    Directory of Open Access Journals (Sweden)

    Luciana eCampos

    2012-01-01

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

  14. Prorenin receptor regulates more than the renin-angiotensin system.

    Science.gov (United States)

    Müller, Dominik N; Binger, Katrina J; Riediger, Fabian

    2012-06-01

    The (pro)renin receptor (PRR) was initially believed to be a contributor to the pathogenesis of cardiovascular diseases via the amplification of renin- or prorenin-induced angiotensin (Ang) formation. However, a recent paradigm shift suggests a new role for PRR, separate from the renin-angiotensin system (RAS), in contributing to cellular homeostasis. Specifically, PRR is thought to be essential for vacuolar H(+) -ATPase (V-ATPase) activity and acts as an adaptor between the V-ATPase and the Wnt signalling pathway. Recent PRR conditional knock-out studies have confirmed this link between V-ATPase and PRR, with deletion resulting in the accumulation of autophagic vacuoles and animal lethality. The molecular mechanism by which PRR contributes to V-ATPase activity, and whether multiple signalling pathways are affected by PRR loss, is currently unknown. Additionally, cleavage by furin at a single site within full-length PRR results in the production of a soluble form of the receptor, which is detectable in plasma. Soluble PRR is hypothesized to bind to specific ligands and receptors and mediate signal transduction pathways. Understanding the physiological function of full-length and soluble PRR will be important for establishing its role in pathology.

  15. Lead, hypertension, and the renin-angiotensin system in rats

    Energy Technology Data Exchange (ETDEWEB)

    Victery, W.; Vander, A.J.; Shulak, J.M.; Schoeps, P.; Julius, S.

    1982-03-01

    Rats were exposed continuously to Pb in utero and after birth by giving their mothers, during pregnancy and lactation, drinking water containing 0, 100, or 500 ppm Pb (as Pb acetate) and then continuing this regimen after weaning. Male rats receiving 100 ppm developed a significant elevation of systolic blood pressure (152 +/- 3.7 mm Hg vs. 135 +/- 5.6 for controls) at 3 1/2 months and remained hypertensive until sacrifice at 6 months; 500 ppm rats remained normotensive. Both 100 ppm and 500 ppm females remained normotensive. At 6 months plasma renin activity (PRA) was significantly reduced in the 100 ppm male group but was normal in the 500 ppm group. There was dose-dependent decreases in the All/PRA ratio and in renal renin. Pulmonary converting enzyme activity was not changed by Pb exposure. Blood (Pb) was 40 and 71 ..mu..g/dl, respectively, and kidney (Pb) was 4.8 and 22.9 ..mu..g/gm. Renal histology was normal in the 100 ppm group. We conclude that doses of Pb which produce blood (Pb) seen in many people are capable of including modest hypertension in male rats; higher doses fail to do so. The hypertension is associated with a reduction in PRA and All and therefore is unlikely to be due to hyperactivity of the renin-angiotensin system (RAS).

  16. 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.

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Zh.P. Sharnova

    2006-01-01

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

  19. 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.

  20. Renin-angiotensin system gene polymorphisms and endometrial cancer.

    Science.gov (United States)

    Pringle, Kirsty G; Delforce, Sarah J; Wang, Yu; Ashton, Katie A; Proietto, Anthony; Otton, Geoffrey; Blackwell, C Caroline; Scott, Rodney J; Lumbers, Eugenie R

    2016-05-01

    Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin-angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2-2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39-0.74), P<0.001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.

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

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

  2. Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis.

    Science.gov (United States)

    Iodice, Carmela; Balletta, Mario M; Minutolo, Roberto; Giannattasio, Paolo; Tuccillo, Stefano; Bellizzi, Vincenzo; D'Amora, Maurizio; Rinaldi, Giorgio; Signoriello, Giuseppe; Conte, Giuseppe; De Nicola, Luca

    2003-06-01

    Elimination of residual proteinuria is the novel target in renoprotection; nevertheless, whether a greater suppression of renin-angiotensin system (RAS) effectively improves the antiproteinuric response in patients with moderate proteinuria remains ill-defined. We evaluated the effects of maximizing RAS suppression on quantitative and qualitative proteinuria in ten patients with stable nonnephrotic proteinuria (2.55 +/- 0.94 g/24 hours) due to primary nonproliferative glomerulonephritis (NPGN), and normal values of creatinine clearance (103 +/- 17 mL/min). The study was divided in three consecutive phases: (1) four subsequent 1-month periods of ramipril at the dose of 2.5, 5.0, 10, and 20 mg/day; (2) 2 months of ramipril 20 mg/day + irbesartan 300 mg/day; and (3) 2 months of irbesartan 300 mg/day alone. Maximizing RAS suppression was not coupled with any major effect on renal function and blood pressure; conversely, a significant decrement in hemoglobin levels, of 0.8 g/dL on average, was observed during up-titration of ramipril dose. The 2.5 mg dose of ramipril significantly decreased proteinuria by 29%. Similar changes were detected after irbesartan alone (-28%). The antiproteinuric effect was not improved either by the higher ramipril doses (-30% after the 20 mg dose) or after combined treatment (-33%). The reduction of proteinuria led to amelioration of the markers of tubular damage, as testified by the significant decrement of alpha 1 microglobulin (alpha 1m) excretion and of the tubular component of proteinuria at sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In nonnephrotic NPGN patients, standard doses of either ramipril or irbesartan lead to significant reduction of residual proteinuria and amelioration of the qualitative features suggestive of tubular damage. The enhancement of RAS suppression up to the maximal degree does not improve the antiproteinuric response and is coupled with a decrement of hemoglobin levels.

  3. Chronic effects of lead on the renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Vander, A.J.

    1988-06-01

    This paper reviews the chronic effects of lead exposure on the renin-angiotensin system in experimental animals and human beings. In rats, when lead exposure is begun several weeks after birth in doses that cause blood lead concentration (PbB) of 30 to 40 ..mu..g/L, the result is an increase in basal plasma renin activity (PRA) and renal renin concentration, with no change in the metabolic clearance of renin; this is presumptive evidence for increased renin secretion. PRA is also increased in 1-month-old animals whose exposure to lead (in doses that raise PbB to 9 ..mu..g/dL) was begun in utero. In contrast, older animals whose exposure was begun in utero manifest no change or a decrease in their PRA and renal renin concentration. Regardless of when the exposure is begun, lead can decrease the plasma concentration of angiotensin II at any given PRA, but the dose required for this effect is highly variable. The hypertension induced by lead exposure is associated with low PRA and a normal anigotensin II/PRA ratio. Chronic human exposure to lead also is associated with highly variable changes in PRA from study to study; it has been reported to be decreased under both basal and stimulated conditions, unchanged, or increased in a manner exponentially related to PbB. The human data are consistent with the tentative hypothesis that lead-exposed persons may have higher PRA than normal during the early periods of modest exposure but normal or depressed PRA following more chronic severe exposures. In a small preliminary study, blood lead concentration was found to be higher in high-renin hypertensive persons than in normotensive persons.

  4. 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.

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

    OpenAIRE

    2001-01-01

    The renin-angiotensin system has long been recognized as crucial factor in the regulation of the systemic blood pressure and renal electrolyte homeostasis. Numerous studies have demonstrated the presence of a local renin-angiotensin system in a variety of organs. A recent study of the pancreatic renin-angiotensin system showed that chronic hypoxia significantly increased the mRNA expression for angiotensinogen II receptor subtypes AT1b and AT2. The activation of the renin-angiotensin system m...

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

    Directory of Open Access Journals (Sweden)

    Lam KY

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Grant G

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Norikazu Ueki

    2015-01-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

  10. HYPERACTIVE TISSUE RENIN-ANGIOTENSIN SYSTEMS IN CARDIOVASCULAR DYSFUNCTION - EXPERIMENTAL-EVIDENCE AND CLINICAL HYPOTHESES

    NARCIS (Netherlands)

    PINTO, YM; BUIKEMA, H; VANGILST, WH

    1995-01-01

    In this review, hypotheses are discussed with regard to the role of local, tissue renin-angiotensin systems in the progression of cardiovascular dysfunction. After local renin-anglotensin systems had been described as functionally distinct systems, recent experimental studies have suggested an assoc

  11. 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...

  12. Improvement of Sodium Status to Optimize the Efficacy of Renin-Angiotensin System Blockade

    NARCIS (Netherlands)

    Laverman, Gozewijn D.; Navis, Gerjan

    2011-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) offers superior renoprotection in the treatment of patients with hypertension, but the efficacy of RAAS inhibition strongly depends on sodium status, presumably in relation to extracellular volume status. Because assessing volume status by

  13. Renal damage after myocardial infarction is prevented by renin-angiotensin-aldosterone-system intervention

    NARCIS (Netherlands)

    Windt, Willemijn A. K. M.; Eijkelkamp, Wouter B. A.; Henning, Robert H.; Kluppel, Alex C. A.; de Graeff, Pieter A.; Hillege, Hans L.; Schaefer, Stefan; de Zeeuw, Dick; van Dokkum, Richard P. E.

    2006-01-01

    Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosterone-system and/or vasoactive peptides that are metabolized by

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

    DEFF Research Database (Denmark)

    Gribouval, Olivier; Morinière, Vincent; Pawtowski, Audrey

    2012-01-01

    , pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review...

  15. Improvement of Sodium Status to Optimize the Efficacy of Renin-Angiotensin System Blockade

    NARCIS (Netherlands)

    Laverman, Gozewijn D.; Navis, Gerjan

    2011-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) offers superior renoprotection in the treatment of patients with hypertension, but the efficacy of RAAS inhibition strongly depends on sodium status, presumably in relation to extracellular volume status. Because assessing volume status by

  16. Mammary renin-angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer.

    Science.gov (United States)

    del Pilar Carrera, Maria; Ramírez-Expósito, Maria Jesus; Mayas, Maria Dolores; García, Maria Jesus; Martínez-Martos, Jose Manuel

    2010-12-01

    Angiotensin II in particular and/or the local renin-angiotensin system in general could have an important role in epithelial tissue growth and modelling; therefore, it is possible that it may be involved in breast cancer. In this sense, previous works of our group showed a predominating role of angiotensin II in tumoral tissue obtained from women with breast cancer. However, although classically angiotensin II has been considered the main effector peptide of the renin-angiotensin system cascade, several of its catabolism products such as angiotensin III and angiotensin IV also possess biological functions. These peptides are formed through the activity of several proteolytic regulatory enzymes of the aminopeptidase type, also called angiotensinases. The aim of this work was to analyse several specific angiotensinase activities involved in the renin-angiotensin system cascade in mammary tissue from control rats and from rats with mammary tumours induced by N-methyl-nitrosourea (NMU), which may reflect the functional status of their target peptides under the specific conditions brought about by the tumoural process. The results show that soluble and membrane-bound specific aspartyl aminopeptidase activities and membrane-bound glutamyl aminopeptidase activity increased in mammary tissue from NMU-treated animals and soluble aminopeptidase N and aminopeptidase B activities significantly decreased in mammary tissue from NMU-treated rats. These changes support the existence of a local mammary renin-angiotensin system and that this system and its putative functions in breast tissue could be altered by the tumour process, in which we suggest a predominant role of angiotensin III. All described data about the renin-angiotensin system in mammary tissue support the idea that it must be involved in normal breast tissue functions, and its disruption could be involved in one or more steps of the carcinogenesis process.

  17. Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

    NARCIS (Netherlands)

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerarda; de Borst, Martin H

    2015-01-01

    Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  18. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    NARCIS (Netherlands)

    Humalda, J.K.; Lambers Heerspink, H.J.; Kwakernaak, A.J.; Slagman, M.C.; Waanders, F.; Vervloet, M.G.; Wee, P.M. Ter; Navis, G.; Borst, M.H. de; Wee, P.M. ter; Vervloet, M.; Bindels, R.J.; Hoenderop, J.G.J.; Hillebrands, J.L.

    2015-01-01

    BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  19. Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

    NARCIS (Netherlands)

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerarda; de Borst, Martin H

    2015-01-01

    Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  20. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    NARCIS (Netherlands)

    Humalda, J.K.; Lambers Heerspink, H.J.; Kwakernaak, A.J.; Slagman, M.C.; Waanders, F.; Vervloet, M.G.; Wee, P.M. Ter; Navis, G.; Borst, M.H. de; Wee, P.M. ter; Vervloet, M.; Bindels, R.J.; Hoenderop, J.G.J.; Hillebrands, J.L.

    2015-01-01

    BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  1. Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

    NARCIS (Netherlands)

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerarda; de Borst, Martin H

    Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many

  2. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    NARCIS (Netherlands)

    Humalda, J.K.; Lambers Heerspink, H.J.; Kwakernaak, A.J.; Slagman, M.C.; Waanders, F.; Vervloet, M.G.; Wee, P.M. Ter; Navis, G.; Borst, M.H. de; Wee, P.M. ter; Vervloet, M.; Bindels, R.J.; Hoenderop, J.G.J.; Hillebrands, J.L.

    2015-01-01

    BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many

  3. 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

  4. Inhibition of the renin-angiotensin system for prevention of atrial fibrillation.

    Science.gov (United States)

    Zografos, Theodoros; Katritsis, Demosthenes G

    2010-10-01

    Atrial fibrillation (AF) is a source of considerable morbidity and mortality. There has been compelling evidence supporting the role of renin-angiotensin system (RAS) in the genesis and perpetuation of AF through atrial remodeling, and experimental studies have validated the utilization of RAS inhibition for AF prevention. This article reviews clinical trials on the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for the prevention of AF. Results have been variable, depending on the clinical background of treated patients. ACEIs and ARBs appear beneficial for primary prevention of AF in patients with heart failure, whereas they are not equally effective in hypertensive patients with normal left ventricular function. Furthermore, the use of ACEIs or ARBs for secondary prevention of AF has been found beneficial only after electrical cardioversion. Additional data are needed to establish the potential clinical role of renin-angiotensin inhibition for prevention of AF.

  5. 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.

  6. Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

    OpenAIRE

    Okada, Hirokazu; Inoue, Tsutomu; Kanno, Yoshihiko; Kobayashi, Tatsuya; Watanabe, Yusuke; Kopp, Jeffrey B; Carey, Robert M.; SUZUKI, HIROMICHI

    2002-01-01

    Recently, the renin-angiotensin system (RAS) was implicated in organ fibrosis. However, few studies have examined the localization of RAS components, such as angiotensin II receptors, renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney. To localize these components in the fibrosing kidney, we used a murine model of renal fibrosis that shows an enhanced expression of angiotensin II type 1A receptor (AT1AR) and AGTN. Our results indicate that th...

  7. Local Renin-Angiotensin System in the Pancreas: The Significance in Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Lai PBS

    2001-01-01

    Full Text Available Acute pancreatitis is a complex disease entity of which the pathogenesis is still not completely known. Research into the initiation and propagation of the diseases would hopefully help to design new treatment strategies for patients, especially those with severe acute pancreatitis. The novel observation of the activation of the local pancreatic renin-angiotensin system in experimental pancreatitis opens up new horizons for research regarding the pathogenesis of acute pancreatitis.

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

    DEFF Research Database (Denmark)

    Skov, Jeppe; Persson, Frederik; Frøkiær, Jørgen

    2014-01-01

    The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to p...... disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control....

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

    OpenAIRE

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Slavnov, V.N.; Yakovlev, A.A.; Gandzha, T.I.; Yugrinov, O.G. (AN Ukrainskoj SSR, Kiev)

    1985-01-01

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

  11. Combined use of renin-angiotensin-aldosterone system-acting agents: a cross-sectional study.

    Science.gov (United States)

    Farcas, Andreea; Leucuta, Daniel; Bucsa, Camelia; Mogosan, Cristina; Dumitrascu, Dan

    2016-12-01

    Background Due to recent EU warnings and restrictions on the combined use of renin-angiotensin-aldosterone system (RAAS)-acting agents, and the seriousness of the associated harm, we analyzed the prescription of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) as dual therapy or associated with spironolactone. Setting An administrative claims database of a regional hospital in Romania. Methods We retrospectively included all adult patients hospitalized during 18 months in 2013-2014, discharged with a prescription of a RAAS-acting agent. Main outcome measures Counts of ACEIs and ARBs co-prescription, of ACEIs or ARBs combined with spironolactone, co-morbidities, co-medication, creatinine, and electrolytes assessment and values. Results Out of 1697 patients with a prescription of a RAAS-acting agent, 24 (1.4 %) were co-prescribed ACEIs and ARBs, and 416 (24.5 %) ACEIs or ARBs with spironolactone. Patients prescribed dual ACEI/ARB therapy and the ones with ACEI or ARB-spironolactone combination had significantly higher prevalence of increased creatinine level before discharge, compared to the ACEI and ARB monotherapy groups (48 and 31 % compared to 17 and 27 %). Subjects with diabetes, heart failure, ischaemic heart disease, or urea ≥40 mg/dL had higher odds of having ACEI or ARB-spironolactone combination compared to monotherapy, while hypertension and renal disease subjects had lower odds. Similar findings were comparing dual ACEI/ARB therapy to monotherapy except heart failure (not statistically significant). Conclusion Overall, the prevalence of use of dual therapy was low. The combined use of RAAS-acting agents was higher in patients with known risk factors for further renal function deterioration, compared to the ones without.

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

    Directory of Open Access Journals (Sweden)

    S A Savelyeva

    2012-09-01

    Full Text Available The purpose of the study was to evaluate the clinical efficacy and safety of dual RAAS blockage during treatment with angiotensin-converting enzyme (ACE inhibitors in combination with a direct renin inhibitor (PIR aliskiren versus combination therapy with ACE inhibitors and angiotensin receptor blocker II (ARB valsartan in patients with type 2 diabetes mellitus (T2DM, arterial hypertension (AH and obesity, without renal dysfunction. Materials and methods. The study included 26 patients with T2DM (10 men and 16 women, mean age 59,0±6,2 years with inadequate control of blood pressure (over 130 and/or 80 mm Hg on prior antihypertensive therapy and without renal dysfunctions (glomerular filtration rate (GFR> 60 ml/min/1, 73 m2 and the of albumin/creatinine (A/C ratio in the morning urine sample <10 mg/mol. After screening with the continuation of the initial therapy, including ACE inhibitors, 14 patients were added aliskiren 150–300 mg/day, 12 patients – valsartan 80–160 mg/day. Evaluation of the treatment effectiveness in terms of blood pressure (mean of three consecutive measurements in the sitting position and the parameters of renal function (serum creatinine and potassium, GFR, A/C ratio in the urine was performed at 4, 12 and 24 weeks of therapy. Results. In the group of patients treated with aliskiren, after 4 weeks of treatment a significant decrease in systolic and diastolic blood pressure (SBP and DBP, respectively was noted as compared to baseline: 146,1 and 138,9 mm Hg, p<0,05, 87,1 and 81,1 mm Hg, p <0,05, respectively; with systolic BP after 24 weeks of treatment decreased to 127,8 (-18,2 mm Hg, p<0,05, diastolic BP to 75,0 (-12, 1 mm Hg, p<0,05, the target blood pressure (≤130/80 mm Hg was achieved in 83% of patients. The group of patients treated with valsartan, after 4 weeks of therapy showed a significant reduction in systolic BP 148 and 141,6 mm Hg, p <0,05, diastolic BP - to 85,8 and 81,7 mm Hg, p=0,059; after 24 weeks

  13. Angiotensin-(1-7): an active member of the renin-angiotensin system.

    Science.gov (United States)

    Kucharewicz, I; Pawlak, R; Matys, T; Chabielska, E; Buczko, W

    2002-12-01

    Angiotensin-(1-7) [Ang-(1-7)] is an active member of renin-angiotensin system (RAS). It counterbalances vasoconstriction, mitogenic, arrhythmogenic and prothrombotic actions of Ang II. Inducing natiuresis and diuresis opposes also the water and sodium retention produced by Ang II. Till now the specific receptor side for Ang-(1-7) has been not cloned, but the current data strongly suggest that an interaction (cross-talk) between angiotensin receptors may play a role in the effects of Ang-(1-7).

  14. Genetic variation in the Renin-Angiotensin system and progression of diabetic nephropathy

    DEFF Research Database (Denmark)

    Jacobsen, Peter; Tarnow, Lise; Carstensen, Bendix

    2003-01-01

    patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR ((51...... independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies....

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

    Directory of Open Access Journals (Sweden)

    Fabrizio Montecucco

    2009-01-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF...

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

    Science.gov (United States)

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

    2016-09-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    AIMS: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin-angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). METHODS: Severe hypoglycaemic events the year preceding pregnancy were recorded...... preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7-11.9), p=0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. CONCLUSIONS: In early...

  19. Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system.

    Science.gov (United States)

    Ferrario, C M; Iyer, S N

    1998-11-30

    Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.

  20. From Rat to Human: Regulation of Renin-Angiotensin System Genes by Sry

    Directory of Open Access Journals (Sweden)

    Jeremy W. Prokop

    2012-01-01

    Full Text Available The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1–7.

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

    Directory of Open Access Journals (Sweden)

    Umar Malik

    2015-11-01

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

  2. Clinical perspectives and fundamental aspects of local cardiovascular and renal renin-angiotensin systems

    Directory of Open Access Journals (Sweden)

    Walmor eDe Mello

    2014-02-01

    Full Text Available Evidence for the potential role of organ specific cardiovascular renin-angiotensin systems (RAS has been demonstrated experimentally and clinically with respect to certain cardiovascular and renal diseases. These findings have been supported by studies involving pharmacological inhibition during ischemic heart disease, myocardial infarction, cardiac failure; hypertension associated with left ventricular (LV ischemia, myocardial fibrosis and left ventricular hypertrophy (LVH; structural and functional changes of the target organs associated with prolonged dietary salt excess; and intrarenal vascular disease associated with end-stage renal disease (ESRD. Moreover, the severe structural and functional changes induced by these pathological conditions, can be prevented and reversed by agents producing RAS inhibition (even when not necessarily coincident with alterations in arterial pressure.In this review, we discuss specific fundamental and clinical aspects and mechanisms related to the activation or inhibition of local renin angiotensin systems and their implications for cardiovascular and renal diseases. Fundamental aspects involving the role of angiotensins on cardiac and renal functions including the expression of RAS components in the heart and kidney and the controversial role of ACE2 on angiotensin peptide metabolism in humans, were discussed.

  3. Polymorphisms in the Renin-Angiotensin System and Migraine in Women

    Science.gov (United States)

    Schürks, Markus; Zee, Robert Y. L.; Buring, Julie E.; Kurth, Tobias

    2008-01-01

    Background Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial. Objective To investigate the association between the AGTR1 1166A>C and AGT Met235Thr polymorphisms with migraine and migraine aura status. Methods We performed an association study among 25,000 Caucasian U.S. women, participating in the Women's Health Study, with information on the AGTR1 1166A>C and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association. Results At baseline, 4,577 (18.3%) women reported any history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine specific subgroups. We also did not find a significant interaction between the polymorphisms. Conclusions Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions. PMID:19178574

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

    DEFF Research Database (Denmark)

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

    2006-01-01

    OBJECTIVE: Several studies have shown activation of the renin-angiotensin-aldosterone system (RAAS) in cirrhosis. Although the activated RAAS may have several determinants, the system is often considered a surrogate marker of effective hypovolaemia. In this study we investigated the activity...

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

    NARCIS (Netherlands)

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

    2008-01-01

    textabstractAims: 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

  6. Renin-angiotensin system mediators and Raynaud's phenomenon.

    Science.gov (United States)

    Wood, Heidi M; Ernst, Michael E

    2006-11-01

    To review the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in the treatment of Raynaud's phenomenon (RP). Biomedical literature was accessed through July 2006 via PubMed, the Iowa Drug Information System (IDIS), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus. PubMed database terms included Raynaud's disease, angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor blockers [pharmacological action]; IDIS terms included hypotensive agents-ace inhib 24080200, raynaud's syndrome 443.0, and hypotensive agents-angioten II 24080400; and CINAHL Plus terms included Raynaud's disease, angiotensin-converting enzyme inhibitors, losartan, and irbesartan. All clinical trials published in English that reported both subjective and objective outcomes of efficacy were reviewed. Several small, short-term studies have evaluated captopril, enalapril, and losartan in the treatment of RP. The studies of ACE inhibitors have found conflicting results in their ability to improve digit blood flow and reduce both frequency and severity of RP attacks. Two studies have focused on the use of losartan for RP treatment, with both finding a statistically significant reduction in attacks and one showing improvement in symptoms of RP in comparison with the commonly utilized calcium-channel blocker, nifedipine. Most of the studies were short term (treatments such as calcium-channel blockers. Larger, randomized controlled trials of longer duration are needed to compare the effectiveness of ACE inhibitors and ARBs with conventional treatment.

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  8. Association between regional cerebral blood flow during hypoglycemia and genetic and phenotypic traits of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Bie-Olsen, Lise Grimmeshave; Pedersen-Bjergaard, Ulrik; Kjaer, Troels Wesenberg;

    2009-01-01

    The risk of severe hypoglycemia in patients with type I diabetes and high basal activity in the renin-angiotensin system (RAS) is significantly higher than in patients with low basal RAS activity. In healthy men, we tested the hypothesis that differences in spontaneous RAS activity are associated...

  9. Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology

    NARCIS (Netherlands)

    M.J.E. van Rijn (Marie Josee); M.J. Bos (Michiel); A.J. Isaacs (Aaron); M. Yazdanpanah (Mojgan); A. Arias-Vásquez (Alejandro); B.H.Ch. Stricker (Bruno); B.A. Oostra (Ben); O.H. Klungel (Olaf); P.J. Koudstaal (Peter Jan); J.C.M. Witteman (Jacqueline); A. Hofman (Albert); M.M.B. Breteler (Monique); C.M. van Duijn (Cock)

    2007-01-01

    textabstractBACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  11. Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Benjamin Goldstein

    2017-01-01

    Full Text Available Objectives. The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. Materials and Methods. NCBI’s built-in statistical tool, GEO2R, was used to calculate Student’s t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak’s multiple comparison correction. Results. Ten genes were found to be significantly associated with adenocarcinoma. Seven of these associations remained statistically significant after correction for multiple comparisons. Notably, AGTR2, which encodes the AT2 angiotensin II receptor subtype, was significantly underexpressed in adenocarcinoma tissue (p<0.01. AGTR1, ACE, ENPEP, MME, and PRCP, which encode the AT1 angiotensin II receptor, angiotensin-converting enzyme, aminopeptidase N, neprilysin, and prolylcarboxypeptidase, respectively, were also underexpressed. AGT, which encodes angiotensinogen, the angiotensin peptide precursor, was overexpressed in adenocarcinoma tissue. Conclusion. The results suggest an association between the expression of the genes for renin-angiotensin system-related proteins and adenocarcinoma. While further research is necessary to conclusively demonstrate a link between the renin-angiotensin system and lung cancers, the results suggest that the renin-angiotensin system plays a role in the pathology of adenocarcinoma.

  12. The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations.

    Science.gov (United States)

    Vargas, Félix; Rodríguez-Gómez, Isabel; Vargas-Tendero, Pablo; Jimenez, Eugenio; Montiel, Mercedes

    2012-04-01

    Thyroid disorders are among the most common endocrine diseases and affect virtually all physiological systems, with an especially marked impact on cardiovascular and renal systems. This review summarizes the effects of thyroid hormones on the renin-angiotensin system (RAS) and the participation of the RAS in the cardiovascular and renal manifestations of thyroid disorders. Thyroid hormones are important regulators of cardiac and renal mass, vascular function, renal sodium handling, and consequently blood pressure (BP). The RAS acts globally to control cardiovascular and renal functions, while RAS components act systemically and locally in individual organs. Various authors have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels. This review analyzes the influence of thyroid hormones on RAS components and discusses the role of the RAS in BP, cardiac mass, vascular function, and renal abnormalities in thyroid disorders.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    . The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7......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...... be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very...

  14. Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?

    Science.gov (United States)

    Emdin, Michele; Fatini, Cinzia; Mirizzi, Gianluca; Poletti, Roberta; Borrelli, Chiara; Prontera, Concetta; Latini, Roberto; Passino, Claudio; Clerico, Aldo; Vergaro, Giuseppe

    2015-03-30

    Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of

  15. 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

  16. Diet-induced hypercholesterolemia impaired testicular steroidogenesis in mice through the renin-angiotensin system.

    Science.gov (United States)

    Martínez-Martos, José M; Arrazola, Marce; Mayas, María D; Carrera-González, María P; García, María J; Ramírez-Expósito, María J

    2011-08-01

    Hypercholesterolemia and low testosterone concentrations in men are associated with a high risk factor for atherosclerosis. It is known that cholesterol serves as the major precursor for the synthesis of the sex hormones. The bioactive peptides of the renin-angiotensin-system localized in the gonads play a key role in the relation between cholesterol and testosterone by modulating steroidogenesis and inhibiting testosterone production. In the present work, we evaluated the effects of diet-induced hypercholesterolemia on circulating testosterone levels and its relationship with the testicular RAS-regulating specific aminopeptidase activities in male mouse. A significant decrease in serum circulating levels of testosterone was observed after induced hypercholesterolemia. The changes found in aminopeptidase activities suggest a role of Ang III and Ang IV in the regulation of steroidogenesis.

  17. Regulation of the Renin-Angiotensin System Pathways in the Human Decidua.

    Science.gov (United States)

    Wang, Yu; Lumbers, Eugenie R; Sykes, Shane D; Pringle, Kirsty G

    2015-07-01

    Pregnancy outcome is influenced, in part, by the sex of the fetus. Decidual renin messenger RNA (REN) abundance is greater in women carrying a female fetus than a male fetus. Here, we explore whether the sex of the fetus also influences the regulation of decidual RAS expression with a known stimulator of renal renin and cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate had no affect on decidual REN expression, since REN abundance was still greater in decidual explants from women carrying a female fetus than a male fetus after cAMP treatment. Cyclic adenosine monophosphate decreased prorenin levels in the supernatant if the fetus was female (ie, prorenin levels were no longer sexually dimorphic) and altered the fetal sex-specific differences in other RAS genes seen in vitro. Therefore, fetal sex influences the decidual renin-angiotensin system response to cAMP. This may be related to the presence of fetal cells in the maternal decidua.

  18. Effects of lead on the renin-angiotensin system. [Rabbits; rats

    Energy Technology Data Exchange (ETDEWEB)

    Keiser, J.A.

    1982-01-01

    The renin-angiotensin system was evaluated in both acute and chronic lead-exposed rabbits and in unanaesthetized chronic lead-exposed rats. In addition, the acute effects of lead on in vitro secretion of renin were evaluated using rabbit and renal cortical slices. The clearance of renin was measured in chronic lead-exposed rats. Basal PRAs were significantly elevated in lead-exposed rats; renal renin activities were also significantly higher. In contrast, renin clearances were not different in the two groups. These findings support the hypothesis that the increase in basal PRA seen in lead-exposed rats is due to increased renin secretion not decreased hepatic removal of renin. In conclusion, we found no evidence for decreased renin degradation in the chronic lead-exposed rabbit or rat; rather, changes in renin secretion appear to account for observed increases in PRA. In contrast, acute lead-exposure inhibits both renin secretion and degradation in the rabbit.

  19. Involvement of the pancreatic renin-angiotensin system in insulin resistance and the metabolic syndrome.

    Science.gov (United States)

    Leung, Po Sing; de Gasparo, Marc

    2006-01-01

    The cardiometabolic syndrome consists of several major components: hypertension, hyperinsulinemia, hyperlipidemia, and hyperglycemia. Central to this syndrome are insulin resistance and generation of reactive oxygen species; these features are particularly prominent in patients with type 2 diabetes mellitus. In this context, large clinical trials have shown that blockade of the renin-angiotensin system (RAS) is protective against type 2 diabetes. In spite of these solid clinical data, the mechanistic pathways by which RAS blockade achieves these protective effects have yet to be resolved. A recently identified local pancreatic islet RAS has, however, been implicated in this regard. Furthermore, RAS blockade was recently shown to enhance islet blood flow, oxygen tension, and insulin biosynthesis, thus improving beta-cell function and glucose tolerance. Meanwhile, RAS activation may also influence islet cell inflammatory responses, apoptosis, fibrosis, and superoxide anion production. This RAS-associated oxidative stress can induce islet cell dysfunction in the pancreas and insulin resistance in peripheral tissues.

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

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2012-01-01

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

  1. Role of Nonclassical Renin-angiotensin system Axis In Renal Fibrosis

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    Linli eLv

    2015-04-01

    Full Text Available The renin–angiotensin system (RAS is a major regulator of renal fibrosis. Besides the classical renin/Angiotensin-converting enzyme 2 (ACE2/angiotensin II (Ang II/AT1 and AT2 axis, multiple new axes have been recently described. The new members have added new dimensions to RAS, including the ACE2/ANG (1–7/Mas receptor axis, the prorenin/(prorenin receptor(PRR/intracelluar pathway axis, and the Angiotensin A (Ang A, alamandine-Mas-related G protein coupled receptor D(MrgD axis. This review summarized recent studies regarding role of the non-classical RAS axis in renal fibrosis, and its possible implications to the intervention of progression of chronic kidney disease.

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

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    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.

  3. 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...... been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although...... to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has...

  4. Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis

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    Maki Urushihara

    2012-01-01

    Full Text Available The intrarenal renin-angiotensin system (RAS has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN. Angiotensin II (Ang II is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1 receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.

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

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    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.

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

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    Indu Dhar

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

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

    Science.gov (United States)

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

    2013-01-01

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

  8. Effect of renin-angiotensin-aldosterone system gene polymorphisms on blood pressure response to antihypertensive treatment

    Institute of Scientific and Technical Information of China (English)

    JIANG Xiao; SHENG Hai-hui; LIN Gang; LI Jian; LU Xin-zheng; CHENG Yun-lin; HUANG Jun; XIAO Hua-sheng; ZHAN Yi-yang

    2007-01-01

    Background The renin-angiotensin-aldosterone system (RAAS) is important for the development of essential hypertension, and many antihypertensive drugs target it. This study was undertaken to determine whether polymorphisms in the renin-angiotensin-aldosterone system are related to the blood pressure (BP) response to diuretic treatment in a Chinese Han ethnic population.Methods Fifty-four patients with essential hypertension received hydrochlorothiazide (12.5 mg, once daily) as monotherapy for four weeks. Seven polymorphisms in RAAS genes were genotyped by gene chip technology. The relationship between these polymorphisms and the change in blood pressure was observed after the 4-week treatment.Results The patients with angiotensinogen (AGT) -6G allele showed a greater reduction in diastolic BP (P= 0.025) and mean BP (P=0.039) than those carrying AA genotype. Patients carrying aldosterone synthase (CYP11B2) CC genotype exhibited a greater BP reduction than those carrying CT and TT genotypes (systolic BP: P= 0.030; diastolic BP: P= 0.026; mean BP: P=0.003). In addition, patients with a combination of CYP11B2 CC genotype and angiotensin converting enzyme (ACE) D allele might have a more pronounced reduction of systolic BP than those with any other genotypic combinations of the two genes (P= 0.007).Conclusions AGT-6G allele, CYP11B2 -344CC genotype and its combination with ACE D allele are associated with BP response to hydrochlorothiazide treatment. Larger studies are warranted to validate this finding.

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

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    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

  10. Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension

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    S.R.S. Freitas

    2007-03-01

    Full Text Available Essential hypertension is a disease multifactorially triggered by genetic and environmental factors. The contribution of genetic polymorphisms of the renin-angiotensin-aldosterone system and clinical risk factors to the development of resistant hypertension was evaluated in 90 hypertensive patients and in 115 normotensive controls living in Southwestern Brazil. Genotyping for insertion/deletion of angiotensin-converting enzyme, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, aldosterone synthase C344T, and mineralocorticoid receptor A4582C polymorphisms was performed by PCR, with further restriction analysis when required. The influence of genetic polymorphisms on blood pressure variation was assessed by analysis of the odds ratio, while clinical risk factors were evaluated by logistic regression. Our analysis indicated that individuals who carry alleles 235-T, 1166-A, 344-T, or 4582-C had a significant risk of developing resistant hypertension (P < 0.05. Surprisingly, when we tested individuals who carried the presumed risk genotypes A1166C, C344T, and A4582C we found that these genotypes were not associated with resistant hypertension. However, a gradual increase in the risk to develop resistant hypertension was detected when the 235-MT and TT genotypes were combined with one, two or three of the supposedly more vulnerable genotypes - A1166C (AC/AA, C344T (TC/TT and A4582C (AC/CC. Analysis of clinical parameters indicated that age, body mass index and gender contribute to blood pressure increase (P < 0.05. These results suggest that unfavorable genetic renin-angiotensin-aldosterone system patterns and clinical risk variables may contribute to increasing the risk for the development of resistant hypertension in a sample of the Brazilian population.

  11. Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

    Science.gov (United States)

    Nogueira-Silva, Cristina; Carvalho-Dias, Emanuel; Piairo, Paulina; Nunes, Susana; Baptista, Maria J; Moura, Rute S; Correia-Pinto, Jorge

    2012-01-01

    Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT1) and type 2 (AT2) receptors of angiotensin II (ANGII) was assessed by immunohisto-chemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT2-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT2 receptor is presented as a putative antenatal therapy for CDH. PMID:22113494

  12. Local fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia.

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    Nogueira-Silva, Cristina; Carvalho-Dias, Emanuel; Piairo, Paulina; Nunes, Susana; Baptista, Maria J; Moura, Rute S; Correia-Pinto, Jorge

    2012-03-27

    Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT₁) and type 2 (AT₂) receptors of angiotensin II (ANGII) was assessed by immunohisto-chemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT₁ receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT₂-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT₂ receptor is presented as a putative antenatal therapy for CDH.

  13. Blood, pituitary, and brain renin-angiotensin systems and regulation of secretion of anterior pituitary gland.

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    Ganong, W F

    1993-07-01

    In addition to increasing blood pressure, stimulating aldosterone and vasopressin secretion, and increasing water intake, angiotensin II affects the secretion of anterior pituitary hormones. Some of these effects are direct. There are angiotensin II receptors on lactotropes and corticotropes in rats, and there may be receptors on thyrotropes and other secretory cells. Circulating angiotensin II reaches these receptors, but angiotensin II is almost certainly generated locally by the pituitary renin-angiotensin system as well. There are also indirect effects produced by the effects of brain angiotensin II on the secretion of hypophyseotropic hormones. In the anterior pituitary of the rat, the gonadotropes contain renin, angiotensin II, and some angiotensin-converting enzyme. There is debate about whether these cells also contain small amounts of angiotensinogen, but most of the angiotensinogen is produced by a separate population of cells and appears to pass in a paracrine fashion to the gonadotropes. An analogous situation exists in the brain. Neurons contain angiotensin II and probably renin, but most angiotensin-converting enzyme is located elsewhere and angiotensinogen is primarily if not solely produced by astrocytes. Angiotensin II causes secretion of prolactin and adrenocorticotropic hormone (ACTH) when added to pituitary cells in vitro. Paracrine regulation of prolactin secretion by angiotensin II from the gonadotropes may occur in vitro under certain circumstances, but the effects of peripheral angiotensin II on ACTH secretion appear to be mediated via the brain and corticotropin-releasing hormone (CRH). In the brain, there is good evidence that locally generated angiotensin II causes release of norepinephrine that in turn stimulates gonadotropin-releasing hormone-secreting neurons, increasing circulating luteinizing hormone. In addition, there is evidence that angiotensin II acts in the arcuate nuclei to increase the secretion of dopamine into the portal

  14. Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension.

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

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-α synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-α, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines.

  15. Vasculoprotective effects of rosiglitazone through modulating renin-angiotensin system in vivo and vitro

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    Li Yanzhi

    2011-01-01

    Full Text Available Abstract Background The peroxisome proliferator-activated receptor-γ (PPARγ agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti-proliferation etc. However, whether renin-angiotensin system (RAS is involved in the vascular protective effects of PPARγ agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARγ agonists. Objective To investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARγ in vivo and in vitro. Methods Rats were fed a regular diet (n = 8, a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10, a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10. The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs were pretreated with 1 μmol/L angiotensin II (ANG II for 6 h and randomly divided into the control group; the ANG II group (1 μmol/L ANG II; the groups respectively treated with different concentration rosiglitazone (20, 30, 50 μmol/L for 12 h; the groups treated with 30 μmol/L rosiglitazone for (6, 12, 24 h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR, western blot, and immunohistochemistry. Results After 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes

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

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    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

  17. The Renin-Angiotensin System: From the Renal Basis to an Organ-Specific Subsystem in the Pancreas

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    Nobiling R

    2001-01-01

    Full Text Available Not only is the renin angiotensin system or its components found morphologically in many organs, it also exerts many different regulatory functions such as contributing to systemic homeostasis as well as to organ-specific regulation. The presence of the components of the renin angiotensin system in the pancreas was discovered only a few years ago. Physiological and pathophysiological stimuli were able to modify, in part, the gene expression and the occurrence of some of these components. Because of the important clinical significance of pancreatic diseases such as pancreatitis, research should follow every traces of the renin angiotensin system in the pancreas: impairment of microcirculation via hypoxia mediated up-regulation with the subsequent further deterioration of the oxygen supply seems to be the most obvious mechanism. There are many possible approaches to a better understanding of problems that are associated with diseases such as different kinds of pancreatitis; basic studies in animal models are oriented toward microcirculation, cellular function and the time course of modified gene expression after stimuli such as hypoxia; a clinical approach must reevaluate different correlations between clinical parameters of hypertension and those of pancreatic diseases.

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

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    Karl Andersen

    2009-03-01

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

  19. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

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    Chappell, Mark C

    2016-01-15

    The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure through peripheral and central mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacological blockade of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) offers an effective therapeutic regimen. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-ANG II-AT1R axis that promotes vasoconstriction; water intake; sodium retention; and increased oxidative stress, fibrosis, cellular growth, and inflammation. In contrast, the nonclassical RAS composed primarily of the ANG II/ANG III-AT2R and the ACE2-ANG-(1-7)-AT7R pathways generally opposes the actions of a stimulated ANG II-AT1R axis. In lieu of the complex and multifunctional aspects of this system, as well as increased concerns on the reproducibility among laboratories, a critical assessment is provided on the current biochemical approaches to characterize and define the various components that ultimately reflect the status of the RAS.

  20. The crosstalk between thyroid hormones and the Renin-Angiotensin System.

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    Barreto-Chaves, Maria Luiza M; Carrillo-Sepúlveda, Maria Alícia; Carneiro-Ramos, Marcela S; Gomes, Dayane A; Diniz, Gabriela P

    2010-01-01

    Thyroid hormones (THs) exert multiple effects on the heart and vascular system. As a consequence, altered cardiovascular function observed in the thyroid diseases corresponds to one of the most important and clinically relevant aspects found in both hyperthyroidism and hypothyroidism. Besides THs' direct effects on the heart and vascular system, in the last three decades several studies have implicated the Renin-Angiotensin System (RAS) in some of the cardiovascular effects of THs, with this interaction suggesting that RAS may be an important mediator of THs actions. In the present review, we discuss the alterations in the circulating RAS, as well as modifications in cardiac and vascular RAS which are involved in the cardiovascular alterations found during the modulation of TH levels. In addition, considering the important role that both systems present during fetal and neonatal periods, we also review the interaction between THs and the RAS in the development of cardiovascular system. A greater understanding of the role of the RAS in hyperthyroidism and hypothyroidism, during early or adult life will presumably facilitate the evolution of newer, targeted therapies. Copyright 2009 Elsevier Inc. All rights reserved.

  1. The renin-angiotensin system and hypertension in autosomal recessive polycystic kidney disease.

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    Goto, Miwa; Hoxha, Nita; Osman, Rania; Dell, Katherine Macrae

    2010-12-01

    Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal rats. PCK rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstrates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.

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

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    Williams, Bryan

    2016-06-01

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

  3. Functional analysis of cardiovascular renin-angiotensin system using a gain or loss of function approach.

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    Morishita, R; Aoki, M; Ogihara, T

    2000-03-01

    The study of the effect of autocrine-paracrine vasoactive modulators on cardiovascular biology is very difficult in vivo, because in vivo studies are limited. In particular, characterization of the role of components of the renin-angiotensin system (RAS) in vivo is limited by the difficulty in manipulating individual components of the RAS as well as by methodological limitations in studying the function of a local RAS in the absence of any contribution by the circulatory system. Recent progress in in vivo gene transfer technologies has provided us with the opportunity to study cellular responses to the manipulation of the individual components (i.e., by overexpression or inhibition). Many researchers have recently developed various in vivo gene transfer techniques for cardiovascular applications. Using in vivo gene transfer approaches, the roles of various tissues in the RAS, such as cardiac angiotensin, have been identified. Such an approach may increase our understanding of the biology and pathobiology of the autocrine-paracrine system. This review discusses the potential utility of in vivo gene transfer methods.

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

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    Jeppe eSkov

    2014-02-01

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

  5. The renin-angiotensin system and its involvement in vascular disease.

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    van Thiel, Bibi S; van der Pluijm, Ingrid; te Riet, Luuk; Essers, Jeroen; Danser, A H Jan

    2015-09-15

    The renin-angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition.

  6. Aliskiren inhibits the renin-angiotensin system in retinal pigment epithelium cells.

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    Simão, Sónia; Santos, Daniela F; Silva, Gabriela A

    2016-09-20

    Observations of increased angiotensin II levels and activation of the (pro)renin receptor in retinopathies support the role of ocular renin-angiotensin system (RAS) in the development of retinal diseases. While targeting RAS presents significant therapeutic potential, current RAS-based therapies are ineffective halting the progression of these diseases. A new class of drugs, the direct renin inhibitors such as aliskiren, is a potential therapeutic alternative. However, it is unclear how aliskiren acts in the retina, in particular in the retinal pigment epithelium (RPE), the structure responsible for the maintenance of retinal homeostasis whose role is deeply compromised in retinal diseases. We firstly analyzed the expression and activity of the main RAS components in RPE cells. Time- and concentration-dependent treatments with aliskiren were performed to modulate different pathways of the RAS in RPE cells. Our data demonstrate that RPE cells express the main RAS constituents. Exposure of RPE cells to aliskiren inhibited the activity of renin and consequently decreased the levels of angiotensin II. Additionally, aliskiren reduced the translocation of the (pro)renin receptor to the cellular membrane of RPE cells preventing the activation of ERK1/2. Our findings of the RPE well-defined RAS, together with the demonstration that aliskiren effectively blocks this system at different steps of the cascade, suggest that aliskiren might be an alternative and successful drug in preventing the deleterious effects derived from the overactivation of the RAS, known to contribute to the pathogenesis of different retinal diseases.

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

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

    2015-05-20

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

  8. Association between a functional polymorphism in the renin-angiotensin system and completed suicide.

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    Hishimoto, A; Shirakawa, O; Nishiguchi, N; Hashimoto, T; Yanagi, M; Nushida, H; Ueno, Y; Maeda, K

    2006-12-01

    Suicide has been suggested to involve disturbances in the stress response system and to be related to genetics. The renin-angiotensin system (RAS) has been shown to affect the stress response, and several functional polymorphisms in RAS-related genes have been predicted to alter protein function. We hypothesized that the dysregulation of RAS was involved in suicide, and examined the association between completed suicides and four functional polymorphisms of RAS-related genes: the angiotensinogen M235T, angiotensin-converting enzyme (ACE) insertion(I)/deletion(D), angiotensin type-1 receptor A1166C, and G-protein-beta3 C825T gene polymorphisms. The I allele of the ACE I/D polymorphism was found to be more frequent in completed suicides than in controls (P = 0.014). The I allele was also found to be more frequent in male completed suicides (P = 0.022) than in male controls, while this was not the case in females. These results suggest that the alteration of RAS function caused by the genetic polymorphism is involved in the susceptibility to suicide in males.

  9. Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus.

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    Leung, Po Sing; Carlsson, Per-Ola

    2005-05-01

    Several regulatory systems are implicated in the regulation of islet function and beta cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced beta cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.

  10. Emerging Therapies for Diabetic Nephropathy Patients: Beyond Blockade of the Renin-Angiotensin System

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    Bassem Y. Tanios

    2012-10-01

    Full Text Available Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials.

  11. The expression of Mas-receptor of the renin-angiotensin system in the human eye.

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    Vaajanen, A; Kalesnykas, G; Vapaatalo, H; Uusitalo, H

    2015-07-01

    The local renin-angiotensin system has been held to be expressed in many organs, including the eye. It has an important role in the regulation of local fluid homeostasis, cell proliferation, fibrosis, and vascular tone. Mas-receptor (Mas-R) is a potential receptor acting mainly opposite to the well-known angiotensin II receptor type 1. The aim of this study was to determine if Mas-R is expressed in the human eye. Seven enucleated human eyes were used in immunohistochemical detection of Mas-R and its endogenous ligand angiotensin (1-7) [Ang(1-7)]. Both light microscopy and immunofluorescent detection methods were used. A human kidney preparation sample was used as control. The Mas-R was found to have nuclear localization, and localized in the retinal nuclear layers and in the structures of the anterior segment of the eye. A cytoplasmic immunostaining pattern of Ang(1-7) was found in the inner and outer nuclear and plexiform layers of the retina and in the ciliary body. To the best of our knowledge, this is the first report showing Mas-R expression in the human eye. Its localization suggests that it may have a role in physiological and pathological processes in the anterior part of the eye and in the retina.

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

    Science.gov (United States)

    Tchelougou, Daméhan; Kologo, Jonas K.; Karou, Simplice D.; Yaméogo, Valentin N.; Bisseye, Cyrille; Djigma, Florencia W.; Ouermi, Djeneba; Compaoré, Tegwindé R.; Assih, Maléki; Pietra, Virginio; Zabsonré, Patrice; Simpore, Jacques

    2015-01-01

    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. PMID:26351579

  13. New Concepts in Malaria Pathogenesis: The Role of the Renin-Angiotensin System.

    Science.gov (United States)

    Silva, Leandro S; Silva-Filho, João Luiz; Caruso-Neves, Celso; Pinheiro, Ana Acacia S

    2015-01-01

    Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus Plasmodium. In humans, Plasmodium falciparum is the most dangerous species responsible for severe disease. Despite all efforts to establish the pathogenesis of malaria, it is far from being fully understood. In addition, resistance to existing drugs has developed in several strains and the development of new effective compounds to fight these parasites is a major issue. Recent discoveries indicate the potential role of the renin-angiotensin system (RAS) in malaria infection. Angiotensin receptors have not been described in the parasite genome, however several reports in the literature suggest a direct effect of angiotensin-derived peptides on different aspects of the host-parasite interaction. The aim of this review is to highlight new findings on the involvement of the RAS in parasite development and in the regulation of the host immune response in an attempt to expand our knowledge of the pathogenesis of this disease.

  14. Intrarenal renin-angiotensin system modulates glomerular angiotensin receptors in the rat

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    Wilkes, B.M.; Pion, I.; Sollott, S.; Michaels, S.; Kiesel, G. (North Shore Univ. Hospital and Cornell Univ. Medical College, Manhasset, NY (USA))

    1988-03-01

    The aim of this study was to test the hypothesis that the intrarenal renin-angiotensin system (RAS) modulates glomerular angiotensin II (ANG II) receptors. In one protocol ANG II receptors were measured 7 days after unilateral denervation of the left kidney in rats. There were 50% more receptors in the glomeruli from denervated compared with innervated kidneys, which was associated with a 63% reduction in left renal vein renin. The differences in ANG II receptors between the left and right kidneys were not longer present when angiotensin-converting enzyme was inhibited with enalapril or when pharmacological amounts of ANG II were infused. In a second protocol, renal cortical renin content was raised in the left kidney by placing a 0.20-mm clip on the left renal artery. At 7 days, glomerular ANG II receptors were reduced by 72.3% in the clipped compared with the contralateral kidneys. The differences in ANG II receptors were no longer present after enalapril treatment. Pharmacological maneuvers that either blocked ANG II formation or increased circulating ANG II resulted in an equal number of ANG II receptors in the right and left kidneys. The data indicate that the intrarenal RAS modulates the density of glomerular ANG II receptors and is a more important receptor modulation than plasma ANG II.

  15. Soya protein attenuates abnormalities of the renin-angiotensin system in adipose tissue from obese rats.

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    Frigolet, María E; Torres, Nimbe; Tovar, Armando R

    2012-01-01

    Several metabolic disturbances during obesity are associated with adipose tissue-altered functions. Adipocytes contain the renin-angiotensin system (RAS), which regulates signalling pathways that control angiogenesis via Akt in an autocrine fashion. Soya protein (Soy) consumption modifies the gene expression pattern in adipose tissue, resulting in an improved adipocyte function. Therefore, the aim of the present work is to study whether dietary Soy regulates the expression of RAS and angiogenesis-related genes and its association with the phosphorylated state of Akt in the adipose tissue of obese rats. Animals were fed a 30 % Soy or casein (Cas) diet containing 5 or 25 % fat for 160 d. mRNA abundance was studied in the adipose tissue, and Akt phosphorylation and hormone release were measured in the primary adipocyte culture. The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin-stimulated Akt activation in adipocytes. Furthermore, Soy consumption varies the expression of RAS and angiogenesis-related genes, which maintain cell size and vascularity in the adipose tissue of rats fed a high-fat diet. Thus, adipocyte hypertrophy and impaired angiogenesis, which are frequently observed in dysfunctional adipose tissue, were avoided by consuming dietary Soy. Taken together, these findings suggest that Soy can be used as a dietary strategy to preserve adipocyte functionality and to prevent obesity abnormalities.

  16. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

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

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    N. F. Renna

    2013-01-01

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

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

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    Sam eSiljee

    2016-05-01

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

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

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    Agata Kujawa-Szewieczek

    2010-08-01

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

  1. Impact of the renin-angiotensin system on cardiac energy metabolism in heart failure.

    Science.gov (United States)

    Mori, Jun; Zhang, Liyan; Oudit, Gavin Y; Lopaschuk, Gary D

    2013-10-01

    The renin-angiotensin system (RAS) plays a key pathogenic role in heart failure. The adverse effects of angiotensin II (Ang II), a major player of the RAS, contributes to the development of heart failure. Heart failure is accompanied by significant perturbations in cardiac energy metabolism that can both decrease cardiac energy supply and decrease cardiac efficiency. Recent evidence suggests that Ang II might be involved in these perturbations in cardiac energy metabolism. Furthermore, new components of the RAS, such as angiotensin converting enzyme 2 and Ang1-7, have been reported to exert beneficial effects on cardiac energy metabolism. As a result, a further understanding of the relationship between the RAS and cardiac energy metabolism has the potential to improve the control of heart failure, and may lead to the development of new therapies to treat heart failure. This review summarizes what effects the RAS has on cardiac energy metabolism, highlighting how Ang II can induce cardiac insulin resistance and mitochondrial damage, and what role reactive oxygen species and sirtuins have on these processes.

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

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    Daméhan Tchelougou

    2015-01-01

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

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

    Science.gov (United States)

    Urushihara, Maki; Kagami, Shoji

    2016-07-05

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

  4. The Effect of Moderate Hypothermia on Renin-Angiotensin – Aldosterone System in Male Rats

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    M. Kourosh Arami

    2004-04-01

    Full Text Available Hypothermia in nature occurs in hibernating animals. It has applications in medicine in open heart surgery,organ and connective tissue preserving, altitude medicine and geriatrics. Despite the vastness of studies on hypothermia many of its biologic and physiologic effects including endocrine system alterations are still poorly recognized. In this study the effect of hypothermia on renin- angiotensin-aldosterone axis was explored. Ten male wistar albino rats (mean age 5 months were anesthetized by intraperitoneal injection of chloralhydrat (0.5 m1/100gr body weight. Then animals were placed in hypothermia apparatus . Their body temperature were reduced to 250 C. AngiotensinI(ANGI and aldosterone (ALD levels of serum were measured by radioimmunoassay before and after hypothermia induction and once every 24 hours for three days. Plasma renin activity (PRA was also measured by using the standard formula of angiotensin determinates at two temperatures of 40C and 370C . The results showed that PRA,ANGI and ALD increased significantly immedietly after hypothermia (p<0.03. Later changes were followed as these factors decreased to basal level, except in the case of aldosterone which maintained its increased level significantly for 24 hours (p<0.05. It seems that moderate hypothermia have stimulatory effect on PRA,ANGI and ALD that results of this study confirm it.

  5. Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma

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    Tanaka, N; Miyajima, A; Kikuchi, E; Matsumoto, K; Hagiwara, M; Ide, H; Kosaka, T; Masuda, T; Nakamura, S; Oya, M

    2012-01-01

    Background: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). Methods: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. Results: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). Conclusion: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy. PMID:22187036

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

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

    2016-08-01

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

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

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    Clara eNAHMIAS

    2015-02-01

    Full Text Available G-protein coupled receptors (GPCRs constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules and vasoactive peptides. Among those, angiotensins (angiotensin II and angiotensin 1-7 are the major biologically active products of the classical and alternative Renin-Angiotensin System (RAS. These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2 and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, Angiotensin II being considered as harmful and Angiotensin 1-7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas, and discuss the potential use of angiotensin receptor agonists and antagonists in clinics.

  8. THE GENDER FEATURES OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN HYPERTENSIVE PATIENTS

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    V. I. Podzolkov

    2010-01-01

    Full Text Available Aim. To study the correlation of the renin-angiotensin-aldosterone system (RAAS activity with the female sex hormone levels and markers of target organ damage in patients with arterial hypertension (HT.Material and methods. Patients with HT (20 men and 39 postmenopausal women were involved into the study. The dynamic renal angioscintigraphy and echocardiography were performed, plasma rennin activity (PRA, levels of aldosterone, estradiole and 17-hydroxiprogesterone were determined by radioimmunoassay.Results. Higher aldosterone level was found in women in comparison with men (212,5±123,9 pg/ml and 148,9±82,5 pg/m, respectively, р=0,03. Negative relations between aldosterone and estradiol levels (r=-0,3; p=0,04, and between aldosterone and 17-hydroxyprogesterone levels (r=-0,318; p=0,04, and positive relations between aldosterone concentration and PRA (r=0,555; p=0,04 was found in women. Besides, correlation between levels of female sex hormones, aldosterone and renal blood flow indicators, glomerular filtration rate, left ventricular mass index (LVMI were found in women. These correlations were not found in men.Conclusion. The gender differences of RAAS activity were revealed with higher aldosterone level in postmenopausal hypertensive women in comparison with men. Relationships between PRA, levels of aldosterone and female sex hormones and renal blood flow indices, LVMI were also found in women.

  9. Renin-angiotensin system inhibitor and statins combination therapeutics - what have we learnt?

    Science.gov (United States)

    Koh, Kwang Kon; Sakuma, Ichiro; Hayashi, Toshio; Kim, Sang Hyun; Chung, Wook-Jin

    2015-05-01

    Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.

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

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    Siew Mei Joyce-Tan

    2016-01-01

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

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

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    Shane D. Sykes

    2015-01-01

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

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

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    Man Lung eFung

    2014-09-01

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

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

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    Thomas Unger

    2004-03-01

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

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

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    Masumi Kamiyama

    2013-11-01

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

  15. Interaction of the renin-angiotensin system and the endothelin system in cardiac hypertrophy.

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    Stula, M; Pinto, Y M; Gschwend, S; Teisman, A C; van Gilst, W H; Böhm, M; Dietz, R; Paul, M

    1998-01-01

    It has been suggested that the renin-angiotensin system (RAS) interacts with the endothelin system in the pathogenesis of cardiac remodeling. We examined endothelin system regulation in a model of chronic RAS dysfunction, which is believed to be an important factor in cardiac remodeling. We used the transgenic rat line TGR(mRen2)27, which overexpresses the mouse Renin-2 gene and shows hypertension and left ventricular hypertrophy compared to Sprague-Dawley (SD) rats. Ren-2 rats (n = 24) received either losartan (LOS), quniapril (QIN), or carvedilol (CARV) for 11 weeks, or no treatment. After 11 weeks left (LV) and right ventricular (RV) weights were determined and total RNA extracted. Ren-2 rats showed a mean systolic blood pressure of 190 mm (+/- SEM), which could be normalized to 110 +/- mm (+/- SEM) by treatment with LOS or QIN. CARV also reduced blood pressure but did not normalize it. LV end-diastolic pressure was normal in both SD and Ren-2 rats. LV weight was increased in the Ren-2 rats compared to SD rats, and was significantly reduced to normal in the LOS and QIN but not in the CARV group. RV weight was normal in all groups. Northern blot analysis of preproendothelin-1 (preproET-1) and endothelin-converting enzyme-1 (ECE-1) expression revealed a significant (p < 0.05) 20% decrease in preproET-1 mRNA in the mRen2 rats in the RV and in the LV, compared to SD rats. ECE-1 mRNA was unchanged. Treatment with LOS, but not with QIN or CARV, induced preproET-1 transcription by threefold (p < 0.01) over baseline in both the LV and RV. ECE-1 mRNA was unaltered in the CARV and LOS group and was decreased by 20% in the QIN group. Similar changes in LV and RV indicated a direct influence of a dysregulated RAS on the endothelin system. In conclusion, the activated RAS downregulates the endothelin system in this model of cardiac hypertrophy. This suggests that in chronic RAS activated, the endothelin system may have a different pathophysiologic impact as a co

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

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2016-04-15

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

  18. Renin-angiotensin system in vertebrates: phylogenetic view of structure and function.

    Science.gov (United States)

    Nishimura, Hiroko

    2017-03-01

    Renin substrate, biological renin activity, and/or renin-secreting cells in kidneys evolved at an early stage of vertebrate phylogeny. Angiotensin (Ang) I and II molecules have been identified biochemically in representative species of all vertebrate classes, although variation occurs in amino acids at positions 1, 5, and 9 of Ang I. Variations have also evolved in amino acid positions 3 and 4 in some cartilaginous fish. Angiotensin receptors, AT1 and AT2 homologues, have been identified molecularly or characterized pharmacologically in nonmammalian vertebrates. Also, various forms of angiotensins that bypass the traditional renin-angiotensin system (RAS) cascades or those from large peptide substrates, particularly in tissues, are present. Nonetheless, the phylogenetically important functions of RAS are to maintain blood pressure/blood volume homeostasis and ion-fluid balance via the kidney and central mechanisms. Stimulation of cell growth and vascularization, possibly via paracrine action of angiotensins, and the molecular biology of RAS and its receptors have been intensive research foci. This review provides an overview of: (1) the phylogenetic appearance, structure, and biochemistry of the RAS cascade; (2) the properties of angiotensin receptors from comparative viewpoints; and (3) the functions and regulation of the RAS in nonmammalian vertebrates. Discussions focus on the most fundamental functions of the RAS that have been conserved throughout phylogenetic advancement, as well as on their physiological implications and significance. Examining the biological history of RAS will help us analyze the complex RAS systems of mammals. Furthermore, suitable models for answering specific questions are often found in more primitive animals.

  19. Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.

    Science.gov (United States)

    Okawada, Manabu; Wilson, Michael W; Larsen, Scott D; Lipka, Elke; Hillfinger, John; Teitelbaum, Daniel H

    2016-12-01

    Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model. A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days. In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines. This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

  20. A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

    Science.gov (United States)

    Hilzendeger, Aline M.; Morgan, Donald A.; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L.; Rahmouni, Kamal; Sigmund, Curt D.

    2012-01-01

    The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR−/−), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR−/− vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake. PMID:22610169

  1. Low LBNP Tolerance in Men is Associated With Attenuated Activation of Renin-Angiotensin System

    Science.gov (United States)

    Greenleaf, John E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N.-J.; Warberg, J.; Videbaeck, R.; Simonson, S. R.; Norsk, P.; Dalton, Bonnie P. (Technical Monitor)

    1999-01-01

    Vasoactive hormone concentrations (epinephrine (pE), norepinephrine (pNE), angiotensin II (pATII), vasopressin (pVP), endothelin 1 (pET1)] and plasma renin activity (pRA) were measured during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the reninangiotensin system is related to LBNP tolerance. Healthy men (2,822 cal per day, 2 mmol per kilogram per day Na (+)) were exposed to 30 min of progressive LBNP to -50mmHg. LBNP was uneventful for 7 men (2512 yr, HiTol group), but 8 men (26 plus or minus 3 yr) reached pre-syncope after 11 plus or minus 1 min (P less than 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by 30%, P less than 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 plus or minus 0.1, HiTol 1.2 plus or minus 0.1 ng Ang1 per milliliter per hour, per hour, P less than 0.05). LBNP increased (P less than 0.05) pRA and pATII more in HiTol (9.9 plus or minus 2.2 ng Ang1 per milliliter per hour and 58 plus or minus 12 pg per milliliter) than LoTol (4.3 plus or minus 0.9 ng Angl per milliliter per hour and 28 plus or minus 6 pg per milliliter). In contrast, pVP was higher (P less than 0.05) in LoTol than in HiTol. The response of the renin-angiotensin system seems linked to the occurrence of pre-syncope, and measurement of resting pRA may be predictive.

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

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Kang Won; Park, Jung Sik; Lee, Jung Sang; Koh, Chang Soon [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1976-03-15

    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<0.001) and normal renin essential hypertension(r=-0.551, p<0.05) and the chronic renal failure with hypertension. (r=-0.790, P<0.001) 2) NaE increased markedly the in chronic renal failure with hypertension (66.9+-8.69 mEq/kg of LBM, p<0.001) and the chronic renal failure without hypertension (54.9+-9.28 mEq/kg of LBM, p<0.05), while mild increase was noted in malignant hypertension (51.7+-6.24 mEq/kg of LBM, 0.050.1) 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<0.001). But PRA was inappropriately high in relation to prevailing NaE in the chronic renal failure with hypertension (eleven of thirteen patients) and malignant hypertension (ten of fourteen patients), while PRA variatiation was within physiologic range in the chronic renal failure without hypertension. 4) The NaE-PRA product was markedly increased in the chronic renal failure with hypertension (514.4+-42.10, p<0.001) and in malignant hypertension (442.7+-55.03, p<0.001), while moderately increased NaE-PRA product was noted in the chronic renal failure without hypertension (402.6+-59.67, p<0

  3. Local Renin-Angiotensin System in Normal Hematopoietic and Multiple Myeloma-Related Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Burak Uz

    2014-03-01

    Full Text Available OBJECTIVE: The prominent functions of the local renin-angiotensin system (RAS in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM-related progenitor cells. METHODS: The study group comprised the total bone marrow cells (CBM of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. RESULTS: RENIN, angiotensinogen (ANGTS, and angiotensin converting enzyme-I (ACE I mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively. Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01. However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89. CONCLUSION: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Maylla Ronacher Simões

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

  6. [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.

  7. Renin-angiotensin system inhibitors and troponin elevation in spinal surgery.

    Science.gov (United States)

    McClendon, Jamal; Smith, Timothy R; Thompson, Sara E; Sugrue, Patrick A; Sauer, Andrew J; O'Shaughnessy, Brian A; Carabini, Louanne; Koski, Tyler R

    2014-07-01

    Renin-angiotensin system (RAS) inhibition by angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) has been shown to reduce cardiovascular mortality and non-fatal myocardial infarction (MI) in high-risk surgical patients. However, their effect in spinal surgery has not been explored. Our objective was to determine the effect of RAS inhibitors on postoperative troponin elevation in spinal fusions, and to examine their correlation with hospital stay. We retrospectively analyzed 208 consecutive patients receiving spinal fusions ⩾5 levels between 2007-2010 with a mean follow-up of 1.7 years. Inclusion criteria were age ⩾18 years, elective fusions for kyphoscoliosis, and semi-elective fusions for tumor or infection. Exclusion criteria were trauma and follow-up troponin elevation (⩾0.04 ng/mL), peak troponin level, and hospital stay. The results featured 208 patients with a mean body mass index (BMI) 28.5 kg/m(2) who underwent 345 spinal fusions. ACEI/ARB were withheld the day prior to surgery in 121 patients with 11 patients noteworthy for intra-operative electrocardiogram changes, 126 patients with troponin elevation, and 14 MI identified prior to discharge. Multivariate logistic regression identified BMI (p=0.04), estimated blood loss (p=0.015), and preoperative ACEI/ARB (p=0.015, odds ratio=2.7) as significant independent predictors for postoperative troponin elevation. Multivariate linear regression showed preoperative Oswestry Disability Index (p=0.002), unplanned return to operating room (p=0.007), pneumonia prior to hospital discharge (ptroponin elevation and increased hospital stay.

  8. Renin-Angiotensin-aldosterone system and hypothalamic-pituitary-adrenal axis in hospitalized newborn foals.

    Science.gov (United States)

    Dembek, K A; Onasch, K; Hurcombe, S D A; MacGillivray, K C; Slovis, N M; Barr, B S; Reed, S M; Toribio, R E

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) and hypothalamic-pituitary-adrenal axis (HPAA) and their interactions during illness and hypoperfusion are important to maintain organ function. HPAA dysfunction and relative adrenal insufficiency (RAI) are common in septic foals. Information is lacking on the RAAS and mineralocorticoid response in the context of RAI in newborn sick foals. To investigate the RAAS, as well as HPAA factors that interact with the RAAS, in hospitalized foals, and to determine their association with clinical findings. We hypothesized that critical illness in newborn foals results in RAAS activation, and that inappropriately low aldosterone concentrations are part of the RAI syndrome of critically ill foals. A total of 167 foals ≤3 days of age: 133 hospitalized (74 septic, 59 sick nonseptic) and 34 healthy foals. Prospective, multicenter, cross-sectional study. Blood samples were collected on admission. Plasma renin activity (PRA) and angiotensin-II (ANG-II), aldosterone, ACTH, and cortisol concentrations were measured in all foals. ANG-II, aldosterone, ACTH, and cortisol concentrations as well as ACTH/aldosterone and ACTH/cortisol ratios were higher in septic foals compared with healthy foals (P < .05). No difference in PRA between groups was found. High serum potassium and low serum chloride concentrations were associated with hyperaldosteronemia in septic foals. RAAS activation in critically ill foals is characterized by increased ANG-II and aldosterone concentrations. Inappropriately low cortisol and aldosterone concentrations defined as high ACTH/cortisol and ACTH/aldosterone ratios in septic foals suggest that RAI is not restricted to the zona fasciculata in critically ill newborn foals. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  9. Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients.

    Science.gov (United States)

    Vlahakos, D V; Balodimos, C; Papachristopoulos, V; Vassilakos, P; Hinari, E; Vlachojannis, J G

    1995-01-01

    A series of observations suggests an interrelationship between the renin-angiotensin system (RAS) and erythropoietin (EPO) secretion. To further evaluate the role of RAS in erythropoiesis of chronic hemodialysis patients, we studied two groups of such patients: Group A consisted of 16 patients (14 male and 2 female, 54.7 +/- 3.3 years old), who maintained a target hematocrit value of 0.30 (0.32 +/- 0.01), without recombinant human EPO (rhEPO) supplementation. Group B consisted of 14 patients (7 male and 7 female, 50 +/- 5.3 years old), who required subcutaneous injections of rhEPO (90.8 +/- 10 IU.kg-1.week-1), to maintain the same target hematocrit value of 0.30 (30 +/- 0.01). Plasma renin activity (PRA) was found to be the major feature to distinguish patients in these two Groups and it was five times higher in Group A (10 +/- 2 ng.ml-1.h-1) compared to Group B patients (1.8 +/- 0.6 ng.ml-1.h-1) (p < 0.001). Moreover, activation of RAS in Group A patients by volume depletion (2.2 +/- 0.2 l) during hemodialysis resulted in a 118 +/- 33 percent increment of PRA (p < 0.01) which was accompanied by a 69 +/- 25 percent increment of serum EPO levels (p < 0.05). Repetition of the same protocol after inhibiting the converting enzyme with 50 mg of Captopril prior to dialysis session, resulted in a 315 +/- 64 percent increment of PRA (p < 0.001), while at the same time completely blocked the expected rise in serum EPO levels (1.25 +/- 12.5 percent increment).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

    Science.gov (United States)

    Lyu, Linmao; Wang, Hui; Li, Bin; Qin, Qingyun; Qi, Lei; Nagarkatti, Mitzi; Nagarkatti, Prakash; Janicki, Joseph S; Wang, Xing Li; Cui, Taixing

    2015-12-01

    Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT1R, and AT2R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT1R and AT2R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.

  11. Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients.

    Science.gov (United States)

    Moreno-Muñoz, Diana; de la Haba-Rodríguez, Juan R; Conde, Francisco; López-Sánchez, Laura M; Valverde, Araceli; Hernández, Vanessa; Martínez, Antonio; Villar, Carlos; Gómez-España, Auxiliadora; Porras, Ignacio; Rodríguez-Ariza, Antonio; Aranda, Enrique

    2015-12-01

    Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS). Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells. The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P AGTR1-overexpressing breast cancer cells. A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti-angiogenic drugs. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

  12. Renin-angiotensin system genetic polymorphisms and brain white matter lesions in older Australians.

    Science.gov (United States)

    Assareh, Amelia A; Mather, Karen A; Crawford, John D; Wen, Wei; Anstey, Kaarin J; Easteal, Simon; Tan, Xiaoyun; Mack, Holly A; Kwok, John B J; Schofield, Peter R; Sachdev, Perminder S

    2014-09-01

    White matter lesions (WMLs), seen as hyperintensities on T2-weighted magnetic resonance imaging brain scans, are common in the brains of healthy older individuals. They are thought to be related to cerebral small vessel disease and to have a genetic component to their aetiology, and hypertension is thought to be an important risk factor. Genetic polymorphisms in hypertension-related genes may therefore be associated with the formation of WMLs. In this study, a sample of 445 Australians aged 60-65 years was drawn from a larger longitudinal epidemiological study, the Personality and Total Health Through Life Project. The associations of single nucleotide polymorphisms (SNPs) in the genes encoding angiotensinogen (AGT, rs699), angiotensin-converting enzyme (ACE, rs4362), and angiotensin II receptor type 1 (AGTR1, rs5182) with WMLs were examined. No individual SNPs showed a significant association with WMLs for the whole sample. When the cohort was stratified by sex, ACE rs4362 and AGT rs699 showed significant associations with WMLs in men only (P = 0.01 and P = 0.03, respectively), and remained significant after controlling for hypertension. Although the AGTR1 SNP did not show any association with WMLs, the interaction of the AGT rs699 and AGTR1 rs5182 SNPs with WMLs was significant before (P = 0.03) and after adjustment for hypertension (P = 0.045). The results provide evidence for association of polymorphisms in the renin-angiotensin system genes with WMLs, independent of hypertension. Male-only associations with WMLs were found for the AGT rs699 and ACE rs362 polymorphisms. Moreover, for the entire sample an interaction between AGT and AGTR1 rs5182 genotypes on WMLs was observed. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Structural libraries of protein models for multiple species to understand evolution of the renin-angiotensin system.

    Science.gov (United States)

    Prokop, Jeremy W; Petri, Victoria; Shimoyama, Mary E; Watanabe, Ingrid K M; Casarini, Dulce E; Leeper, Thomas C; Bilinovich, Stephanie M; Jacob, Howard J; Santos, Robson A S; Martins, Almir S; Araujo, Fabiano C; Reis, Fernando M; Milsted, Amy

    2015-05-01

    The details of protein pathways at a structural level provides a bridge between genetics/molecular biology and physiology. The renin-angiotensin system is involved in many physiological pathways with informative structural details in multiple components. Few studies have been performed assessing structural knowledge across the system. This assessment allows use of bioinformatics tools to fill in missing structural voids. In this paper we detail known structures of the renin-angiotensin system and use computational approaches to estimate and model components that do not have their protein structures defined. With the subsequent large library of protein structures, we then created a species specific protein library for human, mouse, rat, bovine, zebrafish, and chicken for the system. The rat structural system allowed for rapid screening of genetic variants from 51 commonly used rat strains, identifying amino acid variants in angiotensinogen, ACE2, and AT1b that are in contact positions with other macromolecules. We believe the structural map will be of value for other researchers to understand their experimental data in the context of an environment for multiple proteins, providing pdb files of proteins for the renin-angiotensin system in six species. With detailed structural descriptions of each protein, it is easier to assess a species for use in translating human diseases with animal models. Additionally, as whole genome sequencing continues to decrease in cost, tools such as molecular modeling will gain use as an initial step in designing efficient hypothesis driven research, addressing potential functional outcomes of genetic variants with precompiled protein libraries aiding in rapid characterizations.

  14. The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels.

    Science.gov (United States)

    Durand, Matthew J; Phillips, Shane A; Widlansky, Michael E; Otterson, Mary F; Gutterman, David D

    2014-07-01

    Increased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 μm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10(-6) mol/l), or the angiotensin-converting enzyme inhibitor captopril (10(-5) mol/l) prevented the pressure-induced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension.

  15. Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers.

    Science.gov (United States)

    Azizi, Michel; Blanchard, Anne; Charbit, Beny; Wuerzner, Grégoire; Peyrard, Séverine; Ezan, Eric; Funck-Brentano, Christian; Ménard, Joël

    2013-06-01

    Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

  16. 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.

  17. The blockade of renin-angiotensin-aldosterone system in hemodialysis patients to control hypertension and prevent cardiovascular disease: optimal pharmacotherapy.

    Science.gov (United States)

    Morishita, Yoshiyuki; Kusano, Eiji

    2011-10-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in hemodialysis (HD) patients. Hypertension (HT) is a major risk factor for CVD. The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of HT in HD patients. Previous studies suggested that the blockade of RAAS may be effective to control blood pressure (BP) and to prevent CVD in HD patients. A certain level of preventive effects against CVD by RAAS blockade in HD patients has been reported independently from a BP lowering effect. This review focuses on the effect of blocking RAAS in HD patients for the control of HT and the prevention of CVD.

  18. Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer

    OpenAIRE

    Benjamin Goldstein; Malav Trivedi; Speth, Robert C.

    2017-01-01

    Objectives. The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. Materials and Methods. NCBI’s built-in statistical tool, GEO2R, was used to calculate Student’s t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak’s ...

  19. The compensatory renin-angiotensin system in the central regulation of arterial pressure: new avenues and new challenges.

    Science.gov (United States)

    Mendoza, Alberto; Lazartigues, Eric

    2015-08-01

    Hypertension is a widespread condition that affects millions of people around the world and has a major impact in public health. The classic renin-angiotensin system is a complex system comprised of multiple peptides and pathways that have been the driver of drug development over the years to control hypertension. However, there are still patients whose hypertension is very difficult to control with current drugs and strategies, thus motivating further research in this field. In the past two decades, important discoveries have expanded our knowledge of this system and new pathways are emerging that are helping us understand the complex interaction taking place not only in the periphery, but also in the central nervous system where the renin-angiotensin system is also very active. A new arm, called the ACE2/Ang-(1-7)/Mas receptor axis, was shown to exert antihypertensive properties and serve as a counterbalance to the classic ACE/angiotensin II/AT1 receptor axis, in this way modulating or even counteracting the negative effects of angiotensin II in blood pressure regulation and water retention. Modulation of this new axis through ACE2 activation, ADAM17 regulation or AT1 receptor internalization are some of the novel avenues and challenges that have the potential to become a target for new drug research and development for the treatment of hypertension.

  20. Reduced Pulsatility Induces Periarteritis in Kidney: Role of the Local Renin-Angiotensin System

    Science.gov (United States)

    Ootaki, Chiyo; Yamashita, Michifumi; Ootaki, Yoshio; Kamohara, Keiji; Weber, Stephan; Klatte, Ryan S.; Smith, William A.; Massiello, Alex L.; Emancipator, Steven N.; Golding, Leonard A.R.; Fukamachi, Kiyotaka

    2008-01-01

    Background The need for pulsatility in the circulation during long-term mechanical support has been a subject of debate. We compared histological changes in calf renal arteries subjected to various degrees of pulsatile circulation in vivo. We addressed the hypothesis that the local reninangiotensin system (RAS) may be implicated in these histological changes. Methods and Results Sixteen calves were implanted with devices giving differing degrees of pulsatile circulation: six had a continuous flow left ventricular assist device (LVAD); six had a continuous flow right ventricular assist device (RVAD); and four had a pulsatile total artificial heart (TAH). Six other calves were histological and immunohistochemical controls. In the LVAD group, the pulsatility index was significantly lower (0.28 ± 0.07 LVAD vs 0.56 ± 0.08 RVAD, vs 0.53 ± 0.10 TAH; p < 0.01), and we observed severe periarteritis in all cases in the LVAD group. The number of angiotensin II type 1 receptor (AT1R)-positive cells and angiotensin converting enzyme (ACE)-positive cells in periarterial areas was significantly higher in the LVAD group (AT1R: 350 ± 139 LVAD vs 8 ± 6 RVAD, vs 3 ± 2 TAH, vs 3 ± 2 in control; p < 0.001 and ACE: 325 ± 59 LVAD vs 6 ± 4 RVAD, vs 6 ± 5 TAH, vs 3 ± 1 control; p < 0.001). Conclusions The reduced pulsatility produced by a continuous flow LVAD implantation induced severe periarteritis in the kidney. The local RAS was upregulated in the inflammatory cells only in the continuous flow LVAD group. ULTAMINI-ABSTRACT We compared histological changes in calf renal arteries subjected to various degrees of pulsatile circulation; continuous flow left ventricular assist device (LVAD), continuous flow right ventricular assist device, pulsatile total artificial heart and control. We observed severe periarteritis, and upregulation of local renin angiotensin system only in the LVAD group. The necessity of maintaining pulsatility in the systemic circulation during long

  1. Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system

    Science.gov (United States)

    Greenleaf, J. E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N. J.; Warberg, J.; Videbaek, R.; Simonson, S. R.; Norsk, P.

    2000-01-01

    Plasma vasoactive hormone concentrations [epinephrine (p(Epi)), norepinephrine (p(NE)), ANG II (p(ANG II)), vasopressin (p(VP)), endothelin-1 (p(ET-1))] and plasma renin activity (p(RA)) were measured periodically and compared during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system, the latter being one of the most powerful vasoconstrictors in the body, is of major importance for LBNP tolerance. Healthy men on a controlled diet (2,822 cal/day, 2 mmol. kg(-1). day(-1) Na(+)) were exposed to 30 min of LBNP from -15 to -50 mmHg. LBNP was uneventful for seven men [25 +/- 2 yr, high-tolerance (HiTol) group], but eight men (26 +/- 3 yr) reached presyncope after 11 +/- 1 min [P concentrations were similar between groups, however, p(RA) differed between them (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng ANG I. ml(-1). h(-1), P < 0.05). LBNP increased (P < 0. 05) p(RA) and p(ANG II), respectively, more in the HiTol group (9.9 +/- 2.2 ng ANG I. ml(-1). h(-1) and 58 +/- 12 pg/ml) than in LoTol subjects (4.3 +/- 0.9 ng ANG I. ml(-1). h(-1) and 28 +/- 6 pg/ml). In contrast, the increase in p(VP) was higher (P < 0.05) in the LoTol than in the HiTol group. The increases (P < 0.05) for p(NE) were nonsignificant between groups, and p(ET-1) remained unchanged. Thus there may be a causal relationship between attenuated activation of p(RA) and p(ANG II) and presyncope, with p(VP) being a possible cofactor. Measurement of resting p(RA) may be of predictive value for those with lower hypotensive tolerance.

  2. Contributions of renin-angiotensin system-related gene interactions to obesity in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jian-Bo Zhou

    Full Text Available BACKGROUND: Gene-gene interactions may be partly responsible for complex traits such as obesity. Increasing evidence suggests that the renin-angiotensin system (RAS contributes to the etiology of obesity. How the epistasis of genes in the RAS contributes to obesity is still under research. We aim to evaluate the contribution of RAS-related gene interactions to a predisposition of obesity in a Chinese population. METHODOLOGY AND PRINCIPAL FINDINGS: We selected six single nucleotide polymorphisms (SNPs located in angiotensin (AGT, angiotensin converting enzyme (ACE, angiotensin type 1 receptor (AGTR1, MAS1, nitric oxide synthase 3 (NOS3 and the bradykinin B2 receptor gene (BDKRB2, and genotyped them in 324 unrelated individuals with obesity (BMI ≥ 28 kg/m(2 and 373 non-obese controls (BMI 18.5 to <24 kg/m(2 from a large scale population-based cohort. We analyzed gene-gene interactions among 6 polymorphic loci using the Generalized Multifactor Dimensionality Reduction (GMDR method, which has been shown to be effective for detecting gene-gene interactions in case-control studies with relatively small samples. Then we used logistic regression models to confirm the best combination of loci identified in the GMDR. It showed a significant gene-gene interaction between the rs220721 polymorphism in the MAS1 gene and the rs1799722 polymorphism in the gene BDKB2R. The best two-locus combination scored 9 for cross-validation consistency and 9 for sign test (p = 0.0107. This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of the MAS1 rs220721 and the BDKRB2 rs1799722 was associated with a significantly increased risk of obesity (OR 1.82, CI 95%: 1.15-2.88, p = 0.0103. CONCLUSIONS AND SIGNIFICANCE: These results suggest that the SNPs from the RAS-related genes may contribute to the risk of obesity in an interactive manner in a Chinese population. The gene

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

    Science.gov (United States)

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

    2013-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Ip SP

    2001-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

    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. W

  6. 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

    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. W

  7. SELECTIVE AND TIME-RELATED ACTIVATION OF THE CARDIAC RENIN-ANGIOTENSIN SYSTEM AFTER EXPERIMENTAL HEART-FAILURE - RELATION TO VENTRICULAR-FUNCTION AND MORPHOLOGY

    NARCIS (Netherlands)

    PINTO, YM; DESMET, BGJL; VANGILST, WH; MONNINK, S; DEGRAEFF, PA; WESSELING, H

    1993-01-01

    Objective: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensi

  8. 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.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  10. 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.

  11. Combination use of medicines from two classes of renin-angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function.

    Science.gov (United States)

    Esteras, Raquel; Perez-Gomez, Maria Vanessa; Rodriguez-Osorio, Laura; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

    2015-08-01

    European and United States regulatory agencies recently issued warnings against the use of dual renin-angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

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

    Science.gov (United States)

    Mochel, Jonathan P; Danhof, Meindert

    2015-01-01

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

  13. Intrarenal activation of renin angiotensin system in the development of cyclosporine A induced chronic nephrotoxicity

    Institute of Scientific and Technical Information of China (English)

    SHANG Ming-hua; YUAN Wei-jie; ZHANG Shujian; FAN Yu; ZHANG Zheng

    2008-01-01

    Background The relationship between cyclosporine-induced chronic nephrotoxicity (CAN) and renin-angiotenein Ⅱ in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin Ⅱ (ANGII) both in renal tissue and plasma from kidney transplantation patients suffering from CAN.Methods Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity (CAN group) and chronic rejection (control group) were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose (C2). In vitro, human umbilical vein endothelial cells (HUVEC) and rat mesangial cells (MC) were incubated with different concentrations of CsA (0, 250, 500, 1000 μg/L) for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining.Results Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls (P<0.05). The plasma levels of renin, ANGII and C2 in the CAN group were higher than the control group, but no significant difference was found ((0.37±0.12) ng.ml-1·h-1 vs (0.20±0.10) ng.ml-1·h-1, P=0.076; (122.69±26.73) pg/ml vs(121.88±36.35) pg/ml, P=0.977; (719.04±55.89) ng/ml vs (658.80±90.78) ng/ml, P=0.196, respectively). In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours (P <0.05). CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner.Conclusions Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal renin angiotensin

  14. Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence.

    Science.gov (United States)

    Fouda, Abdelrahman Y; Artham, Sandeep; El-Remessy, Azza B; Fagan, Susan C

    2016-02-01

    As our knowledge expands, it is now clear that the renin-angiotensin (Ang) system (RAS) mediates functions other than regulating blood pressure (BP). The RAS plays a central role in the pathophysiology of different neurovascular unit disorders including stroke and retinopathy. Moreover, the beneficial actions of RAS modulation in brain and retina have been documented in experimental research, but not yet exploited clinically. The RAS is a complex system with distinct yet interconnected components. Understanding the different RAS components and their functions under brain and retinal pathological conditions is crucial to reap their benefits. The aim of the present review is to provide an experimental and clinical update on the role of RAS in the pathophysiology and treatment of stroke and retinopathy. Combining the evidence from both these disorders allows a unique opportunity to move both fields forward.

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

  16. New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors -- hype or hope?

    Science.gov (United States)

    Tamargo, Juan; Caballero, Ricardo; Delpón, Eva

    2014-11-01

    Hyperkalemia (serum potassium >5.5 mmol/L) may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or reduced renal excretion. Renin-angiotensin-aldosterone system inhibitors (RAASIs) represent an important therapeutic strategy in patients with hypertension, heart failure, chronic kidney disease, and diabetes, but hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs. We review two new polymer-based, non-systemic agents under clinical development, patiromer calcium and zirconium silicate, designed to increase potassium loss via the gastrointestinal tract for the management of hyperkalemia.

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

    DEFF Research Database (Denmark)

    Persson, Frederik; Lindhardt, Morten; Rossing, Peter

    2016-01-01

    HYPOTHESIS/OBJECTIVES: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can...... prevent development of microalbuminuria. MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis...... was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79-0.88) pTreatment also showed a trend towards a reduction...

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

    DEFF Research Database (Denmark)

    Persson, Frederik; Lindhardt, Morten; Rossing, Peter

    2016-01-01

    Hypothesis/objectives: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can...... prevent development of microalbuminuria. Materials and methods: We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis...... was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79–0.88) p

  19. 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 similarly associated. METHODS: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma...... angiotensinogen concentration and serum ACE activity. RESULTS: Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs...

  20. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

    Science.gov (United States)

    Patel, Vaibhav B; Zhong, Jiu-Chang; Grant, Maria B; Oudit, Gavin Y

    2016-04-15

    Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

  1. Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

    Science.gov (United States)

    Qi, Ying; Wang, Xiaojing; Rose, Kristie L; MacDonald, W Hayes; Zhang, Bing; Schey, Kevin L; Luther, James M

    2016-02-01

    Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.

  2. 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.

  3. 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

    2017-01-01

    AIM 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. METHODS 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. RESULTS 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. CONCLUSION 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. PMID:28101449

  4. Activation of the renin-angiotensin system stimulates biliary hyperplasia during cholestasis induced by extrahepatic bile duct ligation.

    Science.gov (United States)

    Afroze, Syeda H; Munshi, Md Kamruzzaman; Martínez, Allyson K; Uddin, Mohammad; Gergely, Maté; Szynkarski, Claudia; Guerrier, Micheleine; Nizamutdinov, Damir; Dostal, David; Glaser, Shannon

    2015-04-15

    Cholangiocyte proliferation is regulated in a coordinated fashion by many neuroendocrine factors through autocrine and paracrine mechanisms. The renin-angiotensin system (RAS) is known to play a role in the activation of hepatic stellate cells and blocking the RAS attenuates hepatic fibrosis. We investigated the role of the RAS during extrahepatic cholestasis induced by bile duct ligation (BDL). In this study, we used normal and BDL rats that were treated with control, angiotensin II (ANG II), or losartan for 2 wk. In vitro studies were performed in a primary rat cholangiocyte cell line (NRIC). The expression of renin, angiotensin-converting enzyme, angiotensinogen, and angiotensin receptor type 1 was evaluated by immunohistochemistry (IHC), real-time PCR, and FACs and found to be increased in BDL compared with normal rat. The levels of ANG II were evaluated by ELISA and found to be increased in serum and conditioned media of cholangiocytes from BDL compared with normal rats. Treatment with ANG II increased biliary mass and proliferation in both normal and BDL rats. Losartan attenuated BDL-induced biliary proliferation. In vitro, ANG II stimulated NRIC proliferation via increased intracellular cAMP levels and activation of the PKA/ERK/CREB intracellular signaling pathway. ANG II stimulated a significant increase in Sirius red staining and IHC for fibronectin that was blocked by angiotensin receptor blockade. In vitro, ANG II stimulated the gene expression of collagen 1A1, fibronectin 1, and IL-6. These results indicate that cholangiocytes express a local RAS and that ANG II plays an important role in regulating biliary proliferation and fibrosis during extraheptic cholestasis.

  5. Silver and titanium dioxide nanoparticles alter oxidative/inflammatory response and renin-angiotensin system in brain.

    Science.gov (United States)

    Krawczyńska, Agata; Dziendzikowska, Katarzyna; Gromadzka-Ostrowska, Joanna; Lankoff, Anna; Herman, Andrzej Przemysław; Oczkowski, Michał; Królikowski, Tomasz; Wilczak, Jacek; Wojewódzka, Maria; Kruszewski, Marcin

    2015-11-01

    The study was designed to examine the effects of silver AgNPs, 20 nm) and titanium dioxide (Aeroxide(®) P25 TiO2NPs, 21 nm) nanoparticles on brain oxidative stress parameters, its antioxidant potential and brain renin-angiotensin system (RAS) in vivo. The analysis was performed 28 days after single dose injection of TiO2NPs and AgNPs (10 or 5 mg/kg body weight, respectively). The AgNPs, but not TiO2NPs, administration resulted in decreased lipid and cholesterol peroxidation. Antioxidant enzymes gene expression and/or activity were changed differently for TiO2NPs and AgNPs group. The TiO2NPs decreased aromatase gene expression, and glutathione peroxidase and reductase activities. In AgNPs group the sodium dismutase 1 and glutathione reductase mRNA levels were decreased as opposed to their activities. Both NPs altered the expression of brain RAS genes (angiotensinogen, renin, angiotensin I converting enzyme 1 and 2), but only TiO2NPs caused similar changes on protein level. The expression of amyloid beta precursor protein gene was not altered by any kind of injected NPs. The TiO2NPs were more potent modulator of gene expression in the brain than AgNPs, despite the two times lower dosage. These results suggest that AgNPs and TiO2NPs exposure may modulate the brain function, but with different strength.

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    Zohreh Rahimi

    2014-01-01

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

  8. High sugar intake via the renin-angiotensin system blunts the baroreceptor reflex in adult rats that were perinatally depleted of taurine.

    Science.gov (United States)

    Thaeomor, Atcharaporn; Wyss, J Michael; Jirakulsomchok, Dusit; Roysommuti, Sanya

    2010-08-24

    Perinatal taurine depletion leads to several physiological impairments in adult life, in part, due to taurine's effects on the renin-angiotensin system, a crucial regulator of growth and differentiation during early life. The present study tests the hypothesis that perinatal taurine depletion predisposes adult female rats to impaired baroreceptor control of arterial pressure by altering the renin-angiotensin system. Female Sprague Dawley (SD) rats were fed normal rat chow and from conception to weaning drank 3% beta-alanine in water (taurine depletion, TD) or water alone (Control, C). Female offspring ate a normal rat chow and drank water with (G) or without (W) 5% glucose throughout the experiment. To test the possible role of the renin-angiotensin system, 50% of the rats received captopril (an angiotensin converting enzyme inhibitor, 400 mg/L) from 7 days before parameter measurements until the end of experiment. At 7-8 weeks of age, arterial pressure, heart rate, baroreflex control of heart rate and renal nerve activity were studied in either conscious, freely moving or anesthetized rats. Perinatal taurine depletion did not alter resting mean arterial pressure or heart rate in the adult female offspring that received either high or normal sugar intake. Captopril treatment slightly decreased mean arterial pressure but not heart rate in all groups. Compared to controls, only the TDG rats displayed blunted baroreflex responses. Captopril treatment normalized baroreflex sensitivity in TDG. The present data indicate that in perinatal taurine depleted female rats, the renin-angiotensin system underlines the ability of high sugar intake to blunt baroreceptor responses.

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

    Science.gov (United States)

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

    2016-04-01

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

  10. Leptin Mediates 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

    2016-05-01

    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 II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an 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 and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-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 renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    It was hypothesized that primary renal sodium retention blunted the reactivity of the renin-angiotensin-aldosterone system to changes in salt intake in preeclampsia (PE). A randomized, cross-over, double-blinded, dietary intervention design was used to measure the effects of salt tablets or placebo...... 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....

  12. 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.

  13. 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.

    2016-01-01

    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. PMID:27347925

  14. 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

  15. 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.

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

    Science.gov (United States)

    Mattace Raso, Giuseppina; Pirozzi, Claudio; d'Emmanuele di Villa Bianca, Roberta; Simeoli, Raffaele; Santoro, Anna; Lama, Adriano; Di Guida, Francesca; Russo, Roberto; De Caro, Carmen; Sorrentino, Raffaella; Calignano, Antonio; Meli, Rosaria

    2015-01-01

    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 activation of

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

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    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

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

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    Hernán Trimarchi

    2007-10-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

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

    African Journals Online (AJOL)

    nephropathy, Azotemia, Proteinuria, Aldosterone, Renin, Blood pressure. Tropical .... creatinine, MAP: mean arterial blood pressure, NS: not significant, U P/Cr: urinary protein/creatinine ratio .... laboratory and clinical monitoring of these.

  1. Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Uraoka, Maki [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan); Ikeda, Koji, E-mail: ikedak@koto.kpu-m.ac.jp [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan); Nakagawa, Yusuke; Koide, Masahiro; Akakabe, Yoshiki; Nakano-Kurimoto, Ritsuko; Takahashi, Tomosaburo; Matoba, Satoaki; Yamada, Hiroyuki; Okigaki, Mitsuhiko; Matsubara, Hiroaki [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan)

    2009-12-25

    Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.

  2. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control.

    Science.gov (United States)

    de Kloet, Annette D; Liu, Meng; Rodríguez, Vermalí; Krause, Eric G; Sumners, Colin

    2015-09-01

    Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

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

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    Fukasawa Hirotaka

    2012-06-01

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

  4. Renin angiotensin system-regulating aminopeptidase activities in serum of pre- and postmenopausal women with breast cancer.

    Science.gov (United States)

    Martínez-Martos, José Manuel; del Pilar Carrera-González, María; Dueñas, Basilio; Mayas, María Dolores; García, María Jesús; Ramírez-Expósito, María Jesús

    2011-10-01

    Angiotensin peptides regulate vascular tone and natriohydric balance through the renin angiotensin system (RAS) and are related with the angiogenesis which plays an important role in the metastatic pathway. Estrogen influences the aminopeptidases (APs) involved in the metabolism of bioactive peptides of RAS through several pathways. We analyze RAS-regulating AP activities in serum of pre- and postmenopausal women with breast cancer to evaluate the putative value of these activities as biological markers of the development of breast cancer. We observed an increase in aminopeptidase N (APN) and aminopeptidase B (APB) activities in women with breast cancer; however, a decrease in aspartyl-aminopeptidase (AspAP) activity in premenopausal women. These results suggest a slow metabolism of angiotensin II (Ang II) to angiotensin III (Ang III) in premenopausal women and a rapid metabolism of Ang III to angiotensin IV (Ang IV) in pre- and postmenopausal women with breast cancer. An imbalance in the signals activated by Ang II may produce abnormal vascular growth with different response between pre- and postmenopausal women depending on the hormonal profile and the development of the disease.

  5. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology.

    Science.gov (United States)

    Mochel, Jonathan P; Fink, Martin; Peyrou, Mathieu; Desevaux, Cyril; Deurinck, Mark; Giraudel, Jérôme M; Danhof, Meindert

    2013-11-01

    The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis. Its contribution to the development of cardiovascular diseases has long been recognized. Extensive literature has shown that peptides of the RAAS oscillate with a circadian periodicity in humans, under strong influence of posture, sleep, and age. Although observations of time-variant changes in the renin cascade are available in dogs, no detailed chronobiological investigation has been conducted so far. The present studies were designed to explore the circadian variations of plasma renin activity (RA) and urinary aldosterone-to-creatinine ratio (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,fe) renal handling. Data derived from intensive blood and urine sampling, as well as continuous BP monitoring, were collected throughout a 24-h time period, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of day and night observations were compared by parametric statistics. Our results show that variables of the renin cascade, BP, and urinary electrolytes oscillate with significant day-night differences in dogs. An approximately 2-fold (1.6-3.2-fold) change between the average day and night measurements was found for RA (p chronobiology of the renin cascade.

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

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    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.

  7. Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia.

    Science.gov (United States)

    Murphy, Kate T; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S

    2013-09-01

    Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia.

  8. The link between the renin-angiotensin-aldosterone system and renal injury in obesity and the metabolic syndrome.

    Science.gov (United States)

    Thethi, Tina; Kamiyama, Masumi; Kobori, Hiroyuki

    2012-04-01

    Obesity is a risk factor for type 2 diabetes mellitus (DM) and is associated with chronic kidney disease. Activation of the renin-angiotensin-aldosterone system (RAAS) is common in obesity. The RAAS is an important mediator of hypertension. Mechanisms involved in activation of the RAAS in obesity include sympathetic stimulation, synthesis of adipokines in the RAAS by visceral fat, and hemodynamic alterations. The RAAS is known for its role in regulating blood pressure and fluid and electrolyte homeostasis. The role of local/tissue RAAS in specific tissues has been a focus of research. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAAS. Investigators have demonstrated that sex steroids can modulate the expression and activity of the different components of the intrarenal RAAS and other tissues. Our data suggest that obese women without DM and hypertension have significantly higher levels of UAGT than their male counterparts. These differences existed without any background difference in the ratio of microalbumin to creatinine in the urine or the estimated glomerular filtration rate, raising a question about the importance of baseline gender differences in the endogenous RAAS in the clinical spectrum of cardiovascular diseases and the potential utility of UAGT as a marker of the intrarenal RAAS. Animal studies have demonstrated that modifying the amount of angiotensin, the biologically active component of the RAAS, directly influences body weight and adiposity. This article reviews the role of the RAAS in renal injury seen in obesity and the metabolic syndrome.

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

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    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.

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

    Science.gov (United States)

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

    2016-01-01

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

  11. Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney

    Science.gov (United States)

    Domenig, Oliver; Manzel, Arndt; Grobe, Nadja; Königshausen, Eva; Kaltenecker, Christopher C.; Kovarik, Johannes J.; Stegbauer, Johannes; Gurley, Susan B.; van Oyen, Dunja; Antlanger, Marlies; Bader, Michael; Motta-Santos, Daisy; Santos, Robson A.; Elased, Khalid M.; Säemann, Marcus D.; Linker, Ralf A.; Poglitsch, Marko

    2016-01-01

    Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy. PMID:27649628

  12. Comparative Analysis of Renin-Angiotensin System (RAS)-Related Gene Expression Between Hypertensive and Normotensive Rats

    Science.gov (United States)

    Williamson, Chad R.; Khurana, Sandhya; Nguyen, Phong; Byrne, Collin J.; Tai, T.C.

    2017-01-01

    Background The renal renin-angiotensin system (RAS) is physiologically important for blood pressure regulation. Altered regulation of RAS-related genes has been observed in an animal model of hypertension (spontaneously hypertensive rats – SHRs). The current understanding of certain RAS-related gene expression differences between Wistar-Kyoto rats (WKYs) and SHRs is either limited or has not been compared. The purpose of this study was to compare the regulation of key RAS-related genes in the kidneys of adult WKYs and SHRs. Material/Methods Coronal sections were dissected through the hilus of kidneys from 16-week-old male WKYs and SHRs. RT-PCR analysis was performed for Ace, Ace2, Agt, Agtr1a, Agtr1b, Agtr2, Atp6ap2 (PRR), Mas1, Ren, Rnls, and Slc12a3 (NCC). Results Increased mRNA expression was observed for Ace, Ace2, Agt, Agtr1a, Agtr1b, and Atp6ap2 in SHRs compared to WKYs. Mas1, Ren, Slc12a3, and Rnls showed no difference in expression between animal types. Conclusions This study shows that the upregulation of several key RAS-related genes in the kidney may account for the increased blood pressure of adult SHRs. PMID:28138124

  13. Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity.

    Science.gov (United States)

    Slamkova, M; Zorad, S; Krskova, K

    2016-10-01

    Adipose tissue expresses all the renin-angiotensin system (RAS) components that play an important role in the adipogenesis, lipid and glucose metabolism regulation in an auto/paracrine manner. The classical RAS has been found to be over-activated during the adipose tissue enlargement, thus elevated generation of angiotensin II (Ang II) may contribute to the obesity pathogenesis. The contemporary view on the RAS has become more complex with the discovery of alternative pathways, including angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor, (pro)renin receptor, as well as angiotensin IV(Ang IV)/AT4 receptor. Ang-(1-7) via Mas receptor counteracts with most of the deleterious effects of the Ang II-mediated by AT1 receptor implying its beneficial role in the glucose and lipid metabolism, oxidative stress, inflammation, and insulin resistance. Pro(renin) receptor may play a role (at least partial) in the pathogenesis of the obesity by increasing the local production of Ang II in adipose tissue as well as triggering signal transduction independently of Ang II. In this review, modulation of alternative RAS pathways in adipose tissue during obesity is discussed and the involvement of Ang-(1-7), (pro)renin and AT4 receptors in the regulation of adipose tissue homeostasis and insulin resistance is summarized.

  14. Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity

    Directory of Open Access Journals (Sweden)

    Slamkova M

    2016-10-01

    Full Text Available Adipose tissue expresses all the renin-angiotensin system (RAS components that play an important role in the adipogenesis, lipid and glucose metabolism regulation in an auto/paracrine manner. The classical RAS has been found to be over-activated during the adipose tissue enlargement, thus elevated generation of angiotensin II (Ang II may contribute to the obesity pathogenesis. The contemporary view on the RAS has become more complex with the discovery of alternative pathways, including angiotensin-converting enzyme 2 (ACE2/angiotensin (Ang-(1-7/Mas receptor, (prorenin receptor, as well as angiotensin IV(Ang IV/AT4 receptor. Ang-(1-7 via Mas receptor counteracts with most of the deleterious effects of the Ang II-mediated by AT1 receptor implying its beneficial role in the glucose and lipid metabolism, oxidative stress, inflammation, and insulin resistance. Pro(renin receptor may play a role (at least partial in the pathogenesis of the obesity by increasing the local production of Ang II in adipose tissue as well as triggering signal transduction independently of Ang II. In this review, modulation of alternative RAS pathways in adipose tissue during obesity is discussed and the involvement of Ang-(1-7, (prorenin and AT4 receptors in the regulation of adipose tissue homeostasis and insulin resistance is summarized.

  15. The relationship between vitamin D and the renin-angiotensin system in the pathophysiology of hypertension, kidney disease, and diabetes.

    Science.gov (United States)

    Vaidya, Anand; Williams, Jonathan S

    2012-04-01

    Vitamin D has been implicated in the pathophysiology of extraskeletal conditions such as hypertension, kidney disease, and diabetes via its ability to negatively regulate the renin-angiotensin system (RAS). This article reviews the evidence supporting a link between vitamin D and the RAS in these conditions, with specific emphasis on translational observations and their limitations. A literature review of animal and human studies evaluating the role of vitamin D in hypertension, kidney disease, and diabetes was performed. Excess activity of the RAS has been implicated in the pathogenesis of hypertension, chronic kidney disease, decreased insulin secretion, and insulin resistance. Animal studies provide strong support for 1,25-dihydroxyvitamin D(3)-mediated downregulation of renin expression and RAS activity via its interaction with the vitamin D receptor. Furthermore, the activity of vitamin D metabolites in animals is associated with reductions in blood pressure, proteinuria and renal injury, and with improved β-cell function. Many observational, and a few interventional, studies in humans have supported these findings; however, there is a lack of well-designed prospective human interventional studies to definitively assess clinical outcomes. There is a need for more well-designed prospective interventional studies to validate this hypothesis in human clinical outcomes. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. 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.

  17. 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.

  18. [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.

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

    Science.gov (United States)

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

    2012-10-01

    Complicating up to 8% of pregnancies, preeclampsia is the most common glomerular disease worldwide and remains a leading cause of infant and maternal morbidity and mortality. Although the exact pathogenesis of this syndrome of hypertension and proteinuria is still incomplete, a consistent line of evidence has identified an imbalance of proangiogenic and anti-angiogenic proteins as a key factor in the development of preeclampsia. Furthermore, more attention has been recently addressed to the renin-angiotensin aldosterone system (RAAS), to provide understanding on the hypertension of preeclampsia. The imbalance of the RAAS and the imbalance between angiogenic and anti-angiogenic factors, which may be both common to preeclampsia and chronic kidney disease (CKD), might explain why a history of preeclampsia predisposes women to develop CKD. In this review, we briefly describe the characteristics of preeclampsia with a focus on the mechanisms of angiogenesis and the RAAS and its role in the pathogenesis of preeclampsia. Our main focus will be on the intriguing association between preeclampsia and the subsequent increased risk of developing CKD and on the potential mechanisms by which the risk of CKD is elevated in women with a history of preeclampsia.

  20. Cardiovascular Disease, Single Nucleotide Polymorphisms; and the Renin Angiotensin System: Is There a MicroRNA Connection?

    Directory of Open Access Journals (Sweden)

    Terry S. Elton

    2010-01-01

    Full Text Available Essential hypertension is a complex disorder, caused by the interplay between many genetic variants, gene-gene interactions, and environmental factors. Given that the renin-angiotensin system (RAS plays an important role in blood pressure (BP control, cardiovascular regulation, and cardiovascular remodeling, special attention has been devoted to the investigation of single-nucleotide polymorphisms (SNP harbored in RAS genes that may be associated with hypertension and cardiovascular disease. MicroRNAs (miRNAs are a family of small, ∼21-nucleotide long, and nonprotein-coding RNAs that recognize target mRNAs through partial complementary elements in the 3-untranslated region (3-UTR of mRNAs and inhibit gene expression by targeting mRNAs for translational repression or destabilization. Since miRNA SNPs (miRSNPs can create, destroy, or modify miRNA binding sites, this review focuses on the hypothesis that transcribed target SNPs harbored in RAS mRNAs, that alter miRNA gene regulation and consequently protein expression, may contribute to cardiovascular disease susceptibility.

  1. High pulse pressure is not associated with abnormal activation of the renin-angiotensin-aldosterone system in repaired aortic coarctation.

    Science.gov (United States)

    Pedersen, T A L; Pedersen, E B; Munk, K; Hjortdal, V E; Emmertsen, K; Andersen, N H

    2015-04-01

    We investigated the relationship between pulse pressure (PP)--a surrogate marker of arterial stiffness-and activity of the renin-angiotensin-aldosterone system (RAAS) in adult patients with repaired coarctation and normal left ventricular (LV) function. A total of 114 patients (44 (26-74) years, 13 (0.1-40) years at repair) and 20 healthy controls were examined with 24-h ambulatory blood pressure monitoring, echocardiography, vasoactive hormone levels and magnetic resonance of the thoracic aorta. Forty-one patients (36%) were taking antihypertensives (28 RAAS inhibitors). Fifty-one had mean 24-h blood pressures >130/80 mm Hg. Hypertension was not associated with age at repair (P=0.257). Patients had higher PP and LV mass compared with controls (52±11 vs. 45±5 mm Hg and 221±71 vs. 154±55 g, respectively; both Pcoarctation have increased PP and LV mass compared with controls. PP increased with increasing recoarctation. Hypertension was present also in the absence of recoarctation. These changes could not be explained by abnormal activation of the RAAS.

  2. Inhibiting renin angiotensin system in rate limiting step by aliskiren as a new approach for preventing indomethacin induced gastric ulcers.

    Science.gov (United States)

    Halici, Zekai; Polat, Beyzagul; Cadirci, Elif; Topcu, Atilla; Karakus, Emre; Kose, Duygu; Albayrak, Abdulmecit; Bayir, Yasin

    2016-10-25

    Previously blocking the renin angiotensin system (RAAS) has been effective in the prevention of gastric damage. Therefore, the aim of this study was to investigate the effects of aliskiren, and thus, direct renin blockage, in indomethacin-induced gastric damage model. Effects of aliskiren were evaluated in indomethacin-induced gastric damage model on Albino Wistar rats. Effects of famotidine has been investigated as standard antiulcer agent. Stereological analyses for ulcer area determination, biochemical analyses for oxidative status determination and molecular analyses for tissue cytokine and cyclooxygenase determination were performed on stomach tissues. In addition, to clarify antiulcer effect mechanism of aliskiren pylorus ligation-induced gastric acid secretion model was applied on rats. Aliskiren was able to inhibit indomethacin-induced ulcer formation. It also inhibited renin, and thus, decreased over-produced Angiotensin-II during ulcer formation. Aliskiren improved the oxidative status and cytokine profile of the stomach, which was most probably impaired by increased Angiotensin II concentration. Aliskiren also increased gastroprotective prostaglandin E2 concentration. Finally, aliskiren did not change the gastric acidity in pylorus ligation model. Aliskiren exerted its protective effects on stomach tissue by decreasing inflammatory cytokines and oxidative stress as a result of inhibiting the RAAS, at a rate-limiting step, as well as its end product, angiotensin II. Aliskiren also significantly increased protective factors such as PGE2, but not affect aggressive factors such as gastric acidity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. The influence of renin angiotensin aldosterone system blockers on asymmetric dimethylarginine levels in patients with chronic glomerulonephritis

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    Heleniak Zbigniew

    2016-12-01

    Full Text Available Endothelial dysfunction could be related to the limited availability of nitric oxide (NO. NO is synthesized with the participation of an NO synthase whose activity is inhibited by asymmetric dimethylarginine (ADMA. The synthesis of ADMA is exacerbated by oxidative stress, and several studies have shown the efficacy of drugs acting on the renin-angiotensin-aldosterone system (RAAS (converting enzyme inhibitors and angiotensin II receptor antagonists in reducing the level of ADMA. The probable mechanism of drug action is a reduction of oxidative stress through a decrease of angiotensin II formation. The aim of this study was to assess the influence of RAAS blockers on the plasma concentration of ADMA in patients with chronic glomerulonephritis (ChGN. The study included 37 patients, placed into group A and group B, depending on the treatment. Both groups were treated with RAAS blockers. In group B, immunosuppressive drugs were additionally administered. The control visits were at the 0, 6 and 12 months of observation. In both the studied groups (A+B, a significant reduction of ADMA (0.77 vs 0.4 μmol/l; p<0.05 was noticed. In patients suffering from ChGN, the use of RAAS blockers resulted in a significant decrease of plasma ADMA concentration, independently of immunosupressive treatment.

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

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    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.

  5. Evaluation of the contribution of renin angiotensin system polymorphisms to the risk of coronary artery disease among Tunisians.

    Science.gov (United States)

    Abboud, Nesrine; Ghazouani, Lakhder; Kaabi, Belhassen; Ben-Hadj-Khalifa, Sonia; Addad, Fawzi; Marwen, Mahjoub; Almawi, Wassim Y; Mahjoub, Touhami

    2010-10-01

    Recent studies have identified genetic markers that may directly influence the risk of the coronary artery disease (CAD), in particular the renin angiotensin system genes. Since there are no existing data for the Tunisian population, we investigated the association between these polymorphisms (angiotensin-converting enzyme [ACE] insertion/deletion [Ins/Del]; the angiotensinogen T174M and M235T; and the angiotensin II type 1 receptor A1166C polymorphisms) and CAD in Tunisians. Study subjects comprised 341 cases and 316 age- and sex-matched healthy individuals. Clinical characteristics and other biochemical and environmental risk factors were collected for both. The distribution of the Ins/Del genotypes was significantly different between cases and controls (p = 0.049) with the genotype Ins/Ins identified as a risk, p = 0.02. Similarly, the distributions of the T174M and M235T genotypes were significantly different between cases and controls (p = 0.037 and 0.047, respectively) with 174 M/M and 235 T/T as the risky genotypes (p = 0.001 and 0.026, respectively). However, A1166C genotype frequencies were not significantly different between patients and controls. In conclusion, our results suggest that a significantly higher risk of CAD was associated with the Ins/Del, the M235T, and T174M polymorphisms; other environmental variables such as body mass index; and biochemical variables such as cholesterol.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Leung PS

    2001-01-01

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

  9. No evidence for association between the renin-angiotensin-aldosterone system and otosclerosis in a large Belgian-Dutch population.

    NARCIS (Netherlands)

    Schrauwen, I.; Thys, M.; Straeten, K. van der; Fransen, E.; Ealy, M.; Cremers, C.W.R.J.; Dhooge, I.J.; Heyning, P. van de; Offeciers, E.E.; Smith, R.J.; Camp, G. van

    2009-01-01

    HYPOTHESIS/BACKGROUND: Otosclerosis is a frequent cause of hearing impairment in the Caucasian population and is characterized by abnormal bone remodeling of the otic capsule. Associations with several genes have been reported, and recently, an association between the renin-angiotensin-aldosterone

  10. Association between polymorphisms in the renin-angiotensin-aldosterone system genes and essential hypertension in the Han Chinese population.

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    Lindan Ji

    Full Text Available BACKGROUND: Renin-angiotensin-aldosterone system (RAAS is the most important endocrine blood pressure control mechanism in our body, genes encoding components of this system have been strong candidates for the investigation of the genetic basis of hypertension. However, previous studies mainly focused on limited polymorphisms, thus we carried out a case-control study in the Han Chinese population to systemically investigate the association between polymorphisms in the RAAS genes and essential hypertension. METHODS: 905 essential hypertensive cases and 905 normotensive controls were recruited based on stringent inclusion and exclusion criteria. All 41 tagSNPs within RAAS genes were retrieved from HapMap, and the genotyping was performed using the GenomeLab SNPstream Genotyping System. Logistic regression analysis, Multifactor dimensionality reduction (MDR, stratified analysis and crossover analysis were used to identify and characterize interactions among the SNPs and the non-genetic factors. RESULTS: Serum levels of total cholesterol (TC and triglyceride (TG, and body mass index (BMI were significantly higher in the hypertensive group than in the control group. Of 41 SNPs genotyped, rs3789678 and rs2493132 within AGT, rs4305 within ACE, rs275645 within AGTR1, rs3802230 and rs10086846 within CYP11B2 were shown to associate with hypertension. The MDR analysis demonstrated that the interaction between BMI and rs4305 increased the susceptibility to hypertension. Crossover analysis and stratified analysis further indicated that BMI has a major effect, and rs4305 has a minor effect. CONCLUSION: These novel findings indicated that together with non-genetic factors, these genetic variants in the RAAS may play an important role in determining an individual's susceptibility to hypertension in the Han Chinese.

  11. Role of the Renin-Angiotensin-Aldosterone System and Its Pharmacological Inhibitors in Cardiovascular Diseases: Complex and Critical Issues.

    Science.gov (United States)

    Borghi, Claudio; Rossi, Francesco

    2015-12-01

    Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

  12. Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue.

    Science.gov (United States)

    Gálvez-Prieto, B; Bolbrinker, J; Stucchi, P; de Las Heras, A I; Merino, B; Arribas, S; Ruiz-Gayo, M; Huber, M; Wehland, M; Kreutz, R; Fernandez-Alfonso, M S

    2008-04-01

    Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin-angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar-Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT(1a), and AT(2) receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT(1a) receptor were found in perivascular adipose tissue. The AT(1b) receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

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

    Science.gov (United States)

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

    2015-08-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Dimitar Divchev

    2008-06-01

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

  15. Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin-angiotensin-aldosterone system: antihypertensive effects and benefits beyond BP control.

    Science.gov (United States)

    Ferrario, Carlos M

    2010-02-27

    This article reviews the importance of the renin-angiotensin-aldosterone system (RAAS) in the cardiometabolic continuum; presents the pros and cons of dual RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); and examines the theoretical and practical benefits supporting the use of direct renin inhibitors (DRIs) in combination with ACEIs or ARBs. The author reviewed the literature for key publications related to the biochemical physiology of the RAAS and the pharmacodynamic effects of ACEIs, ARBs, and DRIs, with a particular focus on dual RAAS blockade with these drug classes. Although ACEI/ARB combination therapy produces modest improvement in BP, it has not resulted in the major improvements predicted given the importance of the RAAS across the cardiorenal disease continuum. This may reflect the fact that RAAS blockade with ACEIs and/or ARBs leads to exacerbated renin release through loss of negative-feedback inhibition, as well as ACE/aldosterone escape through RAAS and non-RAAS-mediated mechanisms. Plasma renin activity (PRA) is an independent predictor of morbidity and mortality, even for patients receiving ACEIs and ARBs. When used alone or in combination with ACEIs and ARBs, the DRI aliskiren effectively reduces PRA. Reductions in BP are greater with these combinations, relative to the individual components alone. It is possible that aliskiren plus either an ACEI or ARB may provide greater RAAS blockade than monotherapy with ACEIs or ARBs, and lead to additive improvement in BP and clinically important outcomes. Copyright 2009 Elsevier Inc. All rights reserved.

  16. Ovariectomy modify local renin-angiotensin-aldosterone system gene expressions in the heart of ApoE (-/-) mice.

    Science.gov (United States)

    Borges, Celina Carvalho; Penna-de-Carvalho, Aline; Medeiros Junior, Jorge L; Aguila, Marcia Barbosa; Mandarim-de-Lacerda, Carlos A

    2017-10-04

    The evaluation of the local Renin-Angiotensin-Aldosterone system (RAAS) gene expressions in the heart of ovariectomized (OVX) apolipoprotein E deficient mice (ApoE). Four-months old C57BL/6 female mice (wild-type, wt, n=20), and ApoE female mice (n=20), were submitted to OVX or a surgical procedure without ovary removal (SHAM) and formed four groups (n=10/group): SHAM/wt, SHAM/ApoE, OVX/wt, and OVX/ApoE. OVX led to greater body mass, plasma triglycerides (TG) and total cholesterol, and resulted in insulin resistance and altered RAAS gene expressions in the heart tissue. The gene expression of angiotensin-converting enzyme (ACE)-2 was lower in OVX/wt than in SHAM/wt (P=0.0004), Mas receptor (MASr) was lower in OVX/wt compared to SHAM/wt (P<0.0001). Also, angiotensin II receptor type 1 (AT1r) was higher in OVX/wt than in SHAM/wt (P=0.0229), and AT2r was lower in OVX/wt than in SHAM/wt (P=0.0121). OVX and ApoE deficiency showed interaction potentializing the insulin resistance, increasing TG levels and altering ACE and MASr gene expressions. ACE gene expression was higher in OVX/ApoE than in OVX/wt (P<0.0001), and MASr gene expression was lower in OVX/ApoE than in OVX/wt (P<0.0001). The impact of OVX on local RAAS cascade in the heart of ApoE deficient animals, besides the metabolic changes culminating with insulin resistance, involves an upregulation of renin, ACE, and AT1r gene expressions. The findings may contribute to clarify the mechanisms of development of postmenopausal hypertension and the link between RAAS and apolipoprotein E. Copyright © 2017. Published by Elsevier Inc.

  17. Effect of oxygen on the expression of renin-angiotensin system components in a human trophoblast cell line.

    Science.gov (United States)

    Delforce, Sarah J; Wang, Yu; Van-Aalst, Meg E; Corbisier de Meaultsart, Celine; Morris, Brian J; Broughton-Pipkin, Fiona; Roberts, Claire T; Lumbers, Eugenie R; Pringle, Kirsty G

    2016-01-01

    During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. While the RAS and oxygen both stimulate angiogenesis, how they interact within the placenta is unknown. We postulated that low oxygen increases expression of the proangiogenic RAS pathway and that this is associated with increased VEGF in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in one of three oxygen tensions (1%, 5% and 20%). RAS and VEGF mRNA expression were determined by qPCR. Prorenin, angiotensin converting enzyme (ACE) and VEGF protein levels in the supernatant, as well as prorenin and ACE in cell lysates, were measured using ELISAs. Low oxygen significantly increased the expression of both angiotensin II type 1 receptor (AGTR1) and VEGF (both P < 0.05). There was a positive correlation between AGTR1 and VEGF expression at low oxygen (r = 0.64, P < 0.005). Corresponding increases in VEGF protein were observed with low oxygen (P < 0.05). Despite no change in ACE1 mRNA expression, ACE levels in the supernatant increased with low oxygen (1% and 5%, P < 0.05). Expression of other RAS components did not change. Low oxygen increased AGTR1 and VEGF expression, as well as ACE and VEGF protein levels, suggesting that the proangiogenic RAS pathway is activated. This highlights a potential role for the placental RAS in mediating the proangiogenic effects of low oxygen in placental development.

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

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

    2016-07-01

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

  19. Review of renin-angiotensin system%肾素-血管紧张素系统的回顾

    Institute of Scientific and Technical Information of China (English)

    廖梦阳; 程龙献; 廖玉华

    2012-01-01

    The discovery of new members of renin-angiotensin system (RAS) changes the classical opinion that only angiotensin (Ang) Ⅱ converted by angiotensin-convertion enzyme (ACE) has a pathogenic role, besides renin binded renin-prorenin receptors (RPR) and Ang ]V binded insulin-regulated amino peptidase receptors (IRAP). Ang-(l-7) and Ang-(l-9) are converted by newly finding ACE2. Ang-(l-7) binding Mas receptors and Ang-(l-9) binding AT2 receptors lead to cardiovascular protective effect. However, pathogenic role of RAS remains dominant. The discovery of new members of RAS supports new theoretical basis for recognition of the blockade of RAS in results of clinical trials.%肾素-血管紧张素系统(RAS)新成员的发现,改变了既往认为只有血管紧张素转化酶(ACE)催化生成的血管紧张素(Ang)Ⅱ才产生致病作用的观点,证明肾素与前肾素-肾素受体(RPR)的结合及AngⅣ与胰岛素调控氨基肽酶受体(IRAP)的结合同样也会产生致病作用.新发现的ACE2催化Ang-(1-7)和Ang-(1-9)的生成,Ang-(1-7)与Mas受体和Ang-(1-9)与AT2受体结合之后,可产生心血管保护作用,但RAS的致病作用仍然占优势.RAS新成员的发现,对认识RAS抑制剂的临床研究结果提供了新的理论依据.

  20. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution?

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    Athyros, Vasilios G; Mikhailidis, Dimitri P; Kakafika, Anna I; Tziomalos, Konstantinos; Karagiannis, Asterios

    2007-04-01

    This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

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

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    Therese Featherston

    2016-09-01

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

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

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    Eliete Dalla Corte Frantz

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

  3. H(2S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation.

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    Hong Xue

    Full Text Available Decrease in endogenous hydrogen sulfide (H2S was reported to participate in the pathogenesis of diabetic nephropathy (DN. This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS. Cultured renal mesangial cells (MCs and streptozotocin (STZ induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT, angiotensin converting enzyme (ACE, angiotensin II (Ang II type I receptor (AT1, transforming growth factor-β1 (TGF-β1 and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE by DL-propargylglycine (PPG resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.

  4. Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats

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    Nilo César do Vale Baracho

    Full Text Available Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD. Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy, or subjected to sham surgery (control. Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg; ¾ Nephrectomy receiving candesartan (10 mg/kg and ¾ Nephrectomy receiving aliskiren (10 mg/kg. Urine output, water intake, mean arterial pressure (MAP and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

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

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    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.

  6. Correlation between renin-angiotensin system gene polymorphisms and essential hypertension in the Chinese Yi ethnic group.

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    Yang, Yu-Ling; Mo, Yan-Ping; He, Yong-Shu; Yang, Fang; Xu, Yan; Li, Cheng-Cheng; Wang, Jiao; Reng, Hao-Ming; Long, Li

    2015-12-01

    The renin-angiotensin system (RAS) has been considered to play an important role in the regulation of blood pressure. This study aimed to investigate the correlation between RAS gene polymorphisms and essential hypertension (EH) in the Chinese Yi ethnic group. A total of 244 EH subjects and 185 normotensive individuals from the Chinese Yi ethnic group were genotyped for AGT M235T (rs699), AT1R A1166C (rs5186), ACE I/D (rs4340) and ACE G2350A (rs4343) polymorphisms by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Significant differences in the allele and genotype frequency of ACE G2350A were observed between the EH cases and controls (p=0.001, 0.002). After being grouped by gender, significant differences in the allele and genotype frequency of ACE G2350A and AT1R A1166C were observed between females of the EH cases and controls (ACE G2350A: p=0.000, 0.002; AT1R A1166C: p=0.008, 0.011). After excluding the influence of multifactorial interactions, the ACE G2350A polymorphism is significantly associated with the pathogenesis of EH in the Chinese Yi ethnic group (odds ratio (OR)=1.656, 95% confidence interval (CI) 1.807-2.524, p=0.019). The RAS-related ACE G2350A polymorphism is associated with the pathogenesis of EH in the Chinese Yi ethnic group. © The Author(s) 2015.

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

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

    2016-07-01

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

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

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    Annayya R Aroor

    2013-10-01

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

  9. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension.

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    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-07-15

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

  10. Effects of renin-angiotensin-aldosterone system blockade on chlorhexidine gluconate-induced sclerosing encapsulated peritonitis in rats.

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    Koçak, Gülay; Azak, Alper; Astarcı, Hesna Müzeyyen; Huddam, Bülent; Karaca, Gökhan; Ceri, Mevlüt; Can, Murat; Sert, Mehmet; Duranay, Murat

    2012-02-01

    Sclerosing encapsulated peritonitis (SEP) is a rare complication of long term peritoneal dialysis. Renin-angiotensin-aldosterone system (RAAS) may play a role in the development of peritoneal fibrosis in CAPD patients. We aimed to evaluate the effect of aliskiren, valsartan, and aliskiren + valsartan therapy on SEP. The study included 30 Wistar albino rats which were divided into five groups: I (Control) SF solution i.p.; II (CG group) chlorhexidine gluconate i.p.; III aliskiren oral plus CG i.p.; IV valsartan oral plus CG i.p.; and V aliskiren oral, valsartan oral and CG i.p. On the twenty-first day, all of the rats were sacrificed. All of the groups were analyzed in terms of peritoneal thickness, degree of inflammation, vasculopathy, neovascularization and fibrosis. Also, the parietal peritoneal tissue samples were evaluated for matrix metalloproteinase 2 (MMP-2) using the ELISA method. Peritoneal thickness and fibrosis scores were lower in the valsartan group compared to the CG group (P 0.05). Tissue MMP-2 levels were significantly higher in the CG group compared other groups (P < 0.05). There were no statistically significant differences between the aliskiren, valsartan and aliskiren + valsartan groups according to the tissue MMP-2 levels. Due to the antifibrotic properties of valsartan, it is thought to be a possible choice to prevent SEP development. We found no positive impact of aliskiren or aliskiren + valsartan combination compared to valsartan alone. © 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.

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

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    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.

  12. Comparison of intrarenal renin-angiotensin system activity in diabetic versus non-diabetic patients with overt proteinuria.

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    Park, Ji Hyeon; Jang, Hye Ryoun; Lee, Jong-Ho; Lee, Jung Eun; Huh, Wooseong; Lee, Kyu-Beck; Kwon, Young-Joo; Do, Jun Young; Kim, Hye Young; Kim, Yoon-Goo

    2015-04-01

    The intrarenal renin-angiotensin system (RAS) has been reported to be activated in chronic proteinuria patients. This study aimed to compare intrarenal RAS activity between diabetic nephropathy (DN) and non-diabetic nephropathy (NDN) patients with overt proteinuria. A multicenter, cross-sectional study was conducted in 116 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] > 1 mg/mg Cr). To estimate intrarenal RAS activity we measured urinary excretion of angiotensinogen (uAGT) and renin (uRenin) in patients with DN (n = 38) and NDN (n = 78). Both natural logarithms of uAGT/urinary creatinine (ln[uAGT/uCr]) and uRenin (ln[uRenin/uCr]) levels were significantly higher in patients with DN compared with those with NDN (ln[uAGT/uCr]: 4.16 ± 1.13 in DN vs. 3.52 ± 1.21 in NDN, P = 0.007; ln[uRenin/uCr]: 5.66 ± 1.60 in DN vs. 4.29 ± 1.48 in NDN, P proteinuria, both uAGT and uRenin were higher in DN in patients with subnephrotic-range proteinuria (uPCR proteinuria (uPCR ≥ 3.5 mg/mg Cr), only uRenin was higher in DN compared to NDN. In a multiple regression analysis, diabetes showed independent association with uRenin. Consistently elevated uRenin in DN, regardless of the amount of proteinuria, indicates that intrarenal RAS activity may be higher in DN compared to NDN in patients with overt proteinuria. © 2014 Asian Pacific Society of Nephrology.

  13. INFLUENCE OF THE POLYMORPHISM OF THE RENIN-ANGIOTENSIN SYSTEM GENES ON THE CARDIAC ARRHYTHMIAS IN CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY

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    N. A. Berezneva

    2013-01-01

    Full Text Available Hypertrophic cardiomyopathy (HCMP is a genetically determined myocardial disease, characterized by massive hypertrophy of the myocardium of the left and/or (rarely the right ventricle, often associated with obstruction of the left ventricular outflow tract and diastolic dysfunction. The course of disease can be complicated by development of various cardiac arrhythmias.  It was reported that severity of HCMP course depends at certain degree on polymorphism of candidate genes, including genes of the renin angiotensin system (RAS. Influence of RAS genes polymorphism on the frequency and character of cardiac arrhythmias in childhood is almost not studied. Aim: to determine the influence of RAS genes polymorphism on the prevalence and structure of cardiac arrhythmias in children with HCMP. Patients and methods: analysis of influence of RAS genes polymorphism on the prevalence and structure of cardiac arrhythmias was performed in 32 children with HCMP. All the patients were carried out ECG, cardiac ultrasound and ECG Holter monitoring. Polymorphism of the RAS genes (renin gene (REN G83A, angiotensinogen gene (AGT M235T, angiotensin-converting enzyme gene (ACE I/D, angiotensin II receptor type 1 gene (AGTR1 A1166C. Results: in patients with HCMP was established a higher frequency of TT-genotype and T-alleles of angiotensinogen gene than in comparison group. In homozygous patients with T-allele of angiotensinogen gene ventricular arrhythmia was found reliably more often than in patients with MT- and MM-genotypes, which suggested that M235T polymorphism of angiotensinogen gene influenced on intensity of ventricular arrhythmias in children with HCMP. Conclusions: in children with HCMP and cardiac arrhythmias analysis of M235T polymorphism of angiotensinogen gene can be used as an additional criterion for revealing of patients with high risk of arrhythmic complications and for development of preventative measures.

  14. 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.

  15. 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 (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 in preeclampsia involves constrictor AT2 receptors.

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

    Science.gov (United States)

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

    2016-09-01

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

  17. 肾素-血管紧张素系统与缺血性脑血管病%The renin-angiotensin system and ischemic cerebrovacular disease

    Institute of Scientific and Technical Information of China (English)

    梁辉; 范金英; 周盛年

    2003-01-01

    缺血性脑血管病(ischemic cerebrovacular disease,ICD)是临床多发病、常见病.随着对肾素-血管紧张素系统(renin-angiotensin system,RAS)研究的深入,二者的关系已引起人们的注意.本文主要就RAS对ICD各种危险因素以及病理生理变化等方面的影响做一综述.

  18. Improving BP control with combined renin-angiotensin system blockade and thiazide diuretics in hypertensive patients with diabetes mellitus or kidney disease.

    Science.gov (United States)

    Palmer, Biff F

    2008-01-01

    Most hypertensive patients will require more than one antihypertensive drug to lower BP below target levels. The combination of diuretics with renin-angiotensin system (RAS) antagonists offers several advantages to include additive BP-lowering efficacy and enhanced reductions in urinary protein excretion. Thiazide diuretics are associated with metabolic complications that are particularly evident when used in high doses. When used in combination with RAS blockade, metabolic complications such as hypokalemia are minimized. The avoidance of hypokalemia has been linked to less thiazide-induced glucose intolerance. Patient persistence on therapy is dependent on well tolerated drug combinations.

  19. The More Complex Renin-Angiotensin System: New Insights Into An Old System

    NARCIS (Netherlands)

    F. Gembardt (Florian)

    2011-01-01

    textabstractSince the first description of renin by Tigerstedt and Bergmann in 1898,1 the reninangiotensin system (RAS) has been extensively studied. In the last decades, many investigations have demonstrated the importance of the RAS for maintenance and regulation of many physiological processes. O

  20. 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.

  1. 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-specific or

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

    Science.gov (United States)

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

    2016-01-01

    CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P < 0.01), while Sprague-Dawley rats had intermediate content (1.85 ± 0.27 ng/mg tissue). Microinjection of the CB1receptor antagonist SR141716A (36 pmol) into the NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS.

  3. Atrial fibrillation and arterial hypertension: A common duet with dangerous consequences where the renin angiotensin-aldosterone system plays an important role.

    Science.gov (United States)

    Seccia, Teresa Maria; Caroccia, Brasilina; Muiesan, Maria Lorenza; Rossi, Gian Paolo

    2016-03-01

    Atrial fibrillation (AF) represents the most common sustained cardiac arrhythmia, as it affects 1%-2% of the general population and up to 15% of people over 80 years. High blood pressure, due to its high prevalence in the general population, is by far the most common condition associated with AF, although a variety of diseases, including valvular, coronary heart and metabolic diseases, are held to create the substrate favouring AF. Due to the concomitance of these conditions, it is quite challenging to dissect the precise role of high blood pressure in triggering/causing AF. Hence, even though the intimate association between high blood pressure and AF has been known for decades, the underlying mechanisms remain partially unknown. Accumulating evidences point to a major role of the renin-angiotensin-aldosterone system in inducing cardiac inflammation and fibrosis, and therefore electric and structural atrial and ventricular remodelling, with changes in ions and cell junctions leading to AF development. These evidences are herein reviewed with a particular emphasis to the role of the renin-angiotensin-system aldosterone system.

  4. Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia.

    Science.gov (United States)

    Hsu, Ta-Wei; Liu, Jia-Sin; Hung, Szu-Chun; Kuo, Ko-Lin; Chang, Yu-Kang; Chen, Yu-Chi; Hsu, Chih-Cheng; Tarng, Der-Cherng

    2014-03-01

    The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN Prospective cohort study. Taiwan. From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents. Users (n = 14,117) and nonusers (n = 14,380) of ACEIs/ARBs. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. In a median follow-up of 7 months, 20,152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.

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

    Science.gov (United States)

    Duan, Yaqian; Moldovan, Leni; Miller, Rehae C.; Beli, Eleni; Salazar, Tatiana; Hazra, Sugata; Al-Sabah, Jude; Chalam, KV; Raghunandan, Sneha; Vyas, Ruchi; Parsons-Wingerter, Patricia; Oudit, Gavin Y.; Grant, Maria B.

    2016-01-01

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

  6. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Toh, Sengwee; Reichman, Marsha E; Houstoun, Monika; Ross Southworth, Mary; Ding, Xiao; Hernandez, Adrian F; Levenson, Mark; Li, Lingling; McCloskey, Carolyn; Shoaibi, Azadeh; Wu, Eileen; Zornberg, Gwen; Hennessy, Sean

    2012-11-12

    Although certain drugs that target the renin- angiotensin-aldosterone system are linked to an increased risk for angioedema, data on their absolute and comparative risks are limited. We assessed the risk for angioedema associated with the use of angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and the direct renin inhibitor aliskiren. We conducted a retrospective, observational, inception cohort study of patients 18 years or older from 17 health plans participating in the Mini-Sentinel program who had initiated the use of an ACEI (n = 1 845 138), an ARB (n = 467 313), aliskiren (n = 4867), or a β-blocker (n = 1 592 278) between January 1, 2001, and December 31, 2010. We calculated the cumulative incidence and incidence rate of angioedema during a maximal 365-day follow-up period. Using β-blockers as a reference and a propensity score approach, we estimated the hazard ratios of angioedema separately for ACEIs, ARBs, and aliskiren, adjusting for age, sex, history of allergic reactions, diabetes mellitus, heart failure, or ischemic heart disease, and the use of prescription nonsteroidal anti-inflammatory drugs. A total of 4511 angioedema events (3301 for ACEIs, 288 for ARBs, 7 for aliskiren, and 915 for β-blockers) were observed during the follow-up period. The cumulative incidences per 1000 persons were 1.79 (95% CI, 1.73-1.85) cases for ACEIs, 0.62 (95% CI, 0.55-0.69) cases for ARBs, 1.44 (95% CI, 0.58-2.96) cases for aliskiren, and 0.58 (95% CI, 0.54-0.61) cases for β-blockers. The incidence rates per 1000 person-years were 4.38 (95% CI, 4.24-4.54) cases for ACEIs, 1.66 (95% CI, 1.47-1.86) cases for ARBs, 4.67 (95% CI, 1.88-9.63) cases for aliskiren, and 1.67 (95% CI, 1.56-1.78) cases for β-blockers. Compared with the use of β-blockers, the adjusted hazard ratios were 3.04 (95% CI, 2.81-3.27) for ACEIs, 1.16 (95% CI, 1.00-1.34) for ARBs, and 2.85 (95% CI, 1.34-6.04) for aliskiren. Compared with β-blockers, ACEIs or

  7. Correlation of renin angiotensin system (RAS candidate gene polymorphisms with response to Ramipril in patients with essential hypertension

    Directory of Open Access Journals (Sweden)

    S Gupta

    2015-01-01

    Full Text Available Background: The renin-angiotensin system (RAS is an important facet of blood pressure regulation physiology. Treatment of essential hypertension targets the RAS using Angiotensin Converting Enzyme Inhibitors (ACEIs. However, ACEIs are not uniformly effective and show inter-individual pharmacodynamic variations. Aim: To assess the correlation between genetic polymorphisms in the genes coding for RAS components (angiotensin converting enzyme (ACE I/D, α-adducin (ADD1 and β1 -adrenoreceptor (β1-ADR and response to Ramipril. Materials and Methods: We recruited 120 patients with essential hypertension who were administered Ramipril monotherapy initially, followed by combination therapy, if needed, based on their responses. Relationship between genotypes of the three candidate genes and decrease in the blood pressure (BP was analyzed. Results: One hundred and six patients were evaluable at the end of the study period and 21 different genotypes were observed among them. Seven of them were classified as responders after 8 weeks and at the end of 12 weeks, an additional 77 (72.64% were deemed responders. 19/22 non-responders were treated with combination therapy and 7/19 (36.84% showed a response to the same. There was a significant difference between the proportions of responders and non-responders among the genotypes of the ADD1 and β1-ADR genes (P = 0.005 and 0.003, respectively. The best predictors of response to Ramipril 5 mg daily were the II/GG/SS, II/TG/SS, II/GG/SG, ID/GG/SS, ID/GG/SG and ID/TT/SS and DD/GG/SS; II/GG/GG, II/TT/SG, ID/TG/SG, ID/TT/SG, DD/GG/SG and DD/GG/GG were moderately predictive and II/TT/SS, II/TG/GG, ID/TG/GG, DD/TG/SG and DD/TG/GG were poorly predictive of response. Discussion: Variable responses to Ramipril may be the result of genetic factors. Conclusion: Pre-prescription genotyping may help individualize treatment.

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

    Directory of Open Access Journals (Sweden)

    Igor Lucas Gomes-Santos

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

  9. Association between polymorphisms of the renin-angiotensin system genes and breast cancer risk: a meta-analysis.

    Science.gov (United States)

    Xi, Bo; Zeng, Tao; Liu, Liu; Liang, Yajun; Liu, Weina; Hu, Yuehua; Li, Jun

    2011-11-01

    The renin-angiotensin system (RAS) has been considered to be implicated in the development of breast cancer. However, the results are inconsistent. In this study, we conducted a meta-analysis to assess the association between four polymorphisms, including angiotensin I-converting enzyme (ACE) I/D and A240T, angiotensin II type 1 receptor (AGTR1) A1166C and angiotensinogen (AGT) M235T polymorphisms, and breast cancer risk. Published literature from PubMed, ISI web of science, and Embase databases were retrieved. All studies evaluating the association between ACE I/D, ACE A240T, AGTR1 A1166C, or AGT M235T polymorphism and breast cancer risk were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Ten studies (1,650 cases and 9,283 controls) on ACE I/D polymorphism, six studies (1,316 cases and 2,632 controls) on ACE A240T polymorphism, three studies (235 cases and 601 controls) on AGTR1 A1166C polymorphism, and two studies (273 cases and 3,547 controls) on AGT M235T polymorphism were included. Overall, the meta-analysis showed no significant association between I/D or A240T polymorphism and breast cancer risk in either genetic model. Further subgroup analysis by ethnicity also revealed non-significant association in Caucasian or Asian populations except for Africans (the statistically significant association for ACE I/D or A240T polymorphism in Africans derived from only one study). A marginally significant association was observed for AGTR1 A1166C polymorphism in Caucasians (CC vs. AA: OR = 0.31, 95% CI 0.10-0.99). In addition, there was a significant association between AGT M235T polymorphism and breast cancer risk in Caucasians (OR = 1.45, 95% CI 1.12-1.88). The present meta-analysis suggested that ACE I/D and A240T polymorphisms might not be a good predictor of breast cancer risk, while AGTR1 A1166C and AGT M235T polymorphisms might be implicated in the pathogenesis of breast cancer. Given the

  10. Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

    Science.gov (United States)

    Scurrah, Katrina J; Lamantia, Angela; Ellis, Justine A; Harrap, Stephen B

    2017-06-01

    Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis). We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1) were individually associated with lower systolic blood pressure with significant (Ppressure. Four SNP pairs were at the same gene (2 for REN, 1 for AGT, and 1 for AGTR1). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype. © 2017 American Heart Association, Inc.

  11. 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.

  12. Effect of Renin-Angiotensin System on Heart Failure%肾素-血管紧张素系统在心力衰竭中的作用

    Institute of Scientific and Technical Information of China (English)

    韩凌

    2013-01-01

    充血性心力衰竭是心脏病的终末阶段,肾素-血管紧张素系统在心室重塑、心力衰竭的发展过程中起到重要作用.现总结近年来研究发现的肾素-血管紧张素系统在生理、病理生理等方面对心力衰竭中所起的作用,并探讨其涉及的如血管紧张素受体在心力衰竭治疗中的研究进展.%Congestive heart failure is the end stage of heart disease, and renin-angiotensin system plays an important role in heart failure. This article summarizes the function and potential pathogenic mechanisms of renin-angiotensin system found in heart failure, and discusses treatment methods for heart failure.

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

    Directory of Open Access Journals (Sweden)

    Jia Sun

    2016-01-01

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

  14. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome.

    Science.gov (United States)

    Putnam, Kelly; Shoemaker, Robin; Yiannikouris, Frederique; Cassis, Lisa A

    2012-03-15

    The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment.

  15. Administration of exogenous 1,25(OH)2D3 normalizes overactivation of the central renin-angiotensin system in 1α(OH)ase knockout mice.

    Science.gov (United States)

    Zhang, Wei; Chen, Lulu; Zhang, Luqing; Xiao, Ming; Ding, Jiong; Goltzman, David; Miao, Dengshun

    2015-02-19

    Previously, we reported that active vitamin D deficiency in mice causes secondary hypertension and cardiac dysfunction, but the underlying mechanism remains largely unknown. To clarify whether exogenous active vitamin D rescues hypertension by normalizing the altered central renin-angiotensin system (RAS) via an antioxidative stress mechanism, 1-alpha-hydroxylase [1α(OH)ase] knockout mice [1α(OH)ase(-/-)] and their wild-type littermates were fed a normal diet alone or with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a high-calcium, high-phosphorus "rescue" diet with or without antioxidant N-acetyl-l-cysteine (NAC) supplementation for 4 weeks. Compared with their wild-type littermates, 1α(OH)ase(-/-)mice had high mean arterial pressure, increased levels of renin, angiotensin II (Ang II), and Ang II type 1 receptor, and increased malondialdehyde levels, but decreased anti-peroxiredoxin I and IV proteins and the antioxidative genes glutathione reductase (Gsr) and glutathione peroxidase 4 (Gpx4) in the brain samples. Except Ang II type 1 receptor, these pathophysiological changes were rescued by exogenous 1,25(OH)2D3 or NAC plus rescue diet, but not by rescue diet alone. We conclude that 1,25(OH)2D3 normalizes the altered central RAS in 1α(OH)ase(-/-)mice, at least partially, through a central antioxidative mechanism.

  16. Blockade of the renin-angiotensin system in small arteries and anticontractile function of perivascular adipose tissue.

    Science.gov (United States)

    Rosei, Claudia Agabiti; Withers, Sarah B; Belcaid, Laila; De Ciuceis, Carolina; Rizzoni, Damiano; Heagerty, Anthony M

    2015-05-01

    In patients with obesity, there is increased inflammation with attendant oxidative stress in perivascular adipose tissue. This has functional consequences with loss of vasodilator adipokine bioavailability. Part of the inflammatory response is mediated by increased activation of the renin-angiotensin-aldosterone axis. Therefore, this study was designed to investigate whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can improve the anticontractile function of perivascular adipose tissue. Segments of rat mesenteric small artery were dissected and mounted in a wire myograph and contracted to incremental doses of norepinephrine in the presence and absence of perivascular adipose tissue and in conditions of normal oxygenation or after hypoxia and incubated with captopril or telmisartan. Vessels with perivascular adipose tissue contracted significantly less than arteries with perivascular adipose tissue removed under normal oxygenation conditions, indicating that perivascular adipose tissue exerts an anticontractile effect. Hypoxia induced a loss of this anticontractile effect which could be completely prevented with captopril or telmisartan. The in-vitro creation of a hypoxic environment can simulate the loss of anticontractile perivascular adipose tissue function seen in vivo in obese patients, and this can be prevented using inhibitors of the renin-angiotensin cascade.

  17. Protective Effects of Blocking Renin-Angiotensin System on the Progression of Renal Injury in Glomerulosclerosis

    Institute of Scientific and Technical Information of China (English)

    Zequan Ji; Cuiwen Huang; Chengjie Liang; Bo Chen; Shengqiang Chen; Weiwen Sun

    2005-01-01

    To investigate the protective effects of blocking rennin-angiotensin system (RAS) on the progression of renal injury in glomerulosclerosis, a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein. The rats with glomerulosclerosis were randomly divided as ten pergroup into those without further treatment (group D) and those treated with Benazepril (group DB), Losartan (group DL), or sham-operation (group C), respectively. After 6 weeks of administration of Benazepril or Losartan,the mRNA expressions of TGF-β1, Col Ⅳ, Fn, ET-1 and iNOS in renal cortex were measured by RT-PCR. Besides,the expressions of TGF-β1, ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col Ⅳ and Fn were analyzed with immunohistochemistry respectively. Results showed that the rats in group D appeared as obvious proteinuria, hypoalbuminemia and hypercholesterolemia, which had a significant difference compared with group C (p<0.05), and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix. Renal cortex TGF-β1, Col Ⅳ, Fn, ET-1 and iNOS in rats of group D were increased by 3.59, 2.57, 2.21, 2.58 and 3.28 times at mRNA level, and by 2.60, 1.40, 0.75, 1.83 and 2.15 times at protein level, respectively, compared with group C. When the animals were treated with Benazepril (group DB) or Losartan (group DL), however, the biochemical and pathological damages were significantly recovered, and protein expressions of TGF-β, Col Ⅳ, Fn, ET-1 and iNOS were also significantly diminished (p<0.05). This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-β1, Col Ⅳ, Fn, ET-1 and iNOS. Cellular & Molecular Immunology. 2005;2(2):150-154.

  18. Protective Effects of Blocking Renin-Angiotensin System on the Progression of Renal Injury in Glomerulosclerosis

    Institute of Scientific and Technical Information of China (English)

    ZequanJi; CuiwenHuang; ChengjieLiang; BoChen; ShengqiangChen; WeiwenSun

    2005-01-01

    To investigate the protective effects of blocking rennin-angiotensin system (RAS) on the progression of renal injury in glomerulosclerosis, a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein. The rats with glomerulosclerosis were randomly divided as ten per group into those without further treatment (group D) and those treated with Benazepril (group DB), Losartan (group DL), or sham-operation (group C), respectively. After 6 weeks of administration of Benazepril or Losartan, the mRNA expressions of TGF-β1, Col IV, Fn, ET-1 and iNOS in renal cortex were measured by RT-PCR. Besides, the expressions of TGF-β1, ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col IV and Fn were analyzed with immunohistochemistry respectively. Results showed that the rats in group D appeared as obvious proteinuria, hypoalbuminemia and hypercholesterolemia, which had a significant difference compared with group C (p < 0.05), and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix. Renal cortex TGF-β1, Col IV, Fn, ET-1 and iNOS in rats of group D were increased by 3.59, 2.57, 2.21, 2.58 and 3.28 times at mRNA level, and by 2.60, 1.40, 0.75, 1.83 and 2.15 times at protein level, respectively, compared with group C. When the animals were treated with Benazepril (group DB) or Losartan (group DL), however, the biochemical and pathological damages were significantly recovered, and protein expressions of TGF-β1, Col IV, Fn, ET-1 and iNOS were also significantly diminished (p < 0.05). This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-β1, Col IV, Fn, ET-1 and iNOS. Cellular & Molecular Immunology. 2005;2(2):150-154.

  19. 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

  20. 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 no

  1. 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 no

  2. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    Science.gov (United States)

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  4. 肾素-血管紧张素系统与肺部疾病%Renin-angiotensin system and pulmonary diseases

    Institute of Scientific and Technical Information of China (English)

    沈利汉; 肖正伦; 孔天翰

    2008-01-01

    肾素-血管紧张素系统(renin-angiotensin system,RAS)具有调节血压和水钠平衡的生理作用.近年来,研究发现RAS在多种肺部疾病中发挥作用,例如肺动脉高压、肺纤维化、肺血栓栓塞症和急性呼吸窘迫综合征.最近发现RAS中的血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)是SARS冠状病毒的受体,且病毒感染后ACE2下调可能是SARS患者肺损伤显著加重的原因.这些发现提示RAS与肺部疾病存在重要关系.%Renin-angiotensin system(RAS) maintains blood pressure homeostasis,as well as fluid and salt balance. In recent years,researches showed that RAS implicates in the pathogenesis of several pulmonary diseases, such as pulmonary hypertension, pulmonary fibrosis, pulmonary thromboembolism and acute respiratory distress syndrome. In particular, recent studies revealed that angiotensin-converting enzyme 2 (ACE2) is an essential receptor of SARS-CoV,and it will markedly downregulate in lung during SARS-CoV infections. The downregulation of ACE2 might be an important reason of severe lung injury in SARS patients. These discoveries indicate that there are important relations between RAS and pulmonary diseases.

  5. Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

    Science.gov (United States)

    Zhang, Jia-Ying; Yin, Ying; Ni, Li; Long, Quan; You, Li; Zhang, Qian; Lin, Shan-Yan; Chen, Jing

    2016-11-01

    Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

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

    Science.gov (United States)

    Maranon, Rodrigo O; Reckelhoff, Jane F

    2016-02-01

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

  7. First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension.

    Science.gov (United States)

    Xue, Hao; Lu, Zhuang; Tang, Wen Lu; Pang, Lu Wei; Wang, Gan Mi; Wong, Gavin W K; Wright, James M

    2015-01-11

    Renin-angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non-diabetic patients, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear. To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension. We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register. We included randomized, active-controlled, double-blinded studies with at least six months follow-up in people with primary elevated blood pressure (≥130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. Patients with proven secondary hypertension were excluded. Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis. We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were

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

    Directory of Open Access Journals (Sweden)

    Shasanka S Panda

    2013-01-01

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

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

    Science.gov (United States)

    Düsing, Rainer

    2016-06-01

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

  10. Plasma renin-angiotensin system-regulating aminopeptidase activities are modified in early stage Alzheimer's disease and show gender differences but are not related to apolipoprotein E genotype.

    Science.gov (United States)

    Puertas, María Del Carmen; Martínez-Martos, José Manuel; Cobo, Manuela; Lorite, Pedro; Sandalio, Rosa María; Palomeque, Teresa; Torres, María Isabel; Carrera-González, María Pilar; Mayas, María Dolores; Ramírez-Expósito, María Jesús

    2013-06-01

    Alterations in blood pressure and components of the renin-angiotensin system (RAS) contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. Aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN) and aminopeptidase B (APB) catabolise circulating angiotensins, whereas insulin-regulated aminopeptidase (IRAP) has been described as the AT4 receptor. We have found in AD patients a significant decrease of APA activity in men but not in women, and of APN, APB and IRAP in both genders, when compared with control subjects. No changes were found in ASAP activity. Also, APN, APB and IRAP but not APA correlated with the Mini-Mental test, but no relationship with APOE genotype was found. We conclude that several components of the RAS are modified in AD patients, with gender differences. Furthermore, ROC analysis indicates that APN, APB and IRAP activities could be useful non-invasive biomarkers of AD from the earliest stages.

  11. Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study).

    Science.gov (United States)

    Sezai, Akira; Osaka, Shunji; Yaoita, Hiroko; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi; Sakino, Hisakuni

    2016-06-20

    Angiotensin II receptor blockers (ARBs) have been widely used to treat hypertension and large-scale clinical studies have shown various benefits. In this study, we compared olmesartan with azilsartan, the newest ARB. The subjects were outpatients who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. The primary endpoints were the levels of plasma renin activity, angiotensin II, and aldosterone. Home blood pressure exceeded 140/90 mmHg and additional antihypertensive medication was administered to 12 patients (20 episodes) in the azilsartan group versus 4 patients (4 episodes) in the olmesartan group, with the number being significantly higher in the azilsartan group. After 1 year of treatment, both angiotensin II and aldosterone levels were significantly lower in the olmesartan group than the azilsartan group. Left ventricular mass index was also significantly lower in the olmesartan group than the azilsartan group. This study showed that olmesartan reduces angiotensin II and aldosterone levels more effectively than azilsartan. Accordingly, it may be effective in patients with increased renin-angiotensin-aldosterone system activity after cardiac surgery or patients with severe cardiac hypertrophy.

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

    Science.gov (United States)

    Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

    2016-01-01

    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. PMID:27746855

  13. 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

    2015-11-12

    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. Sildenafil further 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.

  14. 肾素-血管紧张素系统的新调节分子:ACE2%New regulator in renin angiotensin system: ACE2

    Institute of Scientific and Technical Information of China (English)

    李怡棠; 程桂芳

    2006-01-01

    血管紧张素转化酶(angiotensin-converting enzyme,ACE)为含锌的金属蛋白酶,是肾素-血管紧张素系统(renin-angiotensin system,RAS)重要的调节分子.血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)是迄今发现的唯一的ACE同系物(homologue),它主要分布于睾丸、肾脏和心脏.ACE2可水解血管紧张素Ⅰ(angiotensin Ⅰ,Ang Ⅰ)和血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)羧基端的1个氨基酸残基,分别形成Ang1-9和有血管舒张作用的Ang1-7.ACE 2的生理病理作用还不甚明了,传统的ACE抑制剂不能抑制ACE2的活性.ACE2在心血管、肾脏系统的作用可能与ACE相反,与ACE共同调节心脏、肾脏等脏器的正常功能.

  15. RELATIONSHIP OF RENIN-ANGIOTENSIN SYSTEM IN PULMONARY FIBROSIS%肾素-血管紧张素系统与肺纤维化的关系

    Institute of Scientific and Technical Information of China (English)

    刘宏伟; 王献华; 马海玲

    2009-01-01

    @@ 肺纤维化是一组以肺泡结构破坏和成纤维细胞增生以及广泛的细胞外基质(extra cellular matrix,ECM),尤其是Ⅰ型和Ⅲ型胶原沉积为特征的疾病.研究表明在肺纤维化组织中血管紧张素转化酶(angiotensin-converting enzyme,ACE)活性及血管紧张素Ⅱ-1型受体(angiotensinⅡtypel receptor,ATlR)表达是增加的,并且给予血管紧张素转化酶抑制剂(angiotensin-converting enzyme inhibititors,ACEI)、AT1受体阻滞剂可以减轻纤维化的程度,提示了肾素-血管紧张素系统(Renin-Angiotensin-System,RAS)在纤维化病变的形成中可能起重要作用.本文就近年来在此方面的研究作一综述.

  16. Vitamin D in the Pathophysiology of Hypertension, Kidney Disease, and Diabetes: Examining the Relationship Between Vitamin D and the Renin-Angiotensin System in Human Diseases

    Science.gov (United States)

    Vaidya, Anand; Williams, Jonathan S.

    2011-01-01

    Objective Vitamin D has been implicated in the pathophysiology of extra-skeletal conditions such as hypertension, kidney disease, and diabetes, via its ability to negatively regulate the renin-angiotensin system (RAS). This article reviews the evidence supporting a link between vitamin D and the RAS in these conditions, with specific emphasis on translational observations and their limitations. Methods Literature review of animal and human studies evaluating the role of vitamin D in hypertension, kidney disease, and diabetes. Results Excess activity of the RAS has been implicated in the pathogenesis of hypertension, chronic kidney disease, decreased insulin secretion, and insulin resistance. Animal studies provide strong support for 1,25(OH)2D mediated down-regulation of renin expression and RAS activity via its interaction with the vitamin D receptor. Furthermore, the activity of vitamin D metabolites in animals is associated with reductions in blood pressure, proteinuria and renal injury, and with improved β–cell function. Many observational, and a few interventional, studies in humans have supported these findings; however, there is a lack of well designed prospective human interventional studies to definitively assess clinical outcomes. Conclusion Animal studies implicate vitamin D receptor agonist therapy to lower RAS activity as a potential method to reduce the risk of hypertension, kidney disease, and diabetes. There is a need for more well designed prospective interventional studies to validate this hypothesis in human clinical outcomes. PMID:22075270

  17. 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.

  18. High potassium promotes mutual interaction between (pro)renin receptor and the local renin-angiotensin-aldosterone system in rat inner medullary collecting duct cells.

    Science.gov (United States)

    Xu, Chuanming; Fang, Hui; Zhou, Li; Lu, Aihua; Yang, Tianxin

    2016-10-01

    (Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release.

  19. 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.

  20. Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis.

    Science.gov (United States)

    Lu, Z; Chen, Y; Li, L; Wang, G; Xue, H; Tang, W

    2017-01-01

    Many randomized clinical trials (RCTs) have investigated the efficacy and safety of renin-angiotensin system inhibitors (RASIs) plus calcium channel blockers (CCBs), compared with other two-drug combinations, but systematic assessment in this aspect is still lacking. We carried out the present meta-analysis of randomized controlled trials to evaluate the long-term effect and safety of RASIs plus CCBs. Literatures were searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials in September 2014. A fixed-effect model was used to estimate the pooled effect of trials identified. Thirty-four trials with 41 694 patients were included. Compared with RASIs plus diuretics, RASIs plus CCBs decreased total cardiovascular (CV) events (relative risk (RR) 0.82, 95% confidence interval (CI): 0.75, 0.91, adjusted RR (ARR) 1.7%) and withdrawals due to adverse effect (WDAE) (RR 0.87, 95% CI: 0.80, 0.94, ARR 1.3%). Compared with CCBs plus diuretics, RASIs plus CCBs decreased WDAE (RR 0.63, 95% CI: 0.45, 0.90, ARR 1.1%). Our meta-analysis indicates that RASIs plus CCBs provide a superior safety and prevention of CV events to RASIs plus diuretics, whereas this combination is also safer than CCBs plus diuretics. We also raise a new hypothesis. More high-quality RCTs focused on hard end points with CV, cerebrovascular and renal events are needed to confirm the hypothesis we have brought out.

  1. The effects of antidiuretic hormone and state of potassium balance on the renin-angiotensin system in rats with diabetes insipidus.

    Science.gov (United States)

    Fernández-Repollet, E; Maldonado, M M; Opava-Stitzer, S

    1982-02-01

    1. The influence of ADH and the state of potassium balance on the renin-angiotensin system was studied in rats with hereditary diabetes insipidus (DI rats). 2. Plasma renin concentration in DI rats was higher than in control Long-Evans rats. 3. Spontaneous reversal of the hypokalaemia normally found in DI rats did not reduce plasma renin concentration (p.r.c.), suggesting that potassium deficiency does not contribute significantly to the elevation of p.r.c. in DI rats. Similarly, a low potassium diet failed to further increase p.r.c. in DI rats. 4. In contrast, the p.r.c. of DI rats was significantly diminished by a high potassium intake both in the presence and absence of ADH. A highly significant inverse correlation was found between p.r.c. and urinary potassium excretion in both ADH-treated and untreated DI rats on low, normal and high potassium diets. 5. Plasma renin concentration was significantly lower in ADH-treated than in untreated DI rats on a high potassium intake, suggesting that the inhibitory effects of ADH and potassium are additive. 6. ADH consistently reduced p.r.c. in DI rats independent of the state of potassium balance. 7. ADH and potassium may inhibit renin secretion via different mechanisms of action.

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

    Science.gov (United States)

    Narita, Yuki; Ueda, Miki; Uchimura, Kohei; Kakizoe, Yutaka; Miyasato, Yoshikazu; Mizumoto, Teruhiko; Morinaga, Jun; Hayata, Manabu; Nakagawa, Terumasa; Adachi, Masataka; Miyoshi, Taku; Sakai, Yoshiki; Kadowaki, Daisuke; Hirata, Sumio; Mukoyama, Masashi; Kitamura, Kenichiro

    2016-02-01

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

  3. Plasma and tissue levels of proangiotensin-12 and components of the renin-angiotensin system (RAS) following low- or high-salt feeding in rats.

    Science.gov (United States)

    Nagata, Sayaka; Kato, Johji; Kuwasako, Kenji; Kitamura, Kazuo

    2010-05-01

    The renin-angiotensin system (RAS) is an essential regulator of the blood pressure and body fluid balance, but the processing cascade or role of the tissue RAS remains obscure. Proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, is assumed to function as a factor of the tissue RAS. To investigate the tissue production of proang-12, we measured the circulating and tissue components of the RAS including proang-12 following low-, normal-, or high-salt feeding in rats. Twelve-week-old male Wistar rats were fed a low-salt 0.3% NaCl or high-salt 8% NaCl diet for 7 days and compared with those fed a normal-salt diet of 0.7% NaCl. Low-salt feeding elevated the plasma renin activity and aldosterone concentration, resulting in significant increases in Ang I and Ang II levels in the plasma or kidney tissue, as compared with the normal- or high-salt group. Despite the increases in plasma renin activity, Ang I, and Ang II, the proang-12 levels in plasma and various tissues including the kidneys, small intestine, cardiac ventricles, and brain remained unchanged following low-salt feeding. These results suggest that peptide levels of proang-12 in rat plasma and tissues are regulated in a manner independent of the circulating RAS.

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

    Science.gov (United States)

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

    2000-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Cheng-Hong Yang

    2015-01-01

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

  6. 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.

  7. Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat.

    Science.gov (United States)

    Malikova, Eva; Galkova, Kristina; Vavrinec, Peter; Vavrincova-Yaghi, Diana; Kmecova, Zuzana; Krenek, Peter; Klimas, Jan

    2016-07-01

    Renin-angiotensin system (RAS) is one of the pathophysiological mechanisms in heart failure. Recently, involvement of the kidney in the disease progression has been proposed in patients with pulmonary arterial hypertension (PAH). We hypothesized that local and systemic RAS could be the central regulators of cardiopulmonary-renal interactions in experimental monocrotaline-induced pulmonary hypertension (PH) in rats. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). The experiment was terminated 4 weeks after monocrotaline administration. Using RT-PCR, we measured the expression of RAS-related genes in right and left ventricles, lungs and kidneys, together with indicators of renal dysfunction and damage. We observed a significantly elevated expression of angiotensin-converting enzyme (ACE) in both left and right ventricles and kidneys (P < 0.05), but a significantly decreased ACE in the lungs (P < 0.05). Kidneys showed a significant 2.5-fold increase in renin mRNA (P < 0.05) along with erythropoietin, TGFβ1, COX-2, NOS-1 and nephrin. Expression of erythropoietin correlated inversely with hemoglobin oxygen saturation and positively with renin expression. In conclusion, monocrotaline-induced PH exhibited similar alterations of ACE expression in the left and right ventricles, and in the kidney, in contrast to the lungs. Increased renal renin was likely a consequence of renal hypoxia/hypoperfusion, as was increased renal erythropoietin expression. Alterations in RAS in the monocrotaline model are probably a result of hypoxic state, and while they could serve as a compensatory mechanism at a late stage of the disease, they could be viewed also as an indicator of multiorgan failure in PAH.

  8. A Detailed Physiologically Based Model to Simulate the Pharmacokinetics and Hormonal Pharmacodynamics of Enalapril on the Circulating Endocrine Renin-Angiotensin-Aldosterone System

    Science.gov (United States)

    Claassen, Karina; Willmann, Stefan; Eissing, Thomas; Preusser, Tobias; Block, Michael

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure. PMID:23404365

  9. Gene variants of the renin-angiotensin system are associated with accelerated hippocampal volume loss and cognitive decline in old age

    Science.gov (United States)

    Zannas, Anthony S.; McQuoid, Douglas R.; Payne, Martha E; MacFall, James R.; Ashley-Koch, Allison; Steffens, David C.; Potter, Guy G.; Taylor, Warren D.

    2014-01-01

    Objective Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. Smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies have investigated longitudinally the effects of genetic variation of RAS on the hippocampus. Method We examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. 138 older adults (age ≥ 60 years) were followed for an average of about four years. Subjects underwent repeated structural MRI and comprehensive neurocognitive testing, and were genotyped for four AGTR1 SNPs with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype. Results Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, rs2675511) were independently associated with accelerated hippocampal volume loss over the four-year follow-up in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss. Conclusions Risk genetic variants of RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders. PMID:25124854

  10. Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age.

    Science.gov (United States)

    Zannas, Anthony S; McQuoid, Douglas R; Payne, Martha E; MacFall, James R; Ashley-Koch, Allison; Steffens, David C; Potter, Guy G; Taylor, Warren D

    2014-11-01

    Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus. The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype. Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss. Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.

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

    Institute of Scientific and Technical Information of China (English)

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

    2013-01-01

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

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

    Science.gov (United States)

    Pöschke, Antje; Kern, Niklas; Maruyama, Takayuki; Pavenstädt, Hermann; Narumiya, Shuh; Jensen, Boye L; Nüsing, Rolf M

    2012-11-15

    Increased cyclooxygenase-2 (COX-2) expression and PGE(2) synthesis have been shown to be prerequisites for renal renin release after Na(+) deprivation. To answer the question of whether EP4 receptor type of PGE(2) mediates renin regulation under a low-salt diet, we examined renin regulation in EP4(+/+), EP4(-/-), and in wild-type mice treated with EP4 receptor antagonist. After 2 wk of a low-salt diet (0.02% wt/wt NaCl), EP4(+/+) mice showed diminished Na(+) excretion, unchanged K(+) excretion, and reduced Ca(2+) excretion. Diuresis and plasma electrolytes remained unchanged. EP4(-/-) exhibited a similar attenuation of Na(+) excretion; however, diuresis and K(+) excretion were enhanced, and plasma Na(+) concentration was higher, whereas plasma K(+) concentration was lower compared with control diet. There were no significant differences between EP4(+/+) and EP4(-/-) mice in blood pressure, creatinine clearance, and plasma antidiuretic hormone (ADH) concentration. Following salt restriction, plasma renin and aldosterone concentrations and kidney renin mRNA level rose significantly in EP4(+/+) but not in EP4(-/-) and in wild-type mice treated with EP4 antagonist ONO-AE3-208. In the latter two groups, the low-salt diet caused a significantly greater rise in PGE(2) excretion. Furthermore, mRNA expression for COX-2 and PGE(2) synthetic activity was significantly greater in EP4(-/-) than in EP4(+/+) mice. We conclude that low dietary salt intake induces expression of COX-2 followed by enhanced renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss.

  13. Antiproliferative effects of palladium(II) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin-angiotensin system in tumoral brain cells.

    Science.gov (United States)

    Illán-Cabeza, Nuria A; García-García, Antonio R; Martínez-Martos, José M; Ramírez-Expósito, María J; Moreno-Carretero, Miguel N

    2013-09-01

    Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH-1)(solvent) and PdCl2(PPh3)2L containing pyrimidine ligands derived from 6-amino-5-nitrosouracil and violuric acid have been prepared and characterized by elemental analysis, IR and NMR ((1)H and (13)C) methods and, two of them, PdCl(DANUH-1)(CH3CN)]·½H2O and [PdCl(2MeOANUH-1)(CH3CN)] by X-ray single-crystal diffraction (DANU: 6-amino-1,3-dimethyl-5-nitrosouracil; 2MeOANU: 6-amino-2-methoxy-5-nitroso-3H-pyrimidin-4-one). The coordination environment around palladium is nearly square planar in the two compounds with different supramolecular arrangements. Crystallographic and spectral data are consistent with a bidentate coordination mode through N5 and O4 atoms when the ligands act in neutral form and N5 and N6 atoms in the monodeprotonated ones. The cytotoxicity of the complexes against human neuroblastoma (NB69) and human glioma (U373-MG) cell lines has been tested showing a considerable antiproliferative activity. Also, the study of the effects of palladium(II) complexes on the renin-angiotensin system (RAS) regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP) shows a strong dependence on the compound tested and the tumoral cell type, also affecting different catalytic routes; the compounds affect in a different way the activities of enzymes of the RAS system, changing their functional roles as initiators of cell proliferation in tumors as autocrine/paracrine mediators.

  14. 肾素-血管紧张素系统与肺动脉高压%Renin-angiotensin system and pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    张云霞; 李积凤; 王辰

    2015-01-01

    Pulmonary hypertension (PH ) is characterized by sustained increase of pulmonary arterial pressure and eventually leading to right heart failure.PH is caused by heterogeneous diseases and different pathogenesis.PH is still incurable and fatal,although current treatments alleviated some symptoms and prolonged survival.Therefore,it is urgent to discover novel targets for safe and effective therapy.The renin-angiotensin system (RAS ) is mainly composed by the vaso-constrictive and proliferative axis called as ACE-AngⅡ-AT1R,and the vaso-protective and anti-proliferative axis called as ACE2-Ang-(1-7)-Mas.The dysfunction ACE-AngⅡ-AT1R axis,has been implicated as a causative factor in the pathogenesis of PH.While because it can antagonize the function of ACE-AngⅡ-AT1R axis,ACE2-Ang-(1-7)-Mas axis may be a novel target in PH treatment.%肺动脉高压(pulmonary hypertension,PH)是一种由异源性疾病和不同发病机制引起的,以肺动脉压力增高为表现的疾病状态,严重者可出现右心衰竭。目前的治疗方式虽然可缓解 PH 患者的部分症状,并在一定程度上延长患者的寿命,但 PH 仍然是一种死亡率极高的疾病,所以亟需发现新的安全有效的治疗方法。研究表明,肾素-血管紧张素系统(renin-angiotensin system,RAS)参与了 PH 的发病过程。该系统由促进血管收缩及增殖的血管紧张素转换酶-血管紧张素Ⅱ-血管紧张素Ⅱ受体1(angiotensin converting enzyme-angiotensinⅡ-angiotensinⅡ receptor 1,ACE-AngⅡ-AT1R)轴与抗血管收缩及增殖的血管紧张素转换酶2-血管紧张素(1-7)-Mas[angiotensin converting enzyme 2-angiotensin (1-7)-Mas,ACE2-Ang-(1-7)-Mas]轴组成。ACE-AngⅡ-AT1R 轴是促进 PH 病情发展的重要机制,而ACE2-Ang-(1-7)-Mas 轴因可以拮抗 ACE-AngⅡ-AT1R 轴的作用,成为 PH 治疗的研究热点。

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

    Science.gov (United States)

    Pelusi, Serena; Petta, Salvatore; Rosso, Chiara; Borroni, Vittorio; Fracanzani, Anna Ludovica; Dongiovanni, Paola; Craxi, Antonio; Bugianesi, Elisabetta; Fargion, Silvia

    2016-01-01

    Background The clinical determinants of fibrosis progression in nonalcoholic fatty liver disease (NAFLD) are still under definition. Aim To assess the clinical determinants of fibrosis progression rate (FPR) in NAFLD patients with baseline and follow-up histological evaluation, with a special focus on the impact of pharmacological therapy. Methods In an observational cohort of 118 Italian patients from tertiary referral centers, liver histology was evaluated according to Kleiner. Independent predictors of FPR were selected by a stepwise regression approach. Results Median follow-up was 36 months (IQR 24–77). Twenty-five patients (18%) showed some amelioration, 63 (53%) had stability, 30 (25%) had progression of fibrosis. Patients with nonalcoholic steatohepatitis (NASH) had similar demographic and anthropometric features, but a higher prevalence of type 2 diabetes (T2D; p = 0.010), and use of renin-angiotensin axis system (RAS) inhibitors (p = 0.005). Fibrosis progression was dependent of the length of follow-up, and was associated with, but did not require, the presence of NASH (p<0.05). Both fibrosis progression and faster FPR were independently associated with higher APRI score at follow-up, absence of treatment with RAS inhibitors, and T2D diagnosis at baseline (p<0.05). There was a significant interaction between use of RAS inhibitors and T2D on FPR (p = 0.002). RAS inhibitors were associated with slower FPR in patients with (p = 0.011), but not in those without (p = NS) T2D. Conclusions NASH is not required for fibrosis progression in NAFLD, whereas T2D seems to drive fibrogenesis independently of hepatic inflammation. Use of RAS inhibitors may contrast fibrosis progression especially in high-risk patients affected by T2D. PMID:27649410

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

    Science.gov (United States)

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

    2016-05-01

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

  17. Early Training-Induced Reduction of Angiotensinogen in Autonomic Areas-The Main Effect of Exercise on Brain Renin-Angiotensin System in Hypertensive Rats.

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    Laiali Jurdi Chaar

    Full Text Available Exercise training (T blunts functional deficits and renin-angiotensin system (RAS hyperactivity in hypertensive individuals. There is no information on T-induced temporal changes of brain RAS. We evaluate now the simultaneous effects of T on functional responses and time course changes in the expression/activity of brain RAS components in autonomic cardiovascular-controlling areas.Spontaneously hypertensive rats (SHR and age-matched normotensive controls (WKY were trained for 0, 1, 2, 4, 8 and 12 weeks. Sedentary (S groups served as time-controls. After arterial pressure (AP and heart rate (HR recordings at rest, fresh and fixed brains were harvested for qPCR and immunofluorescence assays. SHR-S vs. WKY-S exhibited higher mean AP (MAP and HR, increased pressure variability and sympathetic activity, elevated AT1 receptor (AT1 expression in nucleus tractus solitarii (NTS and higher Mas receptor expression in the rostroventrolateral medulla (RVLM. In SHR, T promptly (T2 on reduced sympathetic variability to heart/vessels and largely decreased angiotensinogen expression in the paraventricular hypothalamic nucleus (PVN and NTS, with a late RVLM reduction (T4. AT1 expression was only reduced at T12 (PVN and NTS with transient, not maintained Mas receptor changes in PVN and RVLM. These responses were accompanied by baseline MAP and HR reduction in the SHR-T (from T4 on. In the SHR group, PVN angiotensinogen expression correlated positively with sympathetic activity, resting MAP and HR. In WKY-T, a precocious (T2-T12 RVLM AT1 decrease preceded the appearance of resting bradycardia (from T8 on.Early and maintained reduction of angiotensinogen content in autonomic areas of the SHR is the most prominent effect of training on brain RAS. Down-regulation of PVN RAS expression is an essential factor to drive cardiovascular benefits in SHR-T, while resting bradycardia in WKY-T is correlated to RVLM AT1 reduction.

  18. 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.

  19. 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.

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

    Science.gov (United States)

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

    2015-11-01

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

  1. Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies.

    Science.gov (United States)

    Kunutsor, Setor K; Blom, Ashley W; Whitehouse, Michael R; Kehoe, Patrick G; Laukkanen, Jari A

    2017-07-27

    The renin-angiotensin system (RAS) represents an important target of antihypertensive medications. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), which are widely-used RAS inhibiting drugs, have been suggested to have beneficial effects on bone tissue. We aimed to assess the associations of use of ACEIs and/or ARBs with the risk of fractures using a population-based prospective cohort and a meta-analysis of published prospective cohort studies. Information on antihypertensive medication use (including both ACEIs and ARBs) were assessed in 1743 men and women of the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) [95% confidence intervals (CI)] of ACEIs or ARBs use with incident fractures were calculated. A total of 203 composite (hip, humeral, and wrist) fractures occurred during a median follow-up of 14.8 years. In multivariate adjusted analysis, the HR for composite fractures comparing users of ACEIs or ARBs with non-users was 1.00 (0.59-1.69). The corresponding adjusted HR for hip fractures comparing users versus non-users of ACEIs or ARBs was 0.89 (0.32-2.47). Including the current study, a total of 11 observational cohort studies involving 3526,319 participants and >323,355 fractures were included in a meta-analysis. Comparing ACEI users with non-users and ARB users with non-users, the HRs for composite fractures were 1.09 (0.89-1.33) and 0.87 (0.76-1.01) respectively. The corresponding HRs for hip fractures were 0.91 (0.86-0.95) and 0.80 (0.75-0.85) respectively. Use of RAS inhibitors was not associated with long-term risk of composite fractures in both primary and pooled analyses. Pooled evidence however suggests a beneficial effect of RAS blockers on hip fracture risk.

  2. The association of renin-angiotensin system blockade use with the risks of cognitive impairment of aging and Alzheimer's disease: A meta-analysis.

    Science.gov (United States)

    Zhuang, Shan; Wang, Hai-Feng; Wang, Xin; Li, Jun; Xing, Cheng-Ming

    2016-11-01

    A quantitative meta-analysis was performed to evaluate the association of renin-angiotensin system blockade (RASB) use with the incidence of cognitive impairment of aging and Alzheimer's disease (AD). Pubmed, Embase, and Cochrane Library databases were searched up to October 2015. Ten studies that assessed the relationship between RASB use and the incidence of cognitive impairment of aging or AD were included. When randomized trials and observational studies were combined, the use of RASB was significantly associated with a reduced risk of AD (risk ratio [RR], 0.80; 95% confidence interval [CI] 0.68-0.92) and cognitive impairment of aging (RR, 0.65; 95% CI 0.35-0.94) compared no use of RASB. Meanwhile, in an analysis of subgroups, both subjects with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use were lower incidence of AD (RR, 0.87; 95% CI 0.74-1.00; RR, 0.69; 95% CI 0.44-0.93, respectively) than those without, whereas, indirect comparison between ACEI and ARB revealed no significance in the risk of AD (RR, 1.27, 95% CI 0.85-1.89, p=0.245). In an analysis of cognitive impairment of aging, ARB use (RR, 0.40; 95% CI 0.02-0.78), rather than ACEI use (RR, 0.72; 95% CI 0.36-1.09), was shown to decrease the risk of cognitive impairment of aging. In conclusion, RASB treatments, regardless of the drug class, have benefits on prevention of AD, and the effects of ACEI may analogous to ARB. However, the benefit differs according to drug classes for cognitive impairment of aging, with ARB use, rather than ACEI use, being a potential treatment for reducing the incidence of cognitive impairment of aging.

  3. Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

    Directory of Open Access Journals (Sweden)

    Maria Vanessa Perez-Gomez

    2015-06-01

    Full Text Available Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR loss in chronic kidney disease (CKD stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2 inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.

  4. ANP and BNP responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system.

    Science.gov (United States)

    Adem, Abdu; Al Haj, Mahmoud; Benedict, Sheela; Yasin, Javed; Nagelkerke, Nicolas; Nyberg, Fred; Yandle, Tim G; Frampton, Chris M; Lewis, Lynley K; Nicholls, M Gary; Kazzam, Elsadig

    2013-01-01

    The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

  5. ANP and BNP responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system.

    Directory of Open Access Journals (Sweden)

    Abdu Adem

    Full Text Available The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP and B-type natriuretic peptide (BNP in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6, dehydrated camels (n = 6 and dehydrated losartan-treated camels (n = 6 which were dehydrated and received the angiotensin II (Ang II AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

  6. Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid.

    Science.gov (United States)

    Deckers, Ivette A; van den Brandt, Piet A; van Engeland, Manon; van Schooten, Frederik-Jan; Godschalk, Roger W; Keszei, András P; Schouten, Leo J

    2015-03-01

    Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology. © 2014 UICC.

  7. Renin-angiotensin-aldosterone system polymorphisms: a role or a hole in occurrence and long-term prognosis of acute myocardial infarction at young age

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    Piazza Alberto

    2007-05-01

    Full Text Available Abstract Background The renin-angiotensin-aldosterone system (RAAS is involved in the cardiovascular homeostasis as shown by previous studies reporting a positive association between specific RAAS genotypes and an increased risk of myocardial infarction. Anyhow the prognostic role in a long-term follow-up has not been yet investigated. Aim of the study was to evaluate the influence of the most studied RAAS genetic Single Nucleotide Polymorphisms (SNPs on the occurrence and the long-term prognosis of acute myocardial infarction (AMI at young age in an Italian population. Methods The study population consisted of 201 patients and 201 controls, matched for age and sex (mean age 40 ± 4 years; 90.5% males. The most frequent conventional risk factors were smoke (p Results We found a borderline significant association of occurrence of AMI with the ACE D/I polymorphism (DD genotype, 42% in cases vs 31% in controls; p = 0.056. DD genotype remained statistically involved in the incidence of AMI also after adjustment for clinical confounders. On the other hand, during the 9-year follow-up (65 events, including 13 deaths we found a role concerning the AGTR1: the AC heterozygous resulted more represented in the event group (p = 0.016 even if not independent from clinical confounders. Anyhow the Kaplan-Meier event free curves seem to confirm the unfavourable role of this polymorphism. Conclusion Polymorphisms in RAAS genes can be important in the onset of a first AMI in young patients (ACE, CYP11B2 polymorphisms, but not in the disease progression after a long follow-up period. Larger collaborative studies are needed to confirm these results.

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

    Science.gov (United States)

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

    2017-01-01

    Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071–1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123–1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016–1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996–1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients. PMID:28122064

  9. Periaortic adipose tissue-specific activation of the renin-angiotensin system contributes to atherosclerosis development in uninephrectomized apoE-/- mice.

    Science.gov (United States)

    Kawahito, Hiroyuki; Yamada, Hiroyuki; Irie, Daisuke; Kato, Taku; Akakabe, Yoshiki; Kishida, Sou; Takata, Hiroki; Wakana, Noriyuki; Ogata, Takehiro; Ikeda, Koji; Ueyama, Tomomi; Matoba, Satoaki; Mori, Yasukiyo; Matsubara, Hiroaki

    2013-09-01

    Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease. The perivascular adipose tissue is closely implicated in the development of atherosclerosis; however, the contribution to CKD-associated atherogenesis remains undefined. Eight-week-old apoE-deficient mice were uninephrectomized and fed a high-cholesterol diet starting at 12 wk of age. The atherosclerotic lesion area in the thoracic aorta was comparable in 16-wk-old uninephrectomized (UNX) mice and sham control mice; however, the lesion area was markedly exaggerated in 20-wk-old UNX mice compared with the control (54%, P < 0.05). While the accumulation of monocytes/macrophages and the mRNA expression levels of inflammatory cytokines/chemokines in the thoracic periaortic adipose tissue (PAT) did not differ between the two groups, angiotensinogen (AGT) mRNA expression and the angiotensin II (ANG II) concentration in the PAT were significantly higher in 16-wk-old UNX mice than in the control (1.9- and 1.5-fold increases vs. control, respectively; P < 0.05). ANG II concentrations in both the plasma and epididymal white adipose tissue (WAT) were comparable between the two groups, suggesting that PAT-specific activation of the renin-angiotensin system (RAS) is primarily involved in CKD-associated atherogenesis. The homeostasis model assessment-insulin resistance (HOMA-IR) index and plasma insulin level after glucose loading were significantly elevated in 16-wk-old UNX mice. In vitro stimulation of preadipocytes with insulin exaggerated the AGT mRNA expression along with increased mRNA expression of PPARγ. These findings suggest that PAT-specific RAS activation probably primarily contributes in accelerating atherosclerotic development in UNX mice and could thus represent a therapeutic target for preventing CKD-associated atherogenesis.

  10. Genetic polymorphisms of the renin-angiotensin-aldosterone system in Chinese patients with end-stage renal disease secondary to IgA nephropathy

    Institute of Scientific and Technical Information of China (English)

    HUANG Hai-dong; LIN Fu-jun; LI Xin-juan; WANG Li-rui; JIANG Geng-ru

    2010-01-01

    Background Genetic variability in the renin-angiotensin-aldosterone system may modify renal responses to injury and disease progression. The angiotensin l-converting enzyme (ACE) gene insertion/deletion (l/D), the angiotensinogen (AGT) gene, M235T, the aldosterone synthase (CYP11B2) gene, C-344T, and the angiotensin Ⅱ type 1 receptor (AT1 R)gene, A1166C, have been shown to be associated with IgA nephropathy (IgAN) and its progression. We determined the presence of these polymorphisms in 130 Chinese patients with IgAN, including 47 patients with end-stage renal disease (ESRD) and 120 healthy Chinese subjects, to assess their impact on the susceptibility to disease and the liability of progression to ESRD.Methods Genotyping was performed with DNA isolated from peripheral leucocytes using polymerase chain reaction amplification of the polymorphic sequence, restriction enzyme digestion, and separation and identification of DNA fragments. Clinical data from renal biopsies were collected.Results ACE, AGT, CYP and AT1R genotype distributions were similar in patients with lgAN and in controls. Comparing patients with ESRD (IgAN-ESRD) and those without ESRD (IgAN-non ESRD), there was a significant increase only in the ACE DD genotype (P <0.05) among the four gene polymorphisms. There was significant dominance of the male (P <0.05), more marked hypertension (P <0.01), proteinuria (P <0.01) and increased serum creatinine during renal biopsy (P <0.01) in the IgAN-ESRD group.Conclusion Among the ACE, AGT, AT1R and CYP gene polymorphisms, only the DD genotype may predispose the individual to increased risk of progression to ESRD in the Chinese population.

  11. Relationship between Components of Renin-Angiotensin System (RAS) and Sperm Functions%男性生殖系统的肾素-血管紧张素系统与某些精子功能的关系

    Institute of Scientific and Technical Information of China (English)

    郑松; 王益鑫

    2003-01-01

    在男性生殖系统中已发现有多处存在肾素-血管紧张素系统(renin-angiotensin system, RAS),RAS被认为可能在男性生殖调节中发挥重要作用.本文就RAS中的血管紧张素转化酶和血管紧张素II对某些精子功能,主要包括精子活动力、精子顶体反应和精-卵相互作用等方面的影响作一文献综述.

  12. Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways.

    Science.gov (United States)

    West, Crystal A; Shaw, Stefan; Sasser, Jennifer M; Fekete, Andrea; Alexander, Tyler; Cunningham, Mark W; Masilamani, Shyama M E; Baylis, Chris

    2013-11-15

    We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg(-1)·day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg(-1)·day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg·kg(-1)·day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 ± 0.5% with NIF, 6.33 ± 0.5% with NIF + SPR, 13.3 ± 0.9% with NIF + LOS, and 12.0 ± 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 ± 0.3%), plasma volume factored for body weight was increased by NIF (5.2 ± 0.4%) treatment but not by NIF + SPR (4.3 ± 0.3%), NIF + LOS (3.6 ± 0.1%), or ENAL (4.0 ± 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 ± 16 and 204 ± 22% of CON, respectively). NIF increased the α-subunit of the epithelial sodium channel (α-ENaC) protein in renal outer (365 ± 44%) and inner (526 ± 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or α-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and α-ENaC through the MR.

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

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    Graziela S Ceravolo

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

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

    Institute of Scientific and Technical Information of China (English)

    朱凌倜; 周京敏

    2013-01-01

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

  15. Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Rong-Shuang Huang; Yi-Ming Cheng; Xiao-Xi Zeng; Sehee Kim; Ping Fu

    2016-01-01

    Background:Renin-angiotensin system inhibitor and calcium channel blocker (CCB) are widely used in controlling blood pressure (BP) in patients with chronic kidney disease (CKD).We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and CCB (i.e.,ACEI/ARB + CCB) with ACEI/ ARB monotherapy in patients with hypertension and CKD.Methods:Publications were identified from PubMed,Embase,Medline,and Cochrane databases.Only randomized controlled trials (RCTs) of BP lowering treatment for patients with hypertension and CKD were considered.The outcomes of end-stage renal disease (ESRD),cardiovascular events,BP,urinary protein measures,estimated glomerular filtration rate (GFR),and adverse events were extracted.Results:Based on seven RCTs with 628 patients,ACEI/ARB + CCB did not show additional benefit for the incidence of ESRD (risk ratio [RR] =0.84;95% confidence interval [CI]:0.52-1.33) and cardiovascular events (RR =0.58;95% CI:0.21-1.63) significantly,compared with ACEI/ARB monotherapy.There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] =-1.28 mmHg;95% CI:-3.18 to-0.62),proteinuria (standard mean difference =-0.55;95% CI:-1.41 to-0.30),GFR (WMD =-0.32 ml/min;95% CI:-1.53 to-0.89),and occurrence of adverse events (RR =1.05;95% CI:0.72-1.53).However,ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD =-4.46 mmHg;95% CI:-6.95 to-1.97),compared with ACEI/ARB monotherapy.Conclusion:ACEI/ARB + CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.

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

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    Zhijun Wu

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

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

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    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

  18. 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

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    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

  19. Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials

    Science.gov (United States)

    Fakheri, Robert; Wandel, Simon; Toklu, Bora; Wandel, Jasmin; Messerli, Franz H

    2017-01-01

    Objective To critically evaluate the efficacy of renin angiotensin system inhibitors (RASi) in patients with coronary artery disease without heart failure, compared with active controls or placebo. Design Meta-analysis of randomized trials. Data sources PubMed, EMBASE, and CENTRAL databases until 1 May 2016. Eligibility criteria for selecting studies Randomized trials of RASi versus placebo or active controls in patients with stable coronary artery disease without heart failure (defined as left ventricular ejection fraction ≥40% or without clinical heart failure). Each trial had to enroll at least 100 patients with coronary artery disease without heart failure, with at least one year’s follow-up. Studies were excluded if they were redacted or compared use of angiotensin converting enzyme inhibitors with angiotensin receptor blockers. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, incident diabetes, and drug withdrawal due to adverse effects. Results 24 trials with 198 275 patient years of follow-up were included. RASi reduced the risk of all cause mortality (rate ratio 0.84, 95% confidence interval 0.72 to 0.98), cardiovascular mortality (0.74, 0.59 to 0.94), myocardial infarction (0.82, 0.76 to 0.88), stroke (0.79, 0.70 to 0.89), angina, heart failure, and revascularization when compared with placebo but not when compared with active controls (all cause mortality, 1.05, 0.94 to 1.17; Pinteraction=0.006; cardiovascular mortality, 1.08, 0.93 to 1.25, Pinteraction14.10 deaths and >7.65 cardiovascular deaths per 1000 patient years) but not in those with low control event rates. Conclusions In patients with stable coronary artery disease without heart failure, RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher

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

    Energy Technology Data Exchange (ETDEWEB)

    Slavnov, V.N.; Yakovlev, A.A.; Yugrinov, O.G.; Gandzha, T.I. (Kievskij Nauchno-Issledovatel' skij Inst. Ehndokrinologii i Obmena Veshchestv (Ukrainian SSR))

    1983-02-01

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

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

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xun; HOU Fan-fan

    2007-01-01

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

  2. The effect of renin-angiotensin-system inhibition on survival and recurrence of N3+ breast cancer patients.

    Science.gov (United States)

    Babacan, Taner; Balakan, Ozan; Kuzan, Taha Y; Sarici, Furkan; Koca, Emre; Kertmen, Neyran; Petekkaya, Ibrahim; Altundag, Kadri

    2015-01-01

    The purpose of this study was to evaluate the association between the rennin-angiotensin system (RAS) inhibition and the risk of breast cancer (BC) recurrence and progression in N3 positive patients. The medical records of patients treated for N3 positive BC in Hacettepe Cancer Institute between 2005 and 2012 were evaluated. Angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) users were defined as patients who took these medications for at least 6 months in no evidence of disease (NED) stage after the initial diagnosis. The primary and secondary outcome was disease-free survival (DFS) and overall survival (OS). Kaplan-Meier and Cox proportional hazard models were used. A total of 218 pathologic N3 BC patients were included. Follow up ranged from 12 to 212 months (median 49.58). Thirty one patients used ACE inhibitors/ARBs. Univariate analysis showed BC recurrence was lower and OS was higher among patients who used ACE inhibitors/ ARBs, however without reaching statistical significance (p=0.38 and p=0.24, respectively). RAS inhibition was associated with reduced risk of pathologic N3 BC recurrence. To the best of our knowledge this is the second study showing that the use of ACE inhibitors/ARBs may be effective in N3 BC. Because of the limited therapeutic options in BC, new drugs or new therapeutic modalities should be considered. In the future, studies with long-term follow-up may be helpful for their implication in clinical practice.

  3. [Left-ventricular hypertrophy as a cardiac risk factor: role of the renin-angiotensin-aldosterone system].

    Science.gov (United States)

    Erne, P

    1996-02-20

    Left-ventricular hypertrophy is the result of cardiac adaptation to global or regional overstress and represents an important cardiovascular risk factor, increasing the risk for development of congestive heart failure and incidence of sudden death. This review describes the pathophysiological and biochemical mechanisms involved in the development of left-ventricular hypertrophy and cardiac fibrosis with particular emphasis on the role of angiotensin II and aldosterone. Central to the cascade of cardiac fibrosis is the increased production or reduced degradation of collagen proteins in fibroblasts. Collagen proteins are proteins needed for the alignment of cellular compartments and the development of forces, contraction and relaxation of the heart. If overexpressed, an important rise of wall stiffness is observed in addition to a reduced capacity to provide oxygen to the cardiac tissue. This latter explains why in areas of histologically hypertrophied heart muscle atrophied muscle cells are observed. The characterization of the second-messenger systems involved in the regulation of cardiac cells as well as the identification of angiotensin-II receptor subtype and angiotensin IV is described. Both of these receptors are present on cardiac fibroblasts and stimulate these to collagen production, which can be inhibited by antagonists or the generation of angiotensin II by ACE inhibitors. In some forms of left-ventricular hypertrophy and in patients with congestive heart failure in addition to elevated angiotensin-II levels, increased aldosterone levels are observed. Aldosterone raises upon stimulation by angiotensin II and upon reduction of angiotensin-II generation subsequent to ACE inhibition through an escape mechanism. The contribution of aldosterone to left-ventricular hypertrophy and cardiac fibrosis can be prevented and reduced by the administration of its antagonist, spironolactone. Further and larger clinical trials are needed and in progress to evaluate if the

  4. 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, pproteinuria 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, pproteinuria (1.9±1.4 to 0.8±0.5, pproteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in

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

    Directory of Open Access Journals (Sweden)

    Ferrán Catalá-López

    2016-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Hart Meaghan

    2009-11-01

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

  7. Correlation between Diabetic Nephropathy and Renin-angiotensin-aldosterone System%糖尿病肾病与肾素-血管紧张素-醛固酮系统的关系

    Institute of Scientific and Technical Information of China (English)

    曹丹

    2012-01-01

    Diabetic nephropathy( diabetic kidney disease )is defined as a rise in urinary albumin excretion rate, often associated with an increase in blood pressure, and typically with concomitant retinopathy. It is characterized firstly by albuminuria and then by a progressive decline in glomerular filtration rate, eventually resulting in end-stage renal disease( ESRD ). A diabetic milieu is required for the diabetic glomerular lesion to develop, and renin-angiotensin-aldosterone system is an endocrine system with complex physiological functions, playing an important role in prevention, development and progression of diabetic nephropathy. Using drugs that block the renin-angiotensin-aldosterone system are effective strategies for preventing the development of diabetic nephropathy delaying the progression to more advanced stages of nephropathy.%糖尿病肾病是一种尿蛋白排泄率增加,通常伴有血压升高和典型的视网膜病变的疾病.这种疾病的特点首先是出现蛋白尿,继而肾小球滤过率进行性下降,最终导致终末期肾脏病.糖尿病环境对糖尿病患者肾小球的损伤甚至加重是必要的,肾素-血管紧张素-醛固酮系统是生理功能颇为复杂的内分泌系统,对糖尿病肾病的预防、发生、发展有重要作用.肾素-血管紧张素-醛固酮系统阻断剂药物的应用在阻止糖尿病肾病的进展以及延缓发展到晚期肾脏病阶段是有效的方法.

  8. PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system.

    Directory of Open Access Journals (Sweden)

    Elion Hoxha

    Full Text Available Patients with primary membranous nephropathy (MN who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55% patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis, 16 (48% patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39-9.64; p = 0.009. Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81% compared to PLA2R-Ab negative patients (2 of 17 patients, 12%. PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.

  9. PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system.

    Science.gov (United States)

    Hoxha, Elion; Harendza, Sigrid; Pinnschmidt, Hans; Panzer, Ulf; Stahl, Rolf A K

    2014-01-01

    Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39-9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.

  10. 肾素-血管紧张素系统阻滞剂治疗慢性肾脏病的研究进展%Research progress of renin-angiotensin system blockade in treatment of chronic kidney disease

    Institute of Scientific and Technical Information of China (English)

    刘晓莉; 金惠敏

    2011-01-01

    With the increase of prevalence year by year, chronic kidney disease (CKD) has become one of the major diseases that threaten the public health all over the world.Adipose tissues are important resources of cytokines which cause metabolic disorder in CKD.These cytokines can promote inflammation, and lead to uremia-related insulin resistance, which may play an important role in the occurrence and development of CKD.Renin-angiotensin system blockade, which slows down the development of CKD by regulation of adipocyte dysfunction, is the classical drug in the treatment of CKD.The research progress of renin-angiotensin system blockade in the treatment of CKD is reviewed in this paper.%慢性肾脏病(CKD)的患病率呈逐年上升趋势,已成为威胁全世界公共健康的主要疾病之一.脂肪组织是导致CKD代谢紊乱的重要细胞因子来源,脂肪细胞因子能促进炎症并引起尿毒症相关的胰岛素抵抗,在CKD的发生和发展中起重要作用.肾素-血管紧张素系统(RAS)阻滞剂是治疗CKD的经典药物,通过调节脂肪细胞功能失调而延缓CKD的发展.文章就该方面的研究进展进行综述.

  11. Advances in Renin-Angiotensin System Blockades in Treating Metabolic Syndrome%肾素-血管紧张素系统阻断剂治疗代谢综合征的进展

    Institute of Scientific and Technical Information of China (English)

    张凤; 周华梅; 张霞

    2012-01-01

    代谢综合征以胰岛素抵抗为主要特征,是心血管疾病的危险因素.非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是代谢综合征在肝脏的表现.肾素-血管紧张素系统(renin-angiotensin system,RAS)的激活参与了代谢综合征的发生、发展,阻断RAS的激活是代谢综合征的治疗途径之一.RAS阻断剂包括血管紧张素转换酶抑制剂(angiotensin converting enzyme inhibitor,ACEI)和血管紧张素Ⅱ受体拮抗剂(angiotensin receptor blockade,ARB),可降低血压、改善胰岛β细胞功能和胰岛素抵抗,但RAS阻断剂对NAFLD的疗效尚存在争议.该文就RAS阻断剂治疗代谢综合征的进展进行了综述.%Insulin resistance is a key characteristic of metabolic syndrome, which is considered as a predictor of cardiovascular diseases. Non - alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The activation of renin - angiotensin system (RAS) is involved in the development of metabolic syndrome. The inhibition of RAS activation is an effective treatment of metabolic syndrome. RAS blockades, including angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockade (ARB), can decrease blood pressure, improve islet beta - cell function and insulin resistance. However, there is still a controversy about the effect of RAS blockades on NAFLD. In this article, current evidence concerning RAS blockades in the treatment of metabolic syndrome will be reviewed.

  12. PLA2R Antibody Levels and Clinical Outcome in Patients with Membranous Nephropathy and Non-Nephrotic Range Proteinuria under Treatment with Inhibitors of the Renin-Angiotensin System

    Science.gov (United States)

    Hoxha, Elion; Harendza, Sigrid; Pinnschmidt, Hans; Panzer, Ulf; Stahl, Rolf A. K.

    2014-01-01

    Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39–9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management. PMID:25313791

  13. Original cognition of renin-angiotensin system%肾素-血管紧张素系统的新认识

    Institute of Scientific and Technical Information of China (English)

    潘伟男; 封芬; 陈锋; 陈临溪

    2006-01-01

    肾素-血管紧张素系统(renin-angiotensin system,RAS)通过对心血管和肾脏的影响,发挥稳定血压、平衡水盐和维持内环境稳态的重要作用。大量研究已经形成了较完善的“RAS经典代谢途径”理论。最近发现了这一系统的许多新成员,包括糜蛋白酶(chymase)、血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)、血管紧张素1~7(Ang1-7)和apelin等,大大拓展了对经典RAS的认识。本文就RAS研究新进展予以综述。

  14. 肾素血管紧张素系统与肝纤维化、肝硬化%Renin angiotensin system and liver fibrosis or cirrhosis

    Institute of Scientific and Technical Information of China (English)

    申凤俊; 阴赪宏; 王宝恩

    2003-01-01

    循环肾素-血管紧张素系统(renin angiotensin system,RAS)为一内分泌系统,能分泌血管紧张素Ⅱ(angiotensin Ⅱ,AngⅡ),AngⅡ具有广泛的生物学效应,作用于全身多个器官,主要通过AngⅡ和特异性的膜受体作用来调控。在许多组织或器官,如肾脏、心脏和血管中存在着独立的局部RAS[1],亦可合成AngⅡ,AngⅡ以旁分泌、自分泌、细胞内分泌等形式作用于组织和细胞,与组织细胞特异性受体结合,发挥一。系列功能调控作用。新近研究表明,肝脏亦存在着局部RAS[2,3],肝脏局部RAS、循环RAS与肝纤维化、肝硬化有着密切的关系。

  15. 肾素-血管紧张素-醛固酮系统与糖尿病肾病%Renin-angiotensin-aldosterone system and the treatment of diabetic kidney disease

    Institute of Scientific and Technical Information of China (English)

    潘道延; 沈洁

    2015-01-01

    Diabetic nephropathy as a chronic complications of diabetes, its incidence in recent years along with the increasing incidence of diabetes also showed a trend of rising year. Renin-angiotensin aldosterone system activation in the occurrence of diabetic nephropathy development has the extremely important status, use of RAAS inhibitors can significantly control high blood pressure, reduce urine protein, reduce glomerular filtration, and delay the renal interstitial fibrosis. Some large clinical trials have confirmed that inhibiting renin-angiotensin aldosterone system treatment can significantly reduce microalbuminuria and macroalbuminuria in patients with diabetic nephropathy, delay the progress of diabetic nephropathy, and reduce the incidence of end-stage renal disease. But the combined use of RAAS blocker due to its significantly increased adverse events also needs our further research.%糖尿病肾病作为糖尿病的一种慢性并发症,近年来其发病率随着糖尿病的发病率不断上升也呈现逐年上升的趋势。肾素-血管紧张素-醛固酮系统(RAAS)的激活在糖尿病肾病的发生发展中有着极其重要的地位,使用RAAS抑制剂可以明显地控制血压、减少尿蛋白、减轻肾小球高滤过、延缓肾间质纤维化。一些大型的临床试验已经证实抑制RAAS的治疗可以明显减轻糖尿病肾病患者微量白蛋白尿及大量白蛋白尿的产生及发展,延缓糖尿病肾病的进展,减少终末期肾病的发病率。但目前关于联合应用RAAS阻滞剂因其不良事件的明显增加还需要我们进一步探索解决。

  16. The Roles of Local Renin-angiotensin System in the Dysfunction of Adipocytes%局部肾素-血管紧张素系统对脂肪细胞功能的影响

    Institute of Scientific and Technical Information of China (English)

    高燕

    2013-01-01

    In obese state,the dysfunction of local renin-angiotensin system( RAS )in adipose tissue plays an important role in the occurrence and development of hypertesion,type 2 diabetes and other obesity-related diseases. The local RAS in adipose tissue acts on differentiation of adipocytes, expression and secretion of adi-pocytokines and metabolism of glucose and lipid in a manner of paracrine or autocrine, which deteriorate insulin resistance and interrupt the homeostasis of glucose and lipid of the whole body. The intervention of dysfunctional RAS in adipose tissue may become a potential therapy for obesity-related diseases.%肥胖状态下,脂肪组织中亢进的肾素-血管紧张素系统(RAS)在高血压、2型糖尿病等肥胖相关性疾病中发挥着重要的作用.脂肪组织局部的RAS通过旁分泌或自分泌方式调节脂肪细胞自身的增殖分化、因子的分泌以及糖脂代谢等,继而加剧胰岛素抵抗,影响机体整体糖脂代谢状态.干预脂肪组织局部紊乱的RAS可能成为肥胖及其相关疾病的治疗途径.

  17. Abnormality of Renin-Angiotensin System in Podocyte Dysfunction in Diabetic Kidney Disease%肾素-血管紧张素系统在糖尿病肾病肾脏足细胞损伤中的作用

    Institute of Scientific and Technical Information of China (English)

    邵德翠; 陆利民

    2011-01-01

    糖尿病肾病(diabetic kidney disease,DKD)作为诱发终末期肾脏病(end-stage renal disease,ESRD)的主要原因,至今其病理机制仍不十分清楚.DKD病程中蛋白尿持续增多并伴随肾素-血管紧张素系统(renin-angiotensin system,RAS)过度激活.阻断RAS能改善蛋白尿,有良好的临床肾脏保护作用.足细胞表达RAS的各成员,作为肾小球滤过的最后屏障,其损伤与蛋白尿的发生关系密切.本文就RAS与足细胞损伤在DKD病理中作用作一简单综述.%Diabetic kidney disease (DKD) is currently the leading cause of end-stage renal disease (ESRD). DKD is stamped by proteinuria and progressive renal dysfunction. Excessive activation of RAS under hyperglycemic condition is associated with the development of DKD. Suppression of RAS markedly reduces proteinuria and retards progression of DKD in clinic. Podocyte forms the final barrier to protein in glomerular filtration. Podocyte injury leads to abnormality in glomerular filtration permeability, results in proteinuria. Various components of RAS have been identified to be expressed in podocyte. Here we reviewed the progress on RAS in regulating the function of podocyte and progress of DKD.

  18. Dietary t10,c12-CLA but not c9,t11 CLA reduces adipocyte size in the absence of changes in the adipose renin-angiotensin system in fa/fa Zucker rats.

    Science.gov (United States)

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

    2010-11-01

    In obesity, increased activity of the local renin-angiotensin system (RAS) and enlarged adipocytes with altered adipokine production are linked to the development of obesity-related health problems and cardiovascular disease. Mixtures of conjugated linoleic acid (CLA) isomers have been shown to reduce adipocyte size and alter the production of adipokines. The objective of this study was to investigate the effects of feeding individual CLA isomers on adipocyte size and adipokines associated with the local adipose RAS. Male fa/fa Zucker rats received either (a) control, (b) cis(c)9,trans(t)11-CLA, or (c) t10,c12-CLA diet for 8 weeks. The t10,c12-CLA isomer reduced adipocyte size and increased cell number in epididymal adipose tissue. RT-PCR and Western blot analysis revealed that neither CLA isomer altered mRNA or protein levels of angiotensinogen or AngII receptors in adipose tissue. Likewise, levels of the pro-inflammatory cytokines TNF-α and IL-6 or the anti-inflammatory cytokine IL-10 were unchanged in adipose tissue. Similarly, neither CLA isomer had any effect on phosphorylation nor DNA binding of NF-κB. Our results suggest that although the t10,c12-CLA isomer had beneficial effects on reducing adipocyte size in obese rats, this did not translate into changes in the local adipose RAS or associated adipokines.

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

    Science.gov (United States)

    Sica, Domenic A

    2010-04-01

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

  20. You are what you eat: dietary salt intake and renin-angiotensin blockade in diabetic nephropathy.

    Science.gov (United States)

    Charytan, David M; Forman, John P

    2012-08-01

    Interactions between sodium intake, the renin-angiotensin system, and renal and cardiovascular outcomes are incompletely understood. The analysis by Lambers Heerspink et al. shows that angiotensin receptor blockade improves diabetic nephropathy and cardiovascular disease more when dietary sodium intake is low, and suggests possible harm when sodium intake is high. These findings highlight dietary salt as a modifiable cardiovascular and renal risk factor and emphasize the need for detailed mechanistic studies.

  1. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain.

    Science.gov (United States)

    Takahashi, Hakuo; Yoshika, Masamichi; Komiyama, Yutaka; Nishimura, Masato

    2011-11-01

    The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin-angiotensin-aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na(+)-ENaC-RAAS-EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.

  2. Research progresses of Renin-angiotensin system receptors in breast cancer%肾素-血管紧张素系统相关受体在乳腺癌中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王婷(综述); 陈雪松(审校)

    2016-01-01

    近期研究表明,肾素-血管紧张素系统( Renin-angiotensin system ,RAS)不仅在心血管系统方面起作用,而且在乳腺癌的发生和发展中也扮演着重要的角色。血管紧张素Ⅱ( Angiotensin Ⅱ, AngⅡ)和血管紧张素1-7(Angiotensin 1-7,Ang1-7)是RAS的主要效应分子,它们通过作用于RAS相关受体,可分别促进和抑制乳腺癌的发生和发展。本文就RAS在乳腺癌中的相关研究加以总结,并探讨RAS相关受体靶向治疗药物在乳腺癌临床治疗中的潜在用途。%Recent studies had demonstrated that Renin -angiotensin system ( RAS) plays an important role not only in the cardiovascular system ,but also in the occurrence and development of breast cancer .Associated with RAS receptor ,Angiotensin Ⅱ( Ang Ⅱ) and Angiotensin 1-7 ( Ang1-7 ) which are the major molecules of the RAS,respectively,promote or inhibit the occurrence and development of tumor .In this review,we summarize the current knowledge of the RAS in breast cancer ,and discuss the potential application of RAS related receptors targeted drugs in the clinical treatment of breast cancer .

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

    Science.gov (United States)

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

    2016-04-01

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

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

    Science.gov (United States)

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

    2008-09-03

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

  5. Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

    Science.gov (United States)

    Li, Chunmei; Han, Rui; Kang, Le; Wang, Jianping; Gao, Yonglin; Li, Yanshen; He, Jie; Tian, Jingwei

    2017-01-01

    Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and ±dp/dtmax changes induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-α expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-α. PMID:28091615

  6. Reduced Expression of the Extracellular Calcium-Sensing Receptor (CaSR Is Associated with Activation of the Renin-Angiotensin System (RAS to Promote Vascular Remodeling in the Pathogenesis of Essential Hypertension.

    Directory of Open Access Journals (Sweden)

    Yuan-Yuan Qu

    Full Text Available The proliferation of vascular smooth muscle cells (VSMCs, remodeling of the vasculature, and the renin-angiotensin system (RAS play important roles in the development of essential hypertension (EH, which is defined as high blood pressure (BP in which secondary causes, such as renovascular disease, are absent. The calcium-sensing receptor (CaSR is involved in the regulation of BP. However, the underlying mechanisms by which the CaSR regulates BP are poorly understood. In the present study, the role of the CaSR in EH was investigated using male spontaneously hypertensive rats (SHRs and rat and human plasma samples. The percentages of medial wall thickness to external diameter (WT%, total vessel wall cross-sectional area to the total area (WA% of thoracic arteries, as well as the percentage of wall area occupied by collagen to total vessel wall area (CA% were determined. Tissue protein expression and plasma concentrations of the CaSR, cyclic adenosine monophosphate (cAMP, renin, and angiotensin II (Ang II were additionally assessed. WT%, WA%, and CA% were found to increase with increasing BP, whereas the plasma concentration of CaSR was found to decrease. With increasing BP, the levels of smooth muscle actin and calponin decreased, whereas those of osteopontin and proliferating cell nuclear antigen increased. The CaSR level negatively correlated with the levels of cAMP and Ang II, but positively correlated with those of renin. Our data suggest that reduced expression of the CaSR is correlated with activation of the RAS, which induces increased vascular remodeling and VSMC proliferation, and thereby associated with EH in the SHR model and in the Han Chinese population. Our findings provide new insights into the pathogenesis of EH.

  7. The impact of renin-angiotensin system, angiotensin І converting enzyme (insertion/deletion), and angiotensin ІІ type 1 receptor (A1166C) polymorphisms on breast cancer survival in Iran.

    Science.gov (United States)

    Namazi, Soha; Daneshian, Arghavan; Mohammadianpanah, Mohammad; Jafari, Peyman; Ardeshir-Rouhani-Fard, Shirin; Nasirabadi, Shiva

    2013-12-10

    Several proteins of renin-angiotensin system (RAS) have been implicated in the process of growth promotion or inhibition of breast tissue and cancer cells. This study aimed to investigate the association between angiotensin I converting enzyme (ACE) insertion/deletion (I/D) and angiotensin receptor-1 (AGTR1) A1166C polymorphisms and survival of 110 women with breast cancer. The I/D and A1166C polymorphisms were evaluated by using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) in 110 breast cancer patients who had been treated between 2007 and 2009. Genomic DNA was extracted from a Formalin-Fixed Paraffin-Embedded (FFPE) tissue of breast cancer sample blocks. All the potential clinical and pathological prognostic variables were analyzed to establish the impact of I/D and A1166C polymorphisms on disease-free and overall survival rates. Disease-free and overall survival rates were the primary endpoints of the study. The ACE (I/D) polymorphism was associated with 3-year disease-free survival. Disease-free survival in DD carriers was significantly increased compared to ID plus II carriers (HR=4.75; 95% CI, 1.39-16.24; p=0.013). No significant association was found between AGTR1 (A1166C) and 3-year disease-free survival (p=0.233). Also, the ACE (I/D) and AGTR1 (A1166C) polymorphisms were not associated with breast cancer overall survival. The ACE (I/D) polymorphism was associated with 3-year disease-free survival of the women with breast cancer. Besides, disease-free survival in DD carriers was significantly increased compared to ID plus II carriers. © 2013 Elsevier B.V. All rights reserved.

  8. Multiple Polymorphisms in the renin- angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort.

    Science.gov (United States)

    Henderson, Sean O; Haiman, Christopher A; Mack, Wendy

    2004-11-01

    When compared with other U.S. populations, African Americans have excess hypertension. Genetic variants in elements of the renin-angiotensin-aldosterone system (RAAS), namely the angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2), and angiotensin II type 1 receptor (AGTR1) genes, have been associated with risk of hypertension in some populations. We genotyped the D/I polymorphism in the ACE gene, the C(-344)T polymorphism in the CYP11B2 gene, and the C(-535)T polymorphism in the AGTR1 gene among African American and Latino members of the Multiethnic Cohort Study (MEC) to determine their association with hypertension. We observed no significant increase in the risk of hypertension for either African Americans or Latinos homozygous or heterozygous for the D allele of the ACE gene. Among African Americans we observed carriers of the (-344)T allele of CYP11B2 to be at increased risk of hypertension (versus CC genotype: TC genotype, OR = 1.66 [95% CI: 1.01-2.72]; TT genotype, OR = 1.74 [95% CI: 1.07-2.82]). There was also an increase in risk of hypertension associated with the AGTR1 T allele for African Americans (versus CC genotype: TC genotype, OR = 2.62 [95% CI: 1.46-4.72]; TT genotype, OR = 2.67 [95% CI: 1.51-4.74]). The associations observed with CYP11B2 and AGTR1 genotypes were not observed among Latinos. These data suggest that the (-535)T allele of AGTR1 and (-344)T allele of CYP11B2 may increase hypertension risk among African Americans but not among Latinos. Characterization of the linkage disequilibrium and haplotype patterns in the RAAS pathway genes will be crucial to understanding differences in hypertension susceptibility in these ethnic populations.

  9. Effect of advanced glycation end products on renin-angiotensin system in podocytes%晚期糖基化终产物对足细胞内肾素-血管紧张素系统的影响

    Institute of Scientific and Technical Information of China (English)

    成彩联; 郑振达; 石成钢; 叶增纯; 刘迅; 娄探奇

    2013-01-01

    Objective To investigate the effect and mechanism of advanced glycation end products (AGEs) on the components of renin-angiotensin system (RAS) in the podocytes.Methods Immortalized mouse podocytes were exposed to various concentrations of AGEs for 24 h.The expression levels of renin,angiotensinogen (AGT) and angiotensin Ⅱ type 1 and 2 receptors (AT1R and AT2R),the level of angiotensin Ⅱ (Ang Ⅱ),and the activity of angiotensin-converting enzyme (ACE) were assayed.The levels of Akt and phosphorylated Akt were examined by Western blotting.Cell adhesion was measured in the podocytes pretreated with phosphoinositide 3-kinase (PI3-K) inhibitor LY294002,losartan,captopril and chymostatin,respectively.Results Treatment with AGEs resulted in significant increase in the expression of AGT and AT1R.Moreover,ACE activity and Ang Ⅱ level increased significantly.However,there was no significant change in renin and AT2R expression.AGEs increased the phosphorylation of Akt by 100%.When the podocytes were pretreated with LY294002 (10 μmol/L),the AGEs-induced increase in AGT and AT1R expression reduced remarkably.Likewise,ACE activity and Ang Ⅱ level decreased significantly,and the reduced podocyte adhesive capacity induced by AGEs was improved significantly.Conclusions AGEs activate the RAS via PI3-K/Akt-dependent pathway,and lead to a decrease in podocyte adhesion.%目的 观察晚期糖基化终产物(advanced glycation end products,AGEs)对足细胞内肾素-血管紧张素系统(renin-angiotensin system,RAS)的影响及作用机制.方法 不同浓度的AGEs干预小鼠足细胞24h,分别检测肾素(renin)、血管紧张素原(renin-angiotensin system,AGT)、血管紧张素Ⅱ1型、2型受体(AT1R、AT2R)的表达,血管紧张素转换酶(angiotensin-converting enzyme,ACE)的活性和血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)的浓度,观察蛋白激酶B(Akt)的磷酸化,然后分别加入磷酸肌醇3激酶抑制剂LY294002、Iosartan、captopril和chymastatin,

  10. Structural and theoretical studies on rhodium and iridium complexes with 5-nitrosopyrimidines. Effects on the proteolytic regulatory enzymes of the renin-angiotensin system in human tumoral brain cells.

    Science.gov (United States)

    Illán-Cabeza, Nuria A; Jiménez-Pulido, Sonia B; Ramírez-Expósito, María J; García-García, Antonio R; Peña-Ruiz, Tomás; Martínez-Martos, José M; Moreno-Carretero, Miguel N

    2015-02-01

    The reactions of [RhCl(CO)(PPh3)2], [RhCl(CO)2]2 and [IrCl(CO)(PPh3)2] with different 5-nitrosopyrimidines afforded sixteen complexes which have been structurally characterized by elemental analysis, IR and NMR ((1)H and (13)C) spectral methods and luminescence spectroscopy. The crystal and molecular structures of [Rh(III)Cl(VIOH-1)2(PPh3)], [Rh(III)Cl(DVIOH-1)2(PPh3)] and [Rh(II)(DVIOH-1)2(PPh3)2] have been established from single crystal x-ray structure analyses. The three complexes are six-coordinated with both violurato ligands into an equatorial N5,O4-bidentate fashion, but with different mutually arrangements. Theoretical studies were driven on the molecular structure of [Rh(III)Cl(VIOH-1)2(PPh3)] to assess the nature of the metal-ligand interaction as well as the foundations of the cis-trans (3L-2L) isomerism. An assortment of density functional (SOGGA11-X, B1LYP, B3LYP, B3LYP-D3 and wB97XD) has been used, all of them leading to a similar description of the target system. Thus, a topological analysis of the electronic density within AIM scheme and the study of the Mulliken charges yield a metal-ligand link of ionic character. Likewise, it has been proved that the cis-trans isomerism is mainly founded on that metal-ligand interaction with the relativistic effects playing a significant role. Although most of the compounds showed low direct toxicity against the human cell lines NB69 (neuroblastoma) and U373-MG (astroglioma), they differently modify in several ways the renin-angiotensin system (RAS)-regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). Therefore, these complexes could exert antitumor activity against both brain tumor types, acting through the paracrine regulating system mediated by tissue RAS rather than exerting a direct cytotoxic effect on tumor cells.

  11. 不同亚型库欣综合征患者肾素-血管紧张素-醛固酮系统变化%The changes in renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome

    Institute of Scientific and Technical Information of China (English)

    崔佳; 窦京涛; 杨国庆; 臧丽; 金楠; 陈康; 杜锦; 谷伟军; 王先令

    2015-01-01

    Objective Cushing's syndrome is a clinical condition resulting from chronic exposure to excess glucocorticoid.As a consequence,long-term hypercortisolism contributes significantly to the development of systemic disorders by direct and/or indirect effects.The present study was to analyze the changes of renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome on the standard posture test.Methods We retrospectively reviewed 150 patients with histologically confirmed Cushing's syndrome treated at the PLA General Hospital between 2002 and 2014.Among them,128 patients were diagnosed as adreno-cortico-tropic-hormone (ACTH)-independent Cushing's syndrome,and 22 were ACTH-dependent Cushing's syndrome.All patients were undertaken the posture test.Plasma renin activity (PRA),angiotensin Ⅱ,plasma aldosterone concertration (PAC) levels were measured before and after the test.Results Basal plasma PRA [0.5 (0.2,1.3) μg · L-1 · h-1],angiotensin Ⅱ [(48.9 ± 20.1) ng/L] and PAC [(285.0 ± 128.1) pmol/L] levels were within the normal range in supine position.Compared with the subjects with ACTH-independent Cushing's syndrome,the basal PAC levels were higher in subjects with ACTH-dependent Cushing' s syndrome [(348.0 ± 130.4) pmol/L vs (274.2 ± 125.0) pmol/L,P < 0.05].However,the PAC response in subjects with ACTH-dependent Cushing's syndrome [(49.7 ± 26.4)%] was significantly lower than that in those with ACTH-independent Cushing's syndrome [(81.2 ± 69.3) %] upon upright posture stimulation (P < 0.05).There were no statistical significances in PRA and angiotensin Ⅱ levels between the two groups.The basal PAC and PRA levels were positively correlated with ACTH,whereas PAC response was negatively correlated with ACTH.Conclusions The renin-angiotensin-aldosterone-system activity in subjects with Cushing's syndrome was similar to that in normal control.The basal PAC level and its response to upright posture are differently associated with ACTH

  12. CARDIOVASCULAR ENDOCRINOLOGY Dual RAAS blockade has dual effects on outcome

    NARCIS (Netherlands)

    Heerspink, Hiddo J. Lambers; de Zeeuw, Dick

    Makani and colleagues report that dual blockade of the renin-angiotensin-aldosterone system is associated with harm despite previous studies showing that this approach decreases blood pressure and albuminuria. Do these results imply that we should abandon surrogate markers? Or should we become more

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

    DEFF Research Database (Denmark)

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

    2006-01-01

    ) was investigated during exercise after [alpha]-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s-1 (BL s-1) while Pven, dorsal aortic blood pressure (Pda) and relative cardiac output (Q) was recorded continuously. Heart rate (fH), cardiac stroke volume (SV) and total......The role of the [alpha]-adrenergic system in the control of cardiac preload (central venous blood pressure; Pven) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS...... systemic resistance (Rsys) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after [alpha]-adrenoceptor blockade...

  14. Sodium restriction on top of renin-angiotensin-aldosterone system blockade increases circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline in chronic kidney disease patients

    NARCIS (Netherlands)

    Kwakernaak, Arjan J.; Waanders, Femke; Slagman, Maartje C. J.; Dokter, Martin M.; Laverman, Gozewijn D.; de Boer, Rudolf A.; Navis, Gerjan

    2013-01-01

    Objective:Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection b

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

    Science.gov (United States)

    Sandblom, Erik; Axelsson, Michael; McKenzie, David J

    2006-08-01

    The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of

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

    Directory of Open Access Journals (Sweden)

    Ke Li

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Elena Montes-Cobos

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

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

    Science.gov (United States)

    2017-01-01

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

  19. The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines.

    Science.gov (United States)

    Pawlik, M W; Kwiecien, S; Ptak-Belowska, A; Pajdo, R; Olszanecki, R; Suski, M; Madej, J; Targosz, A; Konturek, S J; Korbut, R; Brzozowski, T

    2016-02-01

    The inhibition of angiotensin-converting enzyme (ACE) or the blockade of angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of acetic-acid-induced gastric ulcers with or without the blockade of Mas receptors by A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and losartan, respectively, the inhibition of ACE by lisinopril, the NO/cNOS inhibition by L-NAME and inhibition of prostaglandin/COX system by indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after ulcer induction, the area of these ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at ulcer margin and gastric oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive nitric oxide synthase (cNOS), superoxide dismutase (SOD), and pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) and plasma level of both cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the luminal content of NO significantly reduced the area of gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at ulcer margin. Similar GMBF changes and significant reduction the area of gastric ulcer was

  20. Serum sodium levels of heart failure and its influence on plasma renin-angiotensin-aldosterone system and brain natriuretic peptide levels%心力衰竭血钠水平对 RAAS 及 BNP 水平的影响

    Institute of Scientific and Technical Information of China (English)

    王玉东; 任松涛; 蔡青云

    2014-01-01

    Objective To study the correlation between serum sodium levels of heart failure and plasma renin-angiotensin-aldosterone system( PAAS) and brain natriuretic peptide(BNP) levels . Methods 122 122 patients with heart failure were divided into control ( serum sodium concentration<135 mmol/L ,57 cases) and observation group ( serum sodium concentration≥135 mmol/L , 65 cases) according to serum sodium levels . PRA , Ang Ⅱ , ALD and BNP levels of two groups were compared and analyzed , the correlation between serum sodium levels and levels of PRA ,AngⅡ ,ALD and BNP were analyzed by Pearson correlation analysis . Results Levels of PRA , Ang Ⅱ ,ALD and BNP of observation group were higher than that in control group significantly( P < 0 .05 ) .Pearson correlation analysis showed , serum sodium levels was positively correlated with levels of PRA , Ang Ⅱ , ALD and BNP( P <0 .05 ) .Conclusion Low level serum sodium of heart failure promotes the release of PRA , Ang , ALD and BNP , serum sodium levels is positively correlated with levels of PRA , Ang Ⅱ , ALD and BNP .%目的:研究心力衰竭患者血钠水平与血浆肾素-血管紧张素-醛固酮系统(RAAS)及脑钠肽之间(BNP)的相关性。方法选择我院收治的122例心力衰竭患者,根据血钠水平分为对照组(血清钠离子浓度<135 mmol/L ,57例)和观察组(血清钠离子浓度≥135 mmol/L ,65例),对2组患者的肾素(PRA)、血管紧张素(AngⅡ)、醛固酮(ALD)及BNP水平进行比较分析,并对血钠水平与AngⅡ、ALD及BNP水平的相关性采用 Pearson相关分析。结果观察组的PRA、AngⅡ、ALD及BNP水平显著高于对照组,差异具有统计学意义(P <00.5),通过 Pearson相关分析可见,患者的血钠水平与PRA、AngⅡ、ALD及BNP水平均呈负相关( P <00.5)。结论心力衰竭患者血钠水平低时能促进PRA、AngⅡ、ALD及BNP的释放,且血钠水平

  1. Advance of research on application of renin-angiotensin-aldosterone system blockers in elderly patients with chronic kidney disease%RAAS阻滞剂在老年慢性肾脏病中应用的研究进展

    Institute of Scientific and Technical Information of China (English)

    张琪; 倪兆慧

    2014-01-01

    全球老龄人(年龄≥65岁)所占的人口比例正逐步上升。老年人由于其特殊的生理状态更易被一些慢性病如,高血压、糖尿病、慢性肾脏病( CKD)所困扰。肾素-血管紧张素-醛固酮系统( RAAS)的过分活跃可导致高血压、心血管事件及CKD的发生。因此,针对RAAS的治疗具有可行性。但老年患者在使用RAAS阻滞剂[主要包括血管紧张素转换酶抑制剂( ACEI)、血管紧张素受体阻滞剂( ARB)、肾素抑制剂、醛固酮拮抗剂]类药物时更易出现肾小球滤过率( GFR)下降、高钾血症、低血压等不良反应,所以临床使用时,需要特别平衡使用该类药物的利弊。尽管目前对老年人使用RAAS阻滞剂药物有限的研究大多获得了肯定的结论,但是,仍需要更多、更长周期的研究结果来探寻老年CKD患者使用RAAS阻滞剂的疗效和安全性,以及是否确实能减缓CKD的进展。%Theproportionofglobalolderpeople(age≥65years)isgraduallyincreasing.Because of their special physiological state,older people are more easily troubled by some chronic diseases such as hypertension,diabetes,and chronic kidney disease( CKD). Overactivity of renin-angiotensin-aldosterone system( RAAS)can lead to hypertension,cardiovascular events,as well as CKD. Therefore,the treatment targeting RAAS is feasible. However,while using RAAS blockers including angiotensin converting enzyme inhibitors( ACEI),angiotensin receptor blockers( ARB),renin inhibitors,and aldosterone antagonists, elderly patients are more likely to be subjected to decrease of glomerular filtration rate ( GFR ), hyperkalemia,and hypotension,etc,indicating that it is specially required to weigh the pros and cons before clinical use of such drugs. Although most limited researches on efficacy of RAAS blocker drugs in elderly patients obtained positive conclusions,more long-term studies are still needed to explore the therapeutic efficacy

  2. 孕期脂多糖刺激诱导子代大鼠高血压的机制研究%Effects of maternal lipopolysaccharide on intrarenal renin-angiotensin system in offspring rats

    Institute of Scientific and Technical Information of China (English)

    郝雪琴; 孔涛; 李晓辉

    2011-01-01

    Objective To explore the mechanism of hypertension caused by maternal exposure to lipopolysaccharide in adult offspring rats. Methods Nulliparous,pregnant,time-matched SD rats were randomly divided into two groups(n = 3):control group and LPS group. On the pregnant day 8,10 and 12,rats in control group and LPS group were administered intraperitoneally with saline 0.5 mL or LPS 0. 79 mg/kg, respectively. Thesystolic blood pressure was measured in offspring once three weeks from 7 weeks of age to 25 weeks of age. The plasma renin activity and angiotensin Ⅱ concentration were measured in adult offspring rats at 7,16 and 25 weeks of age,intrarenal renin was assessed by real-time PCR, AT1-R protein expression was assessed by Western blot and angiotensin Ⅱ-positive cells were determined with immunohistochemical staining. Results The blood pressure in offspring of LPS-treated rats increased constantly and reached hypertensive level at 24 weeks of age. The intrarenal renin mRNA expression and the number of angiotensin Ⅱ-positive cells increased at 7,16 and 25 weeks of age,while the AT1-R protein expression decreased. The plasma renin activity and angiotensin Ⅱ were unchanged. Conclusion Maternal expos s ure to lipopolysaccharide activates intrarenal renin-angiotensin system in adult offspring rats.%目的 探讨孕期脂多糖刺激诱导子代大鼠(简称子鼠)高血压的机制研究.方法 将SD孕鼠6只随机分为两组.对照组 3只:腹腔注射无菌生理盐水 0.5 mL;脂多糖组 3只:腹腔注射脂多糖,剂量为0.79 mg/kg.分别在孕期第8、10、12天08∶00~09∶00 进行腹腔注射.子鼠出生后,观察7~25周龄子鼠血压的变化和肾组织肾素mRNA表达、血管紧张素Ⅱ1型受体(AT1-R)的蛋白表达以及肾组织血管紧张素Ⅱ(AngⅡ)阳性细胞表达.结果 与对照组相比,脂多糖组子鼠血压逐渐升高,至24周龄时达到高血压水平.血浆肾素活性和AngⅡ浓度无变化.7、16、25周龄子鼠肾

  3. Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

    NARCIS (Netherlands)

    Krikken, Jan A.; Dallinga-Thie, Geesje M.; Navis, Gerjan; Dullaart, Robin P. F.

    2008-01-01

    Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the

  4. Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

    NARCIS (Netherlands)

    Krikken, Jan A.; Dallinga-Thie, Geesje M.; Navis, Gerjan; Dullaart, Robin P. F.

    2008-01-01

    Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the pla

  5. Dual RAS Therapy Not on Target, but Fully Alive

    NARCIS (Netherlands)

    Lambers Heerspink, H. J.; de Zeeuw, D.

    2010-01-01

    Inhibitors of the renin-angiotensin system (RAS) form a cornerstone in the treatment of kidney disease. These drugs lower blood pressure and albuminuria, and afford renal protection. Dual therapy with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker have been shown to be m

  6. Association of Renin-angiotensin-aldosterone System Gene Polymorphism with the Effect of Angiotensin Receptor Blockers%肾素-血管紧张素-醛固酮系统基因多态性与血管紧张素受体阻滞剂降压疗效相关性的研究进展

    Institute of Scientific and Technical Information of China (English)

    贾坚; 门琛

    2012-01-01

    People recognize that the difference of genetic polymorphism results in the individual difference of drug effect, as the development of the human genome project and pharmacogenomics. This paper reviews association of renin-angiotensin-aldosterone system gene polymorphism with the effect of angiotensin receptor blockers which are used commonly in clinic. The paper also analyzes the possible causes of the contradiction of the research results in the past.%随着人类基因组计划的实施以及药物基因组学研究的进展,人们认识到基因多态性的不同导致了药物治疗效果的个体差异.现综述肾素-血管紧张素-醛固酮系统基因多态性与临床上常用的血管紧张素受体阻滞剂降压疗效的相关性,并分析以往研究结果矛盾的可能原因.

  7. The role of renin-angiotensin-aldosterone system in salty taste and sodium intake regulation%肾素-血管紧张素-醛固酮系统在咸味觉功能及摄钠调控中的作用

    Institute of Scientific and Technical Information of China (English)

    吕波; 闫剑群

    2011-01-01

    咸味觉感受功能对摄钠行为的引导和调控至关重要,体钠平衡失调将引起一系列神经内分泌变化以产生钠欲,并伴有咸味觉感受功能的变化.肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system,RAAS)的多个成分在体钠平衡失调对咸味觉功能的调控中扮演重要角色.外周及脑源性血管紧张素II(angiotensin II,ANG II)和醛固酮(aldosterone,ALD)可协同作用于中枢相应敏感神经元,调控动物咸味觉喜好及敏感性,进而调控摄钠行为,并帮助机体维持体钠平衡.

  8. A study of renin-angiotensin system and steroidogenesis during the follicular development and atresia%卵泡发育和闭锁过程中肾素-血管紧张素系统与甾体激素的作用

    Institute of Scientific and Technical Information of China (English)

    裴开颜; 吴尔若; 连瑞红; 焦丽红; 王红

    2001-01-01

    Objective: To investigate the relationship between the renin-angiotensin system (RAS) and steroidogenesis during the follicular development and atresia.   Methods: A dual-chamber culture system was prepared. Porcine ovarian follicles were divided into healthy and atretic groups. Granulosa and thecal cells were isolated, and cultured with gonadotropin in the dual-chamber system. After 48 hours, angiotensin II (Ang II), renin activity, estrodiol(E2), progesterone(P) and testosterone(T) in the media were determined by radioimmunoassay (RIA). The follicular fluid was aspirated from both the healthy follicles and the atretic follicles, and all the hormonal levels were measured as well. The immunohistochemistry method was employed for observing the location of Ang II in follicles.   Results: The Ang II levels increased significantly in the atresia follicles, either in follicular fluid or in the medium of cultured thecal cells. At the same time the renin activity levels decreased markedly. No significant change in the levels of both Ang II and renin activity was found in the medium of cultured granulosa cells. The productions of E2, P, T decreased in the atresia follicles, either in follicular fluid or in the media of cultured granulosa and thecal cells.   Conclusions: The follicular atresia was related to high levels of Ang II. At the same time the level of renin activity was declined, it may be resulted from the feedback mechanism in the ovarian RAS. The arise of Ang II was found in thecal cells specially, the reason could be due to an abundance of blood vessels in the thecal cell layer, but not in the granulosa layer. E2, P, T may play very important roles in the follicle development and atresia. The results of immunohistochemistry showed an increase of Ang II levels in the atresia group, which was consistence with the RIA results.%目的:研究在卵泡发育和闭锁过程中,卵巢的肾素-血管紧张素系统(RAS)及其与甾体激素生成

  9. Effect of the inhibitors of renin-angiotensin system on the lipid metabolism of patients with hypertension%肾素-血管紧张素系统抑制剂对高血压患者脂代谢的改善作用

    Institute of Scientific and Technical Information of China (English)

    程军

    2016-01-01

    Current data show that over half of hypertensive patients have lipid metabolic abnormalities. Coexistence of hypertension and lipid metabolic abnormality may significantly increase the morbidity and mortality of coronary heart disease. Effects of different kinds of antihypertensive agents on lipid metabolism vary. Renin-angiotensin system (RAS), widely distributed in human body, plays an important role in regulation of blood pressure, water-electrolyte balance as well as glucose and lipid metabolism. RAS inhibitors (RASI) can also improve lipid metabolism in hypertensive patients besides the effective reduction of blood pressure. This article reviews the interaction of RAS system and lipid metabolism and the improvement of lipid metabolism by RASI in hypertensive patients.%据统计,超过半数的高血压患者合并脂代谢异常,两者并存时,冠心病的发病和死亡风险显著增加。不同降压药物对脂代谢的影响不尽相同。肾素-血管紧张素系统(RAS)在体内广泛分布,在血压调节、水电解质平衡及糖脂代谢等诸多方面发挥重要作用。RAS抑制剂(RASI)在有效降压的同时,在一定程度上对高血压患者的脂代谢具有改善作用。本文拟从RAS系统与脂代谢的相互作用以及RASI对高血压患者脂代谢的改善作用两个方面进行综述。

  10. 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

    Objective: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). Methods: 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/1.73m2. Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. Results: 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)). Conclusions: 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. PMID:25013370

  11. 长期噪声暴露对大鼠心脏肾素-血管紧张素系统的影响及替米沙坦的干预%EFFECTS OF LONG-TERM NOISE EXPOSURE ON CARDIAC RENIN-ANGIOTENSIN SYSTEM AND INTERVENTION BY TELMISARTAN

    Institute of Scientific and Technical Information of China (English)

    佘晓俊; 吴铭权; 崔博; 张娜; 安改红; 徐传香; 刘洪涛

    2012-01-01

    目的 观察长期噪声暴露对大鼠心脏肾素-血管紧张素系统(renin-angiotensin system,RAS)主要成分的影响及替米沙坦(Telmisartan)的干预作用,为噪声损伤心脏的机制研究提供依据.方法 将成年SD大鼠随机分为正常对照组、噪声组、噪声+替米沙坦组、单纯替米沙坦组,每组6只.噪声组和噪声+替米沙坦组暴露于100dB(SPL)白噪声,6 h/d;噪声+替米沙坦组及单纯替米沙坦组用10 mg/(kg·d)盐酸替米沙坦水溶液灌胃,均连续12周.采用ELISA法测定大鼠血浆、心肌组织血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)含量,采用SYBR Green实时荧光定量RT-PCR 法测定心肌组织血管紧张素原(angiotensinogen,AGT)和血管紧张素Ⅱ受体1A亚型(AT1A)的基因表达.结果 暴露12周后,噪声组血浆、心肌AngⅡ分别为(172.246±31.314)pg/ml、(22.250±2.438)pg/ng prot,明显高于正常组[分别为(127.640±29.773)pg/ml、(17.484±1.022) pg/ng prot](P<0.05,P<0.01);噪声+替米沙坦组心肌AngⅡ含量为(13.002±2.457) pg/ng prot,明显低于正常组和噪声组(P<0.01);噪声组AT1A基因表达明显高于对照组(P<0.05);噪声+替米沙坦组AGT、AT1A基因表达明显低于噪声组(P<0.05,P<0.01).结论 噪声暴露可兴奋RAS,RAS兴奋可能是噪声致心肌损伤的途径之一.%To study the effects of long-term noise exposure on cardiac renin-angiotensin system (RAS) and the intervention by Telmisartan in rats, so as to provide the evidence for studying the mechanisms of heart damage by noise exposure.Methods Twenty-four SD rats were divided into four groups:control group(C group),noise exposure group( N group), noise exposure plus Telmisartan group( N + T group), and Telmisartan group( T group), with six rats per group. The N group and N + T group were exposed to the white noise 100 dB( SPL) 6 h/day; the N + T group and T group were administered Telmisartan(10 mg/kg per day) for 12 weeks. Angiotensin II (AngⅡ ) content

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

    Directory of Open Access Journals (Sweden)

    Smita I. Negi

    2015-01-01

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

  13. Renin-angiotensin-aldosterone system changes in pediatric severe sepsis treated with continuous blood purification%儿童严重脓毒症连续性血液净化治疗时肾素-血管紧张素-醛固酮系统的变化

    Institute of Scientific and Technical Information of China (English)

    朱艳; 张育才; 肖政辉; 崔云; 戎群芳; 徐梁; 蒋慧

    2015-01-01

    Objective To explore the changes of renin-angiotensin-aldosterone system in pediatric severe sepsis treated with continuous blood purification(CBP).Methods Prospective study,35 cases of critically ill children diagnosed with severe sepsis and admitted to PICU of Shanghai Children's Hospital of Shanghai Jiaotong University from June 2012 to May 2014 served as reseach objective.Based on the monitoring of vital signs,including central venous pressure,arterial blood pressure,mean arterial pressure,patients were treated with conventional therapy,as antibiotics,fluid therapy,and CBP by mode of continuous veno-venous hemodiafiltration or high volume hemofiltration.Plasma levels of rennin activity,angiontensin Ⅱ and aldosterone were measured by radioimmunoassay before and 24 h after CBP.Twenty-five cases of blood samples taken from the children collected from health care for liver function examination were matched as control group.Results Plasmalevelsofrenninactivitywere(2.11 ±1.93) pg/(L·h),(1.27±1.56) μg/(L·h),(0.37 ± 0.22) μg/(L· h) before and 24 h after CBP and control group,respectively.The levels of angiontensin Ⅱ were (426.78 ±332.37) ng/L,(364.40 ± 325.51) ng/L,(41.70 ± 10.81) ng/L,respectively.And the levels of aldosterone were (255.12 ± 218.18) ng/L,(134.92 ± 104.13) ng/L,(106.88 ±43.18) ng/L,respectively.The plasma levels of rennin activity,angiontensin Ⅱ,and aldosterone were higher in sepsis cases than in control group,while decreased obviously after CBP treatment(P <0.01,P <0.05).Eleven cases died and mortality was 31.4% (11/35).After 24 h of CBP,the mean arterial pressure improved in 26 cases with septic shock and dopamine dose reduced(P < 0.01).Conclusion The reaction of renin-angiotensin-aldosterone system is increased significantly in pediatric severe sepsis.CBP can down-regulate the levels of rennin activity,angiotensin Ⅱand aldosterone,but not worsen the circulation function.%目的

  14. 不同术后镇痛方法对血浆肾素-血管紧张素Ⅱ-醛固酮系统的影响%Influence of postoperative analgesic method on plasma renin-angiotensin-aldosterone system in patients undergoing hysterectomy

    Institute of Scientific and Technical Information of China (English)

    余微萍; 徐旭仲; 温怀凯; 寿红艳

    2001-01-01

    目的:观察不同术后镇痛方法对子宫切除术患者血浆肾素-血管紧张素-醛固酮(R-A-A)系统的影响。方法: 将36例ASAⅠ~Ⅱ级子宫切除术患者,随机分为持续硬膜外输注镇痛(CEA)组、持续静脉输注镇痛(CIA)组和哌替啶肌注镇痛(MA)组,每组12例。分别于麻醉前(T0)、术毕使用镇痛药前(T1)、术后4小时(T2)和术后第一天晨7时(T3)采静脉血测定血浆肾素、血管紧张素Ⅱ和醛固酮浓度。结果: 与T0比较,肾素水平CEA组、CIA组在T3升高,MA组在T2显著降低(P<0.01);血管紧张素ⅡCEA组在T2、T3和MA组在T3均显著降低(P<0.01);醛固酮CEA组在T3显著降低(P<0.01),MA组在T2升高(P<0.01),而T3时降低(P<0.01)。组间比较,CEA组、MA组在T2和T3时肾素、血管紧张素Ⅱ、在T3时醛固酮浓度显著低于CIA组(P小于0.05或 0.01)。结论:CIA患者R-A-A系统较稳定,CEA患者R-A-A系统被抑制。%Objective:To study the effects of postoperative analgesia on plasma renin-angiotensin-aldosterone(R-A-A)system in patients undergoing hysterectomy.Methods:Thirty-six patients,ASA gradeⅠ~Ⅱ,scheduled for elective hysterectomy ,were randomly divided into continuous epidural analgesia(CEA),continuous introvenous analgesia(CIA) and traditional meperidine intramuscular analgesia(MA) groups. Plasma renin,angiotensin and aldosterone concentrations were measured before anesthesia(T0),operation over and before analgesia(T1),4h after operation(T2),and 7o'clock of next day after surgery.Results:Compared with T0 ,renin levels at T3 were significantly higher in CEA and CIA groups (P<0.05),but in MA group, it was markedly low at T2 (P<0.01),Angiotensin concentrations at T2 and T3 were significantly low in CEA group(P<0.01),and significantly low at T3 in MA group(P<0.01),aldosterone constrations increased significantly in three groups at T1(P<0.05 or 0.01),but decreased markedly at T3 in CEA group

  15. Renin-angiotensin-aldosterone system (RAAS) and its pharmacologic modulation

    OpenAIRE

    Giestas, A.; Palma, I.; Ramos, M. (ed.)

    2010-01-01

    O sistema-renina-angiotensina-aldosterona (SRAA) é um sistema neuroendócrino complexo responsável pela modulação do equilíbrio hidroelectrolítico e regulação da pressão arterial. Através das suas múltiplas interacções contribui para a protecção do tecido endotelial, cardíaco, cerebral e renal. Adicionalmente, regula ainda a resposta do endotélio à inflamação e lesão. A sua activação crónica/desregulação induz hipertensão e perpetuação de uma cascata pró-inflamatória, pró-trombó...

  16. Optimal blockade of the renin angiotensin system in cardiorenal dysfunction

    NARCIS (Netherlands)

    Wal, Rudy Martinus Adrianus van de

    2006-01-01

    The kidneys are responsible for regulating the body’s fluid volume, mineral composition and acidity. In order to do so, the kidneys depend on an adequate cardiac output. When the cardiac output is reduced, the interplay between kidneys and endocrine tissue will provoke activation of the renin angiot

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

    Directory of Open Access Journals (Sweden)

    Ruchika Nandha

    2012-01-01

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

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

    NARCIS (Netherlands)

    Harst, Pim van der

    2006-01-01

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

  19. [Renin-angiotensin-aldosterone system in diabetes insipidus].

    Science.gov (United States)

    Kirillov, G; Ankov, V

    1980-01-01

    Plasma renin activity (PR) and plasma aldosterone level (PA) were investigated in 38 patients with central diabetes incipidus under conditions of standard sodium intake and after a three-day reduction of sodium in the diet with an additional furosemide load. Blood was recovered for examination in the morning under complete rest and after a two-hour slow walk. Apparently healthy volunteers (20) served as control. The PR and PA content was determined by the radioimmunological method. Not only the basic, but also the stimulated renin secretion was increased in patients with diabetes incipidus. The basic PA level was significantly diminished; after stimulation its level did not differ from that in healthy persons. At rest and with decreased sodium intake the patients displayed two types of PR activity: in some (n=18) there was no elevation, and in other (n=19) the rise was marked. It is supposed that in diabetes incipidus hyperreninemia was compensatory, directed to water retention in the organism; apparently it participated in the mechanism of hypovolemic thirst. An unusual combination of increased PR with diminished PA level is described for the first time.

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

    OpenAIRE

    van der Harst, Pim

    2006-01-01

    Summary and Future Perspectives Impaired endothelial function is recognized as one of the earliest events of atherogenesis.1, 2 In Part I, chapter 1, we discussed the clinical value of the different techniques to evaluate endothelium-dependent vasomotor function. We also reviewed the efficacy of both angiotensin converting enzyme inhibitors and the HMG-CoA reductase inhibitors on improving vascular function. Despite the extensive experimental evidence and some clinical trials studies using qu...

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

    NARCIS (Netherlands)

    Harst, Pim van der

    2006-01-01

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

  2. Progress on the association between ACE (I/D) gene polymorphism and renin-angiotensin- aldosterone system and cardiovascular disease%ACE基因插入/缺失多态性与肾素-血管紧张素-醛固酮系统及相关心血管疾病的关系研究进展

    Institute of Scientific and Technical Information of China (English)

    于彦彦; 董天葳; 隋小芳; 彭鹏; 杨军

    2015-01-01

    肾素-血管紧张素-醛固酮系统(RAAS)是人体内重要的体液调节系统。RAAS存在于血管壁、心脏、肾脏和肾上腺等组织中,作用于循环系统,参与对靶器官的调节。在正常情况下,它具有调节水、盐平衡,血管张力和交感神经活性,维持内环境稳定,调节血压以及对心血管系统的正常发育、功能稳态等作用而被认为与心血管疾病的发生、发展及预后有密切联系;因此编码该系统的各个基因就成为许多课题研究的很有吸引力且极具价值的候选基因。RAAS 在健康和疾病中发挥着中心作用,但该系统活性的决定因素尚未完全阐明。血管紧张素转换酶(ACE)是RAAS中的一种关键酶,它主要将血管紧张素Ⅰ(AngⅠ)水解转化成具有强大生物活性的血管紧张素Ⅱ(AngⅡ),同时降解缓激肽使之失活。目前,ACE基因插入/缺失(I/D)多态性与冠心病、心肌病、高血压等心血管疾病的关系已引起人们广泛的注意,研究报道很多,但结果不一。因此探讨ACE基因多态性与RAAS及相关心血管疾病关系的重要性,无论是在阐明疾病的分子生物学发病机制,还是指导临床药物的应用,都会带来前所未有的启发。%Renin-angiotensin-aldosterone system (RAAS) is the most important endocrine mechanism in our body. It works on circulation system and involves in the regulation of target organs. It is thought to be associated with the occurrence, development and prognosis of cardiovascular disease, because it has the effects such as adjusting water and salt balance, participateing vascular tone and sympathetic activity, maintaining environmental stability, regulating blood pressure, effecting the normal development of the cardiovascular system and cardiovascular homeostasis and other local effects. Therefore, each gene encoding RAAS becomes very attractive and valuable candidate genes. RAAS plays a

  3. Renin-angiotensin System Activation Correlates with Organ Failure and Severity in Patients with Septic Shock%肾素-血管紧张素系统在感染性休克患者中的变化和意义

    Institute of Scientific and Technical Information of China (English)

    夏炎火; 童秋玲; 周小洁; 陈俊; 王晓蓉; 高秋琦; 林锡芳

    2013-01-01

    目的:探讨感染性休克患者中肾素-血管紧张素系统的变化和意义.方法:对21例感染性休克患者和24例非感染性休克患者分别测定血浆肾素活性(PRA)和AngⅡ浓度,以及血乳酸水平(LAC),并进行急性生理及慢性健康状况(APACHE)Ⅱ评分和序贯器官功能衰竭评分(SOFA),计算病死率,进一步将患者按预后分为死亡组和存活组进行分析,对结果进行比较,并对PRA、AngⅡ浓度和APACHEⅡ评分、SOFA评分、LAC进行相关分析.结果:与非感染性休克组相比,感染性休克组患者PRA、AngⅡ、APACHEⅡ、SOFA评分、LAC和病死率明显增高;与存活组患者相比,死亡组患者PRA、AngⅡ、APACHEⅡ、SOFA评分、LAC明显升高(P<0.05).相关分析结果,PRA和APACHEⅡ、SOFA、LAC之间相关系数分别为0.409、0.601和0.671(P<0.01);AngⅡ和APACHEⅡ、SOFA、LAC之间相关系数分别为0.491、0.776和0.690(P<0.01).结论:感染性休克激活了肾素-血管紧张素系统,PRA和AngⅡ浓度明显升高,过度激活的肾素-血管紧张素系统可能参与器官功能损伤过程,PRA和AngⅡ水平与病情严重程度相关性较好,对病情预后和严重程度判断有重要作用.%Objective: To investigate the variation and value of renin - angiotensin system ( RAS ) in patients with septic shock. Methods: We studied 21 patients with septic shock and 24 patients with non - septic shock, assessed all patients with A-PACHE II score system and the Sequential Organ Failure Assessment ( SOFA ) system. Furthermore, all patients were divided into two groups( survival vs dead ) by prognosis . Plasma renin activity ( PRA ) and angiotensin ( Ang ) II concentration in serum was assayed u-sing a commercial radioimmune assay ( RIA ) kit. A Pearson correlation coefficient was calculated to compare linear relationships between PRA ,Ang Ⅱ and APACHE Ⅱ s,SOFAs,and LAC. Results:Compared with non - septic shock group , PRA and Ang Ⅱ were significantly

  4. 肾内血管紧张素系统在2型糖尿病大鼠的肾脏发育中异常活化的机制%Aberrant Activation of Intrarenal Renin-angiotensin System during Kidney Development in Type 2 Diabetic Rats

    Institute of Scientific and Technical Information of China (English)

    孙永新; 范愈燕; 支楠; 西山成; 刘雅; 黄雯; 姚丽

    2012-01-01

    Objective To define the precise patterns of intrarenal renin-angiotensin system (RAS) activities during kidney development in OLETF rats. Methods Angiotensin E (Ang II ) contents and mRNA levels of RAS components were measured in male OLETF and control LETO rats at postnatal 1,5, 14 days and 4-30 weeks of age. Results In both LETO and OLETF rats,kidney Ang II levels hit the peak at one day postnatal and decreased age-dependently during the pre- and post-weaning periods. During the pre- and post-weaning periods ( 1 day-4 weeks), Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin and angiotensin-converting enzyme were not different between the animals (P> 0.05). In LETO rats,kidney Ang II levels further decreased during puberty (from 7 to 11 weeks of age), whereas no further age-dependent decline was observed in the kidney Ang H levels in OLETF rats during puberty. At 11 weeks of age,kidney Ang II levels,urinary excretion rate of AGT,and mRNA levels of AGT and renin were higher in OLETF than in LETO rats (P < 0.05 ), while no difference was observed of the blood glucose levels between the animals. Conclusion These data indicated that a lack of proper reduction in intrarenal Ang II during pubescent may contribute to the onset and development of diabetic nephropathy in their later life.%目的 明确在糖尿病OLETF大鼠模型的肾脏发育中肾内血管紧张素系统(RAS)的活性作用.方法 测定雄性糖尿病OLETF大鼠和正常LETO大鼠出生后第1、5、14天及第4~30周时,肾内血管紧张素Ⅱ(AngⅡ)的含量和RAS系统各组成成分的mRNA水平.结果 正常LETO大鼠和糖尿病OLETF大鼠中,AngⅡ含量在出生后第1天达到高峰,在断奶期前后(出生后1 d~4周)随着年龄的增长而逐渐下降.在出生后1d~4周龄期间,肾脏AngⅡ的含量和RAS组成成分的基因表达2组动物比较差异无统计学意义(P>0.05).正常LETO大鼠肾内AngⅡ水平在青春期(7~11

  5. Biochemical Remodeling of Myocardial Collagen and Its Relation to Car diac Renin-angiotensin System in Rats after Myocardial Infarction%心肌梗塞大鼠心室胶原生化改建与心脏肾素-血管紧张素系统的关系

    Institute of Scientific and Technical Information of China (English)

    黄英; 雷立权; 高广道; 王树人; 孙晓明

    2001-01-01

    目的 研究心肌梗塞(MI)后心室胶原生化改建与心脏肾素-血管紧张素系统(RAS)的关系。方法 采用放射免疫等方法动态观测了大鼠MI后3、15及42天左、右心室胶原含量、总量和血管紧张素Ⅱ(AngⅡ)含量以及血浆AngⅡ含量的变化。结果 血浆AngⅡ含量仅在MI后3天有一过性升高;MI鼠左、右心室AngⅡ含量于3天时就明显升高,此后一直保持在3天时水平。MI后左、右心室胶原基质均发生了生化改建,除右心室胶原生化改建稍滞后于其AngⅡ的变化外,左、右心室的胶原生化改建与其心肌AngⅡ的变化形式基本一致。结论 MI后心脏RAS被明显激活;心肌AngⅡ在心肌胶原生化改建的过程中可能起着重要的作用,而且其作用不依赖于循环RAS。%Objective This study aimed at the biochemical rem odeling ofmyocardial collage n and its relation to cardiac renin-angiotensin system (RAS) after myocardial i n farction(MI).Methods The ventricular and plasma angiotensin Ⅱ(Ang Ⅱ) content , total collagen content, and collagen concentration in left ventricle(LV) and right v entricle(RV) of MI and sham-operated control(SOC) rats on 3,15 and 42 days afte r operation were measured dynamically by means of radioimmunoassay etc. Results The plasma Ang Ⅱ content increased only in MI rats on day 3. The Ang Ⅱ content in LV of the MI group increased markedly on day 3 after MI as compared with that of the SOC group.It sustained at this higher level on the 15 th and 42th days,and the similar changes were observed in RV as well.The biochem ical remodeling of collagen in LV and RV occurred after MI and the remodeling of collagen showed similar patterns with its Ang Ⅱ content, except that collagen remodeling in RV was delayed than the change of Ang Ⅱ content.Conclus ion The cardiac RAS was obviously activated after MI. Ventricular Ang Ⅱ mi ght play an important role in the biochemical remodeling of

  6. Influential factors of renin-angiotensin-aldosterone system in patients with essential hypertension%原发性高血压病患者肾素-血管紧张素-醛固酮系统活性的影响因素

    Institute of Scientific and Technical Information of China (English)

    符春晖; 严华; 陆永光; 陈湘桂; 黄军章

    2011-01-01

    Objective To study the influential factors of renin-angiotensin-aldosterone system in essential hypertension. Methods One hundred patients with essential hypertension were divided into groups according to blood pressure grades, ages and body mass indexes. The levels of plasma renin activity, angiotensin Ⅱ and aldosterone were measured with radioimmunoassay at erect and decubitus position. Multiple linear regression analysis was performed to evaluate the relationships of age,height, body mass, systolic blood pressure and diastolic blood pressure with plasma renin activity,angiotensin Ⅱ and aldosterone. Results With the severity of the blood pressure, the levels of plasma renin activity decreased, but angiotensin Ⅱ and aldosterone increased, which showed significant differences in three hypertension groups(P<0.05). The levels of plasma renin activity, angiotensin Ⅱ and aldosterone decreased with the aging in three different ages groups(P<0.01), and showed no significant differences in three different body mass index groups(P>0.05). Multiple linear regression analysis showed systolic blood pressure and diastolic blood pressure were the positive independent predictors, and the age was the negative independent predictor for angiotensin Ⅱ and aldosterone.The age, systolic blood pressure and diastolic blood pressure were the negative independent predictors for plasma renin activity. The height, body mass and body mass index were not correlated with plasma renin activity, angiotensin Ⅱ and aldosterone. Conclusion The over-reactivity of reninangiotensin-aldosterone system could be observed in patients with essential hypertension, which is closely correlated with the age and blood pressure.%目的:探讨原发性高血压病患者血浆肾素-血管紧张素Ⅱ-醛固酮水平的影响因素.方法:原发性高血压病男性患者100例分别按高血压级别、年龄及体质量指数(body mass index,BMI)进行分组,采用放射免疫方法测定立位

  7. 广西西部地区壮族难治性肾病综合征患儿肾素-血管紧张素系统基因多态性研究%Study on Gene Polymorphism of Renin Angiotensin System in Refractory Nephrotic Syndrome Children in Zhuang Population of West Guangxi Zhuang Autonomous Region

    Institute of Scientific and Technical Information of China (English)

    尤燕舞; 林栩; 王洁; 杨发奋

    2012-01-01

    目的 研究肾素-血管紧张素(RAS)系统3个关键基因血管紧张素Ⅱ1型受体(AT1R)基因A1166C多态性、血管紧张素Ⅰ转化酶(ACE)基因插入/缺失(I/D)多态性和血管紧张素原(AGT)基因M235T多态性在广西西部地区壮族原发性肾病综合征(PNS)患儿激素敏感组和难治组中的分布,探讨RAS基因多态性在儿童难治性肾病综合征(NS)中的作用.方法 选取原籍广西西部地区的壮族PNS患儿62例(肾病组),根据其对激素的治疗反应分为显效组42例(激素敏感型NS组)和难治组20例(难治性NS组),并选取50例健康儿童作为健康对照组.采用直接PCR和PCR-限制性片段长度多态性技术检测RAS ACE基因I/D多态性、AT1R基因A1166C多态性和AGT基因M235T多态性在各组中的分布,并进行统计学比较.结果 肾病组ACE基因I/D多态性与健康对照组比较差异有统计学意义,D等位基因在肾病组中占显著优势(P<0.05),AT1R基因A1166C、AGT基因M235T多态性在2组中分布的差异无统计学意义.难治性NS组与激素敏感型NS组比较,AT1R A1166C、ACE 1/D和AGT M235T基因型与等位基因分布频率差异均无统计学意义.结论 ACE I/D多态性的D等位基因是广西西部地区壮族PNS患儿易感因素之一,未能发现RAS基因多态性在广西西部地区壮族儿童难治性NS中的作用.%Objective To study the distributions of angiotensin D type 1 receptor( ATI R) gene A1166C polymorphism, angiotensin I converting enzyme( ACE) gene insertion/deletion( I/D) polymorphism and angiotensinogen( AGT) gene M235T polymorphism in Zhuang children of West Guangxi Zhuang Autonomous Region with primary nephrotic syndrome(PNS) .which included steroid sensitive group and refractory group. To explore the effect of renin angiotensin system ( RAS) gene polymorphism in children with refractory nephrotic syndrome (NS). Methods Sixty — two cases of West Guangxi Zhuang Autonomous Region with PNS( nephropathy group) were

  8. 5/6肾切除大鼠肾组织肾素-血管紧张素-醛固酮系统的昼夜节律%Rhythmic Renin-Angiotensin-Aldosterone System Expression in Circulating and Kidney in 5/6 Nephrectomy Rats

    Institute of Scientific and Technical Information of China (English)

    梁鸿卿; 高秀伦; 朱双益; 黄小妹; 张介眉; 丁国华; 梁伟; 马威; 何达; 熊飞; 程力

    2011-01-01

    Objective: To explore diurnal variation of renin - angiotensin - aldosterone system( RAAS ) in plasma and kidney of chronic kidney disease( CKD ) . Methods: A rat model of CKD was set up by 5/6 subtotal nephrectomy( STNx ) . Wistar rats were randomly divided into sham STNx group( Group A ), STNx group( Group B ), Rats were housed in a temperature - controled room ( 22 ± 2 )℃ and synchronized 12 weeks to the light( L )dark( D )cycle 12:12 with light on from 7:00 a. M. ( Zeitgeber time ZT 0 ). Urinary protein excretion in 24 h and blood urea nitrogen and serum creatinine were examined on week 11 and week 12 respectively. The expression of renin activity( RA ) , angiotensin Ⅱ ( Ang Ⅱ )and aldosterone( Ald ) in plasma and kidney tissue were examined by ra-dioimmunoassay( RIA ) on week 12. Results: Urinary protein excretion in 24 h and blood urea nitrogen and serum creatinine were elevated significantly in STNx rats( P <0. 001 ). The expression of RA , Ang Ⅱ and Ald in kidney tissue showed different circadian rhythm to that of in plasma. The peak and trough time of kidney renin activity( KRA ) in group A and group B were opposite to that of plasma rein activity( PRA ), the peak time of Ang Ⅱ moved from ZT20( GroupA ) or ZT16( Group B ) in plasma to ZT4 in kidney . The rhythms of the expression of RAAS components in group B were also different to that of in group A. Conclusion: The expression rhythm of RAAS components in kidney were quite different to that in plasma, and it also changed in CKD rats.%目的:研究慢性肾衰竭大鼠循环及肾局部肾素-血管紧张素-醛固酮(RAAS)的近日节律.方法:60只Wistar大鼠建立5/6肾衰竭大鼠模型,随机分为两组:肾衰组(A组,30只),假手术组(B组,30只).大鼠在恒温(22±2)℃,12:12 h明(L):暗(D)交替的环境中饲养12周.早上7:00开灯,记为ZT0时,依次类推,晚上19:00时关灯,记为ZT12时.在11周时留尿测24 h尿蛋白定量.12周时分别留取血及肾标本.放免法

  9. Risk of hospitalization for community acquired pneumonia with renin-angiotensin blockade in elderly patients: a population-based study.

    Directory of Open Access Journals (Sweden)

    Sachin Shah

    Full Text Available OBJECTIVE: To characterize the 90-day risk of hospitalization with pneumonia among patients treated with different anti-hypertensive drug classes. DESIGN: Population based cohort study using five linked databases. PARTICIPANTS: Individuals over the age of 65 who filled a new outpatient prescription for one of four anti-hypertensive medications: ACE inhibitors (n = 86 775, ARBs (n = 33,953, calcium channel blockers (CCB, n = 34,240, beta blockers (BB, n = 35,331 and thiazide diuretics (n = 64 186. PRIMARY OUTCOME: Hospitalization with pneumonia within 90 days of a qualifying prescription. We adjusted for ten a priori selected covariates, including age, sex, diabetes and number of visits to a family doctor. RESULTS: Baseline characteristics of the groups were relatively well matched, except for age, sex, diabetes and frequency of family doctor visits. 128 of the 86 775 patients (0.15% initiated on an ACE inhibitor and 43 of the 33953 patients (0.13% of patients initiated on an ARB were hospitalized with pneumonia in the subsequent 90 days. 135 of 64 186 patients (0.21% initiated on a thiazide, 112 of 35 331 patients (.32% initiated on a BB, and 89 of 34 240 (0.26% patients initiated on a CCB achieved the primary outcome. Compared to calcium channel blockers, ACE inhibitors (adjusted OR 0.61, 95% CI 0.46 to 0.81 and ARBs (adjusted OR 0.52, 95% CI 0.36 to 0.76 were associated with a lower risk of pneumonia. No benefit was seen with thiazides (adjusted OR 0.87, 95% CI 0.66 to 1.14 or beta blockers (adjusted OR 1.21, 95% CI 0.91 to 1.60. CONCLUSION: Initiating medications that block the renin angiotensin system, compared to other anti-hypertensive medications, is associated with a small absolute reduction in the 90 day risk of hospitalization with pneumonia.

  10. Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review.

    Science.gov (United States)

    Stragier, Bart; De Bundel, Dimitri; Sarre, Sophie; Smolders, Ilse; Vauquelin, Georges; Dupont, Alain; Michotte, Yvette; Vanderheyden, Patrick

    2008-09-01

    For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin-angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT(1) receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP's neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer's disease, epilepsy and ischemia.

  11. Inhibition of renin angiotensin axis may be associated with reduced risk of developing venous thromboembolism in patients with atherosclerotic disease.

    Directory of Open Access Journals (Sweden)

    Young Kwang Chae

    Full Text Available BACKGROUND: Arterial and venous thrombosis may share common pathophysiology involving the activation of platelets and inflammatory mediators. A growing body of evidence suggests prothrombotic effect of renin angiotensin system (RAS including vascular inflammation and platelet activation. We hypothesized that the use of angiotensin converting enzyme inhibitors (ACEIs or angiotensin receptor blockers (ARBs plays a role in protecting against venous thromboembolism (VTE in patients atherosclerosis. METHODS: We conducted a retrospective study, reviewing 1,100 consecutive patients admitted to a teaching hospital with a diagnosis of either myocardial infarction or ischemic stroke from 2005 to 2010. Patients who had been treated with anticoagulation therapy before or after the first visit were excluded. The occurrence of VTE during the follow up period, risk factors for VTE on admission, and the use of ACEIs or ARBs during the follow up period were recorded. RESULTS: The mean age of the entire study population was 68.1 years. 52.0% of the patients were female and 76.5% were African American. 67.3% were on RAS inhibitors. The overall incidence of VTE was 9.7% (n = 107. Among the RAS inhibitor users, the incidence of VTE events was 9.0% (54/603 for the ACEI only users, 7.1% (8/113 for the ARB only users, and 0% (0/24 for the patients taking combination of ACEI and ARB. Among patients on RAS inhibitors, 8.4% (62/740 developed a VTE, compared with 12.5% (45/360 in the nonuser group [HR (hazard ratio, 0.58; 95% CI (confidence interval, 0.39-0.84; P<0.01]. Even after controlling for factors related to VTE (smoking, history of cancer, and immobilization, hormone use and diabetes, the use of RAS inhibitors was still associated with a significantly lower risk of developing VTE (AHR, 0.59; 95% CI, 0.40-0.88; P = 0.01. CONCLUSIONS: The use of RAS inhibitors appears to be associated with a reduction in the risk of VTE.

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

    Science.gov (United States)

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

    2016-03-01

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

  13. Long-term renin-angiotensin blocking therapy in hypertensive patients with normal aorta may attenuate the formation of abdominal aortic aneurysms.

    Science.gov (United States)

    Silverberg, Daniel; Younis, Anan; Savion, Naphtali; Harari, Gil; Yakubovitch, Dmitry; Sheick Yousif, Basheer; Halak, Moshe; Grossman, Ehud; Schneiderman, Jacob

    2014-08-01

    Renin-angiotensin system (RAS) has been implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Angiotensin II type 1 receptor blocker (ARB), when given with angiotensin II prevents AAA formation in mice, but found ineffective in attenuating the progression of preexisting AAA. This study was designed to evaluate the effect of chronic RAS blockers on abdominal aortic diameter in hypertensive patients without known aortic aneurysm. Consecutive hypertensive outpatients (n = 122) were stratified according to antihypertensive therapy they received for 12 months or more, consisting of ARB (n = 45), angiotensin converting enzyme inhibitor (ACE-I; n = 45), or nonARB/nonACE-I (control therapy; n = 32). Abdominal ultrasonography was performed to measure maximal subrenal aortic diameter. Eighty-four patients were reexamined by ultrasonography 8 months later. The correlation between the different antihypertensive therapies and aortic diameter was examined. Aortic diameters were significantly smaller in ARB than in control patients in the baseline and follow-up measurements (P = .004; P = .0004, respectively). Risk factor adjusted covariance analysis showed significant differences between ARB or ACE-I treated groups and controls (P = .006 or P = .046, respectively). Ultrasound that was performed 8 months later showed smaller increases in mean aortic diameters of the ARB and ACE-I groups than in controls. Both ARB and ACE-I therapy attenuated expansion of nonaneurysmal abdominal aorta in humans. These results indicate that RAS blockade given before advancement of aortic medial remodeling may slow down the development of AAA.

  14. Effect of topical propranolol gel on plasma renin, angiotensin II and vascular endothelial growth factor in superficial infantile hemangiomas.

    Science.gov (United States)

    Tang, Yu-juan; Zhang, Zai-zhong; Chen, Shao-quan; Chen, Shu-ming; Li, Cheng-jin; Chen, Jian-wei; Yuan, Bo; Xia, Yin; Wang, Lie

    2015-10-01

    The effect of topical propranolol gel on the levels of plasma renin, angiotensin II (ATII) and vascular endothelial growth factor (VEGF) in superficial infantile hemangiomas (IHs) was investigated. Thirty-three consecutive children with superficial IHs were observed pre-treatment, 1 and 3 months after application of topical propranolol gel for the levels of plasma renin, ATII and VEGF in Department of General Surgery of Dongfang Hospital from February 2013 to February 2014. The plasma results of IHs were compared with those of 30 healthy infants of the same age from out-patient department. The clinical efficiency of topical propranolol gel at 1st, and 3rd month after application was 45%, and 82% respectively. The levels of plasma renin, ATII and VEGF in patients pre-treatment were higher than those in healthy infants (565.86 ± 49.66 vs. 18.19 ± 3.56, 3.20 ± 0.39 vs 0.30 ± 0.03, and 362.16 ± 27.29 vs. 85.63 ± 8.14, P 0.05). It was indicated that the increased renin, ATII and VEGF might play a role in the onset or development of IHs. Propranolol gel may suppress the proliferation of IHs by reducing VEGF.

  15. Brief status of study on renin-angiotensin system and the interaction of their metobolic fragments%肾素-血管紧张素系统及其代谢片段间相互作用的研究概况

    Institute of Scientific and Technical Information of China (English)

    杨德玲

    2007-01-01

    @@ 1 血管紧张素主要代谢产物及生物学作用 血管紧张素原在肝脏合成并分泌入血,经肾小球旁细胞分泌的肾素裂解成十肽的Ang Ⅰ,在氨基肽酶(Aminopep tidase,AMP)、ACE、ACE2和中性内肽酶(Neutralendopep tidase,NEP)作用下分别生成去天门冬氨酸AngⅠ、AngⅡ和Ang1-7,随后由不同的酶进一步水解生成一系列代谢产物,包括Ang Ⅲ、Ang Ⅳ、Ang5-8、Ang1-5、Ang2-7、Ang3-7、Ang5-7等[1].1.1主要的酶系统肾素-血管紧张素系统(Renin angioeensin system,RAS)中主要的酶系统包括肾素、ACE、ACE2、氨基肽酶等.

  16. 体位性心动过速综合征患儿24小时尿钠变化与肾素-血管紧张素-醛固酮系统调节的关系%Relationship between 24-hour urinary sodium and renin-angiotensin-aldosterone system in children with postural tachycardia syndrome

    Institute of Scientific and Technical Information of China (English)

    李佳蔚; 廖莹; 杜军保; 张清友

    2015-01-01

    Objective To analyze the relationship between 24 hours urinary sodium and reninangiotensin-aldosterone system (RAAS) in children with postural tachycardia syndrome (POTS) and to explore low blood volume related pathogenesis of POTS.Methods A total of 39 POTS children who were at the clinic or admitted to the Department of Pediatrics,Peking University First Hospital from June 2012 to February 2013 and 21 healthy children (control group) were enrolled,level of RAAS in plasma,24-hour urinary sodium and plasma sodium were detected,respectively.Baseline data,levels of RAAS and hemodynamic parameters were compared between POTS and control group,as well as groups with different 24-hour urinary sodium levels of POTS.Results The angiotensin Ⅱ levels of POTS children were significantly higher than that of control group ((105 ± 50) vs (84 ± 28) ng/L,P =0.041),while no statistical significance was found in plasma renin and aldosterone (P > 0.05).Pearson correlation analysis showed that 24-hour urinary sodium and angiotensin Ⅱ in children with POTS was negatively correlated (r =-0.536,P <0.001).Angiotensin Ⅱ,symptom score,upright heart rate and changes of heart rate were significantly higher in urinary sodium < 124 mmol/24 h group than that in urinary sodium ≥ 124 mmol/24 h group (P < 0.05).Conclusion The regulating function disorder of RAAS may involve in the pathogenesis of POTS and cause sustained low blood volume in patients with POTS.%目的 分析体位性心动过速综合征(POTS)患儿24 h尿钠与肾素-血管紧张素-醛固酮系统(RAAS)之间的关系,探讨POTS与血容量降低相关的发病机制.方法 收集2012年6月至2013年2月就诊于北京大学第一医院儿科诊断为POTS的39例患儿(POTS组)和21名健康体检的对照组儿童资料.所有研究对象均检测血浆RAAS、血钠水平及24 h尿钠水平.比较POTS组与对照组,以及不同24h尿钠水平组POTS患儿的基本资料、RAAS水平

  17. 肾血管性高血压和肾上腺腺瘤患者肾素-血管紧张素-醛固酮含量分析%Clinical assay of renin-angiotensin-aldosterone system,endothelin and nitric oxide in renovacular hypentension and adrenocorticoadenoma

    Institute of Scientific and Technical Information of China (English)

    马伦; 吴照芝

    2008-01-01

    Objective To investigate the roles of renin-angiotens in system(RAS)and aldosterone(ALD),endothelin(ET),nitricoxide(NO)in patients with renal hypertension(40 cases)and adrenocorticoadenomas(35 cases),35 normal subjects were included in the study as controls.Methods Radioimmunoassay(RIA)was used to de termine the plasma concentrations of the renin,angiorensin Ⅱ(AⅡ),aldosterone,ET in the abovecases.Enzymicas say was adopted to examine the plasma concentration of the nitricoxidesynthase(NOS).Results TIhe plasma concentrations of renin,angiotennsin Ⅱ,aldosterone,endothefin in the patients with renal hypertension were significantly higher than those in the control group(P<0.01)except with the concentration of NOS,which were lower than that in controls(P<0.05);the plasma concentrations of the ALD,ET,in the patients with adrenocorti-caladenoma were higher that those in controls(P<0.01)but renin and A Ⅱ were lower(P<0.05).Conclusion Determination of the plasma renin,angiotensionⅡ,aldosterone and NO might be able diagnose renal hypertension and adrenocorti coadenoma earlier.%目的 探讨肾素-血管紧张素-醛固酮系统、内皮素、一氧化氮在肾血管性高血压患者、肾上腺腺瘤患者中的作用和意义.方法 采用放射免疫分析的方法测量肾血管性高血压组(40例)、肾上腺腺瘤组(35例)和健康对照组(35例)血清肾素、血管紧张素Ⅱ、醛固酮、内皮素含量,用酶免疫法测定上述人群一氧化氮合酶(NOS)的含量来表示NO的量.结果 肾血管性高血压患者肾素、血管紧张素、醛固酮、内皮素含量高于健康对照组(P<0.01),NOS含量低于健康对照组(P<0.05);肾上腺腺瘤组醛固酮和内皮素含量高于健康对照组(P<0.01),肾素、血管紧张素低于健康对照组(P<0.05).结论 肾索、血管紧张素、醛固酮、内皮素和NO的检测可为临床早期诊断肾上腺腺瘤、肾血管性高血压提供依据.

  18. 经皮肾脏交感神经射频消融术对顽固性高血压患者肾素血管紧张系统的影响%The effect of catheter based renal symthetic denervation on renin-angiotensin-aldosterone system in patients with resistant hypertension

    Institute of Scientific and Technical Information of China (English)

    王丽; 卢成志; 张欣; 罗迪; 赵斌; 于翔; 夏大胜; 陈欣; 赵向东

    2013-01-01

    Objective to explore the effect of catheter based renal symthetic denervation on reninangiotensin-aldosterone system(RAAS)and blood pressure reduction in patients with resistant hypertension.and assess the validity and security of the treatment.Methods Ten patients with resistant hypertension from June 2011 to December 2011 were retrospectively reviewed,and then all of 10 patients screened for eligibility were allocated to renal denervation.Primary endpoints were changes of office blood pressure at 1week,1,3 and 6 months after procedure.We assessed the effectiveness of renal sympathetic denervation with heart rate (HR),renin activity (PRA),angiotensin Ⅱ (Ang Ⅱ),aldosterone(Ald),and creatinine(Cr)before and 2 weeks after procedure.Results Office blood pressure after catheter-based renal denervation decreased by 22.8/9.1 mm Hg(1 mm Hg =0.133 kPa),34.8/14.7 mm Hg,42.6/20.7 mm Hg,43.2/21.6 mm Hg,at 1 week,1,3 and 6 months,respectively(P < 0.001).Meanwhile,the level of PRA,Ang Ⅱ,Alddecreased by (1.11±0.89)ng· ml-1 · h-1(P=0.003),(17.06±13.82) ng/L (P=0.004),(404.5 ±285.8) ng/L (P =0.002),respectively; and heart rate decreased by 5.1 bpm (P =0.002).However,the Cr level and eGFR did not change significantly (P > 0.05).Conclusion Catheter-based renal sympathetic denervation can reduce the level of renin activity,angiotensin Ⅱ and aldosterone,and causes substantial and sustained blood-pressure reduction.%目的 观察经皮肾交感神经射频消融对顽固性高血压患者肾素-血管紧张素-醛固酮系统(RAAS)的影响及降压效果,并对肾交感神经射频消融的安全性及有效性进行分析.方法 连续入选白2011年6月至12月在我科住院治疗的顽固性高血压病患者10例,行经皮肾交感神经射频消融术,观察术前及术后1周、1、3和6个月的血压变化及肾素、血管紧张素Ⅱ、醛固酮、肌酐、尿常规、心率等指标,评价手术的有效性与安全性并探讨其机制.结果 经

  19. Effects of water-electrolyte metabolism related to renin-angiotensin system and imprinting in the offspring rats induced by maternal hypoxia during pregnancy%妊娠期母鼠缺氧对子代肾素-血管紧张素系统及其水盐代谢调控的“印迹”效应

    Institute of Scientific and Technical Information of China (English)

    何睿; 曹莉; 李世刚; 陈宁静; 徐智策; 茅彩萍

    2012-01-01

    Objective To determine the effects of perinatal exposure to hypoxia on water-electrolyte metabolism related to rennin-angiotensin system (HAS) and "imprinting" effects in the offspring. Methods SD pregnant rats were individed into two groups randomly and were given different treatments. Fetal body weight, brain weight were measured at gestation 21 day (GD21). Blood gases, electrolytes and plasma osmotic pressure of both fetus and five-month old offsprings were measured. Intake of the 1.8% NaCl and water was measured following subcutaneous injection hypertonic saline in the offsprings, and an-giotensin receptors in the brain were determined. Results Maternal hypoxia during gestation significantly decreased GD21 fetal body weight, brain weight and plasma PO,and S03% level, but there were no different in offsprings. And there was no different of blood Na + /K+ concentrations and plasma osmolality either in fetus or in adult offspring rats regardless of perinatal exposure to hypoxia. To the offsprings following perinatal exposure to hypoxia, their salt appetite was significantly increased by subcutaneous injection hypertonic saline. Furthermore, in the forebrain of the offsprings with perinatal exposure to hypoxia, expression of angiotensin AT2 R but AT, R was reduced, and the ratio of AT, R/AT2 R was significantly increased compared to control offspring. Conclusion The results showed that stimulated salt intake can be affected by exposure to hypoxia in fetal origins, and the changed behavior was associated with the remodeled expression of AT5 and AT2 receptors in the forebrain of the offspring.%目的 研究妊娠期母鼠缺氧对子代肾素-血管紧张素系统(RAS)及其调控的水盐代谢的“印迹”效应.方法 妊娠母鼠随机分成缺氧组和对照组,缺氧组于妊娠第4~21 d放入缺氧舱(10.5%O2),对照组同期放入缺氧舱(21%O2).在妊娠21 d(GD21)测量对照组和缺氧组胎鼠的脑质量、体质量及其血液电解质、血

  20. Effect of Exercise on Blood Pressure and Renin-Angiotensin System in a Rat Model of Sleep Apnea%运动对睡眠呼吸暂停模型大鼠血压及肾素血管紧张素系统的影响

    Institute of Scientific and Technical Information of China (English)

    袁春华; 徐劲松; 李国印; 陈艳华; 吴迪

    2016-01-01

    ABSTRACT:Objective To investigate the effect of exercise on blood pressure and renin-angio-tensin system in a rat model of sleep apnea.Methods Thirty-two young male SD rats were ran-domly divided into four groups:sleep apnea group,exercise intervention group,exercise control group and blank control group,with 8 rats in each group.The sleep apnea model was established by intermittent hypoxia exposure and multi-platform sleep deprivation.Exercise intervention was carried out with moderate intensity treadmill exercise.The duration of experiment was 8 weeks. Invasive arterial blood pressure and plasma levels of rennin,angiotonin Ⅱ and aldosterone were measured at the end of the experiment.Results The invasive arterial blood pressure in exercise intervention group was lower than that in sleep apnea group(P 0.05).The levels of plasma rennin and angiotonin Ⅱ in exercise intervention group were lower than those in sleep apnea group,but higher than those in exercise control group(P 0.05).The levels of aldosterone in sleep apnea group were higher than those in other three groups(P 0.05).Conclusion Exercise can inhibit the increase in blood pressure and reduce plasma levels of renin,angiotensinⅡ and aldosterone in rats with sleep apnea.%目的:探讨运动对睡眠呼吸暂停模型 SD 大鼠肾素血管紧张素系统及血压的影响。方法选取 SD 雄性3月龄大鼠32只,按随机数字表法分为4组,分别为睡眠呼吸暂停组、运动睡眠呼吸暂停组、运动对照组及空白对照组,每组8只。采用间歇性缺氧、多平台水环境睡眠剥夺法构建睡眠呼吸暂停动物模型,采用中等强度跑台运动进行干预,实验时间8周。实验终点测量大鼠有创动脉压,取血测定血浆肾素、血管紧张素Ⅱ、醛固酮水平。结果各组间有创动脉压比较差异有统计学意义(P <0.05),两两比较显示睡眠呼吸暂停组有创动脉压高于其余3组,差

  1. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system

    Science.gov (United States)

    Jacob, G.; Robertson, D.; Mosqueda-Garcia, R.; Ertl, A. C.; Robertson, R. M.; Biaggioni, I.

    1997-01-01

    PURPOSE: Orthostatic intolerance is the cause of significant disability in otherwise normal patients. Orthostatic tachycardia is usually the dominant hemodynamic abnormality, but symptoms may include dizziness, visual changes, discomfort in the head or neck, poor concentration, fatigue, palpitations, tremulousness, anxiety and, in some cases, syncope. It is the most common disorder of blood pressure regulation after essential hypertension. There is a predilection for younger rather than older adults and for women more than men. Its cause is unknown; partial sympathetic denervation or hypovolemia has been proposed. METHODS AND MATERIALS: We tested the hypothesis that reduced plasma renin activity, perhaps from defects in sympathetic innervation of the kidney, could underlie a hypovolemia, giving rise to these clinical symptoms. Sixteen patients (14 female, 2 male) ranging in age from 16 to 44 years were studied. Patients were enrolled in the study if they had orthostatic intolerance, together with a raised upright plasma norepinephrine (> or = 600 pg/mL). Patients underwent a battery of autonomic tests and biochemical determinations. RESULTS: There was a strong positive correlation between the blood volume and plasma renin activity (r = 0.84, P = 0.001). The tachycardic response to upright posture correlated with the severity of the hypovolemia. There was also a correlation between the plasma renin activity measured in these patients and their concomitant plasma aldosterone level. CONCLUSIONS: Hypovolemia occurs commonly in orthostatic intolerance. It is accompanied by an inappropriately low level of plasma renin activity. The degree of abnormality of blood volume correlates closely with the degree of abnormality in plasma renin activity. Taken together, these observations suggest that reduced plasma renin activity may be an important pathophysiologic component of the syndrome of orthostatic intolerance.

  2. The renin-angiotensin system in obesity : metabolic and hemodynamic effects

    NARCIS (Netherlands)

    Goossens, G.H.

    2006-01-01

    Abdominal obesity plays a central role in the metabolic syndrome and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Unravelling the underlying mechanisms of obesity and obesity-related metabolic and hemodynamic disorders, such as insulin resistance and hypertension,

  3. Comparative effectiveness analysis of amlodipine/renin-angiotensin system blocker combinations.

    Science.gov (United States)

    Ram, C Venkata S; Vasey, Joseph; Panjabi, Sumeet; Qian, Chunlin; Quah, Ruth

    2012-09-01

    A comparative effectiveness analysis of antihypertensive therapy amlodipine (AML) and angiotensin receptor blocker (ARB) fixed- and loose-dose combinations (FDCs and LDCs) in achieving blood pressure (BP) reduction and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) goal attainment was made using retrospective electronic medical record (EMR) data. Treatment goal rates ranged from 35.0% for LDC AML/losartan to 45.7% for FDC AML/olmesartan (OM). FDC AML/OM achieved significantly greater reductions in systolic BP than FDC AML/benazepril (BEN), FDC AML/valsartan (VAL), and LDC AML/ARBs, respectively, and significantly greater reductions in diastolic BP than FDC AML/VAL and LDC therapy, respectively. Compared with patients treated with AML/OM, patients prescribed AML/VAL and LDC AML/ARB were significantly less likely to attain JNC 7 BP goal. Among subpopulations, AML/OM yielded higher rates of goal attainment among both African Americans and obese/overweight patients relative to AML/VAL and combined LDCs. Switchers from monotherapy with AML, OM, or VAL to AML/OM were significantly more likely to attain JNC 7 goals than those switching to AML/VAL or AML/BEN.

  4. Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?

    NARCIS (Netherlands)

    Hahntow, I.N.; Mairuhu, G.; Valkengoed, I.G.M.; Koopmans, R.P.; Michel, M.C.

    2010-01-01

    ABSTRACT: BACKGROUND: Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may hav

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

    Institute of Scientific and Technical Information of China (English)

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

    2004-01-01

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

  6. Imaging the renin-angiotensin system: an important target of anti-hypertensive therapy.

    Science.gov (United States)

    Kang, Jung Julie; Toma, Ildikó; Sipos, Arnold; McCulloch, Fiona; Peti-Peterdi, János

    2006-09-15

    Multiphoton fluorescence microscopy allows visualization, manipulation, and quantification of the structure-function relationships between pharmacological interventions and their physiological effects. The application of these methods to live animals permits direct observation of acute physical responses that lack chemically detectable signals in the blood or urine and would otherwise remain unknown. With the use of special fluorescent dyes, chemical/hormonal responses may also be detected. The delivery and site-specific effects of drugs can be monitored in real-time. The capacity to simultaneously visualize both proximal and distal segments of the nephron permits observation of the dynamic processes within the living kidney and a quantitative assessment of the various operations. Consequently, a clinically valuable and pending application for multi-photon microscopy will be to provide real-time, quantitative imaging of basic organ functions and their responses to therapeutic intervention. Imaging of the intra-renal renin content and enzymatic activity of renin in situ and in real-time is a new, more informative measure of RAS activity. Direct visualization of the molecular and cellular components of renin release signals and the interactions between the vascular endothelium, tubular epithelium, local mediators, and the renin producing cells provides great insight for drug development. Examples of how the effects of various RAS inhibitors can be visualized in the intact kidney are provided: including angiotensin converting enzyme inhibition (captopril), angiotensin II type 1 receptor blockade (olmesartan), and renin inhibition (aliskiren). The site-specific actions of diuretics, like furosemide, have also been visualized. Quantitative imaging of basic renal functions in health and disease can provide key information to assess the delivery and effects of pharmaceutical interventions.

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2000-01-01

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

  9. Multiple short-term effects of lead on the renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Goldman, J.M.; Vander, A.J.; Mouw, D.R.; Keiser, J.; Nicholls, M.G.

    1981-02-01

    We previously demonstrated that lead (3 mg/kg iv) sharply raises PRA in dogs. In the present study, the short-term effects of the same dose of lead on renin secretion, hepatic removal of renin, and arterial All levels were measured in anesthetized dogs. Despite large increases in PRA in all nine lead-treated dogs, renin secretion increased in only three out of nine lead-treated animals (those whith the lowest baseline renin secretion). Hepatic extraction of renin was eliminated by lead, and so total hepatic removal of renin became zero by 2 or 3 hr after lead administration. Finally, despite large increases in PRA, All levels did not rise after lead. The linear relationship of All to PRA seen in animals not treated with lead was changed, so that after lead, All levels were disproportionately low for the corresponding level of PRA. It is concluded that lead may increase renin secretion in animals otherwise unstimulated to secrete but that the major mechanism for the short-term rise in PRA after lead is elimination of hepatic removal of renin; further, lead prevents All from rising proportionately with PRA, presumably by inhibiting angiotensin-converting enzyme.

  10. 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

    activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the 'dead-in-bed syndrome'. METHODS AND RESULTS: Nine subjects with high RAS activity and nine subjects with low RAS activity were subjected to single-blinded placebo...

  11. 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...... receptor, MrgD. Binding of alamandine to MrgD is blocked by D-Pro7-Ang-(1-7), the MrgD ligand β-alanine and PD-123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-lasting anti-hypertensive effect...... in spontaneously hypertensive rats and anti-fibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or anti-proliferative effect in human tumoral cell lines. Conclusions: The identification of these two novel components of the RAS, alamandine and its receptor, provides new...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Adverse events during fetal development can predispose the individual for cardiovascular disease later in life, a correlation known as fetal programming of adult hypertension. The "programming" events are not known but might reside in the kidneys due to these organs significant role in extracellu......Adverse events during fetal development can predispose the individual for cardiovascular disease later in life, a correlation known as fetal programming of adult hypertension. The "programming" events are not known but might reside in the kidneys due to these organs significant role...... in extracellular volume control and long term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number has been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus...... lesions that has been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional...

  13. 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...

  14. Antihypertensive agents acting on the renin-angiotensin system and the risk of sepsis.

    Science.gov (United States)

    Dial, Sandra; Nessim, Sharon J; Kezouh, Abbas; Benisty, Jacques; Suissa, Samy

    2014-11-01

    In response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients. We performed a nested case-control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs. From the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83-1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42-1.93). Users of ARBs, β-blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure. Hypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk. © 2014 The British Pharmacological Society.

  15. The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling

    Directory of Open Access Journals (Sweden)

    Maricica Pacurari

    2014-01-01

    Full Text Available The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS’s role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors.

  16. Neuroprotective effect of renin angiotensin system blockers on experimentally induced Alzheimer's disease in rats

    Directory of Open Access Journals (Sweden)

    Wafaa A. Hewedy

    2015-10-01

    Conclusions: This study reports that candesartan and perindopril can reverse the free radical induced damages and resultant memory defects, and may suggest candesartan as worthy drugs for prevention of Abeta-P deposition in this animal mo